isopp standards of practice safe handling of...

ISOPP Standards of Practice

Safe Handling of Cytotoxics

DisclaimerThe contributors to this standard have attempted to create a document containing the most up-to-date information available. However, it is not possible to claim that this document is completely comprehensive and free of errors. Persons using this standard remain responsible for its use and subsequent actions. Neither ISOPP nor the contributors can be held responsible for any consequences that may result from applying this standard to their practice.The content of this document is entirely the work of ISOPP, and has not been influenced by any commercial sponsor.

First published in Journal of Oncology Pharmacy Practice, Volume: 13 Supplement. © 2007 SAGE Publications Ltd. ISSN 1078-1552

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Journal of Oncology Pharmacy Practice

DOI: 10.1177/1078155207082350 2007; 13; 1 J Oncol Pharm Pract

Thomas Connor, Robert McLauchlan and Johan Vandenbroucke Preface

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Preface

In 2003, the president of the International Society ofOncology Pharmacy Practitioners (ISOPP) approveda recommendation of the secretariat to establisha new Standards Committee. It was envisaged thatthis committee would be composed of ISOPPmembers from a number of different regions of theworld. With this in mind, and considering theimportance of the work of this committee, three co-chairs were appointed from different ISOPP regions:

� Thomas Connor (USA)� Robert McLauchlan (Australia)� Johan Vandenbroucke (Belgium)

The first task for the co-chairs was to establisha working committee of motivated and enthusiasticISOPP members from around the globe. In March2003, an individual invitation letter was sent to everyISOPP member seeking expressions of interestin joining the committee. Anyone who hadpreviously expressed an interest in the workingsof the committee was also approached. This recruit-ment resulted in a core team of hardworkingcommittee members without whom this Standardwould not be possible.

The co-chairs decided that existing regulations,guidelines, standards or recommendations fromaround the world should be examined prior tostarting work on an ISOPP Safe Handling Standard.In order to keep track of all these documents and tobe able to analyse these guidelines in a consistent andlogical way, a structured database was established.This is a web-based tool to allow committee membersfrom around the world to enter data and accessinformation over the internet. The database wasdivided into 29 different sections, covering all pos-sible items related to the safe handling of chemo-therapy including good manufacturing practice(GMP) for sterile cytotoxic products, clinical oncol-ogy pharmacy, medication error prevention andpatient related issues.

A total of 15 documents were entered into thedatabase and analysed. The sources of documentsexamined included:

� Workers Compensation Board of BritishColumbia (CAN)

� British Columbia Cancer Agency (CAN)� German Cytotoxic Workgroup (GER)

� National Board of Occupational Safety andHealth (USA)

� Occupational Safety and Health Administration(UK)

� Brazilian Society of Oncology Pharmacy (BRA)� Society of Hospital Pharmacists of Australia

(AUS)� UK Pharmaceutical Isolator Group (UK)� Worksafe – Victoria Workcover Authority (AUS)� Guidelines of University Hospital Gent (BEL)

At the ISOPP IX Symposium in Torino, Italy in 2004,the committee co-chairs presented the results of theanalysis of the database to the ISOPP secretariat and itwas decided that work could proceed into the nextphase of writing an ISOPP Standard for the SafeHandling of Cytotoxic Drugs. From previous experi-ence with the database, it was decided that the ISOPPwebsite would be used for communication betweencommittee members, and to this end the Standard ofPractice Discussion Forum was set up by the ISOPPpublications committee.

All committee members were invited to participatein the writing process or to become part of areviewing panel. To ensure coverage of all itemsexamined in the database, writers with different areasof expertise were chosen for different chapters of theStandard.

Ten ISOPP members were actively involved in thewriting of the Standard:

� Asuncion Albert-Mari, Spain� Thomas Connor, USA� Sylvie Crauste-Manciet, France� Harbans Dhillon, Malaysia� Dianne Kapty, Canada� Robert McLauchlan, Australia� Ioanna Saratsiotou, Greece� Graziella Sassi, Italy� N Victor Jimenez Torres, Spain� Johan Vandenbroucke, Belgium

In the writing of the Standard, a number of otherresources were consulted, including:

� EudraLex GMP Guideline� US NIOSH Alert� US OSHA Guideline� GMP Hospital, Netherlands� GMP Hospital, France

J Oncol Pharm Practice (2007) Supplement to 13: 1–81

� SAGE Publications 2007Los Angeles, London, New Delhi and Singapore 10.1177/1078155207082350



� Italian Guideline for Safe Handling� MARC Guidelines (Internet)� QuapoS (Quality Standard for the Oncology

Pharmacy Service) DGOP� Kwaliteitshandboek Cytostatica, NKI-AVL,

Netherlands� Handling Cytotoxic Drugs – Industrial Medicine

Assurance Company, Switzerland� Professional Organisation for Health and

Industrial Medicine, Germany� ASHP guide for Compounding Sterile

Preparations� Preparation and Administration of Anti Cancer

Drugs, France� CAMROQ Education and Training CD ROM, Risk

Control and Quality of Chemotherapy Handling– 5 European Countries (France, Belgium, Spain,Portugal, Poland)

� Quality Standard on Oncology PharmacyServices (DGOP/ESOP 2nd Polish Germanannual conference for oncology pharmacy‘‘Therapy for practice’’)

In addition, the personal experience of the writersplayed an important role in the creation of this work.Where specific references are used, these are quotedand listed at the end of the appropriate Section.

Drafts of each Section were reviewed and dis-cussed by the writing team and the reviewing group,consisting of members from Mexico, Japan,Singapore, Canada, Belgium, Germany and SouthAfrica. Each reviewer was able to provide comments.These comments were discussed and integrated into

the draft document upon agreement of the majorityof the committee. Not everyone will agree with everydetail given in the final document, but the StandardsCommittee considers this Standard ‘‘Evidence Based’’in some parts and ‘‘Best Practice’’ in others.

As discussed during the General Assembly of ISOPPin Torino, Italy, in 2004, the committee is aiming ata high level with this Standard. This means thatperhaps many practitioners may not fully complywith the Standard as written today, but the Standardshould be seen as something we all can worktowards. There is a clear goal for ISOPP membersaround the world. Whereas some of us will success-fully comply within a relatively short period oftime, others will struggle to fully comply withthis Standard. However, they will have at theirdisposal, documentation of what is regarded as bestpractice and will know exactly what should beasked of Pharmacy Directors and HospitalAdministrators.

We wish all our ISOPP colleagues good luck in thedevelopment of a safe and high quality oncologypharmacy service.

Regards

Thomas ConnorRobert McLauchlanJohan Vandenbroucke

ISOPP Standards Committee Co-ChairsApril 2006

2 ISOPP Standards of Practice






Section 1 � Introduction


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Section 1 – Introduction

Cancer is the uncontrolled growth and spread of cellsthat may affect almost any tissue of the body.Worldwide, lung and stomach cancers are the mostcommon cancers for men and breast and cervicalcancer are the most common for women. More than11 million new cases of cancer are diagnosed eachyear and that number is expected to rise to 16 millionby 2020. Cancer is responsible for 7.6 million or 13%of all deaths worldwide.1

1.1 Cytotoxic drugsCytotoxics (chemotherapy drugs, antineoplasticdrugs) have been in clinical use for decades and areof great importance in the treatment of cancer andcertain other diseases.2 With close to 100 cytotoxicdrugs now in use and many more under develop-ment, chemotherapy has opened up new avenuesranging from improving patients’ quality of life toachieving a cure.

Cytotoxic drugs are chemicals that affect cellgrowth and proliferation, most of which either binddirectly to genetic material in the cell nucleus, oraffect cellular protein synthesis. Typically, cytotoxicdrugs do not distinguish between normal andcancerous cells.

Cytotoxic drugs are often administered to immuno-compromised patients, and as most of these drugs aremyelosuppressive this may place patients at a highrisk of developing severe infections. For this reason,when parenteral cytotoxics are prepared, asepticprocedures must be strictly adhered to in order toprevent microbial contamination. In addition, as mostof these agents have a narrow therapeutic index, theaccuracy of the preparation must be assured.Pharmacy departments should have rigid checkingprocedures in place (See Section 11 – CheckingProcedures).

1.2 Hazardous drugsIn terms of occupational exposure, a hazardous drugis defined as an agent that due to its inherent toxicitypresents a danger to healthcare personnel.

These drugs are identified based on one or more ofthe four following characteristics; they are carcino-genic; genotoxic; teratogenic; or toxic at low doses inanimal models or treated patients.3–5

Hazardous drugs include antineoplastic andcytotoxic agents, some hormonal agents,

immunosuppressants, antiviral medications, andsome monoclonal antibodies.

A list of hazardous drugs that require specialhandling should be posted in every facility at allrelevant working places that provides drug prepara-tion and administration services.

1.3 Impact of hazardous drug exposureIn the 1970s, secondary malignancies were reportedin patients who received cytotoxic drugs for other,usually solid, primary malignancies. The most com-monly seen secondary malignancies were leukaemiaand bladder cancer reported after a latency period of1–10 years.

Studies carried out by Falck et al. in the 1970’sindicated that unprotected nurses who workedin environments in which hazardous drugs wereprepared and administered had higher levels ofmutagenic substances in their urine as compared tonon-exposed workers.6 This study suggested thatnursing personnel were being occupationallyexposed to cytotoxic drugs, many of which aremutagenic. This study was confirmed by numerousstudies examining urine mutagenicity, chromosomalaberrations, sister chromatid exchanges and otherendpoints in pharmacists and nurses who handlecytotoxic drugs.7–9

In addition, workers experienced other adversehealth effects. A review of 14 studies described anassociation between exposure to antineoplastic drugsand adverse reproductive effects, and 9 studiesshowed some positive association.10 The mostcommon reproductive effects found in these studieswere increased fetal loss,11,12 congenital malforma-tions,13 low birth weight and congenital abnormal-ities,14 and infertility.15

Because these measures were indirect, and a directcause-and-effect relationship could not be deter-mined, more direct methods of determining exposurehave been developed. These methods includeurinalysis to determine the presence of parentdrugs or metabolites of hazardous drugs handled byhealthcare workers, and environmental air andsurface sampling techniques.

1.4 Occupational exposureOccupational exposure to hazardous drugs and thepotential health risk to healthcare workers firstbecame a recognized safety concern in the 1970s.

ISOPP Standards of Practice 3



Published data related to the issue of occupationalexposure prompted the US Occupational Safety andHealth Administration (OSHA) to issue guidelines in1986 for the handling of antineoplastic and otherhazardous agents by healthcare personnel whichwere updated in 1995.4

A number of other organizations in the US alsopublished reports related to the safe handling ofhazardous drugs, including the National Institutesof Health (NIH),16 the National Study Commissionon Cytotoxic Exposure (NSCCE),17 the AmericanMedical Association’s (AMA) Council on ScientificAffairs18 and, most recently, the National Institute forOccupational Safety and Health (NIOSH).5

These guidelines are the work of governmentinstitutions, but additional safe handling guidelineshave been developed by professional organizations ofhospital pharmacists and nursing associations(Australia,19 New Zealand,20 USA,3 Canada,21). Somerecent updates of guidelines include the Society ofHospital Pharmacists of Australia,22 Quality Standardfor the Oncology Pharmacy Practice,23 the DGOP/ESOP (2005) 2nd Polish–German annual conferencefor oncology pharmacy ‘‘Therapy for practice’’,24

Kwaliteitshandboek Cytostatica,25 the OncologyNursing Society26 in the US and the AmericanSociety of Health-System Pharmacists.3 In Europe,most countries have published guidelines concerningthe safe handling of cytotoxic drugs or for protectionagainst carcinogenic agents in general.

Some of these publications have the status ofnational law and are enforceable, other are Europeandirectives (to be translated into national laws).Some are pure guidelines (non-enforceable butrecommended as ‘‘best practice’’) and some areeven from insurance companies, refusing anassurance for the hospital if their standard is notfollowed.

Sources of exposure of health care providers tocytotoxic drugs are varied and the routes of exposureare typically inhalation, dermal or oral.

One route of exposure is inhalation via droplets,particulates and vapours. Many procedures can resultin aerosol generation. For example; drug injectioninto an IV line, removal of air from the syringe orinfusion line, and leakage at the tubing, syringe, orstopcock connection, clipping used needles andcrushing used syringes. Drug particles can becomeairborne after drying of contaminated areas.

Vaporization of antineoplastic agents has beenrecorded with various drugs such as carmustine,ifosfamide, thiotepa and cyclophosphamide.27–28

Dermal contamination can arise from cytotoxicdrug contamination on the outside of vials.29-35

Thus, the environment of operators may becontaminated even before cytotoxic reconstitutionhas begun. Researchers have detected measurableair levels of cytotoxic drugs inside and outsidebiological safety cabinets from wipe samples ofcytotoxic drugs on surfaces of workstations and atpoints distant from places of preparation andadministration of drugs.

Studies have demonstrated that most work surfacesin areas where cytotoxic drugs are handled arecontaminated with the drugs.9,28,29,36–48 The workingsurfaces of biological safety cabinets, counter tops,floors, equipment and most other surface have beenshown to be contaminated in studies from severalcountries around the world.

Inadvertent ingestion is also problematical. Whenfood or beverages are prepared, stored, or consumedin work areas, they may easily become contaminatedwith airborne particles of cytotoxic drugs.

Similarly, hands, cigarettes, cosmetics and chewinggum, can be contaminated.

The greatest risk is direct skin contact with thedrug in the event of a spill or leakage wherecontamination or personnel and the environmentmay occur.

1.5 ConclusionsWorking with or near hazardous drugs in health caresettings may cause skin rashes, has been associatedwith infertility, miscarriage and birth defects, andraises concerns about the possible development ofleukaemia or other cancers. To provide workers withthe greatest protection, employers should:

(a) Implement necessary administrative and engi-neering controls and

(b) Assure that workers use sound proceduresfor handling hazardous drugs.

In addition, employees, by their work practicesinfluence their own occupational exposure and thatof those around them. Employees can help minimisetheir potential exposure to these agents by:

(a) Staying current on the knowledge of theoccupational risk posed by these agents and

(b) Ensuring that their work practices follow thebest current recommendations.

These standards represent an international consensuson steps to prevent occupational exposure tohazardous drugs in healthcare settings.




REFERENCES

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6 Falck K, Grohn P, Sorsa M, Vainio H, Heinonen E, Holsti

LR. Mutagenicity in urine of nurses handling cytostatc

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7 Baker ES, Connor TH. Monitoring occupational exposure

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8 Sorsa M, Anderson D. Monitoring of occupational expo-

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12 Stucker I, Caliiard J-F, Collin R, Gout M, Poyen D,

Hemon, D. Risk of spontaneous abortion among

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13 Hemminki K, Kyyronen P, Lindbohm M-L. Spontaneous

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W. Toxic effects on reproduction in hospital personnel

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personel. Netherlands; Elsivier, 1999.

15 Valanis B, Vollmer WM, Steele P. Occupational exposure

to antineoplastic agents: Self-reported miscarriages and

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the safe use of handling of cytotoxic drugs. Available at:

http://www.nih.gov/od/ors/ds/pubs/cytohttp://dohs.ors.

od.nih.gov/pdf/Recommendations_for_the_Safe_Use_of_

Handling_of_Cytotoxic_Drugs.pdf Accessed January

2007.

17 NSCCE (National Study Commission on Cytotoxic

Exposure). Recommendations for handling cytotoxic

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Scientific Affairs. Guidelines for handling parenteral

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20 Colls BM. Cytotoxic chemotherapy: A potential hazard to

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pharmaceuticals (Including cytotoxic drugs), Ottawa,

Canada,1993.

22 SHPA (Society of Hospital Pharmacists in Australia)

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Harsley S, Kirsa S, McLauchlan R, Ng L-L, Ooi S-C,

Stefanou A.) SHPA Standards of practice for the safe

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Pharmazie). Quality Standard for the Oncology

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English at: http://www.esop.li/countries/uk/quapos-

2003-en.pdf Accessed February 2007.

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Franfort/Oder-S_ubice. 2005.

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Leeuwenhoek Hospital). Kwaliteitshandboek Cytostatica.

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27 Connor TH, Shults M, Fraser MP. Determination of the

vaporization of solutions of mutagenic antineoplastic

agents at 238 and 378C using a desiccator technique.

Mutat Res 2000; 470: 85–92.

28 Kiffmeyer TK, Kube C, Opiolka S, Schmidt KG,

Schoppe G, Sessink PJM. Vapor pressures, evapora-

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ous drugs: implications for occupational safety.

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29 Sessink PJM, Boer KA, Scheefhals AP, Anzion RB, Bos RP.

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urine of exposed workers. Int Arch Occup Environ

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30 Ros JJW, Simons KA, Verzijl JM, de Bijl GA, Pelders MG.

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35 Connor TH, Sessink PJM, Harrison BR, et al. Surface

contamination of chemotherapy drug vials and evaluation

of new vial-cleaning techniques: results of three studies.

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performance liquid chromatography/tandem mass spec-

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Colombi A. Measurement of surface contamination by

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Power LA. Surface contamination with antineoplastic

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Effectiveness of a closed-system device in containing

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ifosfamide in an i.v. admixture area. Am J Health Syst

Pharm 2002; 59: 68–72.

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Section 2 � Transport of cytotoxics


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Section 2 – Transport of cytotoxics

All cytotoxic drugs should be packaged, stored andtransported in such a way as to prevent damage andsubsequent contamination of the environment, thedrug itself, and all personnel involved in the routinehandling and transportation of these drugs.

Transportation must be in accordance with alllocal, state, provincial or federal legislation concern-ing the transport of hazardous agents. The transportof cytotoxics may be considered in terms of theexternal transport from drug suppliers, the internaltransport of commercial product within the institu-tion, and finally the transport within the institution ofthe compounded admixture.

For transportation of cytotoxic waste, seeSection 15.

2.1 External transport from supplier

2.1.1 Primary containersPrimary containers and shelf cartons should bedesigned to minimise the risk of breakage byusing break resistant materials. This includes vialsmanufactured from an unbreakable plastic material,glass vials provided in specially designed outerplastic containers, or glass vials over-wrapped inplastic to prevent contamination in the event ofbreakage of the glass. Pharmacy departments shouldpreferentially purchase products manufacturedin this way.

2.1.2 PackagingTo prevent damage to the primary containers, allproducts for transportation from the manufacturer orwholesaler should preferably be protected with highimpact resistant moulded foam, or other suitablepackaging material. The packaging must also ensurecontainment of cytotoxic material in the event ofspillage. The product should then be placed incorrugated cardboard shippers for example, whichhave strong insulating properties, to protect thecontents from inadvertent rough handling duringtransport.

For refrigerated products, the use of ice bricks orice packs is recommended to maintain the temper-ature within an acceptable range. All refrigeratedshipments should ideally have a temperature monitorinside, usually a digital temperature gauge, whichconstantly monitors internal temperatures within the

shipper during shipment. Packaging should alsocontain enough foam to ensure the products do notmove in transit. In addition, the load should bearranged so that cartons will not move excessively intransit.

2.1.3 LabellingCytotoxic drugs must be easily identifiable by allpersonnel involved in their handling. The outerpackaging of containers should display clear warninglabels stating the goods are cytotoxic in nature. Mostcountries have a recognised symbol representingcytotoxic agents. This will vary, but in many cases ispurple in colour, and will often contain a diagram-matic representation of a cell in telophase. In somecountries this may be a yellow label with a crab-likesymbol. It may say ‘‘Danger/Caution Cytotoxics’’ orcould contain an exclamation mark. Whatever warn-ing sign is attached it should be clear and instantlyrecognisable.

Appropriate temperature and light conditions mustbe clearly labelled on the outer packaging. Theshipper itself must have full instructions on thenature of the contents and what to do in case of anemergency, especially in a spill or breakage. It mustbe clearly stated that the driver avoid contact withany apparent leaked material. There should be clearcontact details to source advice should this berequired.

2.1.4 Cytotoxic spill managementAll personnel involved in the storage and transport ofcytotoxic drugs should receive appropriate instruc-tion concerning the potential hazards, correct hand-ling, and procedures to deal with breakages andspills. Either a cytotoxic spill kit should be availablein the delivery vehicle, or delivery personnel shouldhave a mobile telephone and a contact number to callfor immediate advice in the event of a spill.

2.1.5 Receiving and inventory controlThe results of several European and American studiesshow that surface contamination exists on commer-cially supplied vials and primary packaging ofcytotoxic drugs supplied by manufacturers to phar-macies. Persons involved in receiving and inventorycontrol should be informed of the possibilityof surface contamination on cytotoxic drug vials.




Staff should wear single use chemotherapy gloveswhen handling cytotoxic drug vials.

Packages with visual signs of damage should bequarantined immediately and the supplier should becontacted. It is not advisable to return damagedcytotoxic vials to the supplier but should instead bedisposed of appropriately. Staff should wash theirhands after handling cytotoxic drug vials. Gloves arenot a substitute for hand washing.

Potentially contaminated items such as glovesshould be disposed of as hazardous waste.Employers are encouraged to make sure the storagearea has sufficient general exhaust ventilation todilute and remove any airborne contaminants.Depending on the physical nature and quantity ofthe stored drugs, consideration should be given toinstalling a dedicated emergency exhaust fan. The fanshould be large enough to quickly purge airbornecontaminants from the room in the event of a spilland prevent contamination in adjacent areas. (SeeSections 1 and 6).

Whenever available, drugs supplied in unbreakablepacks are preferred to cytotoxic drugs packaged inglass containers.

2.1.6 Responsibilities of drug manufacturersIt is the responsibility of drug manufacturers tosupply cytotoxics in containers which are guaranteedto be free of contamination. It is highly desirablethat manufacturers provide some form of certifica-tion that vials and primary packaging are notcontaminated with cytotoxics. This analysis shouldpreferably be carried out by an independent labora-tory. Hospitals and buying groups should preferen-tially purchase products which are verified to be freefrom external contamination.

Manufacturers must provide Material Safety DataSheets (MSDS) on all of their cytotoxic productswith explicit details on decontamination, andprotection measures to be followed in the caseof a spill or other accident. Each institution shouldretain a compilation of these Material Safety DataSheets, should ensure that they are current andreflect the actual products used within the institu-tion, and should update the list whenever pur-chased products change. These MSDS should bereadily available in all areas where hazardous drugsare stored or used (see Section 21.9). The manu-facturer must also provide details on physical andchemical stability, recommended storage conditionsand requirements for light protection.

2.2 Internal transport of commercial productThe transport of commercial cytotoxic products andthe safety measures required will depend on thequantity of drugs being transported.

2.2.1 PackagingIf large quantities of cytotoxic vials need to betransported, it is advisable to use a wheel drivenvehicle and the products must be in their originalpackaging. The outer boxes containing drugs must bewrapped with protective plastic in order to avoidaccidents through shock, and they should also befastened with belts on the wheel driven vehicle toprevent accidents.

If the need arises to unpack and transport smallerquantities, unbreakable and leak tight boxes shouldbe used. For extra safety, the internal part ofthese boxes should be made of moulded foam or asponge-like material, so that the drugs are securelypositioned. Such foam should be customised to thesize of drugs being transported. The risk of damagemay be minimised by manufacturers providing vialscontained in shock absorbing plastic containerswhich are designed to position the vials they contain.

2.2.2 LabellingIn the case of transporting large quantities, thelabelling should very clearly indicate that thecontents are cytotoxic. If smaller quantities of drugneed to be transported after unsealing the primarypackaging, then this label should be attached to thetransport box.

There should be another label attached stating thatthe inner contents are sealed and considered safe fortransport. This label should also mention whom toinform in case of a spill or other accident.

2.2.3 SpillsPersons transporting commercial product within theinstitution should have a spill kit available. Thecontents and use of a spill kit are described in detailin Section 14. In case of an accident, the appropriatestaff member should be contacted. Until the relevantstaff member arrives, the people transporting thedrugs should don their protective clothing (con-tained within the spill kit) and, in order to deterpeople from stepping into the contaminated area,clearly mark the area of danger using a warningsign (contained within the spill kit) or specialcoloured chalk.




2.3 Internal transport of compoundedadmixtureThis section describes the guidelines for the trans-portation of prepared cytotoxic drugs from phar-macy departments to wards and day care centreswithin the hospital for in-house use.

All cytotoxic drugs should be packaged, stored andtransported in such a way as to prevent damage andsubsequent contamination of the environment, thedrug itself and all personnel involved in routinehandling and transportation of these drugs. Cytotoxicdrugs must be transported so as to provide adequatephysical and chemical protection for the drug and thedrug handler. During transport, if drugs are spilledor become separated from other contents beingtransported, handler protection is of paramountconcern and must be appropriately anticipated andplanned for.

2.3.1 PackagingCytotoxic admixtures should be packaged in alabelled, sealed, leak-proof container, with outerbags heat sealed whenever possible. This ensuresthat the container offers protection from light whererequired, protects the drugs from breakage in transitand, contains leakage if breakage occurs.

2.3.2 Drug transportDelivery of cytotoxic products must be made directlyto the wards and day care centres within the hospitalby the personnel transporting these drugs. Nodetours should be allowed when transporting thesedrugs. All personnel involved in the transport ofcytotoxic drugs should receive appropriate instruc-tion concerning the potential hazards, correct hand-ling, and procedures to deal with breakages andspills.

Containers used for transporting prepared cyto-toxic drugs should be hard-walled and robust, madefrom moulded foam or other suitable packagingmaterial capable of protecting the product from ashock equivalent to a drop of one metre onto aconcrete surface.

Wherever possible, disposable containers shouldbe used (for example, sealed plastic bags). For safetyreasons, the transport containers may be lined withabsorbent material in case there is a spillage of thedrug from its container.

The containers should be dedicated for the trans-portation of cytotoxic drugs only.

The use of pneumatic tubes to transport cytotoxicdrugs is NOT RECOMMENDED. Practice standardsfrom some countries, for example Australia, Canadaand the United States explicitly prohibit their use. Ifthis transport system is to be used for cytotoxics, itmust first be checked and validated using containersfilled with a NON cytotoxic product of the same size,weight and volume. All preparations transported inthis way must be heat sealed in plastic bags and mustbe shown not to leak or break under stress.Containers used in pneumatic tubes which carrycytotoxics must be clearly labelled as cytotoxic andreserved for the transport of cytotoxic agents only.There should also be written procedures for dealingwith a spillage or other incident involving cytotoxicsin pneumatic tubes.

2.3.3 LabellingAs previously described, cytotoxic drugs should beeasily identifiable by all personnel involved in theirhandling. Any opaque outer packaging of containersshould clearly display warning labels stating thecontents are ‘‘cytotoxic’’ in nature. Such labels shouldcarry an identifying symbol for cytotoxic drugs.Appropriate temperature and light conditions, aswell as expiry dates must be clearly labelled on theouter packaging.

2.3.4 Cytotoxic spill managementCytotoxic drug spill kits must be readily available topersonnel involved in the transport of cytotoxicdrugs.

All personnel involved in the storage and transportof cytotoxic drugs should receive appropriateinstruction concerning the potential hazards, correcthandling, and procedures to deal with breakages andspills. All training must be documented and recordskept. Re-training must be carried out an annual basisand these records kept. (See also Sections 4 and 21).

2.3.5 Documentation of cytotoxic drugstransportationRecords may be maintained of transportation ofprepared cytotoxic drugs from the pharmacy to thevarious units where these drugs are used. (See alsoSection 21).







Section 3 � Personnel


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Section 3 – Personnel

3.1 Education and trainingThis section relates specifically to institutions wherecytotoxic agents are prepared in–house. If cytotoxicagents are outsourced (purchased from a commercialsupplier), then some of the following may not apply.For example, it may not be pharmacy personnelpreparing the cytotoxic agents.

All personnel involved in the preparation andadministration of cytotoxic drugs should posses arecognised qualification or should have receivedcertified training in accordance with localregulations.

An assessment of practice should be undertaken ona regular basis for all personnel preparing andadministering chemotherapy.

All personnel involved in the handling of cytotoxicdrugs, including transportation, storage, and cleaningof facilities, should be trained in the use of personalprotective equipment (PPE) and safe handlingprocedures. These staff members should be evalu-ated on a regular basis in order to verify compliancewith procedures.

Cytotoxic drugs should be handled and storedwithin the pharmacy by trained employees.

The preparation of parenteral cytotoxicdrugs should be undertaken only by pharmacypersonnel

Transportation of cytotoxic drugs may be a task ofauxiliary personnel.

Administration of chemotherapy should beperformed only by certified/qualified health carepersonnel (See also Sections 4 and 12).

3.2 Health considerationsAll personnel involved in any aspect of the handlingof cytotoxic drugs should be informed about the risksof occupational exposure to hazardous drugs.

3.2.1 Exclusions from working in cytotoxicpreparation

Illness

Whenever possible, personnel with upperrespiratory infections or cutaneous infections mustbe excluded from preparing cytotoxics. Personnel on

immunosuppressive therapy should also beexcluded.

Family planning

Personnel who are pregnant or breastfeeding andpersonnel planning imminent parenthood should bepermitted to avoid working with cytotoxic drugs.Such staff should be given alternative tasks orrostered to another area of the pharmacy if sorequested. Institutions should develop a writtenpolicy on how to deal with this issue.

Abnormal pathology results

Personnel with abnormal pathology results shouldnot prepare cytotoxic drugs until the abnormality hasbeen investigated.

3.2.2 Medical examinationsThere are no direct measurements to indicate totalexposure to cytotoxic drugs. Non-specific measure-ments have been used as baseline and routineindicators. Staff whose responsibilities involveparenteral cytotoxic drug manipulation shouldreceive a baseline examination that includes assess-ment of indices such as full blood examination, liverfunction tests, urea, creatinine and electrolytes.

These measurements may then be used to compareany subsequent measures taken either routinely orfollowing accidental exposures. Regular monitoring,which includes a full blood examination and differ-ential, should be offered at a minimum of six-monthintervals. Institutions should have a written policy forbaseline and regular monitoring of staff involvedin the preparation of cytotoxic drugs. (See alsoSection 19).

3.3 FacilitiesThe facility should be designed to allow easy andadequate access for personnel, equipment, andcleaning. The cleanroom area should be designedwith ergonomic considerations in mind for thecomfort of staff working in the area for prolongedperiods. For the safety of personnel working in thecleanroom, there must be adequate visibility into thearea for people working in isolation.

Access to the cytotoxic preparation suite must berestricted to individuals working within the area.




A sign restricting the access of unauthorised person-nel should be prominently displayed.

Due consideration should be given to the availabil-ity of an emergency shower in close proximity to thecytotoxic preparation suite. Emergency eye washingfacilities should also be available. (See also Section 6).

3.4 HygieneStrict hygiene procedures must be developed andfollowed in the cytotoxic preparation suite. Eating,drinking, chewing gum and the application ofcosmetics must be strictly prohibited. In addition,personnel in the preparation facility should not wearrings, earrings, bracelets or other jewellery.

3.5 Staffing levelsPolicies and procedures should be developed andimplemented that consider the following:

3.5.1 Number of staff membersA sufficient number of staff members must beavailable to provide for the expected workload.Staffing should allow for the workload during the

busiest period and should take into account thecomplexity of products manufactured.

3.5.2 Work breaksThe staff allocation must be sufficient to allow foradequate breaks for those working in the cytotoxiccleanroom. It is recommended that no more than twohours be spent working at the cabinet or isolatorwithout a break. Often staff work in isolation, andsufficient breaks must be provided to maintainconcentration.

3.5.3 DocumentationRecords of the work shifts of personnel working incytotoxic reconstitution should be established andmaintained. The information stored may include theduration of shifts worked, the location (if more thanone isolator or biological safety cabinet exists), thenumber of manipulations, and the total amount ofdrug handled. Some other measure of complexity orrisk may be incorporated; such as whether the drug isin powder form or solution, and whether the agent issupplied in a vial or ampoule. (See also Section 21).







Section 4 � Education and training


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Section 4 – Education and training

4.1 Education on cytotoxic risks and safehandlingIn order to understand the risks involved and toensure the safe handling of these agents, all staff whowill be involved in the handling of cytotoxic drugsmust be provided with adequate education. All staffwho handle, or are likely to handle, cytotoxic drugsshould receive appropriate education prior to expo-sure to risk. This will include pharmacy staff, nursingand medical staff, and other support staff includingporters, and cleaners who may transport cytotoxicagents or may clean a potentially contaminated area.When available, specific educational courses shouldbe attended.

In addition, patients and carers who are involved inthe delivery of chemotherapy in the home shouldreceive some basic education and training in theprinciples of safe handling, and dealing with spills,waste disposal and patients’ excreta. Written instruc-tions should be given to the patient or carer,including information on the use of oral chemother-apeutic agents.

4.1.1 Content of educational coursesAn education program on the risks of exposure tocytotoxic agents and the measures required for safehandling should be developed and implemented.This program should be structured and may containthe following elements:

(a) The potential risks of exposure to cytotoxicagents

(b) Basic pharmacology of cytotoxic agents(c) Theory of aseptic technique(d) Use of personal protective equipment (PPE)(e) Theory of containment devices and barriers(f) Theory of hierarchy of protection measures(g) Handling of cytotoxic waste(h) Cytotoxic spills and accidental exposure(i) Prescribing of cytotoxic agents(j) Validation of cytotoxic prescriptions(k) Hospital policies and procedures on cyto-

toxic management(l) Cytotoxic drug use processes (drug selection,

prescription validation, preparation, dispen-sing, drug administration and drug useevaluation)

The education provided should be tailored to theneeds of the individual after consideration of thejob description, previous level of education, andtheir specific responsibilities relating to cytotoxicdrugs. This education should be ongoing withattendance at in-house or external courses, seminarsand symposia strongly encouraged. Considerationshould be given to the re-education of staffmembers who have had a prolonged break fromworking in the area.

4.1.2 Education providersEducation should be provided by appropriate aca-demic, clinical, or technical specialists. This require-ment will vary depending on the specific educationrequired. If an accredited course is available, thenstaff should attend such a course. A specified numberof hours to be completed should be determined bythe course provider.

4.1.3 DocumentationEducation sessions or attendance at courses shouldbe documented and records retained indefinitely inthe staff members’ human resources file.

4.1.4 CertificationEducational courses offered by professional bodiesshould preferably have received some form ofaccreditation and an allocation of continuing educa-tion hours.

4.1.5 EvaluationFeedback on educational courses attended shouldbe an integral part of any program. The effective-ness of the educational process should be assessedand reviewed on a regular basis. This may beachieved by the administration of a competencytest or examination at the end of the educationprogram.

4.1.6 Re-educationIt is recommended that the education program berepeated every 2–3 years to cover the introduction ofnew drugs into practice or any other technicalinnovations. Education should be repeated wheneverany major change in practice occurs.




4.2 Training in the manipulation and safehandling of cytotoxic drugsBefore being permitted to work in the cytotoxicpreparation facility, all staff must be trained in thesafe handling of cytotoxic drugs and related waste.This training may be provided for pharmacists,pre-registration pharmacy graduates and pharmacytechnicians. Other pharmacy staff and supportpersonnel may also need to be trained in dealingwith cytotoxic spills, transporting cytotoxics, and thecorrect storage of cytotoxic agents.

The training of nurses should concentrate on safehandling during cytotoxic administration, wastehandling, management of extravasation and spillmanagement.

This training may be offered in-house or by anexternal training provider. If internal training isprovided adequate resources must be available.

Staff members handling cytotoxic drugs should besupplied with appropriate up-to-date information onall aspects of the safe handling of cytotoxic drugs aswell as the reported hazards of low level exposure tothese agents.

4.2.1 Content of training coursesA training program in cytotoxic reconstitution shouldbe developed and implemented. This program shouldbe structured and may contain the followingelements:

(a) The potential risks of exposure to cytotoxicagents

(b) Use of safety cabinet/isolator(c) Working in a cleanroom(d) Aseptic technique(e) Use of personal protective equipment(f) Use of containment devices(g) Use of specialised equipment(h) Handling of cytotoxic waste(i) Dealing with cytotoxic spills(j) Emergency procedures(k) Documentation(l) Labelling and packaging(m) Transport of cytotoxics(n) Environmental monitoring(o) Cleaning procedures(p) Health monitoring(q) Validation processes

After consideration of the job description and relatedrisk, training should be tailored to the specific needsof the individual. Training should be ongoing withregular updates for any new procedures or products,

and should include periodic tests of staff compe-tency. Whenever a new hazardous drug is introducedinto the workplace, staff should receive adequateinformation about the risks of potential exposure tothe agent.

Each institution should develop and maintain aprocedure manual which details the policies andprocedures for the appropriate manufacture andadministration of cytotoxic agents. This shouldinclude a description of aseptic technique, standardoperating procedures for cytotoxic reconstitutionand administration, cleaning procedures, informationon dealing with spills, transporting cytotoxics, andinformation on health monitoring. It should contain afull description of all personal protective equipmentand special containment devices to be used in thepreparation of cytotoxics. This manual should beregularly updated and should be available to staff atall times.

4.2.2 TrainersTraining of staff in the manipulation of parenteralcytotoxic drugs should be undertaken by an experi-enced operator. If an accredited training course isavailable it is recommended that personnel attend.Standard operating procedures for training should bedeveloped and maintained. Each type of procedure tobe undertaken should have a specific and detailedstandard operating procedure. Before personnelattempt to prepare or administer an item for apatient they must be trained in that particularstandard operating procedure.

4.2.3 DocumentationThe training of staff in cytotoxic reconstitutionmust be structured and all stages should be docu-mented. Records of training received should beretained indefinitely in the staff members’ humanresources file.

4.2.4 Validation

Validation of processes

The objective is to demonstrate that the processesused during the aseptic preparation and the staffundertaking the aseptic manipulation are capable ofmaintaining the sterility of the product. The media

fill test (or Broth test) is intended to simulateroutine aseptic operations, but uses microbiologicalmedia to produce units that can be tested forcontamination.




The test must be representative of the routineactivity in terms of the number of simulatedpreparations produced and must be performedusing the same devices and same transfer methodsas the routine procedure. Tryptone soya culturemedia is normally used for the test. The sterility of theculture media must be checked before performingthe media fill test to ensure that the installation doesnot interact with the sterility. For example, whensterilized isolators are used, the sterilization methodcan inhibit the microbiological growth and give falsenegative results when performing the media fill test.The test must be performed at least 3 times, and filledunits should be incubated at the designed tempera-ture for 14 days. The expected results are that notone positive unit is found. In the case of a positiveresult, the cause of the failure must be investigatedand focus on whether the facility, process or operatoris the root cause. Revalidation of the process shouldbe performed when this root cause of the failure isidentified. In addition, revalidation of the processshould be performed when any change is made toeither the process or the facilities.

Validation of the operator

One objective is to demonstrate that the aseptictechnique of the operator undertaking the asepticmanipulation is capable of maintaining the sterility ofthe product. All aseptic manipulation should bebroken into a number of key steps (i.e. withdrawingsolution from a vial, addition of a solution to aninfusion bag) and each key step may be investigatedusing a media fill test. The operator should also beable to demonstrate an understanding of the safehandling techniques required to prevent exposure tohazardous drugs.

A second objective is to ensure that the operatorcan carry out these aseptic manipulations withoutcontaminating herself/himself or the environment.The use of a fluorescein dye detected with ultravioletlight is most commonly employed.

Validation of training

The objective is to confirm that all staff have asatisfactory level of knowledge and competency forthe duties they are required to undertake. Thetraining program should be validated and shouldinclude the critical steps especially aseptic processand chemical contamination risks. The impact oftraining on the trainee should be validated byperforming competency checks.

Re-validation should occur on a regular basis. Thefrequency of this re-validation will depend on anumber of factors including the staff turnover in thearea, and the duration of rosters in the area. As aminimum, staff regularly reconstituting cytotoxicsshould undergo a validation test annually.

4.2.5 EvaluationOngoing feedback on the training provided should bean integral part of the program. The effectiveness ofthe training should be assessed and reviewed on aregular basis.

4.2.6 Re-trainingTo cover the introduction of new drugs into practiceor any other technical innovations, it is recom-mended that the training program be repeatedevery 2–3 years.

Training should be repeated whenever any majorchange in practice occurs.







Section 5 � Hierarchic order in protection measures


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Section 5 – Hierarchic order in protectionmeasures

It is very common in the setting of standards forindustrial hygiene to include an obligation to follow ahierarchic order of level of protection for employeesat their workplace.

An example of this obligation can be found inDirective 2004/37/EC of the European Parliamentand the Council of 29 April 2004 on the protection ofworkers from the risks related to exposure tocarcinogens or mutagens at work,1 or in most ofthe national regulations or laws on industrial healthand safety.

According to the provisions of these laws andregulations, the employer must perform a riskanalysis comprising the following steps:

� Definition of the work areas to be evaluated (e.g.cytotoxic preparation facility, reception ofgoods, transport, administration, etc.)

� Ascertainment of hazards and burdens (e.g.classification of substances)

� Evaluation of these hazards and burdens� Specification of the necessary measures� Testing and evaluation of the effectiveness of the

measures (to ensure the protective measureshave achieved the intended aim or whether theyhave possibly resulted in the generation of newhazards)

� Documentation

It is not logical to install a level of protection farhigher or to accept a level far lower for cytotoxicdrugs compared to the measures taken for othertoxic or carcinogenic products.

However, it is imperative that the sequence ofprotection levels starts with level 1 and ends at level4¼TOP!BOTTOM

In other words, one is not free to choose themeasures in protection to exposure of cytotoxicdrugs.

The levels of protection measures are in descend-ing order of importance:

5.1 Level 1: Elimination, substitution,replacement

Change the product to another product which isnon-toxic or less toxic

Currently, this is rarely possible in the treatment ofcancer patients, but this level could become veryimportant as more targeted therapies becomeavailable.

If level 1 is impossible or is insufficient, thenthe next level is applied

5.2 Level 2: Isolation of the hazard/sourcecontainment

Contain the toxic product in its container or atsource

By containing the product at its source, thecontamination of persons or materials is prevented.

If possible, source containment should be contin-uous throughout the entire process of productionand administration of the product.

If levels 1 and 2 are impossible or insufficient,then the next level is applied

5.3 Level 3: Engineering controls/ventilation

Apply local and general ventilation or extractionin order to dilute the toxic product

Any form of dilution will reduce the concentrationof the contamination. Any form of extraction willreduce the amount of contamination. (e.g. opening awindow and/or door to a patient’s room to allowventilation)

Biological safety cabinets and isolators should beconsidered as level 3 measures. These ventilationtools offer additional protection features; for biolog-ical safety cabinets this would include such things ascontrolled airflow, protection shields, and HEPAfilters.

For isolators this would include such things ashatches, glove ports, HEPA filters, and a physicalbarrier between the product and operator.

None of these features will prevent contaminationwithin the biological safety cabinet or isolator fromoccurring. Once contamination has occurred, it willinevitably enter the environment.

Some laws and regulations use a 5th level ofhierarchic order. In this case there is an additionallevel between levels 3 and 4 – Level 3B




5.3.1 Level 3 B: Administrative controls/organization measuresOrganise the work in such a way that the duration ofexposure is reduced. Organise the work in such away that the number of employees exposed isreduced. If levels 1, 2, and 3 are impossible orinsufficient, then the next level is applied.

5.4 Level 4: Personal protective equipment

Individual protection by using personal tools

Gloves, masks, gowns, goggles or face shields, andother equipment create a temporary barrier betweenthe contamination and the operator.

It is important to use ‘‘proven’’ resistant material;tested for these specific products and conditions.

Terminology such as ‘‘cytotoxic glove’’ is notsufficient to ensure adequate protection unlessaccompanied by test results.

For such tests, the specific conditions should betaken into account. e.g:

(a) HYPEC procedure (direct contact withcytotoxic drug for 30 minutes at tempera-tures of 428C)

(b) temperature of glove after only 3 minutes onthe hand reaches 348C

(c) continuous stretching of the glove duringpreparatory or administration activitiesversus static test conditions.

Safe work practices should be incorporated intoStandard Operating Procedures (SOP) and theseprocedures should be reviewed and updated on aregular basis. All staff should be educated and trainedin accordance with these procedures and perfor-mance should be reviewed periodically.

REFERENCE

1 Directive 2004/37/EC of the European Parliament and the

Council of 29 April 2004 on the protection of

workers from the risks related to exposure to carcino-

gens or mutagens at work (Sixth individual

Directive within the meaning of Article 16(1)

of Council Directive 89/391/EEC 2004). Available

at: http://europa.eu/scadplus/leg/en/cha/c11137.htm

Accessed February 2007.







Section 6 � Facilities for sterile cytotoxic reconstitution and personal protective equipment


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Section 6 – Facilities for sterile cytotoxicreconstitution and personal protective

equipment

Facilities for the sterile reconstitution of cytotoxicagents need to ensure both the protection of theproduct and the protection of the drug handlers.

Aseptic drug manipulation must take place in acontrolled environment to ensure the sterility of theend product. Additional protective measures arerequired to guarantee the safety of the operators.

6.1 Centralised preparationCentralised preparation of parenteral cytotoxic drugsshould be implemented to protect the final productagainst microbiological and particulate contamina-tion and to protect handlers against exposure tohazardous drugs. Taking into account the pharma-ceutical analysis and the quality control implemen-ted, centralised preparation improves the entirequality of the preparation and thus the safety ofpatients is enhanced. Centralisation of services alsoprovides economic benefits.

Centralisation is commonly located in the phar-macy department. Many institutions site the prepara-tion facility within an oncology outpatientdepartment or close to the inpatient ward wherechemotherapy is most commonly administered (thatis, a satellite pharmacy). This offers advantages interms of ease of transport of cytotoxics as well asenhanced communication between pharmacy,medical, and nursing staff.

The satellite pharmacy must be under thecontrol of a pharmacist.

Under no circumstances should nursing staffbe permitted to prepare/reconstitute cytotoxic

agents on the ward.

6.2 FacilitiesDue to the risk of contamination, cytotoxic recon-stitution must be performed in a room dedicatedsolely to that task with similarly dedicatedequipment.

Access to the room where cytotoxic preparation isperformed must be restricted to trained and validatedpharmacy personnel. A warning sign must clearly

identify that the access is controlled and limited toauthorised personnel only. The use of standardsymbols and colours to depict cytotoxic agents isrecommended. This sign should contain wordingsuch as:

‘‘Cytotoxic Preparation Area.Access Restricted to Authorised Personnel

Only’’

The cytotoxic facility should be designed to alloweasy and adequate access for personnel, equipment,and cleaning. The room surfaces should be designedto minimise particle shedding and to prevent thebuild-up of particulate matter. The design mustfacilitate effective cleaning. Walls must be linedwith a smooth, durable surface, lighting recessedinto the ceiling, and the room should contain as fewprojecting ledges or shelves as possible. Floorsshould be poured and seamless if possible. Vinyltiles have been shown to trap and hold drugs.

In the event of contamination of the eye withhazardous material, there should be emergency eyewash facilities available for use by staff. Eyes thatbecome contaminated should undergo sustainedirrigation with either a commercial eye irrigationsolution or sodium chloride (0.9%). Due to thepotential for water pressure damage to the eye, it isnot recommended to irrigate the eye directly withrunning water from a tap. Consideration should alsobe given to the installation of an emergency shower.

6.2.1 Class of cleanroomGeneral classification of the cleanroom (‘‘Class’’) isgiven by the ISO 14644-1 international standard.1

This classification is based on the maximum level ofparticulate contamination. For sterile medicinalproducts, classification of the room must be referredto the classification (‘‘Grade’’) given by the EudraLexGood Manufacturing Practices Annex 1, Volume 4,Manufacture of Sterile Medicinal Products,2 and bythe draft PIC/S Guidelines.3 EudraLax applies to thepharmaceutical industry while the draft of the PIC/S




Guidelines are meant for the pharmaceutical inspec-tion services controlling (hospital) pharmacies.

This classification takes into account both partic-ulate and microbiological contamination. The roomshall be designed to facilitate asepsis in the handlingand preparation of cytotoxic drugs, and shall also bedesigned to provide containment of cytotoxic drugs,particularly in the event of the failure of thebiological safety cabinet/isolator or spillage outsidethe cabinet/isolator. The requirements for ‘‘Class’’ or‘‘Grade’’ environments will depend upon both thetype of preparation and the equipment used.

(a) Type of Preparation

Preparation of sterile cytotoxic drugs can bedefined as an aseptic preparation.

(b) Environmental Setting

Sterile cytotoxic preparation using aseptic tech-nique must be performed in a Grade A environment.Characteristics of a Grade A environment are shownin Table 1 (particlulate contamination) and Table 2(microbial contamination). Table 3 summarises therelationship between the ISO classification1 theEudraLex2 classification, and the US federal standard209E with regard to particulate contamination.Note: Federal standard 209E has been replaced

with ISO Standard 14644-1. Taking into account

that some suppliers and users may not yet have

switched over, this data is provided for information

only.The Grade A environment corresponds approxi-

mately to the ISO Class 5.Both laminar airflow hoods and isolators are able to

guarantee a Grade A environment. The main differ-ence between these two approaches is related to therequirements for the immediate environment of theequipment used.According to the PIC/S draft Guidelines,3 when

a laminar airflow hood (biological safety cabinet) isused for aseptic manipulations, the recommendedgrade of background environment is:

Aseptic preparation of products with shelf life524 hours: at least Grade D

Aseptic preparation of products with shelf life424 hours: at least Grade B*

* If aseptic procedures are extensively documen-ted, grade C could be accepted for existing facilities.In that case, grade B clothing should be worn.

If an isolator is used (permanently closed – seeSection 8), the recommended grade of backgroundenvironment is:



For terminally sterilised products, the backgroundenvironment for filling these products is at leastGrade C.

Note that an anteroom leading to a positivepressure room may be ISO Class 8 (see Table 3) butan anteroom leading to a negative pressure roomshall meet at least ISO Class 7 (see Table 3) criteria

Table 1. Airborne particulate classification2

At rest In operation

Grade Maximum permitted number of particles/m3

equal to or above0.5 mm 5 mm 0.5mm 5 mm

A 3500 1 3500 1

B 3500 1 350 000 2000C 350000 2000 3 500 000 20 000

D 3500000 20 000 Not defined Not defined

Table 2. Recommended limits for microbial contamination2

Grade Air sample

cfu/m3

Settle plates

(diameter

90mm)

cfu/4 hours

Contact plates

(diameter

55mm)

cfu/plate

Glove print

5 finger

cfu/glove

A 51 51 51 51

B 10 5 5 5

C 100 50 25 –D 200 100 50 –

Table 3. Relationship between ISO classification,1 EudraLexClassification,2 and US federal standard No. 209 E (US FS 209E)

Grade/Class Maximum permitted number of particles/m3

equal to or above0.1 mm 0.2 mm 0.3 mm 0.5 mm 5 mm

Class ISO 5

(US FS 100)

100 000 23 700 10 200 3520 29

Grade A and

B (at rest)

/ / / 3500 1

Class ISO 7

(US FS 10,000)

/ / / 352 000 2930

Grade C 350000 2000

Class ISO 8

(US FS 100,000)

/ / / 3 520 000 29 300

Grade D / / / 3 500 000 20 000

*Note: US FS 209 E has been replaced with ISO Standard 14644-1.




so that air drawn into the negative pressure environ-ment is of the same ISO Class 7 (see Table 3) quality.

A pressure indicator shall be installed that can bereadily monitored for correct room pressurization.

The BSC and Compounding Aseptic Isolator shallbe 100% vented to the outside air through HEPAfiltration.Additional comments related to the use of

isolators: When isolator technology is used, therequirements for the immediate surroundings willdepend upon the pressure type of the isolator, andthe type of pass through hatches. Positive air pres-sure isolators, which are totally and permanentlyenclosed, may be located in an uncontrolled room ora D Grade (ISO 8) environment. Negative air pressureisolators must be located at least in a Grade C (ISO 7)environment.

In the case of preparation of cytotoxic agents,containment is the most important aspect to beconsidered, and special attention must be paid to thetransfer system/pass through hatches used betweenthe isolator and the environment. Type F4 passtransfer devices are highly recommended to removewaste and end-products. These devices use doubleinterlocking doors to ensure both the containment ofany chemical contamination and the sterility of thefinal product. Type A4 transfer devices must beavoided because during the transfer, inside isolator aircan be directly exhausted into the isolator environ-ment, especially when using a positive air pressureisolator. See Section 8.According to USP Chapter 57974,5 where

three risk levels are introduced, the requirements ofa Class D cleanroom for low-risk operations and aClass C cleanroom for medium and high-riskoperations must be achieved. Those risk levels areassigned according to the conditions in which sterilepreparations are compounded.

According to USP 579745 Hazardous Drugs asCSPs (Compounded Sterile Preparations):

Low-risk conditions

(1) The CSPs are compounded with asepticmanipulations entirely within ISO Class 5(see Table 1) or better air quality using onlysterile ingredients, products, components,and devices.

(2) The compounding involves only transfer,measuring, and mixing manipulations usingno more than three commercially manufac-tured sterile products and entries into one

container package (e.g., bag, vial) of sterileproduct to make the CSP.

(3) Manipulations are limited to aseptically open-ing ampoules, penetrating sterile stoppers onvials with sterile needles and syringes, andtransferring sterile liquids in sterile syringesto sterile administration devices, packagecontainers of other sterile products, andcontainers for storage and dispensing.

For a low-risk preparation, in the absence of passing asterility test,5 the storage periods cannot exceed thefollowing time periods: before administration, theCSPs are properly stored and are exposed for notmore than 48 hours at controlled room temperature,for not more than 14 days at a cold temperature, andfor 45 days in solid frozen state at �208C or colder.5

Examples of low-risk compounding:

(1) Single volume transfers of sterile dosageforms from ampoules, bottles, bags, andvials using sterile syringes with sterile nee-dles, other administration devices, and othersterile containers. The solution content ofampoules should be passed through a sterilefilter to remove any particles.

(2) Simple aseptic measuring and transferringwith not more than three (3) manufacturedproducts including an infusion or diluentsolution to compound drug admixtures andnutritional solutions.

Medium-risk conditions

Medium-risk conditions include multiple individualor small doses of sterile products that are com-pounded or pooled to prepare a compound sterileproduct that will be administered either to multiplepatients or to one patient on multiple occasions.

Examples of medium risk conditions:

(1) The compounding process includes complexaseptic manipulations other then a single-volume transfer.

(2) The compounding process requires anunusually long duration, such as thatrequired to complete dissolution or homoge-neous mixing.

(3) The compounded sterile products do notcontain broad-spectrum bacteriostatic sub-stances, and they are administrated overseveral days.

For medium-risk preparations, in the absence ofpassing a sterility test the storage periods cannot




exceed the following time periods: before adminis-tration, the CSPs are properly stored and are exposedfor not more than 30 hours at controlled roomtemperature, for not more than 7 days at a coldtemperature, and for 45 days in solid frozen state at�208C or colder.

Examples of medium risk compounding:

(1) The compounding of Total ParenteralNutrition fluids by using manual or auto-mated devices that require multiple injec-tions and detachments and attachments ofthe nutrient source products to the device ormachine to deliver all nutritional compo-nents to the final sterile container.

(2) The filling of reservoirs of injection andinfusion devices with multiple sterile pro-ducts and evacuation of air from thesereservoirs before the filled device isdispensed.

(3) The filling of reservoirs of injection andinfusion devices with volumes of steriledrug solutions that will be administeredover several days at ambient temperaturesbetween 258 and 408C.

(4) The transfer of multiple ampoules or vialsinto a single, final sterile container orproduct.

High-risk conditions

High-risk conditions include:

(1) The compounding of non sterile ingredients,including manufactured products for routesof administration other than those listedunder c in the introduction of the officialPharmacopeial Forum that are incorporatedor a non sterile device that is employedbefore terminal sterilization.

(2) The compounding of sterile ingredients,components, devices and mixtures exposedto air quality inferior to ISO Class 5; thisincludes the storage in environments inferiorto ISO Class 5 or opened or partially usedpackages of manufactured sterile productsthat lack microbial preservatives.

(3) The compounding of non sterile productsexposed to air quality inferior to ISO Class 5for at least 6 hours before sterilization.

For high-risk preparations, in the absence of passinga sterility test, the storage periods cannot exceed thefollowing time periods: before administration, theCSPs are properly stored and are exposed for not

more than 24 hours at controlled room temperature,for not more than 3 days at a cold temperature, andfor 45 days in solid frozen state at �208C or colder.

Examples of high-risk compounding:

(1) The process of dissolving non sterile bulkdrug and nutrient powders to make a solu-tion, which will be terminally sterilized.

(2) The situation when sterile ingredients, com-ponents, devices and mixtures are exposedto air quality inferior to ISO Class 5.

(3) The process of measuring and mixing sterileingredients in non sterile devices beforesterilisation is performed.

6.2.2 Pressure differentialsAccording to USP 57974,5 there is no option for thepressure of the preparation room which should benegative.

According to the PIC/S draft guidelines3:

‘‘Aseptic operations (open and closed procedures)

should be performed in a grade A environment in a

laminar flow cabinet (LFC) or a positive pressure

pharmaceutical isolator. The room should have a

positive pressure (ideally 10 – 15 Pascals) and air

flow relative to the surrounding areas of a lower

grade in order to protect the product from

contamination.’’

‘‘Preparation under negative pressure, protecting

operator and environment from contamination

should only be used for preparation of hazardous

pharmaceuticals (e.g. cytotoxic drugs, radiophar-

maceuticals and radio labelled blood products),

together with appropriate precautions against con-

tamination of the medicinal product (e.g. appro-

priate background room air quality, positive

pressure airlock systems).’’

‘‘LFCs are not suitable for the preparation of

hazardous drugs. Biohazard safety cabinets

(BSCs) should be used instead, with a vertical

down flow exhausting vertically from the cabinet

and not towards the operator.’’

Therefore, combining both recommendations, BSC’sof Grade A (ISO 5) are located in a negative airpressure room of Grade C (ISO 7). Positive pressureisolators Grade A (ISO 5) are located in a negative airpressure room of Grade D (ISO 8) or uncontrolledGrade room. Negative air pressure isolators Grade A(ISO 5) are located in a negative air pressure room ofGrade C (ISO 7).




Pressure differentials should be established withinthe cytotoxic preparation facility with the doubleobjective of protecting the operators and maintainingthe sterility of parenteral product. Two possibilitiesexist: Positive and negative pressure differentials withthe surrounding environment.

(a) Positive Pressure Differential

Positive air pressure of the preparation room andnegative air pressure of the airlock hatches and theanteroom. In this case, the negative air pressure ofthe hatches and personnel zone acts as a trap toisolate potentially contaminated air.

(b) Negative Pressure Differential

Negative air pressure of the preparation room andpositive air pressure of the airlock hatches and theanteroom. In this case, the positive air pressure of thehatches acts as a barrier.

(c) Pressure Differential Between AdjacentRooms

EudraLex2 recommends a 10–15 Pa pressure differ-ence between adjacent rooms of different grade.Note: this does not apply in the case of a negativepressure room.

For example, a typical graduation configuration fora cleanroom used for aseptic preparation is givenbelow:

� 10–15 Pa between Grade A and B� 8–10 Pa between Grade B and C� 2–6 Pa between Grade C and D� 2 Pa between Grade D and surrounding zone

Note that this example of graduation has to beadapted in order to reach the above proposedpressure differential (a) or (b) for aseptic preparationof toxic drugs.

In all cases, it is recommended that the roomwhere cytotoxic agents are stored is under negativepressure to prevent the dissemination of contamina-tion in the event of breakage.According to USP _797`,5 Hazardous drugs asCSP’s (Compounded Sterile Preparations): TheISO Class 5 (see Table 3) BSC or CompoundingAseptic Isolator (see definition below) shall be placedin an ISO Class 7 (see Table 3) room that is physicallyseparated, i.e., a different room, from other prepara-tion areas, and optimally has no less than 0.01-inch(0.0254 cm) water column [2.4905Pa] negativepressure to adjacent positive pressure ISO Class 7,or better, anterooms, thus providing inward airflowto contain any airborne drug.

If a compounding isolator that meets the require-ments for asepsis and containment is used outside ofa cleanroom, the room must maintain a minimumnegative pressure of 0.01 inch (0.0254 cm) watercolumn (2.4905Pa) and have a minimum of 12 airchanges per hour.

6.2.3 Air changesA minimum air change of 20 room volumes per houris required. Areas known to generate large numbersof particles, for example changing rooms, may havean air change rate of up to 60 volumes per hour.

6.2.4 External exhaust of air fromthe work areaThe air from the workplace must be exhausted to theatmosphere to prevent exposure of personnel.A HEPA exhaust filter should be used to decreasecontamination of the air exhausted. However, it isknown that some anticancer drugs are vaporised andthen pass through HEPA filters. Some countries, forexample Australia, may mandate the use of activatedcarbon filters to trap vapourised cytotoxics.However, it should be noted that these filters maynot guarantee complete retention in all cases.See Section 8.

The location of the exhaust point of the ductis usually 2 m above the nearest building.

6.2.5 Temperature and humidityIn order to prevent microbiological contaminationand to ensure comfort of the personnel working inthe area, the temperature of the preparation roomsmust be controlled. A temperature in the range of18–228C is acceptable.

The humidity must be controlled in order to preventcorrosion and condensation on any work surfaces andalso to provide operator comfort. In addition, forisolators which are sterilized by hydrogen peroxidevapour, the humidity of the surrounding environmentmust be strictly controlled. The human comfort zoneis generally in the range of 30% to 70% relativehumidity. For isolators sterilized by hydrogenperoxide a 50% relative humidity level must bereached and controlled between 40% and 60%.

6.2.6 Access of personnel to the cleanroomAccess to the cleanroom should be through ananteroom. An effective airlock must exist betweenthe cytotoxic suite and the external environment.Adequate procedures must be in place to prevent thesimultaneous opening of doors and pass-through




hatches. If interlocking doors are used, a safetyoverride switch should be installed for emergencysituations. The doors should preferably be fitted withan audible or visual alarm to prevent both doorsbeing opened simultaneously.

This anteroom must be the only access to thecytotoxic cleanroom. If possible, this anteroomshould not share access to other non-cytotoxiccleanrooms in order to prevent any cross contami-nation occurring. The anteroom should providefacilities for gowning of personnel entering thecleanroom and should be ventilated through a HEPAfilter. A full length mirror should be available in theanteroom so that staff can check that they areappropriately gowned prior to entering the clean-room. Consideration should be given to the use ofsticky mats. Step-over barriers should be used toseparate the different stages of change. Attentionshould be paid to the exit of persons and separatecirculation zones should be identified allowingdiscarding of protective gowns and gloves beforeexiting the restricted access zone.

The pressure within the anteroom may be positiveor negative depending on the concept chosen (seeSection 6.2.2)

6.2.7 Pass-through hatchesA pass-through hatch is essential to prevent directaccess between the cytotoxic cleanroom and theexternal environment. There are two possibilities forthe location of such hatches. These hatches mayeither be between the cleanroom and the anteroomor between the cleanroom and the external environ-ment. If the latter option is selected, then interlock-ing doors must be used and the unit must be HEPAfiltered. Hatch doors should preferably be fitted withan audible or visual alarm to prevent doors beingopened simultaneously.

For specific hatches used for entry to a pharma-ceutical isolator see Section 8.

In order to minimise cross contamination, separatehatches for entry and exit of products are preferable.

6.2.8 Storage roomAccording to USP 57974,5 hazardous drugs shall bestored separately from other stock in a manner toprevent contamination and personnel exposure.Such storage is preferably within a containmentarea such as a negative pressure room. The storagearea must have sufficient general exhaust ventilation,e.g. - at least 12 air exchanges per hour to dilute andremove any airborne contaminants. Hazardous drugs

shall be handled with caution using appropriatechemotherapy gloves during distribution, receiving,storage, preparing for administration, and disposal.

6.2.9 Monitoring of facilitiesAn ongoing monitoring program should be estab-lished. In controlled workplaces, the parametersto be monitored are microbiological contamination,particulate contamination, HEPA filtration, airvelocity, and pressure differentials. Visual inspectionof the surfaces and joints should be performedregularly for cracks or other damage. Specificationsto be maintained depend on the grade of the room(see Section 6.2.1).

A check list should be used to assess the confor-mity of the room and equipment before daily use.Pressure differentials must be checked before entryinto the cleanroom. Consideration should be given tothe installation of manometer alarms, preferablyvisual, which alert staff to inadequate pressuredifferentials.

Particulate contamination and air velocity shouldbe assessed on a regular basis.

Microbiological contamination should be checkedon a daily basis by sampling surfaces (contact plates).Passive air sampling should be done daily with settleplates (Petri dishes of diameter 90 mm) and active airsampling done on a regular basis. Testing must becarried out more frequently if any abnormality in anytest is detected, or if any maintenance or repair workis carried out.

Frequency of monitoring3

Table 4. Minimum frequency of physical monitoring

Laminar flow cabinets

(LFCs)/Biohazard Safety

Cabinets (BSCs):

Frequency

Pressure differentials

between rooms

Before beginning of work,

usually dailyPressure differentials across

HEPA filters (workstation)


usually dailyParticle counts Yearly at rest and in the

operational stateRoom air changes per hour Yearly

Air velocities on workstations Yearly

HEPA filter integrity checks Yearly

Isolators:Isolator glove integrity Visual checks every session

Pressure differentials across

HEPA filters


usually dailyIsolator pressure hold test

(with gloves attached)

Weekly




6.2.10 Microbiological monitoringPassive air sampling is performed usingsettle plates which must be placed according to asampling plan previously defined. This plan may bedeveloped in conjunction with the institution’sdepartment of microbiology. Settle plates should beexposed under normal operating conditions for aperiod of 4 hours. Maximum acceptable levelsof microbiological contamination depend on theenvironment grade2:

Grade A environment _1 cfu/plateGrade B environment 5 cfu/plateGrade C environment 50 cfu/plateGrade D environment 100 cfu/plate

Active air sampling is performed using bio-collectors. The sampling method is based oncollecting a known volume of air during a definedperiod of time. Air is drawn over a nutrient agarsurface at such velocity that any particulatecontaminants are impacted onto the surface.Active air sampling is a more sensitive methodthan passive air sampling. Maximum acceptablelevels of microbiological contamination depend onthe environment grade2:


Microbiological monitoring of surfaces can beperformed either by contact plates (diameter55 mm) or using swabs. Contact plates provide ahigher degree of reproducibility than swabs and areeasier to use. However, swabs could be useful forsampling inaccessible places such as corners. Inaddition, no recommendation of maximum accept-able levels is available for the swabs. For thecontact plate method, contact with the surface tobe sampled must be applied at a defined pressurefor a defined period of time. A standard procedure

of a light hand pressure for 2–5 seconds is likely tobe satisfactory.

Maximum acceptable levels of microbiologicalcontamination for contact plates depend on theenvironment grade2:


6.2.11 Air particle samplingAir particle sampling is performed to verify that theenvironment reaches specification. Particle measure-ment is based on the use of a discrete airborneparticle counter to measure the concentration ofparticles at designated sizes equal or greater than thethreshold stated.

Maximum acceptable levels of particulate con-tamination depend on the environment grade2 – seeTable 1. Maximum permitted levels are given bothat rest and under normal operating conditions.The particulate conditions given at rest should beachieved after a short clean up period of 15–20minutes (guidance value) after completion ofoperations. For the grade A environment, it isaccepted that the ‘‘In Operation’’ specifications maynot be achieved under normal operating conditionsdue to the nature of the work being carried out(for example, over wrapping of sterile medicaldevices). In this case, particle counts above thespecifications can be generated without compro-mising the quality of the preparation. Consequently,the particle control should be focussed on the ‘‘atrest’’ conditions.

6.2.12 Certification and Quality AssuranceWhenever possible, all equipment and processesused for cytotoxic preparation which affectproduct sterility or product attributes should bequalified or validated. Any certificates issued shallbe reviewed, approved, and signed off by adesignated pharmacist, and retained indefinitely.This will vary according to local practice andregulations.

Qualification is required for the room and for theequipment used. This includes the biological safetycabinet, pharmaceutical isolator, and automatedfilling pump among other equipment. This qualifica-tion process consists of four steps:

(1) Design (Design Qualification [DQ]): Thedocumented verification that the proposed

Table 5. Minimum frequency for microbiological monitoring

Settle plates Every working session in the

Grade A (ISO 5) zone

Once a week in clean room

Surface samples Weekly

Active air samples Weekly

Glove finger dabs At the end of each working session




design of facilities, systems and equipment issuitable for the intended purpose.

� Approval of the design and drawing:This approval must be obtained, in accor-dance with local regulations, by the bodyresponsible for pharmacy practice, forexample a state board of pharmacy,a pharmaceutical society, or licenceinspector, and by the pharmacistresponsible for the unit.

(2) Installation (Installation Qualification[IQ]): The documented verification that thefacilities, system and equipment, as installedor modified, comply with the approveddesign and the manufacturer’s recommenda-tions. At this stage, the installation is on sitebut is not operational. The objective at thispoint is to review the compliancewith specifications.

(3) Operation (Operational Qualification[OQ]): The documented verification that thefacilities, systems, and equipment, asinstalled or modified, perform as intendedthroughout all anticipated ranges. The objec-tive is to check that the installation operateseffectively under normal working conditionsbut without activity. Examples of operationalcertification for rooms are given below:

� HEPA filter integrity test� Functional check of pressure regulation

and alarms� Air change rate per hours� Particle count� Pressure differential� Noise level� Light Level

(4) Performance (Performance Qualification[PQ]): The documented verification that thefacilities, system and equipment takentogether, can perform effectively and repro-ducibly, based on the approved processmethod and product specification. The objec-tive is to check that the installation operateseffectively under normal operating condi-tions during routine activity. Examples ofperformance certification are given below:

� Checking procedures of use and monitor-ing of the installation

� Air distribution studies

6.2.13 ValidationValidation is the documented evidence that theprocess, operating within established parameters,can perform effectively and reproducibly to producecytotoxic drugs meeting all predetermined specifica-tions and quality attributes. In terms of sterilefacilities, validation that the processes used duringthe aseptic preparation maintain the sterility of theend product is required.

Validation of the process (see Section 4.10.1)

6.3 Clothing & PPEThe correct selection and use of personal protectiveequipment (PPE) is required to both ensure thesterility of the end product and protect the operator.PPE must be worn to protect personnelduring cytotoxic reconstitution and during otheractivities where they may come into contact withhazardous drugs. Activities may include opening drugpackaging, handling vials or finished product, label-ling drug containers, or disposing of waste. PPEincludes gloves, gowns or coveralls, boots or over-shoes, masks, head coverings, and protectiveeyewear.

The specific protective equipment required willdepend upon the grade of room in which theoperator is working. The highest level of protectionis for zones A/B where the aseptic manipulations areperformed (BSC in a Grade B room). Examples of PPErequired are shown in Table 6.

(a) Gowns

The use of disposable coveralls or gowns made ofnon-linting and non-absorbent polyethylene-coatedpolypropylene material is recommended.6 Thegown used should have the followingcharacteristics:

� Long and closed at the neck� Long sleeves with cuffs gripped at the wrist� Disposable sleeve covers to protect the wrist

and lower arm� Waterproof material for the front and sleeves� Sterile� Non-linting

Integrated coveralls which include head and footcoverings are very suitable in terms of both micro-biological and chemical contamination.




(b) Overshoes should be worn:

� If shoes are worn in the production zone.Dedicated shoes should be used for thispurpose.

� In the event of any accidental contamination

(c) Masks

Surgical masks should be used during production incleanroom. A mask (type P2 or P3 for solids andliquids) is required when changing the pre-filter, inthe event of any accidental contamination and fororal preparations. Common surgical masks offer noprotection against aerosols.

(d) Protective Goggles

Goggles are recommended when any projection riskis present. In most cases the glass screen of thebiological safety cabinet should offer adequate pro-tection against any possible spray of solutions duringcytotoxic reconstitution. Goggles must be wornwhen cleaning a spill. See Section 14.

(e) Gloves

Gloves used must be proven to be resistant tochemotherapy and labelled as chemotherapy gloves.Gloves used should have the followingcharacteristics:

� Sterile, non-powdered� Latex (consider latex-sensitive workers),

nitrile, or neoprene gloves may be used if

they have been validated for the specificpurpose of cytotoxic reconstitution

A double pair of gloves may be used. The outerglove must extend over the cuff of the the gown.Gloves should be changed at least every 30 minutes orwhenever damage or obvious contamination occurs.Gloves should not be decontaminated with alcohol.

(f) Hair Covering

The hair must be covered with a separate headcovering or an integrated hood of a coverall. Menwith beards may need to wear a separate covering forthis purpose

(g) Personal protective equipment for Isolatorand BSC III users

The gowning procedure will depend on the grade ofthe room where the isolator or BSC III is located (seeabove table 2). In addition, personal protectiveequipment has to be considered for tasks performedoutside the barrier enclosure where the risk ofchemical contamination is present (e.g. handlingvials).

REFERENCES

1 ISO (International Organization for Standardization)

14644-1: cleanrooms and associated controlled

environments – Part 1: classification of air cleanliness.

1999.

2 EudraLex. Volume 4 Medicinal Products for Human

and Veterinary Use: good Manufacturing Practice.

Annex 1 Manufacture of Sterile Medicinal Products.

2003. Available at: http://ec.europa.eu/enterprise/-

pharmaceuticals/eudralex/homev4.htm. Accessed

January 2007.

3 PIC/S Guide to Good Practices for Preparation

of Medicinal Products in Pharmacies. PE 010-1

(Draft 2) 2006. Available at: http://www.picscheme.org/

index.php. Accessed February, 2007.


14644–7: Cleanrooms and associated controlled environ-

ments- Part 7: Separative devices (clean air hoods, glove

boxes, isolators, mini-environments). 2004.

5 USP (U.S. Pharmacopeia) Pharmaceutical compounding –

sterile preparations (general test chapter 797).

In: The United States Pharmacopeia 28 rev., and

The National Formulary, 23rd ed Rockville, MD:

United States Pharmacopoeial Convention; 2005:

2471–77.

Table 6. Clothing required for differing grades ofenvironment2

Grade of Room Requirements for PPE

Grade D Hair/Beard Covering Normal

Protective ClothingGrade C Hair/Beard Covering

Clothes gripped at wrist with raisedCollar

Clothing must not shed fibres or particles

Grade A/B Hood or other head covering

MaskSterile, Non-powdered gloves

Sterile or disinfected boots or overshoes

Sterile clothing which must not shed

fibres or particlesSterile clothing must be capable of

retaining particles shed by operator




6 NIOSH Alert: Preventing occupational exposures to







BIBLIOGRAPHY

ASPEC (Prevention et Etude de la Contamination)

Isolators Qualifications, Paris, France: ASPEC;

2004.8#Beaney AM. ed. Quality Assurance of Aseptic

Preparation Services, Third edition. London, England:

Pharmaceutical Press; 2001.







Section 7 � Special devices


Published by:
















Section 7 – Special devices

In the late 1990s, much information became availableconcerning the possible occupational exposure tocytotoxic drugs and environmental contaminationwith these agents. These problems may arise duringroutine handling of the drug vials or ampoules,during an aseptic preparation process, or during theadministration of the cytotoxic drug.

These observations have been confirmed objec-tively by examinations using fluorescein dye anddirect analysis of the product by wipe sampling.

Around this time, pharmaceutical companiesbegan to promote special devices for the reconstitu-tion and administration of cytotoxic drugs. The aimof these devices is to prevent or minimize anypossible contamination.

These special devices may be considered in 3categories:

(a) Devices to protect the handler of the vial/ampoule

(b) Devices to protect the operator duringpreparation

(c) Devices to protect the administrator duringadministration of the cytotoxic drug to thepatient

7.1 Devices to protect the handler of the drugvial or ampouleIn the late 1990s, several studies indicated that vialsand ampoules delivered from pharmaceutical com-panies may be contaminated on the outside with thecytotoxic drug. In some cases contamination wasdetectable in up to 30 to 50% of the vials examined.

This was the result of contamination during themanufacturing process (for example, foam forming ordust from powder form of drug) and/or inadequatewashing of the vials before packaging. Many compa-nies have now focussed more attention on thisproblem but with different levels of success.

It is strongly recommended that cytotoxicdrug vials be enclosed in plastic coating inorder to contain any possible contaminationon the outside of the vial. This plastic coatingshould also cover the bottom of the vial.Many manufacturers now supply cytotoxicsin plastic shrink wrap for this purpose.

Some manufacturers supply their cytotoxicagents encased in specially designed mouldedplastic containers to contain any possible con-tamination, and also to protect against anyshock during transport.

Some manufacturers supply their cytotoxicagents encased in specially designed mouldedplastic containers to contain any possible con-tamination, and also to protect against anyshock during transport.

Many manufacturers now supply cytotoxicagents in this way.

Individual packaging in shock absorbentmaterial is required.

Test reports should document the ability of thepackaging to adequately contain all contents in theevent of a cracked vial or ampoule

It is the responsibility of pharmaceutical manufac-turers to guarantee that the external surfaces of drugvials are free of contamination. One objective way toensure commitment to deliver contamination-freeproducts is to mandate analysis by an independentlaboratory, detailing the amounts of product on theouter surface of the first, middle, and last vial/ampoule of the batch prepared. See also Section2.1.6. Pharmacists should favour manufacturers whotake this problem seriously and are prepared to workto ensure contamination-free vials.

7.2 Devices to protect the operator duringpreparationNumerous studies have shown that aseptic manipu-lation using a classic syringe and needle techniquealmost universally results in contamination. Droplets,leakage from vial stoppers after multiple punctures,and aerosol generation resulting from increasedpressure inside drug vials have also been observed.Some measures have been employed to protectoperators using this classic technique. This includesthe use of Luer connections on needles and syringesto minimise the risk of separation. To reduce the riskof high pressure syringing, wide bore needles (18 G/1.2 mm) are preferable when reconstituting cytotoxicdrugs. The maximum recommended bore size forpiercing additive ports is 21 G/0.8 mm. The use of




filter needles is best avoided unless the drug has beenremoved from a glass ampoule or particulate matteris clearly visible.

Techniques which prevent a pressure differentialbetween the inside and outside of cytotoxic drugvials are recommended. Air venting devices fittedwith a 0.2 micron hydrophobic filter may be used forthis purpose.

In order to comply with the 28 level in thehierarchy of protection measures, various manufac-turers have promoted the use of ‘‘closed systems’’ forthe preparation of hazardous drugs.

It is very important that the term ‘‘closedsystem’’ is clearly defined.A clear distinction must be made between aclosed system in the context of microbiologicalcontamination and a closed system in thecontext of chemical contamination and occu-pational exposure.

7.2.1 The word ‘‘closed’’ in terms ofmicrobiological contaminationExamples of definitions:

(a) Product is not in open communication withthe surroundings.

(b) When a product is in a closed container andthe activity is just an addition of a fluid.(Netherlands)

(c) A system allowing the removing and transferof a sterile product to another sterile con-tainer in which the seal and the transfermaterial (sterile needle, tube or set), remainsin place during the whole process. (France)

(d) With toxic products, the removal of fluidfrom an ampoule in a class A environment isto be considered a closed system. (France)

(e) Aseptic transfer of a sterile, non pyrogenicfinished pharmaceutical (e.g. from vials orampoules) obtained from a licensed manufac-ture into sterile final container. (United States)

(f) One withdraw out of an ampoule or onepuncture trough a rubber stopper of a vialand in a class A environment. (UnitedKingdom)

(g) A system that tends to provide protectionagainst contamination (WHO GMP)

It is clear that these definitions focus only on themicrobiological quality of the end product wherethe concern is purely introducing micro-organismsinto a sterile product. In this context, there isno consideration of the sterile product coming out

of the vial or ampoule thus contaminating theenvironment.

7.2.2 The word ‘‘closed’’ in terms of chemicalcontaminationExamples of definitions:

(a) Semi-closed system (fluid or powder) Whenan overpressure occurs in the vial, the air canescape through a venting filter into thesurrounding air. (Netherlands)

(b) Closed system (powder): When an over-pressure occurs in the vial, the air can NOTescape into the surrounding air(Netherlands).

(c) A system which can operate without an openconnection between the contaminated innerspace and the surroundings during themixing and preparative procedure. (QualityStandards – DGOP & ESOP)

(d) A drug transfer device that mechanicallyprohibits the transfer of environmental con-taminants into the system and the escape ofhazardous drug or vapour concentrationsoutside the system. (USA)

The terminology semi-closed is misleading and shouldnot be used, either a system is closed or it is not (incomparison, either a device is sterile or it is not).

The USA (NIOSH) definition is the only definitionwhich includes drug vapours. Filters with a diameterof 0.22 mm and HEPA filters DO NOT retain thevapour of cytotoxic products. Filters with activecarbon can absorb vapours on a temporary basis onlyand therefore should be accompanied with studiesindicating the maximum loading, working conditionsand the minimum and maximum retention time ofthe filter capacity.

In cytotoxic reconstitution both microbiologicalcontamination and hazardous drug containment areconcerns. The NIOSH definition is therefore the mostcomprehensive and complete.

Closed System Drug Transfer DeviceA drug transfer device which mechanically

prohibits the transfer of environmentalcontaminants into the system and the escapeof hazardous drug or vapour concentrationsoutside the system

Manufacturers of special preparation devices mustclearly indicate:

(a) If the device covers all steps in the prepara-tion process or if it covers only some of thesteps in the process. If the latter applies, then




the manufacturer should indicate clearlywhere the closed properties of the deviceare NOT retained.

(b) If the device retains its closed characteristicswhen more than one vial is used for aparticular preparation

(c) If studies have shown the device to fulfil theaim of eliminating or reducing the environ-mental contamination in daily practice and towhat degree.

To avoid confusion, it is strongly recom-mended that if a device claims to preventchemical contamination the term used shouldbe Containment Device (This is a Leakproof,airtight device).

7.3 Devices to protect the admistrator duringdrug administrationPreparation is only one part of the process and manymore people are working in drug administration thandrug preparation.

Administration systems include infusion bags,infusion lines, ambulatory pump systems, and othermaterials used in administering a drug by anotherroute. Other routes include direct intravenous injec-tion (IV Push), intraperitoneal, intramuscular, intra-dermal, intravesical (bladder instillation), and localregional perfusion.

The NIOSH definition of a closed system drugtransfer device may also be applied to the adminis-tration of hazardous drugs:

A contained administration system is a drugadministration device that mechanically prohibitsthe transfer of environmental contaminants into thesystem and the escape of hazardous drug or vapourconcentrations outside the system.

In addition the manufacturer of special administra-tion devices must clearly indicate:

(a) For which routes of administration the con-tainment is guaranteed.

(b) If the device covers all steps in the adminis-tration process or if it covers only some ofthe steps. If the latter applies, then themanufacturer should indicate clearly wherethe closed properties of the device are NOTretained.

(c) If the device retains its closed characteristicswhen more than one administration of haz-ardous drug is to be performed using thesame device

(d) If studies have shown the device to fulfil theaim of eliminating or reducing the environ-mental contamination in daily practice and towhat degree.

It is strongly recommended that if a deviceclaims to prevent chemical contaminationduring drug administration then the term usedshould be Containment Device (This is aLeakproof, airtight device).

7.4 Techniques to protect the patientConsiderations may be given to the filtering ofcytotoxic drug solutions intended for intrathecaladministration. Due to the high risk nature of thisroute of administration, some sources recommendpassing the final solution through a 0.22 micron filterduring the reconstitution process. However, there aredisadvantages to filtering these solutions. Firstly,some drug volume will be lost on the filter,which may be an important issue if very smallvolumes are involved. Secondly, the use of a 0.22micron filter will increase the pressure in the systemand will pose a risk to the operator performing themanipulation.

REFERENCES





Pharm 2002; 59: 68–72.

2 Gustavsson B. Evaluation of technetium assay for

monitoring of occupational exposure to cytotoxic

drugs. J Oncol Pharm Pract 1997; 3: 46.

3 Harrison BR, Peters BG, Bing MR. Comparison of surface

contamination with cyclophosphamide and fluorouracil

using a closed-system drug transfer device versus stan-

dard preparation techniques. Am J Health Syst Pharm

2006; 63: 1736–44.








5 Nygren O, Gustavsson B, Strom L, Eriksson R,

Jarneborn L, Friberg A. Exposure to anti-cancer

drugs during preparation and administration.

Investigations of an open and closed system.

J Environ Monit 2002; 4: 739–42.





contamination observed on the outside of drug vials. Ann

Occup Hyg 2002; 46(6): 555–57.

7 Poirier S, Jones C, Calvert MJ. Practical implementation of

a closed system (PhaSeal) for the preparation,administra-

tion and disposal of cytotoxic drugs in a busy ambulatory

cancer centre. J Oncol Pharm Pract 2004; 10(2): 81.

8 Sessink PJM, Rolf M-AE, Ryden NS. Evaluation of the

PhaSeal hazardous drug containment system. Hosp

Pharm 1999; 34: 1311–17.

9 Spivey S, Connor TH. Determining sources of workplace

contamination with antineoplastic drugs and comparing

conventional IV drug preparation with a closed system.

Hosp Pharm 2003; 38(2): 135–39.

10 Tans B, Willems L. Comparative contamination study

with cyclophosphamide, fluorouracil and ifosfamide:

standard technique versus a proprietary closed-handling

system. J Oncol Pharm Pract 2004; 10: 217–23.

11 Vandenbroucke J, Robays H. How to protect environment

and employees against cytotoxic agents, the UZ Ghent

experience. J Oncol Pharm Pract 2001; 6(4): 146–52.

12 Wick C, Slawson MH, Jorgenson JA, Tyler LS. Using a



Pharm 2003; 60: 2314–20.







Section 8 � Ventilation tools


Published by:













Section 8 – Ventilation tools

Specific equipment is required for the preparation ofparenteral cytotoxics. This includes biological safetycabinets and isolators.

Due to the high risk of exposure to workers,horizontal laminar airflow hoods must NEVERbe used when preparing cytotoxics.

8.1 Biological safety cabinetsThere are several types of biological safety cabinets(BSC). They are classified (EN 12469 2000) into 3main classes (I, II, III). A Class I BSC is designed toprotect only the operator and the environment andmust NOT be used for the preparation of sterileproducts and will not be described here.

8.1.1 Class II Biological safety cabinetsThis is a ventilated BSC that protects the operator, theproduct and the work environment. A Class II BSChas an open front inward airflow for personnelprotection, downward HEPA-filtered laminar airflowfor product protection and HEPA-filtered exhaustedair for protection of the environment. There are 4 subclassifications of the Class II BSC (A1, A2, B1, B2).

Only Class II cabinets designed and constructed forcytotoxic preparation should be used. Since somecytotoxic drugs vaporize and pass through HEPA-filters (for example, cyclophosphamide), a BSCwhere air is exhausted into the workroom must beavoided. Class II A cabinets are not recommended asthey are not suitable for the manipulation of volatiletoxic chemicals (A1) or for only minute quantities ofvolatile chemicals (A2) unless special containmentdevices (leakproof, airtight devices) are used duringthe preparation (see Section 7). In Class II A cabinets,30–70% of the air is recirculated within the cabinet.A Class II A1 cabinet has a positive plenum, and aClass II A2 cabinet has a positive plenum surroundedby a negative plenum.

Class II B1 (inflow air partially recirculated) orpreferably Class II B2 (total exhaust) are suitable forcytotoxic preparation. Class II B2 cabinets maintain aminimum inflow velocity of 0.35 m/s and have HEPA-filtered downflow air drawn from the workroom orthe outside. These cabinets exhaust all inflow anddownflow air to the atmosphere after filtrationthrough a HEPA filter without recirculation insidethe cabinet or return to the workroom. They also

have containment ducts and plenums either undernegative pressure or are surrounded by directlyexhausted negative-pressure ducts and plenums.

Some countries, for example, Australia, requirethe inclusion of an activated carbon filter fitteddownstream of the exhaust HEPA filter to counter theproblem of cytotoxic drugs which may vapourise andpass through the HEPA exhaust filter. However,concerns exist over the effectiveness of activatedcarbon in removal of these volatile substances. Thesefilters absorb vapour in a dynamic equilibrium withthe surroundings. Potentially, if the concentration ofthe drug in the environment drops, the drug may bereleased from the filter. Australian Standard AS2567–1

suggests that the minimum mass of activated charcoalmust be 28 g/l/s of airflow. The choice and frequencyof changing of carbon filters must be validated duringthe qualification stages.

8.1.2 Class III Biological safety cabinetsA Class III BSC is a totally enclosed vented cabinet ofgas tight construction. Operations are conductedthrough attached gloves and observed through a nonopening view window. This BSC is maintained undernegative pressure and air is drawn into the cabinetthrough HEPA filters. The exhaust air is treated bydouble HEPA filtration. Passage of material in and outthe cabinet is generally performed through a doubledoor pass through box. Class III BSCs have theadvantage that there is a physical barrier between theproducts and the handler. Class III BSCs are anintermediate configuration between a Class II BSCand an isolator. See Section 8.2.1 for comparison ofdefinitions of an isolator and a class III BSC.

Definition of compounding aseptic isolator(CAI) (USP _797`)2—The CAI is a form of barrierisolator specifically designed for compoundingpharmaceutical ingredients or preparations. It isdesigned to maintain an aseptic compoundingenvironment within the isolator throughout thecompounding and material transfer processes.Air exchange into the isolator from the surroundingenvironment should not occur unless it hasfirst passed through a microbially retentive filter(HEPA minimum).

There are four transfer systems used in aClass III BSC.




Transfer system A: (‘‘Mouse Hole’’): This is a hole inthe wall of the BSC III and there is direct contactbetween the inside air and the surroundings.

Transfer system B: This is a pass-through hatchwithout any HEPA filtration. Thus, the risk ofcontamination of the surroundings and/or inside airof the BSC III exists.

Transfer system C: This is a pass-through with oneHEPA filter, but there exists a risk of microbiologicalcontamination with the BSC III operating in negativeair pressure, and a risk of chemical contamination ofsurroundings with the BSC III operating in positiveair pressure.

Transfer system D: This is a double door pass-through with HEPA filtration. This may be used butnote that it is unable to contain the end product andwaste.

According to USP 579742 Hazardous drugs asCSP’s (Compounded Sterile Preparations):

‘‘Hazardous drugs shall be prepared in an ISOClass 5 (see Table 3, Section 6) environment withprotective engineering controls in place, andfollowing aseptic practices specified for the appro-priate contamination risk levels defined in thischapter. Access shall be limited to areas wheredrugs are stored and prepared to protect personsnot involved in drug preparation. All hazardousdrugs shall be prepared in a Class II or IIIbiological safety cabinet (BSC), or a com-pounding aseptic isolator (CAI) that meets orexceeds the standards for CAI in this chapter.When primary engineering controls, e.g., closed-system vial-transfer devices (CSTD) are used, thisshall be within the BSC or CAI to provide backupcontainment and ISO Class 5 (see Table 1 inSection 6) environment.’’

8.1.3 Airflow

(a) Within the BSC

In a Class II B1 BSC, approximately 60% ofdescending air is pulled directly through the reargrille of the work area into a dedicated negativepressure plenum. To enhance containment ofhazardous materials within the cabinet, all poten-tially contaminated zones should be under negativepressure relative to their immediate surroundings.All zones under a positive pressure shall be

surrounded by zones under a negative pressurerelative to the workroom atmosphere. This airpasses through an exhaust HEPA filter, then to anappropriate treatment system or outdoors via thefacility’s exhaust system. Approximately 40% ofthe descending air is pulled forward where itmixes with room air entering the perforatedfront grille. This air then passes through a HEPAfilter directly below the work surface, and isthen circulated under positive pressure through aduct to the top of the cabinet, then throughanother HEPA supply filter, where the process isrepeated.

(b) Recirculation of Air

In a Class II B1 BSC, some of the air produced by thecabinet is recirculated. Approximately 60% of the airis recirculated through a HEPA filter with theremaining 40% of the air exhausted through a HEPAfilter and replaced with fresh air. Due to the potentialfor chemical contamination of the cabinet during thecytotoxic preparation process, it is preferable tochoose a BSC that does not use any recirculated air.In Class II B2 and Class III BSCs the air is notre-circulated.

According to USP 579742 Hazardous drugs asCSP’s (Compounded Sterile Preparations):

The BSC and CAI optimally shall be 100% vented tothe outside air through HEPA filtration.

(c) External Exhaust of Air

The external exhaust of air directly to the atmo-sphere is highly recommended for the protection ofboth handlers and the environment. A HEPA filtershould be employed for the exhaust air and 100%of the filtered air should be exhausted directly tothe outside. An extraction system incorporating abooster ventilator at the distal end to ensure anegative pressure in the pipeline is highly recom-mended to ensure that the air is effectively andpermanently exhausted outside the room. Thebooster ventilator should be coupled to the BSCairflow to prevent the retro-contamination of theair in the event of failure of the laminar airflow.This means that if the BSC airflow fails and thebooster ventilator continues to operate, then dirtyair would be pulled into the cabinet from theroom, resulting in particulate and microbiologicalcontamination of the cabinet. The booster ventila-tor should also have an alarm that sounds in theevent of failure.




(d) HEPA filtration

The Class II BSC specially designed for cytotoxicpreparations must have 3 HEPA filters located inaccordance with figure 1:

In Australia, the use of an activated carbon filterdownstream of the HEPA exhaust filter is compul-sory. Figure 2 shows the possible arrangement of thelaminar flow cytotoxic drug safety cabinet in accor-dance with Australian Standard AS2567 – 2002.1

Additional non-HEPA filters (pre-filters) are com-monly used to increase shelf life of the HEPA filters.When used, these pre-filters are installed on theupstream side of the exhaust HEPA filter.

(e) Alarms

Airflow alarms that detect insufficient internal air-flow or insufficient inflow of air must be installed toindicate a disruption in the cabinet’s normal airflowpattern. When the airflow alarm sounds, thisrepresents an immediate danger to the operator andthe product. Work should cease immediately and thecause of the disruption investigated. Considerationshould be given to the installation of visual ratherthan audible alarms which may startle operators.

8.1.4 MonitoringPhysical monitoring must be performed on a regularbasis. The aim is to monitor whether the BSC is

performing to specification. A series of physical testsmust be carried out upon installation, wheneverchanges are made to the installation (for examplereplacement of a HEPA filter), and on a regular basisas a preventative measure. Physical tests includechecking the integrity of the HEPA filters (DOP test),checking the airflow velocity, checking the aircirculation (smoke test), checking the airflow reten-tion (KI [Potassium Iodide] disk test), checking thepressure, checking particulate contamination, check-ing temperature and humidity, and also a noise test.The frequency with which these tests should beconducted varies according to the test. The leak test(BSC Class III and Isolators only) and the smoke testshould be performed monthly. Air velocity andparticulate count tests should be done every threemonths, and the DOP test every 6–12 months. Thesetests are discussed more thoroughly below:

(a) HEPA Filter Integrity Test (DOP TEST)3

The objective of this test is to check the integrity ofall the HEPA filters (inlet, outlet, exhaust, andrecirculation if applicable). Each HEPA filter leavesthe factory with a manufacturer’s certificate.Transport and assembly can affect its performance.It is necessary to test the integrity of the media, lute,seals and assembly of the filter into the BSC. This testmay be carried out using the EMERY 3004� aerosoltest instead of DOP (Di Octyl Phtalate) which is toxic.The test is usually carried out by applying the aerosolchallenge upstream of the filter and measuring the airquality downstream with an aerosol photometer.Acceptance criteria: permeation through the filtermust be 50.01% for HEPA filter type H14 with99.995% efficiency at MPPS (Most PenetratingParticle Size). In addition there must be no particu-late emission detected outside the BSC.

(b) Leak test

The leak test applies only to totally enclosed cabinets(BSC Class III). The objective of the test is to ensurethat the enclosure is performing to specification.There are two parameters tested – the presence andposition of any leaks and the leakage rate. The leaktest is discussed in section 8.2.8 (b).

(c) Smoke test3

The objective of this test is to visualize the airflowin order to check the proper circulation of air.The smoke test is a simple test, enabling visualisationof the air circulation. A camera recording makes

HEPA Filters

Figure 1. BSC for Cytotoxic Reconstitution The HEPA filter

located below the workstation is designed (cassette) to be easily

removed during maintenance operations and contributes tooperator safety.




it possible to obtain an analysis enabling mapping ofthe air circulation in the cabinet. For unidirectionalair flow, the objective is to check its laminarity andthe absence of dead zones or turbulence which mayresult in possible particulate and/or microbiologicalcontamination. For Class III BSCs, where the airflowmay be turbulent, this test enables the detection ofdead zones. The most common equipment used is asmoke stick (Drager�) of smoking sulphuric acid.

(d) Air velocity test3

Airflow velocity is measured using an anemometer.The downflow air speed is measured (between 0.36and 0.54 m/s) and the mean speed of the incomingair is calculated (minimum 0.4 m/s). At least 8measurements are done 20 cm from the flow.

No value should be different from �20% of thereference value.

(e) Airflow Retention Test (KI [Potassium Iodide]disk test)

The objective of the KI test is to determine theretention efficacy of a BSC at the front opening. It ismeasured by creating in the BSC, by means of a rotarydisc, an aerosol of a solution of KI and by counting thenumber of particles detected outside the BSC. Themeasurement is made by air samplers with a filtrationmembrane incorporating palladium chloride. Theparticles of KI show up brown on the filter.

NOTE: A cylinder placed in the front opening makesit possible to simulate the effect of the operator’s armwhich disturbs the incoming air flow.

Positive pressureplenum seal Outer shell

HEPAfilter seal

Return airplenum

Removableperforated guard

Work zone

Rear slot

Prefilter

Sump

Challengeaerosol100%referencetubes

Removableperforatedguard

Negative pressure plenum

Positive pressureplenum seal

Positive pressureexhaust plenum

Adsorbentfilter seal

Removableperforatedguard

Perforatedguard

Exhaustblower

Activated carbonfilter

Prefilter

Sump



Removablework floor

Part sectional front viewSection A

A

Work zone

Exhaust blower

Front access panel

Laminar flow blower

Perforated guard

Positive pressurelaminar flow plenum

Laminar flow HEPA filter

Fluorescent lamp fitting

Access panel to lamps

Viewing window

Side access panel

Side cavity withcontrol enclosure

Work access opening

Removableair intake grille

Exhaust HEPA filter

Front access panel

Negative pressure plenum

Figure 2. Laminar flow cytotoxic drug safety cabinet.




(f) Noise test4,5

The objective of this test is to check that the noisegenerated by the BSC during normal operation is nottoo high for the operators. The sound level meter isinstalled 1 m from the BSC. The noise level must notexceed 85 dB(A), regardless of the room backgroundnoise.

(g) Light level4

This objective of this test is to ensure optimumlighting conditions for the operator working at thesafety cabinet. The lighting of the BSC and theroom is turned on and a mapping of luminousintensity is carried out using a light meter on allworking surfaces at several points. The luminousintensity measured during normal operations mustbe at least 400 Luxes.

(h) Temperature and humidity testing

Temperature and humidity are two parametersthat must be controlled both for the comfort ofthe operators and to reduce the risk of microbiolo-gical contamination in the BSC. The equipmentrequired consists of a temperature sensor andhygrometer.

(i) Microbiological testing

Microbiological monitoring must be performed rou-tinely as previously described (see Section 6). Themaximum level of microbiological contaminationmust be investigated by air sampling (active and/orpassive sampling) and by surface sampling and mustcorrespond to a Grade A environment.6 Surfacesampling must be performed upon completion ofthe manipulation and before the surfaces are cleanedand decontaminated. Immediately after sampling, thezone must be thoroughly cleaned to avoid any culturemedium favouring the microbiological contaminationof the zone.

The operator’s gloves must be checked by dabbingon an agar plate (the five fingers must be simulta-neously printed on the growth medium).

Recommended limits for microbiological contami-nation of glove are:

1 cfu/glove in a Grade A environment (BSC)5 cfu/glove in a Grade B environment (immediatesurroundings of the Grade A environment)

It is recommended that the biological safetycabinet be left running 24 hours a day, 7 days aweek in order to prevent microbiological andchemical contamination.


8.2 Pharmaceutical isolators

8.2.1 DefinitionA comprehensive definition of an isolator hasbeen published by the Parenteral Drug Association(PDA) and is found in the PDA Technical ReportNo. 348 Design and Validation of Isolator Systemsfor the Manufacture and Testing of Health CareProducts.

‘‘An isolator is sealed or is supplied with airthrough a microbially retentive filtrationsystem (HEPA minimum) and may bereproducibly decontaminated. Whenclosed, it uses only decontaminated inter-faces or Rapid Transfer Ports (RTPs) formaterial transfer. Isolators offer significantadvantages over barrier systems: isolatorscan be decontaminated using reproducibleand validated methods, do not allow theentry of airborne contamination from thesurrounding environment, and prevent theintroduction of personnel borne contami-nation into the isolator. In contrast abarrier system is an open system whichcan exchange unfiltered air with the sur-rounding environment, can only be


Pressure differential

between rooms

Daily

Pressure differential

across filters

Daily on BSC’s; Every six

months on ceiling HEPA filtersParticle counts Minimum of twice a year at

rest and in operational statesRoom air changes per hour Yearly

Air velocities on work stations Twice a year

HEPA filter integrity check Yearly



Grade A (ISO 5) zone. Once a

week in clean room

Surface samples WeeklyActive air samples Weekly





manually disinfected, and is directlyaccessed by gowned personnel.’’ (SeeSection 8.1.2 above)Comparison of Definitions for the BSC IIIand Isolator

The Class III BSC is a unidirectional laminar airflowcabinet where the front is ‘‘closed’’ by a windowfitted with sleeves and gloves to allow the manipu-lation inside the cabinet. Due to the laminar airflow itoperates usually in a negative air pressure. Passthrough hatches are used for the entry of productsand for the exit of the finished preparation. Onehatch is used for entry and one for the exit of thefinished product and waste. A manual decontamina-tion process (different from sterilisation) is usuallyperformed in the pass through before materials enterthe cabinet. The cabinet is NOT sterile and is NOTsterilized. For cleaning and decontamination of thecabinet, the window of the cabinet may be openedperiodically.

An isolator, on the other hand, is a totally enclosedsystem running usually in positive air pressure withturbulent airflow and which is sterilized by gassterilization. Products and preparation devices areintroduced into the isolator using pass-throughswhich are always sterilized.

The two definitions may overlap if the Class III BSCis sterilised and provides an uncompromisedand continuous isolation by the use of special transfersystems. Examining the ISO 14644–79 can lead tofurther confusion. Here synonyms include isolator ¼glove boxes ¼ containment enclosures.

In the area of cytotoxic reconstitution, closedisolators intended for asepsis and containment arerecommended because they are well suited to thepreparation of sterile and toxic materials. The use ofsupplementary PPE by the workers is highly recom-mended especially when handling vials or finalproducts outside the isolator.

Isolator specifications for the preparation ofparenteral cytotoxics can be summarised as follows:

The air pressure may be positive or negative.Positive air pressure is most commonly used foraseptic preparation. Negative pressure isolators arealso used in this application, but in this caseadditional measures are required to achieve thenecessary level of product protection (for example,the location and surroundings of the isolator).Negative pressure isolators are preferable whenasepsis is not required, and when the risk forexposure is high; for example, during the handlingof powder forms for solid preparations.

Pressure Differential of the Isolator with theImmediate Surroundings

Positive pressure isolators usually run atoperating pressures in the range of Q35PatoQ60Pa.Negative pressure isolators usually run atoperating pressures in the range of Z50PatoZ200Pa.

For the pressure differential between adjacent rooms,that described in Section 6.2.2 is suitable for isolators.Preferably, the positive differential (rooms) [Section6.2.2 (a)] should be used for negative pressureisolators, and the negative differential (rooms)[Section 6.2.2 (b)] should be used for positive airpressure isolators.

The PDA position8 of a ‘‘closed isolator intendedfor asepsis and containment’’ has been adopted inthe writing of this standard.

For asepsisThey must not exchange air with the surround-ing environment except when air passesthrough a microbially retentive filter (HEPA).They must be decontaminated in a reproducibleand quantifiable manner (avoiding the use ofmanual decontamination). The decontamina-tion to be used is specified precisely which isgas/vapour decontamination (ie. peracetic acid,hydrogen peroxide). (Decontamination is alsocalled surface sterilization or contact steriliza-tion but the term sterilization has been used inthis standard to avoid confusion with manualdecontamination by spray).All work or handling of materials within theisolator enclosure must be accomplishedremotely; no human operator or part thereofcan directly enter the isolator during operation.All materials that enter the isolator must bedecontaminated or sterilized and must entereither directly or through a decontaminating orsterilizing system or via a rapid transfer port.

For containmentThey must not exchange air with the surround-ing environment and so an external exhaustmust be put in place.All work or handling of materials within theisolator enclosure must be accomplishedremotely. No human operator or part thereofcan directly enter the isolator during operation.All material exiting the isolator must becontained in such a way that hazardousmaterials are not released to the surrounding




environment. This is done by the use of doubleinterlocking doors fitted with closed containers(for example with the E and F transfer systems).They must be cleanable in a reproducible andquantifiable manner.

Since chemical decontamination is not possible witha wide variety of drugs being handled simultaneouslyand no universal method of decontamination isavailable, containment using disposable closed trans-fer systems for the removal of finished products ishighly recommended. Products available includeBiosafe� containers (IDC), Tubing� and DPTE -BetaBag� (La Calhene). (See Section 8.2.7 TransferSystems). The use of these devices ensures thecontainment of any possible contamination up tothe point of opening the package. Nursing staff muststill wear PPE when opening the sealed bag, andduring administration of the drug.

8.2.2 Isolator designIsolators are either of a rigid walled design, madefrom polycarbonate, acrylic glass or tempered glass,or of a flexible wall construction and made frompolyvinyl chloride (PVC). The flooring material canbe stainless steel (316 L) both for the rigid andflexible wall isolator or a one-piece assembly inwhich the flexible floor (PVC) and flexible wall are ofa single unbroken piece.

8.2.3 AirflowAirflow in the isolator may be either turbulent orunidirectional (formerly called laminar flow). The airchange rate should be determined on a case-by-casebasis. Normal data used for conventional cleanroomsare often used for isolators, but may not directlyapply.

The following values may be useful:

(a) Under turbulent airflow (non-unidirectional)the air change rate should not be less than 20air changes per hour. The entire volume ofthe isolator should be purged by the airflowwith no stagnant areas or dead zones (poorlyventilated zones).

(b) Under unidirectional airflow, the averageairflow velocity is normally within the rangeof 0.25 ms�1 to 0.5 ms�1. As a minimumrequirement, the isolator air supply systemmust be equipped with HEPA grade filters.

The air is continuously renewed and removed via anextraction HEPA filter. The air from inside the isolatoris vented to the outside of the building via a ducting

system, enabling the dilution of eventual contami-nants in the atmospheric air. The length of theextraction system must be as short as possible toavoid any Venturi effect. Airflow alarms that detectinsufficient internal airflow or insufficient inflow ofair must be installed.

8.2.4 Operator interfaceThe isolator shall be accessed via a glove port and/ora half suit. The system shall be designed to allowoperator access to the interior of the isolator whilstmaintaining the aseptic environment and contain-ment within the isolator.

(a) Gloves

The Glove/Sleeve assembly is the device used foraseptic manipulations within the isolator. The glovematerial commonly used is either Neoprene� orHypalon� and this material should be of a greaterthickness than classic surgical gloves, in the order of0.4 - 0.6mm. Gloves are potentially the weakest linkin the isolator system and they must be visuallychecked before each use and changed regularly.When changing gloves, an aseptic change proceduremust be used allowing the old gloves to be replacedby new sterile gloves. This procedure must ensurecontainment of cytotoxics and maintenance of steril-ity. Once removed, potentially contaminated glovesmust be immediately discarded with cytotoxic waste.

(b) Half-suits

Half-suits offer greater physical flexibility thangloves/sleeves, and are used for large volumeisolators (3–5 m3). For comfort and operator safety,full ventilation should be used and the air supply maybe filtered.

8.2.5 SterilizationIsolators for aseptic preparation must be surfacesterilized (or biodecontaminated) by gas or vapour ofperacetic acid or hydrogen peroxide. In the hospitalpharmacy, the most widely used system is the « online » evaporation method, without recycling of theagent in the circuit. Sterilizers consist of a tank inwhich the sterilising agent is heated to approximately458C. The vapours produced are then distributedthroughout the chamber using a current of com-pressed air. As the sterilizing agent is a non penetrat-ing component, contact with all the surfaces to besterilised must be guaranteed in the course of thecycle. Free circulation of the gas must be ensured by




raising components, repositioning them during treat-ment, and hanging up gloves and sleeves.

Drug vials and preparation devices must also besurface sterilized before being introduced into thesterilised isolator. The principle of surface (contact)sterilization is that the sterilising gas treats only thesurface and does not penetrate into the heart of theload. This presupposes that the interior of anyelement entering the isolator must be sterile.

Containers or transfer devices are used for thatoperation. The connecting systems between isolatorand pass through should use interlocking doubledoors to ensure the containment and sterility of theenclosure. Sterilization must be confirmed usingbiological indicators.

The two sterilizing agents that are commonly usedare peracetic acid and hydrogen peroxide. Peraceticacid is easy to use and has long proved its efficacy inhospital pharmacies. Peracetic acid is corrosive andirritant, and precautions must be taken whenhandling this agent. Consideration should be givento collecting it in a closed system. The absence ofpenetration of plastic materials must be validated.

Hydrogen peroxide is less corrosive than peraceticacid, but requires stringent control of temperatureand humidity. The reproducibility of the load is alsoan important aspect when using hydrogen peroxide,and this may be difficult to achieve in everydaypractice in the hospital setting.

8.2.6 Isolator location (immediatesurroundings)There has been much debate about the requirementsand classification of the room in which an isolator islocated. The PDA Technical Report No. 348 states thefollowing:

Classification of the isolator room: Thereneed not be a specific particulate clean airclassification requirement for the roomsurrounding isolators. Regardless of theirspecific usage, properly designed isolatorsdo not allow the exchange of contaminantswith the surrounding environment.Therefore, the quality of the surroundingroom is a very minor consideration relativeto the quality of the internal environmentof the isolator. The surrounding roomshould have a limited access, and shouldbe easily cleanable and well organized. Onthe other hand, the EC GMP recommends atleast a Grade D environment withoutspecifying the pressure differential, and

giving no precise details about the isolatorpressure.

Taking into consideration the risk of chemical con-tamination, the negative pressure differential design(see Section 6.2.2) for the positive air pressureisolator and the positive pressure differential design(see Section 6.2.2) should be implemented. Withregards to the risk of microbial contamination, anegative pressure isolator used for aseptic prepara-tion of cytotoxics should preferably be located in aGrade C controlled area (see Section 6 – Facilities forCytotoxic Reconstitution).

8.2.7 Transfer systemsA transfer system should be used which guaranteesthe sterility of the final product and the containmentof cytotoxic drugs. Double interlocking doors andclosed transfer systems should be used. For exit ofend products, the use of interlocking double doorsfitted with a sterile disposable container ensurescontainment of the toxic product.

The sealed, sterile container associated with afemale door is positioned and sealed over themale door. Once in position, communication ispossible between the isolator and the sealed sterilecontainer (it is then possible to open the door)enabling the removal of the preparations madein a closed system in the sealed plastic bag.(See Section 8.2.1).

Only the use of transfer systems E and F guaranteespermanent enclosure of contents and protection ofthe operator. All other transfer systems are suitablefor aseptic preparation if the isolator is running inpositive air pressure, but are not thought to besuitable for chemical containment.

Transfer system A (‘‘Mouse Hole’’): NOT TO BEUSED. This is a hole in the wall of the apparatus andthere is direct contact between the inside air and thesurroundings.

Transfer system B: NOT TO BE USED. This is a passthrough hatch without any HEPA filtration andso there exists the risk of contamination of thesurroundings and/or inside air of the apparatus.

Transfer system C: NOT TO BE USED This is a passthrough with one HEPA filter, but there exists a riskof microbiological contamination with the apparatusoperating in negative air pressure, and a risk ofchemical contamination of surroundings with theapparatus operating in positive air pressure.




Transfer system D: NOT TO BE USED. This isa double door pass through with HEPA filtration. Thismay be used but it is important to note that thissystem does not to contain the end productand waste.

Transfer system E: This is a pass through withdouble doors and double HEPA filtration which isalways gas sterilised (with or without load) beforeconnection with a previously sterilised isolator. Thedevice is usually dedicated for the entry of productsinto the sterile area of the isolator

Transfer system F: This system (rapid transfersystem) has double interlocking doors, allowing theconnection between two separate sterile enclosures(for example, isolators and disposable plastic sterilecontainers). The F transfer system is usually used forexit end-product in a sealed plastic container withoutcontact with the surrounding environment. It pre-serves both the sterility of the product and providescontainment of any chemical contamination. Thedouble interlocking doors will also allow the con-nection between two sterile isolators without affect-ing the integrity (seal) of the enclosure.

There are other sealed removal devices available,including tubing and bin removal. Bin removalenables the removal of waste in a sealed bag withoutany contact with the outside environment. This isquite distinct from the removal system used forfinished preparations

8.2.8 MonitoringMonitoring must be performed on a regular basis.The goal of monitoring is to determine whether theisolator is performing to specification. Physical testsshould have been conducted during the installationof the isolator, and on a routine basis after that aspreventive measures. In addition, tests must berepeated whenever changes are made to the instal-lation (i.e. changing of HEPA filters). Physical tests areintegrity checks of HEPA filters (DOP testing), airflowvelocity for unidirectional airflow isolators, air circu-lation (smoke test), leak testing, pressure checks,particulate contamination, temperature and humidity,and a noise test.

The leak test should be performed on a monthlybasis, the particle count every three months and theDOP test every 6-12 months.

(a) HEPA Filter Integrity Test (DOP TEST)

HEPA-filters must be assessed as previously describedin Section 8.1.4 (a).

(b) Leak Test

The sealing of an isolator is an essential and criticalfactor that must be regularly checked. The objectiveof the test is to ensure that the enclosure isperforming to specification. There are two para-meters tested – the presence and position of anyleaks and the leakage rate.

Location of any leakThe principle of this test is based upon the evapo-ration of ammonia inside the chamber and of tracingleaks manually using a developer impregnated withbromophenol. Bromophenol changes colour in thepresence of ammonia. To perform the test, acontainer with a large evaporation surface of ammo-nia solution is left open inside the chamber that israised to a maximum overpressure of 100 Pa. Afterapproximately 15 minutes, when the chamber hasbeen saturated with the ammonia, the developer isplaced over the entire surface of the envelope andthe seals. Any change in colour from yellow to blueindicates the presence of a leak. Other methods maybe used but require more complex equipment, forexample, the Freon� method, where the ammonia isreplaced by Freon�.

As for the isolator gloves, a simple test for theirintegrity involves filling the gloves with compressedair and then immersing them in water. Any micro-perforations will produce bubbles. However, thissimple and sensitive method for testing the integrityof gloves is not recommended in the case of handlingtoxic products. The risk of chemical contaminationof the environment is too high. In this case it ispreferable to systematically change gloves, depend-ing on their thickness and physical strength. It ispossible to test the integrity of the gloves using anegative pressure technique. This means that thegloves may be tested in situ without any outsidehandling. However, this is an expensive procedureand is difficult to perform with gloves that are part ofa half suit.

Leak rate10

The objective of this test is to determine the leak rateof the isolator (Lr) by pressure drop. The testpressure must be 20 or 50 Pa above the workingpressure. For example, 100 Pa for a flexible wallisolator and 150 Pa for a rigid wall isolator. When thetest pressure is reached, the pressure drop isrecorded with a manometer for one minute.Temperature must be controlled during the testand temperature variation must be no more than�0.058C. Common values of Lr are 0.1% for a




flexible wall isolator (test pressure 100 Pa) and0.5% for rigid wall isolator (test pressure 150 Pa).

(c) Smoke Test

The smoke test must be performed as described inSection 8.1.4 (c).

With an isolator where the airflow may be turbu-lent, this test enables the detection of dead zones.

(d) Air Velocity Test

For isolators with unidirectional airflow, this testmust be preformed as described in Section 8.1.4 (d).

(e) Noise Test

The noise test must be performed as described inSection 8.1.4 (f).

(f) Pressure Differential Test

The pressure of the isolators must be continuouslymonitored, and alarms must be used to detectpressure failure. The pressure regulation should bechecked using a reference manometer. This testallows the evaluation of the reaction time of theisolator when the pressure is altered followingoperations such as introducing and withdrawinggloves, entering and exiting the half-suit, and con-nection to an additional volume. The aim of the test isto ensure that the pressure regulation at rest is stable.The test can also be used to determine that thepressure alarm values are compatible with the normaloperation of the isolator.

(g) Air Change Rate3

The air change rate per hour of the isolator (in V/h) is determined by the ratio of the inlet airflowrate divided by the volume of isolator.Instantaneous speed measurements are recordedby an anemometer. The flow rate is obtained usingan average value. The result must be in accordanceto the specification of the isolator. For positive airpressure isolators of 1 m3, a value of 20 Volume/hour is acceptable.

(h) Microbiological Monitoring

Microbiological monitoring must be performedroutinely as previously described (see Section 6).The maximum level of microbiological contamina-tion must be investigated by air sampling (activeand/or passive sampling) and by surface samplingand must correspond to a Grade A environment.6

Surface sampling must be performed upon comple-tion of the manipulation and before the surfaces

are cleaned and decontaminated. After sampling,the zone must be immediately and thoroughlycleaned to avoid leaving behind any culturemedium likely to encourage the microbiologicalcontamination of the zone.

The operator’s gloves must be checked by dabbingon an agar plate (the five fingers must be simulta-neously printed on the growth medium).

Recommended limits for microbiological contami-nation of glove are:41 cfu/glove in a Grade A environment (BSC)5 cfu/glove in a Grade B environment (immediate

surroundings of the Grade A environment)

(i) Particle Counts11

The objective of this test is to check that theconcentration of particles found within the isolatoris in accordance with the specifications of a Grade Aenvironment (see Section 6).

The probe of an optical particle counter is the onlydevice which has to be positioned inside the isolator.The locations tested should be those where criticalfunctions are carried out. Examples include workstations, connection and junctions with gloves,sleeves, and doors.

(j) Efficiency of Sterilization

The objective of this test is to check the efficiency ofthe surface sterilization using Biological Indicators(B.I.). Each B.I. is inoculated with a 6 log of spore ofBacillus subtilis or Bacilus stearothemophilus andthey are distributed at distinct locations within theisolator, with particular emphasis on the criticalzones (for example: near doors). After exposure tothe sterilizing agent, the BIs are inoculated in culturemedium (Tryptocaseine soya) and incubated for 14days at adequate temperature according to the BI(55–608C for Bacillus stearothermophilus or30–358C for Bacillus subtilis). No growth must befound after 14 days and a reduction of 6 log must beachieved on three consecutive tests.

In addition, an aeration test must be performedafter a complete sterilization cycle. The aim ofthis test is to determine the aeration timerequired to obtain a residual concentration of thesterilizing agent compatible with the safety ofoperators, the environment and the end product. Areactive Drager� tube (sensitive to hydrogen perox-ide or peracetic acid) may be used to perform thistest. An aeration delay is defined after the aerationtest depending on the cycle of sterilisation, ventila-tion procedure and the volume of the isolator.




It is recommended that the isolator be leftrunning 24 hours a day, 7 days a week inorder to help prevent microbiological andchemical contamination.


8.3 Validation and certificationAll equipment and processes used in the preparationof parenteral cytotoxics which affect product sterilityor product attributes should be validated and/orcertified. Documentation to this effect should beapproved, maintained, reviewed and signed off by adesignated pharmacist.

For Certification see Section 6.2.12.For Process Validation see Section 6.2.13.Most of the monitoring tests described above may

be used for Operational Certification (OC) and/orPerformance Certification (PC). Commonly appliedtests are listed in Table 5.

Table 5. Common tests performed during operational and performance certification

Test BSC – Cleanroom Isolator OC PC

HEPA Filter Integrity Test (DOP) X X X N/A

Airflow: check Unidirectional Flow and Air velocity X X(1) X(2) X(3)

Leak Testing of the Enclosure X(4) X X X

Air Distribution Studies X X X X

Air Change Rate per Hour X X X X

Particle Counting X X X X

Pressure Regulation and Alarm X X X X

Sterilisation N/A X X(5) X(6)

Aeration/Ventilation after Sterilisation N/A X X(5) X(6)

Noise Level X X X N/A

Light Level X X X N/AChecking Procedure X X N/A X

Note: This is not an exhaustive list. (N/A ^ not applicable)

(1) Applies only to isolator with unidirectional airflow

(2) Without final equipment (for example, shelving, filling pump)

(3) With final equipment

(4) Applies only to Class III biological safety cabinets

(5) Without load

(6) With load.


Laminar flow cabinets (LFCs)/Biohazard

Safety Cabinets (BSCs):

Frequency

Pressure differentials

between rooms


usually dailyPressure differentials across

HEPA filters (workstation)


usually dailyParticle counts Yearly at rest and in the

operational stateRoom air changes per hour Yearly

Air velocities on workstations YearlyHEPA filter integrity checks Yearly

Isolators:

Isolator glove integrity Visual checks every

sessionPressure differentials across

HEPA filters


usually dailyIsolator pressure hold test

(with gloves attached)

Weekly



Grade A (ISO 5) zoneOnce a week in clean room

Surface samples Weekly

Active air samples Weekly





REFERENCES

1 Australian Standard AS2567 Standards Association of

Australia, Committee on Controlled Environments

Australian Standard AS2567: Laminar flow cytotoxic

drug safety cabinets. Sydney, Australia; 2002.


sterile preparations (general test chapter 797). In: The

United States pharmacopeia 28 rev., and The national

formulary, 23rd edn Rockville, MD: United States

Pharmacopoeial Convention; 2004:2461–77.


14644–3: cleanrooms and associated controlled environ-

ments – Part 3: test methods. 2005.

4 EN (European Standard) 12469. Biotechnology. Perfor-

mance criteria for microbiological safety cabinets. 2000.

5 ISO (International Organization for Standardization) 3744:

Acoustics – determination of sound power levels of noise

sources using sound pressure – engineering method in an

essentially free field over reflecting plane. 1994.

6 EudraLex. Volume 4 Medicinal Products for Human

and Veterinary Use: good Manufacturing Practice.

Annex 1 Manufacture of Sterile Medicinal Products.

2003. Available at: http://ec.europa.eu/enterprise/-

pharmaceuticals/eudralex/homev4.htm. Accessed

January 2007.

7 PIC/S Guide to Good Practices for Preparation of

Medicinal Products in Pharmacies. PE 010-1 (Draft 2)

2006. Available at: http://www.picscheme.org/

index.php. Accessed February, 2007.

8 PDA Technical Report No 34. Design and validation of

isolator systems for the manufacturing and testing of

healthcare products. PDA J Pharm Sci Technol 2001;

55(5) (Suppl TR34).


14644-7: Cleanrooms and associated controlled environ-

ments – Part 7: separative devices (clean air hood, gloves



10648-2: Containment enclosures - Part 2: classification

according to leak tightness and associated checking

methods. 1994.


14644-1: Cleanrooms and associated controlled

environments – Part 1: classification of air cleanliness.

1999.

BIBLIOGRAPHY

Midcalf B, Mitchell PW, Neiger JS, Coles TJ. eds.

Pharmaceutical Isolators. London, England:

Pharmaceutical Press; 2004.13.

NIOSH Alert: Preventing occupational exposures to






Publication No 2004-165.







Section 9 � Non sterile preparations


Published by:













Section 9 – Non sterile preparations

Occasionally, oral cytotoxic drugs (tablets, capsules

or syrup) or the topical application of a cytotoxic

drug may be used by the physician. As more and

more agents become available for use by the oral

route since this route of administration is becoming

more important. This is also an important consider-

ation in paediatric oncology.The crushing of tablets and the mixing of powders

goes hand in hand with the generation of airborneparticles of the products used, and is to be avoidedwherever possible. The crushing of cytotoxic tabletsor the opening of capsules in an open mortar shouldbe avoided. For mixtures, many tablets may bedispersed in pre-calibrated bottles. Single dosemixtures are recommended. Staff are vulnerable tocontamination by either direct contact or by theinhalation of these potentially toxic products. Thehierarchic order in prevention, as highlighted inSection 5 is also applicable to this kind of activity. Asreplacement or the use of a contained system isunlikely, reliance is on ventilation and the use ofpersonal protective equipment.

As a general rule, the opening of capsules, crushingtablets, and dissolving powders should not be doneoutside of the pharmacy.

The extemporaneous preparation of cytotoxicdrugs should be performed under the same condi-tions as for parenteral cytotoxic drugs. This operationshould be carried out in a separate room speciallydedicated to this purpose

Tablets and capsules must be handled in a mannerthat avoids skin contact, liberation of drug into theair, and chemical cross contamination with otherdrugs. All equipment used in the dispensing ofcytotoxic solid dosage forms must be dedicated tothis purpose and clearly labelled as such. Cytotoxictablets or capsules should not be counted using acounting machine. Containers with damaged con-tents should be discarded.

As in the case of preparation of sterile cytotoxicdrugs, the preparation of non sterile drugs should beperformed in a separate room, specially dedicatedto this purpose. This room must have a warning signoutside the room and must be restricted in access totrained staff only.

The room should operate at negative pressure, thusminimizing the risk of spreading the ‘‘dust’’ ofproducts throughout the rest of the pharmacy.All activities likely to result in particle gener-

ation, for example, weighing, crushing, mixingor filling capsules, should be performed in aClass I Biological Safety Cabinet (BSC). A Class Icabinet extracts the air from behind the opera-tor, flowing over the arms, hands and theproduct itself before being exhausted via thetop of the cabinet.

A Class II B2 could also be used, but this cabinetshould not be used for a mixed activity of sterile andnon sterile preparation. This is because of theliberation of powders and other particulate contam-ination into the clean room. The risk of this type ofcontamination is high. Possibly some disposablesystem would be a better option (for example, bagfitted with gloves for containment in laboratory). Inaddition, a negative air pressure BSC III (MUSTbe negative) is an alternative to a dedicated BSCClass II B2. Normally a HEPA filter is located withinthe cabinet exhaust. An additional filter such as anactive carbon filter may also be installed.

In order to create a negative pressure in thepipeline of the ducting system, the extracted airshould be ventilated to the external environment,supported with booster ventilation on the rooftop.

As for the cabinets used for the sterile preparation,these cabinets should also be validated, preferablyevery 6 months.

Hygiene conditions similar to those described forthe preparation of sterile products also apply to thepreparation of non sterile products; no eating,drinking or smoking is permitted.

In addition, personal protective equipment mustbe used by the personnel. This consists of gowning,the use of non sterile gloves and a mask (P2-3 inEurope/Australasia, N95 in North America) in thecase of cleaning activities inside the class 1 cabinet orin the event of spills or other incidents.

All equipment used in the extemporaneous prep-aration of cytotoxics must be dedicated to thispurpose and clearly labelled as such. This equipmentshould be cleaned immediately after use with astrongly alkaline solution.







Section 10 � Chemical contamination monitoring


Published by:
















Section 10 – Chemical contaminationmonitoring

10.1 BackgroundExposure to cytotoxic drugs in the workplace mayresult from one or more of the common routes ofexposure. While dermal and inhalation routes arelikely to be the primary routes of exposure tocytotoxic drugs in health care facilities, hand-to-mouth exposure or accidental needle sticks mayalso contribute to exposure.

Therefore, surface wipe sampling and sampling forairborne drugs have been the two main proceduresfor determining work place contamination withcytotoxic drugs. To determine the level and extentof contamination of the workplace and to establishsafe working levels for hazardous substances, thesemethods have been employed routinely in manyother occupational settings

10.2 Sampling strategiesThe primary method employed for monitoring ofchemical (cytotoxic) contamination in the healthcare facility has been the recovery of a number ofmarker cytotoxic drugs from wipe samples.1

Relatively sensitive sampling and analytical proce-dures have been developed for some of the morecommonly used cytotoxic drugs and have beenemployed as markers of overall surface contamina-tion. The more common drugs sampled include:cyclophosphamide, ifosfamide, 5-fluorouracil, metho-trexate, paclitaxel, doxorubicin, and platinum con-taining drugs (e.g. cisplatin and carboplatin).1

10.2.1 Surface contamination samplingStudies of surface contamination with cytotoxicdrugs typically employ a collection matrix (e.g.tissue or filter paper wipes) and a solvent systemproven to aid recovery of the drugs being studied.1

Specific strategies have been developed for collect-ing wipe samples for other chemicals in variousindustries and these have been applied to thesampling of cytotoxic drugs.2,3 Based on publishedstudies, a sampling scheme should be developedfor the health care facility to incorporate the areasof interest. Any program designed to examinesurface contamination for cytotoxic drugs in the

health care facility must have the resources tocarry out the appropriate analytical techniquesnecessary to identify and quantify the drugs thatare being measured. Several analytical methodshave been employed by researchers and areavailable in the published literature.1

These include high-performance liquidchromatography with ultraviolet detection(HPLC–UV), gas chromatography coupled withmass spectrometry or tandem mass spectrometry(GC–MS or GC–MS–MS) or high-performanceliquid chromatography-tandem mass spectroscopy(LC–MS–MS). With the use of CG–MS (orGC–MS–MS) for drugs such as cyclophosphamideand ifosfamide, derivatisation is required prior toanalysis.4 Platinum containing compounds can beanalysed using either voltammetry5,6 or inductivelycoupled plasma mass spectrometry (ICP–MS).7,8

If contract laboratories are used to analyze surfacewipe samples, the methods used for collection,storage and shipping must be carefully documentedand controlled. Both negative (blanks) and positive(spiked samples) controls should be included foranalysis and samples should be coded so that they areanalysed blindly.

Since the early 1990s, studies by a numberof researchers have examined environmental con-tamination of areas where cytotoxic drugsare prepared and administered in health carefacilities.4,6,7,9–21 Using wipe samples, all investiga-tors measured detectable concentrations of one ormore hazardous drugs in various locations such assurfaces in biological safety cabinets (BSCs), pharma-ceutical isolators, floors, counter tops, storageareas, tables and chairs in patient treatment areas,and locations adjacent to drug-handling areas. All ofthe studies reported some level of contaminationwith at least one drug, and several reported contam-ination with all the drugs for which assays wereperformed.

Several studies have documented that the outersurfaces of cytotoxic drug vials are often contami-nated with the drug contained in the vial.9,22–27

Various methods have been utilized to measure theamount of drug on the outer surface of the vials.




These include wipe sampling, rinsing and totalemersion of the vials using a suitable solvent.However, because of the nature of the surfacesbeing sampled, it is difficult to determine therecovery efficiencies with drug vials. Once thesamples are collected, analytical methods similar tothose that have been used for surface wipe samplingcan be utilized for determination of the externalcontamination levels.

10.2.2 Air samplingTo a lesser extent, air sampling for cytotoxic drugshas been used to evaluate environmental contamina-tion of workplaces where cytotoxic drugs arehandled. The most commonly used drugs in airsampling studies include: cyclophosphamide, ifosfa-mide, 5-fluorouracil, and methotrexate.1

Several studies have measured airborne concentra-tions of antineoplastic drugs in health care set-tings.4,5,10,18,28–33 In most cases, the percentage ofair samples containing measurable airborne concen-trations of cytotoxic drugs was low, and the actualconcentrations of the drugs, when present, were quitelow. Most studies have employed glass fiber or paperfilters to capture airborne particulates. These lowresults may be attributed to the inefficiency ofsampling and analytical techniques used in thepast.33 A solid sorbant material may be more efficientat collecting particulate forms of cytotoxic drugs. Bothparticulate and gaseous phases of one antineoplasticdrug, cyclophosphamide, have been reported in twostudies.18,33 Many occupational studies have estab-lished exposure levels for toxic chemicals. However,no exposure levels have been established for airborneconcentrations of cytotoxic drugs. There are, how-ever, some exposure limits set for soluble platinumsalts and inorganic arsenic which would include someof the cytotoxic drugs such as cisplatin, carboplatin,and arsenic trioxide.34,35 Some pharmaceutical man-ufacturers have developed occupational exposurelimits (OELs) that are used in manufacturing facil-ities.36 However it should be noted that within thepharmaceutical industry, OELs have been establishedwhere a single drug is handled in an almost fullyautomised production line.The situation within a hospital pharmacy is

completely different and this makes the use ofOELs inappropriate. For genotoxic products,there is no such thing as a safe or maximalexposure limit and zero contamination shouldbe the target.

10.2.3 Biological monitoringA number of methods have been employed tomonitor worker exposure to cytotoxic drugs. Theseinclude: determining the mutagenicity of urine ofworkers, or measuring endpoints such as chromo-somal aberrations, sister chromatid exchanges andmicronuclei induction in white blood cells of theworkers. Other studies have measured HPRT muta-tions and damage to the DNA. However, theseendpoints are non-specific and can be affected bysmoking and other factors. More recently, the deter-mination of cytotoxic drugs and/or their metabolitesin the urine of workers has been employed formonitoring worker exposure to these drugs.1 Thismethod is very specific for the drugs being analyzedand can be very sensitive, depending on the drug andthe analytical procedure that is used. The same drugsthat have been assayed for in the environmentalsampling studies are typically those used to monitorworker exposure and, to date, have been usedprimarily in research studies and not for routinemonitoring.

The analytical procedures employed in monitoringworker exposure to cytotoxic drugs in the urine aresimilar to that for the environmental sampling. Urinesamples are collected from potentially exposedworkers and they may be concentrated or extractedby various procedures.4,5,7,9,19,37-51

The analysis of cytotoxic drugs in the urine hasbeen used to determine if workers have beenexposed to these drugs. However, because there areno established limits for cytotoxic drugs in the urine,this procedure has only been used on a researchbasis. Cyclophosphamide, ifosfamide, 5-fluorouracil,methotrexate, and platinum-containing drugs havebeen the most commonly measured drugs in studiesreported in the literature.1

10.3 Alternative techniquesThe use of fluorescent markers has been employed insome situations to simulate environmental contami-nation with cytotoxic drugs. Kromhout et al.52

developed a semi-quantitative fluorescent methodto evaluate environmental contamination and Spiveyand Connor53 employed a fluorescent marker todemonstrate sources of environmental contaminationduring simulated drug preparation and administra-tion. Prepared test kits that utilize a fluorescentmarker are available to evaluate worker skills andtraining during drug preparation andadministration.54




A combined test (visual under ultraviolet light, anda quantitative measurement using a fluorimeter)using quinine hydrochloride as a marker has theadvantage that the base is colourless and that thegloves, worksheets etc., can pass a quantitative testindicating the precise amounts of spillage duringactivities.55

ConclusionsContamination of areas where cytotoxic drugs areprepared or administered has been well documentedin a number of studies from countries in many partsof the world. Drug vials themselves are known to becontaminated with the drug that is contained in thevials. Since the majority of worker exposure resultsfrom dermal or inhalation routes, surface wipesampling and air sampling have been employed toestimate the level of environmental contamination inareas where cytotoxic drugs are handled. Sensitivemethods have been developed for a number of themore commonly used cytotoxic drugs, but, sincethere are many cytotoxic and other hazardous drugsin use in the health care setting, studies can onlyestimate what the actual total exposure might be.

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38 Ensslin AS, Pethran A, Schierl R, Fruhmann G. Urinary

platinum in hospital personnel occupationally exposed to

platinum-containing antineoplastic drugs. Int Arch Occup

Environ Health 1994; 65: 342.

39 Ensslin AS, Stoll Y, Pethran A, Pfaller A, Rommelt H,

Fruhmann G. Biological monitoring of cyclophosphamide

and ifosfamide in urine of hospital personnel occupa-

tionally exposed to cytostatic drugs. Occup Environ Med

1994; 51: 229–33.

40 Sessink PJM, Cerna M, Rossner P, et al. Urinary cyclopho-

sphamide excretion and chromosomal aberrations in

peripheral blood lymphocytes after occupational expo-

sure to antineoplastic agents. Mutat Res 1994; 309:

193–99.

41 Sessink PJM, Van de Kerkhof MCA, Anzion RB,

Noordhoek J, Bos RP. Environmental contamination and

assessment of exposure to antineoplastic agents by

determination of cyclophosphamide in urine of

exposed pharmacy technicians: Is skin absorption an

important exposure route? Arch Environ Health 1994;

49: 165–69.

42 Mader RM, Rizovski B, Steger GG, Wachter A, Kotz R,

Rainer H. Exposure of oncologic nurses to methotrexate

in the treatment of osteosarcoma. Arch Environ Health

1996; 51: 310–14.

43 Ensslin AS, Huber R, Pethran A, et al. Biological

monitoring of hospital pharmacy personnel occupation-

ally exposed to cytostatic drugs: urinary excretion and

cytogenetics studies. Int Arch Occup Environ Health

1997; 70: 205–08.




44 Sessink PJM, Wittenhorst BCJ, Anzion RBM, Bos RP.

Exposure of pharmacy technicians to antineoplastic

agents: reevaluation after additional protective measures.

Arch Environ Health 1997; 52(3): 240–44.

45 Burgaz S, Karahalil B, Bayrak P, et al. Urinary cyclopho-

sphamide excretion and micronuclei frequencies in

periperal lymphocytes and in exfoliated buccal epithelial

cells of nurses handling antineoplastics. Mutat Res 1999;

439: 97–104.

46 Minoia C, Turci R, Sottani C, et al. Risk assessment

concerning hospital personnel participating in the prep-

aration and administration of antineoplastic drugs.

(in Italian). Giornale Italiano di Medicina del Lavoro

ed Ergonomia 1999; 21: 93–107.

47 Deschamps F, Marinutti-Liberge and Lamiable D.

Biological monitoring of occupational exposure to

cytostatic drugs with platinum. Cancer Detect Prev

Online. Available at: http://www.cancerprev.org/

Journal/Issues/26/101/1193/4393. Accessed January

2007.

48 Turci R, Sottani C, Ronchi A, Minoia C. Biological

monitoring of hospital personnel occupationally

exposed to antineoplastic agents. Toxicol Lett 2002;

134: 57–64.

49 Favier B, Gilles L, Ardiet C, Latour JF. External contam-

ination of vials containing cytotoxic agents supplied by

pharmaceutical manufacturers. J Oncol Pharm Pract

2003; 9: 15–20.

50 Pethran A, Schierl R, Hauff K, Grimm C-H, Boos K-S,

Nowak D. Uptake of antineoplastic agents in pharmacy

and hospital personnel. Part I: Monitoring of

urinary concentrations. Int Arch Environ Health 2003;

76: 5–10.

51 Mason HJ, Blair S, Sams C, et al. Exposure to antineo-

plastic drugs in two UK hospital pharmacy units. Ann

Occup Hyg 2005; 49: 603–10.

52 Kromhout H, Hoek F, Uitterhoeve R, et al. Postulating a

dermal pathway for exposure to antineoplastic drugs

among hospital workers. Applying a conceptual model to

the results of three workplace surveys. Ann Occup Hyg

2000; 44: 551–60.

53 Spivey S, Connor TH. Determination of sources of

workplace contamination with antineoplastic drugs and

comparison of conventional IV drug preparation versus a

closed system. Hosp Pharm 2003; 38: 135–39.

54 Harrison BR, Godefroid RJ, Kavanaugh EA. Quality-

assurance testing of staff pharmacists handling

cytotoxic drugs. Am J Health Syst Pharm 1996; 53:

402–07.

55 Bonabry P. Use of a tracer for handling techniques

assessement. Workshop plenary session lecture pre-

sented at: 4th European GERPAC conference; October

4–6, 2006; Presq’ile de Giens Hye’res.

BIBLIOGRAPHY

ASHP (American Society of Health-System Pharmacists).

ASHP guidelines on handling hazardous drugs. Am J


OSHA (Occupational Safety and Health Administration)

Technical Manual, TED 1-0.15A, Section VI, Chapter 2,

Jan 20, 1999. Available at: http://www.osha.gov/

pls/oshaweb/owadisp.show_document?p_table¼DIREC

TIVES&p_id¼2276. Accessed February 2007.







Section 11 � Checking procedures


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Section 11 – Checking procedures

Ideally, pharmacists should receive a computerisedprescription or at least a printed prescription. Theprescription should comply with the following med-ication safety principles:

All orders written with the full generic name ofthe drugNo abbreviations should be used (eg. CDDP forCisplatin is not acceptable)Spell out the word ‘‘units’’ as this could bemistaken for a zeroA leading zero should always be used (eg.0.5 mg and not .5 mg)A trailing zero should never be used (eg. 2mgand not 2.0 mg)

Where possible, the clinical oncology pharmacistwho reviews the chemotherapy prescription shouldnot be the same pharmacist involved in the prepa-ration process. There should be as many independentchecks as possible built into the checking system.Standard operating procedures should be developedwhich include signed documentation that all therequired checks have been carried out. To allow lateranalysis and possible future preventative action, anyproblems detected and rectified should be recorded.

An institution may develop a standardised work-sheet for every patient that includes the date, patientdemographics, chemotherapy regimen, doses andvolumes of each drug, and any other specialinstructions.

11.1 Clinical checksIt is recommended that before chemotherapy isprepared the prescription is reviewed by a clinicalpharmacist. This clinical oncology pharmacist shouldwork with other health professionals in ensuringoptimal drug therapy for patients with cancer. Muchof this clinical work is beyond the scope of thisdocument, but there are several essential checks thatshould be completed before preparation workbegins.

11.1.1 Chemotherapy regimenThe chemotherapy regimen used must bedocumented on the patient’s profile. A set of standardprotocols used by the institution should be developed.The pharmacist should work with other healthprofessionals in the design of both chemotherapy

and supportive care pathways aimed at developingoptimal drug therapy for patients with cancer. In orderto maintain best possible practice, it is important thatthese treatment protocols are reviewed and updatedregularly. A standard procedure must be followed inthe case of non-compliance with a standard protocolor the use of a non-standard protocol. It is recom-mended that deviation from a standard protocoloccurs only after consultation with the senior medicalofficer responsible for the patient. With each treat-ment, the pharmacist should verify the cycle number,day of cycle and that the appropriate time interval haspassed since the previous treatment. The pharmacistshould document agreed upon changes including anyrelevant reference citations.

11.1.2 Patient profileIt is recommended that pharmacy-based profiles beestablished and maintained for all patients receivingchemotherapy. To do this effectively, pharmacistsmust have easy and ready access to patient profileswhich include, height, weight, calculated body sur-face area (BSA), treating physician, disease and stage,chemotherapy regimen, aim of therapy, relevantlaboratory measurements, allergies and adverse drugreactions, and past and current medications. Thisinformation must be current, and referred to prior toeach administration of chemotherapy.

11.1.3 Body surface area (BSA)The pharmacy department must have procedures inplace for checking the body surface area calculatedby the prescriber. If possible, this should be anautomated function of the computer program used inprocessing cytotoxic prescriptions. A standard oper-ating procedure should be developed which includessigned documentation that this check has beencarried out. Any corrective action taken by thepharmacist should also be documented.

11.1.4 Dose calculationsThe prescription must be checked against the che-motherapy regimen being used. Doses calculated bythe prescriber must be rechecked by the pharmacistusing the checked BSA against the appropriatetreatment regimen. Consideration must also begiven to the patient’s renal and hepatic functionand any possible drug interactions. When possible,




the calculation function should be automated in anelectronic prescription and patient dossier. An insti-tution may also choose to set a maximum daily doseand maximum cumulative dose parameter within thechecking system. It must be documented that thischeck has taken place and any corrective actiontaken must also be recorded.

11.1.5 PremedicationsIt must be checked that all appropriate premedica-tions have been included on the chemotherapy order.This may include appropriate anti-emetic therapies,anti-histamines, steroids, fluids, and diuretics.

11.1.6 Laboratory parametersIt is recommended that appropriate laboratoryparameters are checked by the pharmacist beforecytotoxic preparation commences. This includes fullblood examination including differential white cellcount, and, where appropriate, serum creatinine,creatinine clearance, liver and lung function tests,and left ventricular ejection fraction. As new agentsbecome available, other tests may be required. Ifchemotherapy is prepared ahead of time, there mustbe stringent procedures in place to ensure thatchemotherapy is not released from the pharmacy oradministered until the appropriate laboratory resultshave been checked and approved by either thepharmacist or treating physician.

11.2 Preparation checksThere are a number of checks which must becompleted at various stages of the preparationprocess. This will include an assembly check of allraw materials required, a check of dosage and volumecalculations and a final check of the finished productincluding products and volumes used and labellingand packaging. For every preparation, all data shouldbe recorded on a standardised worksheet. Writteninstructions should be available for the reconstitu-tion, dilution, mixing, labelling, and packaging of alladmixtures prepared. There should be a standardprocedure in place to retrieve the batch number andexpiry of all drugs and diluents used in the prepara-tion of cytotoxic preparations.

11.2.1 Assembly of raw materialsAll items required for the preparation of a productshould be assembled and then checked by adesignated person before entering the safety cabinetor isolator. At this point, the designated personshould check that the correct drug and strength has

been selected and that the selected reconstitutionfluid and infusion bag are appropriate. (This desig-nated person may be a pharmacist or a seniortechnician given this responsibility). The quantity offull vials and volumes of any partially used vials ischecked. The storage conditions and expiry dates ofall components should be verified at this time. Labelsgenerated and completed worksheets, if used, shouldbe checked for accuracy. The designated personshould sign that this check has been completed.

11.2.2 PreparationVolumes of drugs should be calculated independentlyby the operator performing the aseptic manipulation.If this calculation is performed electronically itshould be rechecked manually. Preferably, someform of validated computer program should be usedif available. If dose-rounding is employed to facilitateeasy preparation, this should be documented andstandardised. If a volume of drug is added to aninfusion fluid, the volume added must be documen-ted by the operator and there must be a system inplace to allow checking, particularly if a non-phar-macist performs the manipulation (see Section11.2.4). The signature of the operator must berecorded against each preparation made.

Only one patient’s treatment should be prepared ata time, and only one particular drug should be in thesafety cabinet or isolator at any one time.

An institution may choose to select vial sizesclosest to the actual dose required. For example, ifpreparing 70mg doxorubicin, then a 50mg plus a20mg vial would be used. This approach minimizesthe risk of adding too much drug and removes theneed to pass cytotoxic solutions back out of thesterile room. This approach also allows the operatorto work more independently in the sterile areawithout multiple volume checks by the pharmacist.Using this method, no unopened or used vials are leftin the safety cabinet or isolator for later use. Thedisadvantage of this approach is that the pharmacyhas to stock a range of vial sizes which maypotentially lead to selection error.

If multidose vials are used, a procedure must be inplace to ensure that the added volume and theselected drug are checked before the preparation isremoved from the safety cabinet or isolator. Thischeck must be performed by a pharmacist. Leftoversolution should then be kept in a dedicated, visuallymarked area, for later use. (See also Section 20.5).

The disadvantage of this approach is that volumechecking by the pharmacist becomes crucial.




Potentially contaminated vials have to be stored forlater use. A validated procedure with regards bothchemical and microbiological contamination riskmust be in place when keeping partially used vialsfor later use (See also section 20.5). The advantage ofthis approach is the reduction in the range ofproducts that have to be stocked by the pharmacy,and will be more economical. In addition, the asepticmanipulation will be simpler, faster, and the wholeoperation may be safer for the operator.

Procedures must be in place to allow the checkingof volumes of drug added to infusion bags. A volumereconciliation method may be used where volumes ofdrug entering and leaving the safety cabinet orisolator are documented and checked visually by apharmacist. Some institutions may prefer to check (a)volume marked on syringe before added to infusionbag or (b) used syringes drawn back to the volume offluid used. Note that (b) may be subject to somerecall bias. A product may also be checked bybarcode and volume added by weight using inte-grated balances and software. Whichever method isused, items should be properly sealed before leavingthe cleanroom or isolator to prevent contamination.

11.2.3 Finished productThe finished product must be checked by a suitablyqualified pharmacist. A volume calculation checkshould be carried out and the pharmacist must checkthat all components used are appropriate. A visualinspection of the finished product should beperformed by a pharmacist. A system must be inplace to allow the checking of volumes used in thepreparation process (see Section 11.2.4). Details onthe label should be checked including patient name,hospital registration number, drug, dose, fluid,volume, route of administration, duration of infusion,date and time of preparation and expiry, recom-mended storage conditions and any additional warn-ing or advisory notes. The integrity of the seal of theproduct should be checked before release. Thepharmacist must sign that the final check of theproduct has been performed.

11.2.4 Non-pharmacist staffNon-pharmacist staff involved in the preparation ofcytotoxics may include qualified pharmacy techni-cians and pre-registration graduate pharmacists.Different countries will have different requirementsfor the certification of technicians. They must at leasthave completed some in-house training to the satis-faction of an experienced pharmacist (See Section 4).

Unqualified technicians, unqualified pharmacy assis-tants and pharmacy undergraduates should not bepermitted to prepare these agents.

11.3 Validation

11.3.1 Validation of the productThe objective of validation of the product is toconfirm that the processes used will reproduciblyresult in a product containing the correct constitu-ents at a concentration that is within acceptablelimits and that the chemical and microbiologicalintegrity of the product is maintained throughout itsdesignated shelf-life.

Validation of the microbiological quality of theproduct cannot be performed with conformity to theEuropean Pharmacopoeia (sterility test) since pre-parations are currently adapted for one patient andthe final volume of the preparation could be too smallto reach the Pharmacopoeia requirements.Investigation of the microbiological quality of thefinal product could be done periodically by amicrobiological analysis of extra preparations. Themicrobiological integrity throughout the product’sshelf-life should be tested by the media fill test.Alternate methods such as advanced solid phasecytometry can be used as a quantitative and quicktest, with results available in less than one hour.

Validation of the concentration of the final productis also difficult to perform. Analytical methods foreach cytotoxic drug should be available. The volumeof sampling must not affect the final dosage of thepreparation to be given to the patient. If an extravolume for sampling is added to the preparation, arisk of error in the final dosage to be given to thepatient exists. Methods should be developed duringthe preparation process to ensure the correctconcentration of the final product. Double checkingduring withdrawing and injection of drug must beimplemented. Weighing procedures during the prep-aration process and on final product check could be ahelpful method to guarantee the final concentration.Dosage of extra preparations could also be doneperiodically.

Chemical integrity throughout shelf-life should bedocumented using data from international stabilitystudies. Chemical stability is the responsibility of thepharmacist and must take into consideration thefollowing criteria:

(a) Commercial formulation used(b) Dilution solvent used(c) Final concentration




(d) Final container used(e) Storage Temperature(f) Light protection during storage

11.3.2 Validation of the lack of crosscontaminationCross contamination can be defined as the contam-ination of one drug with another drug during thepreparation process. In the case of cytotoxicsprepared in the hospital, many different drugs aresimultaneously prepared and the risk of cross con-tamination cannot be a priori dismissed.Nevertheless, the risk is low if the process isperformed without opening vials by using contain-ment transfer devices. Taking into account thediversity of analytical methods required, checking ofall cytotoxic drugs routinely used is extremelydifficult. One method to check cross contaminationwould be to choose a commonly used cytotoxic drugand to simulate the process with the chosen drug and

then search for the drug inside placebo preparationswhich are simultaneously prepared.

Another method would be to use a tracer instead ofthe cytotoxic drug and simulate the process in thesame way. Special precautions should be taken andspecial attention paid if the product is of a viablenature, and in the case of gene therapy. Some studieshave demonstrated the risk of cross contaminationwith the use of BCG vaccine and so it is recom-mended that BCG vaccine is NOT prepared in thesame ventilation tool as cytotoxics which will beadministered to immuno-compromised patients. Theuse of one cabinet to prepare both cytotoxics andBCG vaccine is NOT RECOMMENDED.

11.3.3 Validation of computer programThe objective is to confirm that computer hardwareand software systems perform to the required stan-dards, delivering an output that is accurate and freeof error.







Section 12 � Administration of cytotoxic drugs


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Section 12 – Administrationof cytotoxic drugs

Although the administration of cytotoxic drugs ispredominantly the responsibility of nursing staff, it isworth highlighting some points of interest.

The safe handling of cytotoxic drugs is a jointresponsibility for all departments in the hospitaland a multi-disciplinary approach should be taken.The choice of products and devices which are usedwill have a major impact on daily practice in terms ofboth cytotoxic reconstitution and administration. Forexample, the selection of a special containmentdevice for preparation can have implications for theway in which nurses have to administer that drug tothe patient. The pharmacy has a very important roleto play in the choice of these products and/ordevices.

As a general rule, it is clear that safe handlingmeasures do not stop at the door of the pharmacy.Any process undertaken during the preparation ofcytotoxic drugs in the pharmacy which may result incontamination outside of the pharmacy must not bepermitted.

Nurses may be exposed to the commercialcytotoxic product, or a dilution of this product. Ifbags or syringes prepared in the pharmacy arecontaminated on the outer surfaces, nurses willcome into contact with the pure concentratedcytotoxic drug. The same applies when nursescrush tablets or open capsules. During the connec-tion/disconnection of the bag or syringe to theadministration device nurses may come into contactwith the diluted products, prepared in the pharmacy.The disconnection procedure is a risk for nursingstaff and a containment device for administrationshould preferably be used. Tubing should never beremoved from an IV bag containing a cytotoxic drug.Do not disconnect tubing at other points in thesystem until the tubing has been thoroughly flushedwith a non toxic solution. Remove the IV bag andtubing intact whenever possible. Wash hands withsoap and water before leaving the drug administra-tion site.

The excreta of the patient can be considered as asecond dilution of the drug. (See Section 15).

The same hierarchic order in prevention must beapplied for the work of the nurses. If possible,contained systems for parenteral administrationshould also be used. The use of contained bagswith a break-a-way seal, integrated pre-flushed infu-sion lines, and special devices for bolus injectionsshould be considered.

If contained systems cannot be used, nurses mustprotect themselves by using personal protectiveequipment, including gowns of impermeablematerial, gloves, and in the case of incidents, masks(P2/N95) and goggles.

For capsules and tablets, it is advisable that theseoral forms are packed in individual packages (unit-dose) and that where possible patients should selfadminister. In cases where this is not possible,nursing staff should wear gloves when handling oralcytotoxic preparations.

For patients who are unable to swallow or have anasogastric or other feeding tube in place, the use ofOral Liquid Dispensing (OLD) syringes is recom-mended. These syringes have a unique tip size whichmake it impossible to connect a needle or an IV lineor catheter.

An easy way of administering capsules with an OLDis to remove the plunger from the syringe, place thecapsule in the syringe, then replace the plunger.Some warm fluid is then drawn into the OLD syringeand after a couple of seconds the capsule is dissolvedand the fluid/suspension can be administrateddirectly into the mouth of the patient or by meansof the feeding tube.

Topical applications such as creams or lotionsshould be covered with bandages if possible in orderto protect clothing and linen.

Administration over longer periods usingambulatory pump systems must be managed insuch a way that safe filling and administration isassured.

Devices that need to be flushed with cytotoxicdrugs instead of a inert solution should not be used.

All methods and strategies employed in the admin-istration of cytotoxic drugs should be documented inwritten protocols.




If cytotoxics are administered outside the hospital,sufficient information must be made available aboutthe products used and the safe handling required.Consideration should be given to the supply ofspill kits and waste containers to ensurecompliance with all safe handling recommendations.

Additional written protocols about cytotoxic drugadministration should be delivered to the health careworker together with instructions for using the pump(electronically or mechanically), what to do in thecase of alarms and dealing with incidents oraccidents.







Section 13 � Cleaning procedures


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Section 13 – Cleaning procedures

13.1 Cleaning the ventilation toolThe cleaning, disinfection, and organizing of theventilation tool is the responsibility of trainedoperators (pharmacists and technicians) followingwritten procedures.

13.1.1 Personal protective equipmentWear personal protective equipment (i.e., goggles orface shield, protective double gloves, fluid resistantclosed front gown with long sleeves and tight fittingcuffs, mask – P2/3 in Europe/Australia and N95 inNorth America, and disposable hair cover) forcleaning and decontaminating work. Make sure thegloves are chemically resistant to the detergent,cleaning, disinfection and deactivation agents used.Wear face shields if splashing is possible. Wash handsthoroughly with soap and water immediately afterremoving gloves.

13.1.2 Disinfectants and detergentsDisinfectants and detergents should be selected andused to prevent microbial contamination. Carefulconsideration should be given to compatibilities,effectiveness, and inappropriate or toxic residues.Isopropyl alcohol (IPA) 70% for instance, mayharbour resistant microbial spores. Therefore, IPAused in the clean room should either be filteredthrough a 0.2 um filter to render it sterile or sterileIPA or ethanol 70% may be able to be sourced directlyfrom a supplier. It should be noted that in someisolator applications, IPA 70% may not be used due toan incompatibility with attached neoprene gloves.Here only IPA 50% may be used. Sterile IPA should bechecked periodically for microbial contamination.

The choice of products should be related tothe bio-burden, time and application of theproduct, equipment used, and eventualresistance problems.

The schedule of use and methods of applicationshould be in accordance with written procedures.Diluted solutions should be kept in previouslycleaned containers. They should not be stored forlong periods unless sterilized and chemical stabilityhas been established. Partly emptied containersshould not be topped up. Apply the cleaning solutionto the wiper, in order to avoid soiling the cleaningsolution. Cleaning solutions should be applied to the

wiper and never sprayed in the BSC to avoid damageto the HEPA filter.

13.1.3 Cleaning materialsCleaning materials (for example; wipers, mops, anddisinfectants) for use in the clean room should bemade of materials that generate a low amount ofparticles. Disposable cleaning materials are recom-mended and after use these should be disposed ofalong with other cytotoxic waste.

13.1.4 Timing of cleaning

Beginning of session, after liquids spilled

At the beginning of each compounding activitysession, and after liquids are spilled, all items areremoved from the ventilation tool. All surfaces arefirst cleaned with sterile water for irrigation anddetergent to remove loose material and water-soluble residues. The same surfaces are thendisinfected with sterile 70% IPA, or other effectiveantimicrobial agent, that is left on for a timesufficient to exert its antimicrobial effect. 70% IPAmay damage the clear plastic surface of someventilation tools.

Class II BSC run continuously

A Class II BSC, which runs continuously, should becleaned before the day’s operations begin and atregular intervals or when the day’s work is com-pleted. For a 24-hour service, the BSC should becleaned 2-3 times daily.

BSC turned off

If the biological safety cabinet is turned off betweenaseptic processes for routine maintenance or anyother reason, it should be operated long enough toallow complete purging of room air from the criticalarea (for at least 30 minutes), then cleaned anddisinfected before use. It should be noted that theactual time required for purging will depend on thedesign of the ventilation tool and has to be deter-mined during the performance qualification or vali-dation. If the isolator has been turned off for less than24 hours, a two-minute start-up time is sufficient. Forperiods greater than 24 hours, the chamber shouldbe disinfected and the isolator should not be used fora period of air purging (at least 10 minutes) after




application of the disinfectant. The actual timerequired for purging will depend on the design ofthe ventilation tool and has to be determined duringthe performance qualification or validation.

13.1.5 Procedure for cleaning BSCWipe the surface of the ventilation tool includingfront, sides, and bottom in the direction of thegroove of the surface. Clean from upstream, closestto the HEPA filter, to downstream. Start with therear wall of the BSC and move down. Wipe in acontinuous motion working parallel to the HEPAfilter. When a corner is met, ‘S’ curve and return tothe opposite side while overlapping the previousstroke. Continue with fixtures (for example, gas orvacuum valves, bar and hooks, if present), thesides, and then lastly, the work surface. Aftercompleting the cleaning, do not use the hood forat least 5 minutes. This allows the alcohol to dry.Do not remove the sharps container until full andready for disposal.

13.1.6 Procedure for decontamination

Routine decontamination

The ventilation tool should be decontaminated atleast weekly, any time a cytotoxic spill occurs, beforeand after certification, voluntary interruption, or ifthe ventilation tool is moved. Ideally, the process andthe frequency with which it is performed should bevalidated. Detergent, sterile water for irrigation, anddisinfectant bottles will be placed on a plastic backeddisposable liner outside of the BSC when not in use.The choice of products should be related to thecytotoxic product, time and application of thedecontamination product, equipment used and even-tual resistance problems. Wipe from top to bottom,starting with the top grill (controversial – see Section13.1.10) and following airflow. Repeat using sterilewater for irrigation until residue is removed. Finish bydisinfecting. An alcohol dampened towel may beused to wipe top (see Section 13.1.9) and front grills.Pull the viewing window down and decontaminateboth sides with detergent solution, rinse with sterilewater for irrigation then disinfect. Discard outer pairof gloves and used wipers in the sealable bag.Decontaminate the perimeter of the opening intothe BSC with detergent solution then rinse withsterile water for irrigation. Thoroughly wash protec-tive eye wear with detergent. The decontaminationprocedure should be completed at the end of the daywhenever possible. If it must be completed during

the day, the BSC shall be allowed to run for 30minutes to purge before using for asepticpreparation.

Decontamination after biological product

If a biological product (e.g., BCG vaccine for bladderinstillation) is prepared in the ventilation tool, thetool should be decontaminated following prepara-tion. To prevent iatrogenic transmission of theorganism, some centres dedicate one BSC solely tothe preparation of BCG and prepare chemotherapeu-tic agents in a separate pharmacy location.1 Othercentres prepare BCG on the ward using a contain-ment device. The latter two options are preferred andthe use of one cabinet to prepare both cytotoxics andBCG vaccine is NOT recommended.

Decontamination before admixingnon-cytotoxics

In facilities where the ventilation tool is used foradmixing cytotoxics and non-cytotoxics, the ventila-tion tool should be decontaminated before admixingnon-cytotoxics if it has not been decontaminatedsince it was last used for admixing cytotoxics. Theuse of one cabinet to prepare both cytotoxics andnon-cytotoxics is not recommended.

Decontamination of sump

The lower part of the BSC should be cleaned atleast once a week to reduce the contaminationlevel in the BSC. The fan motor (blower) shouldnot be turned off only while cleaning the lowerpart of the hood (sump), but care must be taken toensure that nothing will be sucked up into the fan.Some BSCs have a screen on the fan to preventanything from being sucked up. Raise the work trayand (a) lean on back surface of BSC or (b) usestainless steel wire to suspend or (c) use stainlesssteel prop to hold up if possible rather thanremoving from the BSC. To prevent back strainwhen decontaminating a 1.8 m (6 foot) BSC, twopeople should lift and replace the work tray.Decontaminate with detergent, rinse with sterilewater for irrigation, then disinfect the work traywith alcohol before replacing.

13.1.7 Waste handlingWaste generated throughout the cleaning or decon-tamination procedures should be collected in suitableplastic bags, sealed and wiped inside the ventilationtool, and removed with minimal agitation.




13.1.8 DocumentationRecord on the quality control log when the dailycleaning/disinfection, weekly decontamination andmonthly sump cleaning is done.

13.1.9 Gas sterilized isolatorsThe above procedures for cleaning and disinfectingmust be implemented. Compatibility with structuralcomponents (for example the plastic wall, isolatorgloves, sleeves, half suit) must be checked beforeuse. The cleaning procedure must be implementedwith respect to the enclosure taking care never todisrupt the sealed enclosure. For example, theisolator attached gloves are removed following a‘‘safe change’’ procedure (without breaking theintegrity of the system) in accordance withISO14644–72 annexe C. If for maintenance reasonsthe isolator integrity is disrupted, personal protec-tive equipment (PPE) must be used in conformitywith the chemical risk. Cleaning and disinfectionof the workstations is performed on a dailybasis. The sterilization of the enclosure is imple-mented periodically and the frequency should bevalidated.

13.1.10 Controversies

Decontaminating the BSC ceiling grill

There is a lack of consensus regarding decontaminat-ing the ceiling grill in the BSC with detergent. Somereferences suggest cleaning in place and some say notto wipe the top grill with detergent. The concern isthat if the HEPA filter becomes wet, this may affectthe integrity of the filter and compromise thefunction of the filter.

Alternate germicides

The ASHP guidelines on quality assurance for sterileproducts describe the need to alternate germicides ascontroversial. According to Akers and Moore,3 thedata do not support alternating germicides. A litera-ture search4 found little evidence for periodic alter-nation of disinfectants; the search did find thatalternating use of acidic and alkaline phenolicdisinfectants reduces resistance arising in pseudo-monas adhering to hard surfaces.’’ It has beensuggested that reported microbial resistancemight be due to situations in which an ineffectivedisinfectant was used or in which a disinfectant wasused at sub-effective dosages or sub-effective contacttimes.5

In general the advice is not to change the disinfec-tant product unless there is a problem. In this case,the source of the problem has to be identified.

Residues left by disinfectants

There are two prevailing opinions on the issues ofresidues left by disinfectants. One opinion is that theresidues left behind from the use of formulatedgermicidal detergents may have bacteriostatic proper-ties, in which case the residue would be beneficial.The other opinion is that no residue is acceptable in aclean room, in which case the residue may simply beremoved with an alcohol or water for irrigationrinse.6

Sporicidal disinfectants

Because routine disinfectants will not be effectiveagainst bacterial endospores such as the Bacillusspecies, a sporicidal agent should also be appliedperiodically (e.g., weekly or monthly). Since mostsporicidal disinfectants are either highly toxic or verycorrosive, they should not be considered fordaily use.7

Deactivation agents

The NIOSH Alert8 recommends that work surfaces becleaned with an appropriate deactivation agent (ifavailable) and cleaning agent before and after eachactivity and at the end of the work shift. Many drugmanufacturers recommend the use of a stronglyalkaline detergent as an appropriate deactivatingagent for some hazardous drugs. Researchers haveshown that strong oxidising agents such as sodiumhypochlorite (bleach) are effective in deactivatingsome hazardous drugs where an oxidative action isappropriate. However, bleach may pit the stainlesssteel surface of the BSC, and may also react withsome cytotoxics. For example, the material safetydata sheet for mitozantrone notes that chlorine gasmay be liberated when the drug is degraded withbleach. Other drugs are deactivated by hydrolysis.

Note that any one product is incapable ofdecontaminating all hazardous products.

13.2 Cleaning roomsFor the purposes of this standard, the terminologyin the USP 7979 will be used to describe thecleanroom (i.e., the area designated for preparingsterile products). The ventilation tool is located inthe buffer zone/room; with the adjacent antearea/room across the buffer zone/room from theventilation tool.




13.2.1 Buffer zone/room

Personal protective equipment

At a minimum, wear goggles or face shield andprotective chemotherapy gloves for cleaning anddouble gloves for decontaminating work. Wear faceshields if splashing is possible. Make sure the glovesare chemically resistant to the decontamination orcleaning agent used. Immediately after removinggloves, wash hands thoroughly with soap and water.

Work surfaces

All work surfaces (e.g., counter tops and supplycarts) are cleaned and disinfected daily. Thesurfaces are first cleaned with water and detergentto remove water- soluble residues. Immediatelythereafter, the same surfaces are disinfected withsterile 70% IPA, or other effective antimicrobialagents, and left on for a time sufficient to exerttheir antimicrobial effects.

Carts and tables

Large pieces of equipment, such as carts and tables,used in the cleanroom should be made of a materialthat can be easily cleaned and disinfected; stainlesssteel is recommended. Stools and chairs should becleanroom quality.

Storage shelving

Storage shelving is emptied of all supplies and thencleaned and disinfected at least weekly, usingapproved agents. Other hard surfaces, such as carts,tables, and stools should be cleaned and disinfectedweekly and after any unanticipated event that couldincrease the risk of microbial contamination.

Nonporous and washable surfaces

The floors of the cleanroom should be nonporousand washable to enable regular disinfection. Carpetor porous floors, porous walls and porous ceilingtiles are not suitable for cleanroom use becausethese surfaces cannot be properly cleaned anddisinfected.

Floors

Floors in the cleanroom are cleaned by moppingat least once daily when no aseptic operationsare in progress. Floor mops may be used in boththe buffer zone/room and the ante area/room,but only in that order. Trained and supervisedcustodial personnel using approved agentsdescribed in the written procedures may performmopping.

Refrigerators, freezers

Refrigerators, freezers, shelves, and other areaswhere pharmacy-prepared sterile products arestored, should be kept clean.

Other equipment

Equipment that does not come in contact with thefinished product should be properly cleaned, rinsed,and disinfected before being placed in the cleanroom.

Decontamination of exterior of ventilation tool

The exterior surfaces of the ventilation tool should bedecontaminated with detergent solution, cleanedwith sterile water for irrigation and disinfectedweekly. 70% IPA may damage the clear plasticsurfaces of some ventilation tools.

Clean from cleanest to dirtiest areas

Cleaning should proceed from the cleanest area tothe dirtiest area of the room. This would involve aceiling to floor cleaning flow, moving outward fromthe ventilation tool to the exit. The orientation of theHEPA filters (if present) should also be consideredwhen conducting cleaning procedures.

Ceilings and walls

Ceilings and walls should be cleaned at least monthly,or as required to maintain cleanliness.

Disinfectants and detergents

Disinfectants and detergents should be selected andused to prevent microbial contamination. Carefulconsideration should be given to compatibilities,effectiveness, and inappropriate or toxic residues.The schedule of use and methods of application andproducts should be in accordance with writtenprocedures. Diluted solutions should be kept inpreviously cleaned containers. They should not bestored for long periods unless sterilized and chemicalstability has been established. Partly emptied contain-ers should not be topped up. In order to avoidcontaminating the cleaning solution, it is recom-mended that the cleaning solution be applied directlyto the wiper.

Cleaning materials

Cleaning materials (e.g., wipers, mops, and disin-fectants) for use in the cleanroom should be made ofmaterials that generate a low amount of particles. Allcleaning tools should be nonshedding and dedicatedto use in the clean room. Most wipers are discarded




after one use. (Disposable cleaning materials arerecommended and after use these should be disposedof along with other cytotoxic waste.) If cleaning toolsare reused, their cleanliness should be maintained bythorough cleaning and disinfection after use and bystoring in a clean environment between uses.

Waste handling

An appropriate method of disposing of waste,including needles, should be established whichdoes not allow accumulation in the cleanroom.Trash should be collected in suitable plastic bagsand removed with minimal agitation.

13.2.2 Ante area/room

Supplies and equipment

In the ante area/room, supplies and equipmentremoved from shipping cartons are wiped with adisinfectant. Alternatively, if supplies are received insealed pouches, the pouches can be removed as thesupplies are introduced into the cleanroom withoutthe need to disinfect the individual supply items. Noshipping or other external cartons may be taken intothe cleanroom.

Custodial personnel

Trained and supervised custodial personnel performcleaning and disinfection of the ante area/room atleast weekly, in accordance with written procedures.

Floors

Floors should be cleaned and disinfected daily, alwaysproceeding from the buffer zone/room to the antearea/room.

Storage shelving

Storage shelving is emptied of all supplies andcleaned and disinfected at least monthly.

13.3 Cleaning material used for oral/externaluse drugs (non sterile)Workers may be exposed to cytotoxic drugs whenthey create aerosols, generate dust, clean up spills ortouch contaminated surfaces during the preparation,administration, or disposal of cytotoxic drugs. Whilecommonly associated with cytotoxic drugs given byparenteral routes, exposure can also occur withdrugs prepared for administration by the oral ortopical routes.

All material used (such as mortar, pestle, glassplate, spatulas, mixing devices, and tube fillers) for

the preparation of oral/external use cytotoxic drugsmust be identified for that use and reserved soley forthese activities. This equipment must not be used fornon cytotoxic preparations. This equipment shouldbe cleaned separately from all non cytotoxicequipment.

13.3.1 Preparation in a biological safety cabinet(BSC)All activities likely to result in particle generation, forexample weighing, crushing, mixing, or fillingcapsules, should be performed in a Class I or II BSC(see Section 9).

Written procedures

Class I BSC should be cleaned and decontaminatedfollowing written procedures.


Wear personal protective equipment (i.e., goggles orface shield, protective double gloves, fluid resistantclosed front gown with long sleeves and tight fittingcuffs, mask, and disposable hair cover) for cleaningand decontaminating work. Make sure the gloves arechemically resistant to the detergent, cleaning, disin-fection and deactivation agents used. Wear faceshields if splashing possible. Wash hands thoroughlywith soap and water immediately after removinggloves.

Beginning of session, after liquids spilled

At the beginning of each compounding activitysession, and after liquids are spilled, all items areremoved from the BSC. All surfaces are first cleanedwith water for irrigation and detergent to removeloose material and water-soluble residues.

Procedure for cleaning

Wipe the surface of the BSC including front, sides andbottom in the direction of the groove of the surface.Wipe in a continuous motion working. When acorner is met, ‘S’ curve and return to the oppositeside while overlapping the previous stroke. Continuewith fixtures (e.g., gas or vacuum valves, bar andhooks, if present), the sides, and then the worksurface.

Decontamination

The BSC should be decontaminated at least weekly(ideally, the process and the frequency with which itis performed should be validated.); any time acytotoxic spill occurs; before and after certification,




voluntary interruption, or if the BSC is moved.Detergent and water for irrigation bottles will beplaced on a plastic backed disposable liner outside ofthe BSC when not in use. Wipe with an aqueous highpH detergent solution (e.g., 5 mL in 235 mL warm tapwater), starting with the grill and following airflow.Repeat using water for irrigation until residue isremoved. A dampened towel may be used to wipegrill. Discard outer pair of gloves and used wipers inthe sealable bag. Decontaminate the perimeter of theopening into the BSC with detergent solution thenrinse with water for irrigation. Thoroughly washprotective eye wear with detergent. Discard innerpair of gloves. Wash hands thoroughly immediatelyafter removing gloves.

Waste handling

Waste generated throughout the cleaning or decon-tamination procedures should be collected in suitableplastic bags, sealed inside the ventilation tool, andremoved with minimal agitation.

Documentation

Record on the quality control log when thecleaning/disinfection and weekly decontamination isdone.

Class II BSC also used for sterile compounding

A Class II BSC, which is also used for sterilecompounding, should be cleaned, decontaminatedand disinfected as described in Section 13.1.Compounding non-sterile forms of hazardous drugsin equipment designated for sterile products is notrecommended and must be undertaken with care.

13.3.2 Preparation outside a BSC


Wear personal protective equipment (i.e., goggles orface shields, protective double gloves, fluid resistantclosed front gown with long sleeves and tight fittingcuffs) for cleaning and decontaminating work. Makesure the gloves are chemically resistant to thedecontamination or cleaning agent used. Washhands thoroughly with soap and water immediatelyafter removing gloves.

Work surfaces

Clean work surfaces with an aqueous high pHdetergent solution (e.g., 5 mL in 235 mL warm tapwater), then rinse with water before and after eachactivity.

Equipment

Contaminated equipment should be cleaned initiallywith gauze saturated with water; decontaminatedwith detergent and then rinsed. The gauze should becontained and disposed of as cytotoxic drug con-taminated waste.

Waste handling

Disposal of unused or unusable non-injectable dosageforms of cytotoxic drugs should be performed in thesame manner as for hazardous injectable dosageforms and waste.

13.4 Validation of cleaning processesThe objective is to confirm that microbiological,chemical, and other contaminants are removed orinactivated during the cleaning process.

13.4.1 Microbiological validationMicrobiological validation of the cleaning processuses contact plates and/or swabs before and after thecleaning operation. In the case of a sterile isolator, aspecific investigation must validate the efficiency ofthe sterilisation process using biological indicators(B.I.).

13.4.2 Chemical validationDue to the large diversity of drugs used simulta-neously in the same controlled area, chemical valida-tion of the cleaning process is more complex whenhandling cytotoxic drugs. One approach would be toinvestigate the most commonly used cytotoxic drugs(eg. 5-fluorouracil, methotrexate, ifosfamide, cyclo-phosphamide) by wipe sampling of the surfacesbefore and after cleaning. If an analytical procedure isavailable, investigation of lipophilic drugs (eg.carmustine, paclitaxel) would also be done toensure that the cleaning procedure is efficient forboth for lipophilic and hydrophilic drugs. In addition,the cleaning carried out should not degrade thecytotoxic drug into more toxic components.

Definitionsante area/room¼ clean area that precedes thebuffer zone/room, for donning of personal protec-tive equipmentbuffer zone/room¼ area in which the cleanestwork surface (i.e., ventilation tool) is located.clean room¼ the area designated for preparingsterile products (i.e., a room in which the concen-tration of airborne particles is controlled, that isconstructed and used in a manner to minimize the




introduction, generation, and retention of particlesinside the room.deactivate¼ treat a chemical agent (such as ahazardous drug) with another chemical, heat,ultraviolet light, or other agent to create a lesshazardous agent.decontamination¼ inactivation, neutralization,or removal of toxic agents, usually by chemicalmeans.detergent¼ cleaning agent with wetting-agent andemulsifying-agent (tensio active) properties.disinfect¼ destroy pathogenic microorganisms orinhibit their grown and vital activity.HEPA¼high efficiency particulate air filterIPA¼ isopropyl alcoholnon-shedding, non-linting, low-lint or lint-free¼materials that generate a low amount ofparticlessanitize¼ to free from dirt, germs, by cleaningsump¼ a chamber at the bottom of a machine intowhich wastes gather before disposal.wiper¼ that which wipes (eg, towel, sponge,gauze, cloth, etc)

Note: for the purposes of this Standard, the termdisinfectant is used and includes antimicrobialagent and sanitizing agent

REFERENCES

1 Stone MM, Vannier AM, Storch SK, et al. Brief report:

Meningitis due to iatrogenic BCG infection in two

immunocompromised children.. N Engl J Med 1995;

333: 561–63.


14644-7: cleanrooms and associated controlled environ-

ments – Part 7: Separative devices (clean air hood, gloves


3 Akers MJ, Moore C. Microbiological monitoring of phar-

maceutical cleanrooms:The need for pragmatism. J Adv

Appl Contam Control 1998; 1: 23–30.

4 Kopis EM. Rotation of disinfectants to combat microbial

resistance. CleanRooms 1996; 10: 48–50.

5 Kopis EM. Regulators put cleanroom sanitizing agents

under the microscope. CleanRooms Supplement. 1999.

6 Kopis EM. Answers to the 10 most common questions

regarding microbial control in cleanrooms. CleanRooms.

1997.

7 Kopis-Sartain E. Regulatory update. Controlled

Environments Magazine. March 2005. Available at:

http://www.cemag.us/articles.asp?pid¼512. Accessed

June 22, 2005.









sterile preparations (general test chapter 797).

In The United States Pharmacopeia 28 rev., and

The National Formulary, 23rd edn. Rockville, MD:

United States Pharmacopoeial Convention; 2004:

2461–77.

BIBLIOGRAPHY

ASHP (American Society of Health System Pharmacists

ASHP). ASHP guidelines on quality assurance for phar-

macy-prepared sterile products. Am J Health Syst Pharm

2000; 57: 1150–69.

ASHP (American Society of Health-System Pharmacists).

ASHP guidelines on handling hazardous drugs. Am J


Canadian Society of Hospital Pharmacists. CSHP

guidelines for the preparation of sterile products in

pharmacies. 1996.

Canadian Association for Pharmacy in Oncology.

Standards of practice for oncology pharmacy in Canada

(Version 1). 2004.







Section 14 � Cytotoxic spills, extravasation and other incidents


Published by:













Section 14 – Cytotoxic spills, extravasationand other incidents

14.1 Cytotoxic spillsA standard operating procedure must be developedand maintained for the handling of cytotoxic spillswithin the institution. When a cytotoxic spill iscleaned, all cleaning should begin from theoutside of the spill area and gradually worktowards the centre. All personnel who may beinvolved in handling cytotoxic drugs must be givenappropriate training in the procedures to be followedin the event of a spill. Records of staff undergoing thistraining should be maintained.

14.1.1 Spills within safety cabinet or isolatorWhen a cytotoxic spill occurs within the safetycabinet or isolator, work should stop and the spillshould be cleaned up immediately. Small spills maybe easily cleaned using absorbent gauze. Large spillsmay require a spill pillow to absorb a larger volume offluid. The area should then be washed with anappropriately diluted strongly alkaline detergent,rinsed thoroughly with sterile water, and thenwiped with sterile isopropyl alcohol (70%) or othersuitable agent.

14.1.2 Spills within cleanroom and anteroomCytotoxic cleanrooms which have a positive pressurein relation to the external environment should befitted with a spill switch. When activated, this switchwill alter the pressure differentials within thecytotoxic suite to minimise any contamination ofthe external environment. The switch should also befitted with an audible alarm to alert other staffworking in the immediate vicinity. The spill shouldthen be cleaned following the procedures outlined inSection 14.1.6.

14.1.3 Spills within storeroomAll staff working in the pharmacy store must betrained in the procedure to be followed in the eventof both a liquid and powder cytotoxic drug spill.Wherever cytotoxic drugs are stored, spill kits withwritten procedures for use must be readily available.

14.1.4 Spills during transportPersonnel transporting cytotoxic drugs must befamiliar with the procedure to be followed in theevent of a spill.

14.1.5 Contents of spill kitA spill kit should contain:

(a) Written instructions for use of the spill kit.(b) Warning signs to alert other staff to the

hazard and isolate the area of the spill.(c) Impermeable protective gown, boots/over-

shoes, headcover, goggles or face shields andsuitable respirator mask.

(d) Pair of large size gloves. May be either glovesmanufactured specifically for handling cyto-toxics (with proven resistance), or if not, twopairs of gloves.

(e) Plastic broom and dustpan to clean up anybroken glass.

(f) Spill mat (alginate impregnated) to absorbsmall volumes of spilled liquid.

(g) Large quantities of swabs for absorbing andcleaning liquid spills.

(h) Concentrated alkaline detergent solution.(i) Bottled water (correct quantity for dilution of

detergent).(j) Clearly labelled cytotoxic waste container.(k) Spill report/incident form.(l) Spill pillow capable of absorbing large

volumes of liquid. This may an integral partof the spill kit or may be supplied separatelywhen required.

An institution may choose to supply all of theseitems within the final cytotoxic waste container.

14.1.6 Spill clean up procedureIn the event of a cytotoxic spill in any area other thanthe safety cabinet or isolator, the following clean upprocedure should be followed:

(a) Alert other staff in the area to the potentialhazard and limit access by placing the warn-ing sign in a prominent position.




(b) Remove the contents of the spill kit and puton in this order: the mask, the head cover, thegoggles or face shield and the gloves.

(c) For a liquid spill, carefully place a sufficientquantity of swabs or the alginate impregnatedmat (or the spill pillow if a large volume ofliquid is involved) over the spilled liquid. Ifthe spill involves a powder, carefully placesufficient swabs over the powder and thencarefully wet the mat with water so that thepowder dissolves and is absorbed by theswab.

(d) Gather up the contaminated swabs/mat/pillow and carefully clean up any brokenglass with the broom and pan. Discard all ofthis waste into the cytotoxic waste container.

(e) Repeat steps (c) and (d) until all the spill hasbeen cleared. When a cytotoxic spill iscleaned, all cleaning should begin fromthe outside of the spill area and graduallywork towards the centre.

(f) Add the detergent concentrate to the bottledwater.

(g) Wash the area of the spill thoroughly,discarding all waste generated into thewaste container.

(h) Rinse the area well with clean water.(i) Dry the area completely to prevent accidental

slippage on wet floor.(j) Discard all used items into the cytotoxic

waste container. Do not compact waste.(k) Arrange for collection of waste according to

institution policy.(l) Wash hands thoroughly with soap and water.(m) Arrange for hospital cleaning staff to re-clean

the area.(n) Complete the spill report card and forward to

pharmacy department. Arrange for a replace-ment spill kit to be obtained.

14.2 Contamination of staff and/or patientIn the event that staff become contaminated with acytotoxic agent, the following procedure should befollowed:

(a) All overtly contaminated protective clothingshould be removed and placed in thecytotoxic waste container.

(b) All contaminated clothing should be removedand if heavily contaminated should be dis-carded into the cytotoxic waste container.Clothing with minimal amount of

contamination should be laundered sepa-rately and rinsed well.

(c) An emergency shower should be used ifappropriate. If this is not available, then thecontaminated area of skin should be washedwith soap and rinsed with large amounts ofwater.

(d) Eyes that have become contaminated shouldbe thoroughly irrigated with 0.9% sodiumchloride or other suitable ophthalmic irriga-tion solutions. It is not recommended toirrigate the eye directly with running waterfrom a tap (faucet) because of the potentialfor water pressure damage to the eye. In allcases where the eye is thought to becontaminated, ophthalmological adviceshould be sought.

(e) If the skin is broken, the affected area shouldbe irrigated with water and bleedingcontrolled.

(f) Medical attention should be sought as soon aspractical.

(g) An incident report should be completed ifthis is institution policy.

14.3 ExtravasationEach institution should develop a policy on dealingwith the extravasation of vesicant cytotoxic drugs.This policy will require input from pharmacy, med-ical, and nursing personnel. The medical and phar-maceutical literature should be consulted and aconsensus decision made about which agents to useto treat each extravasation. An institution may or maychoose not to use a specific antidote for the drugwhich has extravasated.

Recently, a formulation of dexrazoxane (Savene�)has become available in some countries for themanagement of extravasation following anthracy-cline administration. To fully protect against thetissue damage caused by extravasation, the drugshould be given as soon as possible and within6 hours of the extravasation accident. Dexrazoxaneis administered as a 1–2 hour infusion on threeconsecutive days. Cooling and Dimethyl Sulphoxideshould not be used during treatment withdexrazoxane.

A policy on warming or cooling the area should bedeveloped for specific drugs.

A list of vesicant cytotoxics should be maintainedby the pharmacy and this information should be onthe label of any admixtures prepared by thepharmacy.




General recommendations for handling extravasa-tion include:

(a) Stop injection/infusion immediately(b) Leave needle in place(c) Replace infusion lead with 5 ml disposable

syringe and aspirate slowly as much aspossible; Caution! Do not exert pressure

(d) If blisters occur: aspirate with 1 ml syringeand subcutaneous cannula

(e) Elevate limb and immobilise(f) Always consult a plastic surgeon and/or

physician immediately(g) Start substance specific measures on advice

of plastic surgeon.(h) Remote IV access while aspirating after

approval of plastic surgeon.(i) Complete extravasations documentation

sheet(j) Inform and instruct the patient and relatives(k) Regular control (aftercare)

Some protocols include a drastic approach, partic-ularly with products known for tissue damage.

An example of such a protocol is (personalcommunication, Johan Vandenbroucke, 2007):

The (Plastic) Surgeon in that case will withinthe 24 hours after the extravasation infiltratethe extravasation zone with normal salinefollowed by a liposuction.In case of extravasation with products having aneffect on the alpha-receptors, the infiltration isdone with 10 to 15 mg phentolamine in 10 to15 ml normal saline, followed with an extrainfiltration of normal saline and liposuction.An extravasation kit may be prepared by the

pharmacy to make treatment readily available tocommence as soon as possible. Any such kit mustcontain written instructions for treatment of theaffected area and the use of any specific antidotescontained in the kit.

An incident report which reflects the institution’spolicies should be completed whenever a case onextravasation occurs. This will most likely be theresponsibility of nursing staff. An institution maychoose to include an extravasation report within theextravasation kit in a similar way to that described forcytotoxic spills – see previous and following sections.

Consideration should be given to having both anextravasation kit and an anaphylaxis kit available inareas where chemotherapy is administered. In thisway, these items are immediately availablewhen required.

14.4 Inadvertent intrathecal administration ofvincristineVincristine, and the other vinca alkaloids, are allneurotoxic and must only be administered by the IVroute. If given intrathecally, this error in route ofadministration results in a fatal outcome in 85% ofcases with devastating neurological effects in the fewsurvivors. Each institution must develop policies andprocedures to ensure that the risk of accidentalintrathecal administration of these agents is mini-mised. The following are some suggestions:

Vinca alkaloids should NEVER be supplied in asyringe. As intrathecal administration has beenreported despite dilution to 10 and 20 ml, it isrecommended that vincristine and other vincaalkaloids be supplied in a minibag of at least50 ml.All vinca alkaloids products should be labelledclearly with the intended route of administra-tion. For example ‘‘FOR INTRAVENOUS USEONLY – FATAL IF GIVEN BY OTHERROUTES.’’ The use of negative labels such as‘‘Not for Intrathecal Injection’’ should beavoided as the inclusion of the word‘‘intrathecal’’ may actually promote administra-tion by this route.If a patient is scheduled to receive an IV vinca

alkaloid plus an intrathecal dose of a drug, theseshould be administered on different days or at least atdifferent times. The timing of IV vincristine and anyintrathecal injections occurring in the same locationshould be separated.All medications INTENDED for intrathecal

administration should be packaged separatelyfrom other types of medications, and shouldbe supplied by the pharmacy in a distinctivecontainer to prevent confusion with IV drugs.They should display a prominent warningstating ‘‘FOR INTRATHECAL INJECTION ONLY.’’

Health professionals who prescribe, prepare oradminister chemotherapy should be educated aboutthe published case reports or fatal intrathecal admin-istration of vincristine.

14.5 Documentation of incidentsEach institution should develop procedures fordocumenting spills and other incidents that occurwith cytotoxic drugs. It is recommended that suchrecords be maintained indefinitely and that a regularreview takes place to ensure any procedural changesmay be implemented as required. In the case of




cytotoxic spills, a pharmacist must be involved in anychanges to procedures.

14.5.1 Cytotoxic spillsIn the case of cytotoxic spills the institution maychoose to include a spill report card or incidentform within the spill kit to ensure these arereadily available when required. These should bereturned to the pharmacy department whencompleted for review and filing. The followinginformation may be included on such a spillreport from:

(a) Date and time of spill(b) Location of spill(c) Persons involved and titles (eg. nurse,

pharmacist)(d) Drugs involved(e) Brief description of incident(f) Was medical attendance sought(g) Details of doctor if consult occurred(h) Suggestions to avoid future spills

14.5.2 Chemotherapy extravasationIn the case of extravasation, the institution maychoose to include a report card or incident form

within the extravasation kit to ensure proper docu-

mentation of the incident. Details of the incident

should be filed in the patient’s medical history and

also forwarded, if required by hospital procedures, to

the hospital administration for insurance reasons.

These reports should be returned to a designated

person within the institution; possibly a member of

the nursing or pharmacy staff. The information from

the report should be retained indefinitely. The

following information may be included on such an

extravasation report form:

(a) Date and time of extravasation(b) Location of incident within the institution(c) Persons involved(d) Drugs involved(e) Brief description of how extravasation

occurred(f) Action taken(g) Details of follow up

In addition, the inclusion of a photograph of theaffected area can be very useful when following upan extravasation event. Some institutions may wantto use a diagram for marking the extent ofextravasation.







Section 15 � Waste handling and patient excreta


Published by:













Section 15 – Waste handling andpatient excreta

15.1 Handling of cytotoxic wasteThe institution shall have written policies describingrequirements for the segregation, packaging, collec-tion, transport, storage, and on site treatment ofcytotoxic waste within the institution.

The institution shall dispose of all cytotoxic wastein accordance with all relevant federal, regional andmunicipal regulations and legislation.

15.1.1 Cytotoxic wasteCytotoxic waste is considered to be all those materialswhich have come into contact with cytotoxic drugsduring the process of reconstitution and administra-tion. This will include syringes, needles, empty orpartially used vials, gloves, single use personal pro-tective equipment, respirator masks, and materialsfrom the clean-up of cytotoxic spills. Air filters fromventilation tools are also included. In addition,hazardous drugs which have expired, or for anyother reason must be destroyed, are also treated ascytotoxic waste. This waste must be collected inclearly marked dedicated containers made from hard,robust material, which is shock-resistant and canwithstand external pressure during transportation.These containers should be of a dedicated colour anddisplay a recognizable symbol for cytotoxics.

All cytotoxic waste must be placed in a closedsystem before removal from the ventilation tool.All sharps waste must be placed in puncture resistantcontainers. All cytotoxic waste must be placed insecondary packaging and sealed to ensure thatleakage cannot occur, and must be clearly labelledto indicate the presence of cytotoxic waste.

This waste must be segregated, packaged, anddisposed of in a way that personnel and the environ-ment are not contaminated. All relevant regulationsconcerning the disposal of cytotoxic waste must befollowed. Personnel involved in transporting cyto-toxic waste must receive instruction on proceduresfor safe transport and for dealing with spills.

15.1.2 Contaminated wasteSome countries may differentiate between cytotoxicwaste and contaminated waste. Contaminated wastemay be considered to consist of any device used from

patients who have undergone chemotherapy. Thiswill include syringes, needles, catheters, and usedserum bags. These so-called soft trace contaminateditems should be placed in separate chemotherapywaste containers (traditionally yellow chemotherapywaste containers) to protect workers from injury.

Containers are collected by the cleaning personnel,are sealed so that they are airtight and are transportedon wheel-driven carts. These carts can be cleanedand disinfected easily and at the same time offerprotection for the handling personnel. These cartsmust not be used for any other kind of waste.

Some countries may not differentiate betweenwastes based on any concentration of contamination.Here all cytotoxic waste is disposed of in the samecytotoxic waste container.

15.1.3 LabellingAll cytotoxic contaminated waste must be clearlymarked as cytotoxic and clearly identifiable to all staffwho will be involved in handling this waste. Allcontainers and wheel-driven vehicles must bemarked with the same label. A second label on thecontainers may be used with the date of wasteproduction.

15.1.4 Transport and storageCytotoxic waste would normally be collected byhospital auxiliary personnel. This waste is most likelytaken to some temporary storage areas within thehospital. Cytotoxic waste should be stored in adedicated, easily identifiable secure storage area withadequate lighting and ventilation. It should be locatedaway from drains and other sensitive areas. Wastebins should be sealed prior to collection and shouldnot be reopened or reprocessed on site. If it isessential that waste be stored for more than 72 hoursprior to disposal, consideration should be given torefrigerating the waste, particularly where waste ismostly organic and can decompose. A specializedcompany makes the transportation of waste from thetemporary storage areas, to the areas of destruction.These operators should be familiar with theemergency procedures to be followed in the eventof a spill.




15.1.5 DisposalCytotoxic waste must be incinerated in a facilityapproved by an environmental protection authorityfor the destruction of cytotoxic waste.

It should be noted that many countries have theirown guidelines and regulations concerning thedisposal of cytotoxic waste. As described in theintroduction to the Standard, these guidelines andregulations should be followed in addition to thisStandard.

15.2 Handling patient excretaBody fluids from patients receiving chemotherapymay contain traces of cytotoxic drugs and their activemetabolites.Precautions should be taken for up to 7 days

after treatment, as it is known that the majority ofcytotoxic drugs will be excreted within this time.Further information is provided in Table 1 below.

15.2.1 Contamination periodAll excreta, from patients who have received chemo-therapy, should be considered contaminated for up to7 days.

15.2.2 Risk to care-giversAll care-givers, including relatives, should beinformed about the risk of handling contaminatedexcreta.

15.2.3 Precautions during contamination periodFor up to 7 days following treatment, gloves, maskand a non–permeable gown (Personal ProtectiveEquipment) should be worn when handling excretafrom patients who have received chemotherapy.

Personal Protective Equipment (PPE) should beworn when cleaning bathrooms and toilet facilities.

Table 1. Excretion rates for selected cytotoxic agents

Cytotoxic agent Excretion rate Duration after therapy for

which PPE is

recommended when

handling excreta*

5-Fluorouracil Urine: unchanged up to 15% over 24 Hours Urine: 2 Days Faeces: 5 DaysBleomycin Urine: unchanged up to 68% over 24 Hours Urine: 3 Days

Carboplatin Urine: 60% over 24 Hours Urine: 1-2 Days

Carmustine Urine: 55-65% over 24 Hours Urine: 4 DaysChlorambucil Urine: 1-2 Days

Cisplatin Urine: unchanged plus metabolites

up to 75% over 5 Days

Urine: 7 Days

Cyclophosphamide Urine: unchanged up to 25%

over 48 Hours; unchanged

plus metabolites up to 62%

over 48 Hours

Urine: 3 Days Faeces: 5 Days

Faeces: up to 4% after IV dose

Traces in sweat and saliva (in saliva

up to 77% of plasma concentration)Cytarabine Urine: 90% within 24 Hours Urine: 1 Day

Dacarbazine Urine: 1 DayDaunorubicin Urine: 7 Days Faeces: 7 Days

Docetaxel Urine: 60% within 24 Hours Urine: 1 Day Faeces: 2 Days

Doxorubicin Urine: unchanged and metabolites

up to15% over 5 Days


Faeces: unchanged and metabolites up to 85%

Epirubicin Urine: unchanged up to 11% over 24 Hours Urine: 3 Days

Etoposide Urine: unchanged 40-50% over 24 Hours Urine: 3 Days Faeces: 5 DaysFaeces: unchanged 2-15% over 24 Hours

Fludarabine Urine: 40-60% over 24 Hours Urine: 3 Days

Gemcitabine Urine: 1 Day

Ifosfamide Urine: 2 DaysIdarubicin Urine: 3 Days Faeces: 2 Days

Melphalan 30-60% over 24 Hours Urine: 2 Days Faeces: 7 Days

Mercaptopurine Urine: unchanged 10-20% over 24 Hours;

metabolites 10-40% over 24 Hours





A face shield should be worn if splashing is likely. PPEshould be treated and disposed of as contaminated.

15.2.4 Disposable itemsDisposable items, such as bedpans and urinals,should be used in preference to re-usable products.When re-usable items are used, they should be rinsedtwice following use.

15.2.5 Dedicated toiletsIf possible, there should be toilets dedicated for theuse of patients receiving chemotherapy. In order toreduce or eliminate the risk of splashing andaerosolisation, men should be instructed to beseated when urinating.

15.2.6 Collection of body fluidsClosed systems of collecting body fluids are pre-ferred. Drainage systems for body fluids should bedisposed as intact.

15.2.7 Contaminated linensContaminated linen should be placed in a baglabelled ‘‘Hazardous Contamination’’ and forwardedto the laundry (See Section 16). Contaminated linenand clothing should be pre-laundered before washingwith other linen.

15.2.8 Patient protectionPatients suffering from incontinence should havetheir skin protected from their excreta by cleaningwith soap and water and applying a barrier cream to

Table 1. Continued

Cytotoxic agent Excretion rate Duration after therapy for

which PPE is

recommended when

handling excreta*

Methotrexate Urine: unchanged and metabolites 40-50% (low doses)

and up to 90% (high doses) over 48 Hours


Faeces: up to 9%

Mitomycin C Urine: 1 Day

Mitozantrone Urine: unchanged up to 6.5% over 5 Days; Urine: 6 Days Faeces: 7 Days

(¼Mitoxantrone) metabolites up to 3.6% over 5 DaysFaeces: up to 18% over 5 Days

Oxaliplatin Urine: 40-50% over 24 Hours Urine: 3 Days

Paclitaxel Urine: unchanged up to 13% over 24 Hours

Faeces: more than 13% over 24 HoursProcarbazine Urine: unchanged 5% over 3 Days;

metabolites 25-70% over 3 Days

Urine: 3 Days

Teniposide Urine: 3 DaysThioguanine Urine: 1 Day

Thiotepa Urine: 3 Days

Topotecan Urine: 2 Days

Vinblastine Urine: unchanged and metabolites

13-33% over 3 Days


Faeces: unchanged and metabolites

10-41% over 3 DaysVindesineVincristine Urine: unchanged 8% over 3 Days;

metabolites 4% over 3 Days


Faeces: unchanged 30% over 3 Days;

metabolites 40% over 3 Days


Vinorelbine Urine: 4 Days Faeces: 7 Days

*If not specified, at least 48 hours.

Table 1 reproduced with kind permission from Cass and Musgrave.1




the perineal area. Disposable incontinence padsshould be used.

REFERENCES

1 Cass Y, Musgrave CF. Guidelines for the safe handling of

excreta contaminated by cytotoxic agents. Am J Hosp

Pharm 1992; 49: 1957–58.

2 Dimtscheva Q, Mehrtens T, Carstens G.

Vorsichtsmabnahmen beim Umgang mit kontaminierten

Ausscheidungen nach Zytostatikatherapie. ADKA

Jahreskongress 1988.

3 Eitel A, Scherrer M, Kummerer K. Handling

cytotoxic drugs – A practical guide. Manejo de

citostaticos. Bristol-Myers Squibb.

4 Grajny AE, Christie D, Tichy AM, Talashek ML.

Chemotherapy: How safe for the caregiver? Home

Healthcare Nurse 1993; 11(5): 51–58.

5 Harris J, Dodds LJ. Handling waste from patients

receiving cytotoxic drugs. Pharmaceutical J 1985; 235:

289–91.

6 Micromedex Drug Database. Available at: http://www.

micromedex.com/products/healthcare/druginfo.

Accessed January 2007.







Section 16 � Laundry


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Section 16 – Laundry

The risk of contamination exists when people comeinto contact with patient excreta either directly orindirectly.

One example of indirect contact is with clothingand linen which has come into contact with urine,faeces, vomit, sweat, saliva, or blood from a patienttreated with cytotoxic drugs.

In order to minimize the exposure (the ALARAprinciple¼As Low As Reasonably Achievable) thefollowing measures are recommended:

(1) Gloves should be worn when handling thelinen and clothing of a patient receivingcytotoxic chemotherapy. This shouldcontinue for several days after a patient hascompleted treatment with the cytotoxicagent. In the absence of any specific detailedinformation, general recommendationsshould be followed for up to 7 days. (SeeSection 15).

(2) Consider that the middle of the linen andespecially the pillow-case the feet and pelvicarea could be highly contaminated.

(3) Contaminated linen should be labeled asHazardous Contamination.

(4) To avoid the generation of dust, do not stir upthe linen.

(5) If possible, use disposable linen.(6) In order to reduce or contain contamination,

patients who need to be washed in bedshould be washed with disposable moisttissues. When using this technique, nowater will be spilled.

(7) Linen and clothing should be considered aspotentially contaminated materials, andshould be gathered in labeled containers.

(8) Keep the contaminated laundry separatefrom other laundry.

(9) Wash the contaminated laundry separatelyfrom other laundry.

(10) Start the washing process with a cold watercycle.

(11) Restart the washing process with the normalwashing process.

These recommendations are valid for both thehospital and the home situation.







Section 17 � Warning staff of presence of cytotoxic agents


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Section 17 – Warning staff of presenceof cytotoxic agents

It is imperative that all staff are aware of the presenceof cytotoxic agents and the potential, in any situation,for contamination. This applies when cytotoxic drugsare being stored, reconstituted, transported, adminis-tered, and when cytotoxic waste is being handled. Inaddition staff must be warned to avoid an area wherea cytotoxic spill has taken place.

17.1 StorageDedicated storage areas are required for cytotoxicdrugs. These areas must be clearly defined andlabelled as containing cytotoxic agents exclusively(See Section 2). Easily recognisable warning labelsshould be attached to shelving to alert staff to the factthat the contents are cytotoxic. Cytotoxic spill kitsshould be available near the storage area.

17.2 ReconstitutionThe area where cytotoxic drugs are reconstitutedshould be restricted to authorised personnel only andshould be clearly labelled to alert staff to thepresence of cytotoxic agents. (See Section 6). Thiswarning must be clear to all cleaning staff enteringthe area.

17.3 TransportClear and easily recognisable warning signs must bedisplayed whenever cytotoxic agents are transportedboth within the institution and externally (SeeSection 2). Staff must also be notified of who tocontact in case of emergency.

17.4 AdministrationIt is very important that staff members are aware thata particular patient is receiving cytotoxic chemother-apy. The drug itself will be clearly labelled with aprominent warning, but an additional recommenda-tion is that nursing staff attach stickers to the IV lineindicating that the infusion running is cytotoxic innature. This is particularly important if the cytotoxicagent must be protected from light and any labels

attached by the pharmacy may be hidden. Wheneverpatients are transported around the hospital, (forexample; to radiology or to another ward), it isimportant that all staff are aware that a cytotoxicinfusion is running.

Patients who have received cytotoxic chemother-apy in the previous 7 days must also be identifiable tohospital staff. This may be achieved by attaching awarning sign or sticker to the patient’s bed. In thisway, staff will be aware that the patient’s excreta mayhave to be handled as potentially contaminated (SeeSection 15).

17.5 Cytotoxic wasteDuring collection, transport and storage, cytotoxicwaste must be clearly identifiable (See Section 15).This includes any trolleys dedicated to this purposeand also dedicated temporary storage areas withinthe institution.

17.6 SpillsStaff must be warned whenever a cytotoxic spilloccurs in an area. This will usually be achieved by theuse of a specific warning sign contained within thespill kit (See Section 14).

17.7 Home carePatients receiving chemotherapy at home, either by ahome care nursing service or by self/relative admin-istration must be made aware of the importance ofwarning other people in the household and visitorsabout the use of cytotoxic agents in the home. Inparticular, special care should be taken with the useof toilets (See Section 15).

17.8 Pathology and other laboratoriesIf it is not routine practice for an institution’slaboratory to handle all samples/specimens as poten-tially dangerous, then, in order to alert laboratorypersonnel, blood samples/specimens taken from apatient having received chemotherapy in the preced-ing 7 days should be labelled as cytotoxic.







Section 18 � Home care


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Section 18 – Home care

Patients may receive cytotoxic drug therapy at homeor in a residential care facility for the elderly.Nursing,medical staff, and others often care forpatients in these situations.

Households that are unable to provide theappropriate facilities and level of care asdescribed in this Section should not attempt toprovide home care to patients receiving cytotoxicdrug therapy. Instead, these patients shouldreceive treatment in a hospital or other healthcarecentre.

Any unused medications in the patient’s homeshould be returned to the pharmacy for appropriatedisposal.

18.1 Home care by nursing staffCytotoxic drugs should be administered only bylicensed nurses with documented knowledge andexperience with cytotoxic agents.

It is the responsibility of the institution provid-ing the home care service to ensure that allcytotoxic drugs taken into the patient’s home areappropriately packaged and labelled, and that thefacilities and equipment meet recommended stan-dards. All chemotherapy used in the home caresituation must be prepared under the sameconditions as all other chemotherapy; specificallyin the hospital pharmacy department or in acommunity pharmacy complying with the samerequirements.

Nursing staff must not reconstitute cytotoxic drugsin the patient’s home.

All nurses administering chemotherapy in thepatient’s home must be adequately trained and havesignificant experience in the administration ofcytotoxic agents.

Before proceeding with chemotherapy in thehome, the nurse must verify that the followingfacilities are available:

(a) Hand washing facilities(b) Laundry facilities(c) Access to sewered toilet(d) Secured waste storage

The nursing staff must also verify that the followingequipment is available:

(a) Spill kit (as described in Section 14)(b) Strong alkaline detergent with a pH4 10(c) Approved container for sharps(d) Cytotoxic waste container(e) Personal protective equipment

The transport of cytotoxic drugs from thepharmacy to the patient’s home must bein accordance with procedures described inSection 2. Nursing staff should have a spill kitavailable and details of whom to contact in caseof emergency.

18.2 Home care by relatives and/or patientIf the home care is to be provided by either relativesor by the patient, it is very important that this care isorganized and coordinated in advance. In this way,with close cooperation between hospital staff, allaspects of the treatment may be explained and fulleducation and training provided. Carers of patientsreceiving cytotoxic drug therapy should be providedwith written information about cytotoxic drugs andthe precautions to be taken while caring for patientsduring the time the drug may be excreted. Carersshould be advised about special requirements of theparticular drug used.

Written instructions should address:

(a) General information about the treatment thepatient is to receive.

(b) Detailed information about the drugs whichwill be administered. For patients receivingoral chemotherapy, this should include infor-mation about potential interactions withover-the-counter medications.

(c) Detailed information on the storage andstability of the prepared drugs.

(d) Information and training on the routes ofadministration which will be utilised.

(e) If applicable, training on the care ofinfusion lines, catheters care, port systemsand any other venous access devices likelyto be used.




(f) Instructions and training on the use ofvarious types of apparatus which may beused; for example, contained transfer devices,elastomeric infusion devices or ambulatoryelectronic pumps.

(g) Instructions and training in the use of anypersonal protective equipment (PPE)

(h) Details of safety precautions required in thehandling of cytotoxic drugs, waste handling,excreta, and laundry.

(i) Strict instructions on how to proceed in theevent of an emergency or other incident. Forexample, extravasation of any vesicant, anyhypersensitivity reaction of the patient to thedrug being administered, alarm of any elec-tronic device being used, or the spill of acytotoxic drug.

(j) Disposal of drugs that are no longer required.(k) Provision of contact details for all staff likely

to be of assistance. This will include homecare nurses and hospital staff including med-ical and pharmacy personnel.

(l) Precautions to be taken where a care giver ispregnant or breast feeding.

In some countries there may be legal implications ofhaving home care provided by a relative or by thepatients. It may be that the administration ofparenteral drugs is restricted to physiciansand nurses. In the event of any accident or otherincident it may be that the person administering thedrug could be prosecuted for the illegal exercise of amedical act. This area may be quite controversial inthe paediatric setting.







Section 19 � Risk management


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Section 19 – Risk management

19.1 Introduction

19.1.1 Hazard identificationIn the past, safe handling guidelines have only dealtwith cytotoxic or antineoplastic drugs with respectto health care worker exposure issues.1,2 Morerecently, organizations and agencies have expandedthe concept to include all hazardous drugs.3–5 TheNational Institute for Occupational Safety and Health(NIOSH) in the United States identifies approximately140 agents that fit its definition of hazardous drugs.The classification was based on a six-point definitionmodified from the ASHP definition of what constitu-tes a hazardous drug.2 Two-thirds or approximately90 of the hazardous drugs identified are classified asantineoplastic drugs.

Therefore, the first step in hazard identification fora health care institution would be to compile a list ofall drugs used in the facility and to identify thosedrugs that are listed as hazardous drugs. A list ofhazardous drugs should be made available to anyonewho has the potential to come in contact with thesedrugs, including pharmacists and pharmacy techni-cians, nursing personnel, physicians, operating roompersonnel, shipping and receiving personnel, wastehandlers, maintenance workers, workers in veteri-nary practices, and health and safety personnel.

19.1.2 Exposure assessmentOnce the hazardous drugs for a facility have beenidentified, an exposure assessment should be com-pleted by identifying the path that the hazardousdrugs follow from when they enter the facility towhen they leave as patient waste, contaminatedlaundry, IV bags, contaminated medical equipmentetc. This includes materials receiving, transportationwithin the facility, storage (including refrigerators andfreezers), drug preparation and administration, oper-ating rooms, and laundry and waste handling. Allpotential sources of exposure should be identified. Itis also important to identify all individuals who havethe potential to come into contact with the hazard-ous drugs.

Environmental contamination within these areascan be determined by surface wipe samples or airsampling (see Section 10). Based on published

reports, any area where hazardous drugs are usedwill most likely be contaminated with those drugs.Because only 6-8 drugs are commonly used as‘‘markers’’ of exposure, this approach can onlyestimate the overall exposure from the dozens ofdrugs that may be in use.6

19.1.3 Exposure control (see also Section 5)The basic components in a hierarchy of industrialhygiene controls have been identified and applied tomany industrial settings. These include:

(a) Elimination of the hazard or substitution witha less hazardous chemical (this is not feasiblein health care) or substitution of a workpractice with a less hazardous one (the use ofneedle-less systems)

(b) Isolation of the hazard (storage of hazardousdrugs separate from other drugs, limitingpreparation of hazardous drugs to dedicatedareas)

(c) Engineering controls (the use of biologicalsafety cabinets, isolators or closed systems)

(d) Administrative Controls (training and educa-tion programs, availability of Material SafetyData Sheets)

(e) Personal Protective Equipment (the use ofprotective gloves, gowns, respiratory protec-tion and eye protection)

19.1.4 Work organizationPersonnel schedules and duties and work processescan be modified to help reduce the potential forexposure to hazardous drugs. These include:

(a) Rotation of staff to reduce fatigue(b) Alternative duty for pregnant or nursing

women(c) Proper identification of hazardous drugs(d) Safe and orderly flow of hazardous drugs

through the facility

19.1.5 Medical surveillanceMedical surveillance involves collecting and inter-preting data to detect changes in the health status ofworking populations potentially exposed to hazard-ous substances.




The elements of a medical surveillance program areused to establish a baseline of workers’ health andthen monitor their future health as it relates to theirpotential exposure to hazardous drugs. The elementsof a medical surveillance program for hazardousdrugs should include (at a minimum):

(a) Reproductive and general health question-naires completed at the time of hire andannually thereafter.

(b) Blood work, including complete blood count,liver function tests, and urinalysis completedat the time of hire and annually thereafter

(c) Physical examination completed at the timeof hire and then annually for any workerwhose health questionnaire or blood workindicates an abnormal finding.

(d) Follow up for those workers who haveshown health changes and/or have beenexposed to hazardous drugs (e.g., throughspills or during routine handling).

19.1.6 Early therapeutic interventionThis can involve medical treatment or interventionfollowing:

(a) Contact of a drug with skin or eyes(b) Development of a rash from exposure to a

drug(c) Abnormal laboratory findings

REFERENCES

1 OSHA. Guidelines for cytotoxic (antineoplastic) drugs.

Washington, DC: Department of Labor, Occupational

Safety and Health Administration, Office of Occupational

Medicine Publication No. 8–1.1. 1986.

2 ASHP (American Society of Hospital Pharmacists). ASHP

technical assistance bulletin on handling cytotoxic

and hazardous drugs. Am J Hosp Pharm 1990;47:

1033–49.

3 OSHA. OSHA Instruction TED (training and education

directive), 1.15 directorate of technical support:

controlling occupational exposure to hazardous drugs.

Washington, DC: Occupational Safety and Health

Administration. 1995.








5 ASHP (American Society of Health System Pharmacists).

Guidelines on handling hazardous drugs. Am J Health

Syst Pharm 2006; 63: 1172–93.

6 Turci R, Sottani C, Spagnoli G, Minoia C. Biological and

environmental monitoring of hospital personnel

exposed to antineoplastic agent: a review of analytical

methods. J Chromatogr B Biomed Sci Appl 2003; 789:

169–209.







Section 20 � Medicines management


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Section 20 – Medicines management

20.1 Procedures for drug selection

20.1.1 Medication selectionMedication selection should be a multidisciplinaryprocess, overseen by the respective institution’sPharmacy and Therapeutics Committee (P&TCommittee) or other appropriate group. The processshould involve medical staff (oncologist/haematolo-gist), pharmacists, nursing and administrative staff.

20.1.2 Documentation – P&T committeeWritten policies and procedures should be developedand implemented to define the functioning of theP&T committee or other appropriate group.

20.1.3 Documentation – medication selectionWritten policies and procedures about the process ofmedication selection in an institution should bedeveloped, approved and implemented, that include:

(a) How to request additions, changes or dele-tions to/from the formulary

(b) Evaluation process(c) Dissemination of information about P&T

Committee decisions(d) Mechanism for updating the formulary or list

(at least annually based on emerginginformation).

20.1.4 Criteria for medication selectionMedication selection should be based on safety, cost-effectiveness, and/or any pharmacotherapy innova-tion (for example, easier route of administration,reduced dosing frequency). Comparison should bemade with alternatives already available at theinstitution.

20.1.5 Criteria for request(s)Qualitative and/or quantitative criteria should bedeveloped and implemented to evaluate the request,including:

(a) Clinical aspects (efficacy, safety)(b) Availability of scientific evidence/

documentation(c) Pharmacotherapeutic criteria (dosages,

administration route, premedication regi-mens, interactions)

(d) Pharmaceutical criteria (drug strength, stabil-ity and compatibility, convenience of drugpresentation to usual doses, ease of manipu-lation, risk of breaking, potential for medica-tion errors (sound alike, look-alike, labelling,packaging, etc.).

(e) Cost(f) Specific criteria

20.1.6 Procuring non-formulary medicationA procedure for procuring non-formulary medicationshould be established.

20.1.7 Medication selection decisionsMedication selection decisions (additions/deletions/changes) and recommendations must be dissemi-nated to health care professionals involved in patientcare.

20.1.8 UpdatesAn updated hospital formulary or pharmacothera-peutic guide (printed or online) should be distributedto all the health-care staff (physicians, pharmacistsand nurses). These documents summarise drugsavailable from the multidisciplinary process of med-ication selection, policies and guidelines of drug useat the institution and the minimum informationneeded to enhance drug rational use.

20.2 Procedures for drug purchasingAll drugs should enter the hospital through thehospital pharmacy, even those intended for clinicaltrial or compassionate use program and samples.

20.2.1 Purchasing decisionsPurchasing decisions are based on the medicationselection process.

20.2.2 Criteria to evaluate purchasing processCriteria are developed and implemented to evaluatethe purchasing process, including: usage, genericpolicies, economic offers (industry promotions, flex-ible pricing and public tenders), pharmaceuticalcriteria (unit-dose packaging, strength of doses avail-able, bar-coding), laboratory facilities (logistics, labo-ratory information), and labelling and patient safetyconsiderations.




20.2.3 High cost/use medications reviewHigh cost or/and high use medications should bereviewed regularly to ensure appropriate use ofresources and compliance with formulary guidelines.Contracts for drug purchase, if entered into by theinstitution or group purchasing organisation of whichthe institution is a member, must be honoured.

20.2.4 Purchase approvalsPurchase of medication from wholesalers or manu-facturers should be approved by a pharmacist ordesignate (such as a pharmacy technician) and mustfollow all applicable local regulatory laws andregulations. Products with very similar packagingshould be avoided wherever possible

20.2.5 Purchase historyThere should be a computerised system that providesinformation on purchase history and use for allmedications managed by the pharmacy department.

20.2.6 Purchasing updatesPeriodic updates on purchasing and use of medica-tion should be made available to the hospital admin-istration, directors of clinical units and the P&TCommittee (to be used in their review process).

20.3 Procedures for stock control

20.3.1 Medication securityMedication must be secured in all storage areas inaccordance with all local laws, regulations, andorganisational policies.

20.3.2 DiscrepanciesDrugs received are checked against the manufac-turer’s/wholesaler’s delivery note/invoice and thepharmacy order form. Discrepancies should bereconciled by the responsible pharmacist ordesignate.

20.3.3 Update drug inventoryAn updated (computerised or manual) drug inven-tory should be available that includes informationabout drug batch and expiry dates.

20.3.4 Drug inventory documentationWritten policies and procedures should be developedand implemented to regularly review drug inventoryinformation with actual drug stock. Discrepanciesshould be analysed and corrective action(s) taken.

20.3.5 Discrepancies documentationWritten policies and procedures should be developedand implemented for handling drug shortages,outages and recalls including proper processes forcommunicating this information with other healthcare professionals.

20.3.6 Expiry datesThere should be a strict procedure for the checkingof expiry dates (manual/automated) throughout theinstitution and for the removal of expired stock.

20.3.7 DisposalPolicies and procedures should be established for thedisposal of expired or damaged stock and mustcomply with all applicable local regulatory laws andregulations.

20.3.8 Documentation – medication storageWritten policies and procedures about medicationstorage system/organisation (alphabetical order, phar-maceutical forms) and labelling (generic, brandnames, expiry, appropriate warnings) should bedeveloped and maintained.

20.3.9 Error preventionTo prevent errors from occurring, medication thatcan be easily mistaken for another (sounds alike,looks alike, similar labelling) must be separated in allareas of the health care organisation. This mustinclude the modification of the medication storagesystem/organisation.

20.3.10 Storage guidelinesDrugs are stored in accordance with the manufac-turer’s recommendations and storage conditions aremonitored periodically following organisationalpolicy to ensure their effectiveness and safety (tem-perature, moisture, light protection).

20.3.11 Documentation – high manipulationrisk drugsPolicies and procedures about drugs with highmanipulation risk (cytotoxic or hazardous drugs)are developed and implemented that include: identi-fication of special handling requirements, separatestorage areas with measures to prevent/minimisebreakage and personnel protection equipmentshould be available. Ideally this storage area shouldhave an extraction fan which can be activated in anemergency. Cytotoxic spill kits should be availablewhere appropriate




20.4 Procedure for re-use of drugs

20.4.1 Responsible partiesThe pharmacy department is responsible for themanagement of all unused medications returned thatwere compounded and/or dispensed for oncologypatients.

20.4.2 Documentation – medication return(s)Written policies and procedures about the process/method of medication return to the pharmacy shouldbe developed and implemented.

20.4.3 Quality controlA quality control policy on returned medicationsshould be developed and implemented to addresspatient safety, including technical (integrity/packag-ing, labelling, defective devices, expiry dates) andphysicochemical aspects (colour/precipitation).

20.4.4 Documentation – disposalWritten policies and procedures for the safe reuse ordisposal of returned medication based on efficacyand safety criteria should be developed and imple-mented. This is mandatory for pharmacy-preparedsterile products. These criteria should considerstability and compatibility under actual handlingconditions including storage or transportation whenoutside the pharmacy (temperature, humidity andlight exposure) and microbial risk level according topotential for microbial growth. Only drugs whichhave remained within formal system controls may bereused. Drugs that have released to a patient, or intothe community, should not be reused for otherpatients.

20.4.5 Causes for medication returnCauses/reasons of medication return are documentedand recorded (manual/computerised) and the phar-macotherapy history is updated if needed.

20.4.6 References for accepted expirationdatesThere is an updated table or chart of acceptedexpiration dates for commonly pharmacy-preparedsterile products according to stability and compati-bility at the usual/standardised concentration range,vehicle and environmental conditions.

20.4.7 Documentation – medication re-useWritten policies and procedures for safelyre-dispensing or recycling returned medicationshould be developed and implemented that include

but are not limited to: process of new expiry dateassignment, identification and labelling as recycled,re-dispensing process, dose banding, and optimumstorage conditions to its immediate re-use.Health-care professionals involved in all thesemedication re-use processes are recorded.

20.4.8 DisposalPolicies and procedures for the disposal of expired orother unusable returned medication must follow allapplicable local regulatory laws and regulations.

20.4.9 BibliographiesBibliographic sources (product approved labellingand reliable published stability data) used to establishcriteria are referenced and available and basic infor-mation (tables/charts) is periodically updated.

20.5 Procedure for partial vials

20.5.1 Final concentrationsIrrespective of different dosage strengths of a drugwhich may be available, the final concentrationshould be the same to avoid medication preparationerrors and facilitate stability concentration limits.

20.5.2 Maximal accepted expiration datesThere should be a table or chart available within thepreparation area listing the maximal accepted expi-ration dates for drugs reconstituted in the sterile areausing validated aseptic technique. This data shouldbe based on the stability and compatibility at the finalconcentration, type and volume of reconstituent,microbial risk level, and optimal storage conditions(light protected, refrigerated).

20.5.3 Drugs in solutionDrugs provided in solution (not requiring reconstitu-tion) which are manipulated using validated aseptictechnique, should have a maximal expiry based onwhen they are first used. The institution should basethis expiry on the microbial risk level and optimalstorage conditions.

20.5.4 LabellingResidual volume in multidose vials generated duringantineoplastic compounding should be labelled withthe reconstitution/first used date and time and theexpiry according to recommended storageconditions.




20.5.5 StorageResidual volumes in vials should be stored approp-riately (strictly adhering to temperature, light,etc. criteria) and should be used before a new vialis opened.

20.5.6 DisposalPolicies and procedures for the disposal of expired orother unusable vials must follow all local applicableregulatory laws and regulations.

20.5.7 BibliographiesBibliographic sources (product approved labellingand reliable published stability data) used to establishcriteria are referenced and available and basic infor-mation (tables/charts) should be regularly updated.

20.6 Procedures for use of unlicensed drugs

20.6.1 Documentation – unlicensed drugsThere should be written policies and procedures inplace regarding the rational and safe use of unli-censed drugs in accordance with regulatory laws,patients’ rights and ethics. Unlicensed drugs include:drugs not approved or licensed in a country butavailable in a foreign country used for a labelledindication (foreign drugs), off-label use of licenseddrugs, and investigational drugs in the setting ofclinical trials.

20.6.2 Foreign drug proceduresA procedure for purchasing, storage and stockcontrol of foreign and compassionate use drugsshould be developed and implemented.

20.6.3 Documentation – off label use drugsWritten policies and procedures should be developedand implemented for the effective and safe use ofapproved drugs for off-label use. This should includeselection, prescription, preparation, dispensing,administration, and monitoring.

20.6.4 Documentation – foreign drugsWritten policies and procedures for the effective andsafe use of foreign drugs should include selection,prescription, preparation, dispensing, administration,and monitoring.

20.6.5 Procedures – investigational drugsA procedure for approving, receiving, storage andstock control of investigational drugs is developedand implemented.

20.6.6 Documentation – investigational drugsWritten policies and procedures for the effective andsafe use of investigational drugs should be developedand implemented including prescription, prepara-tion, dispensing, administration and monitoringaccording to local regulatory laws and institutionalpolicies.

REFERENCES

1 ASHP (American Society of Hospital Pharmacists). ASHP

guidelines on preventing medication errors with anti-

neoplastic agents. Am J Health Syst Pharm 2002; 59:

1648–68.

2 Buchanan C, McKinnon BT, Scheckelhoff D, Scheider PJ.

eds. Principles of Sterile Product Preparation. Revised 1st

edition. American society of health-system pharmacists,

2002.

3 Criterios de Calidad para la acreditacion de los Servicio

de Farmacia Hospitalaria. 1a edicion. Valencia: generalitat

Valenciana. Conselleria de Sanitat, 2005.

4 Joint Commission International Accreditation of

Healthcare Organizations. 1a edicion. Barcelona:

fundacion Avedis Donabedian, 2001.


sterile preparations (general test chapter 797). In The

United States Pharmacopeia 28 rev., and The National

Formulary, 23rd edn.z Rockville, MD: United States

Pharmacopoeial Convention; 2004: 2461–77.

6 Richs DS.. New JCAHO medication management stan-

dards for 2004. Am J Health Syst Pharm 2004; 61:

1349–58.







Section 21 � Documentation


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Section 21 – Documentation

21.1 Staff

21.1.1 Health monitoringIf an institution offers employees routine bloodtesting, or any other test relating to the exposure tocytotoxic drugs, then this should be documented. Ifsuch routine health monitoring occurs it is recom-mended that a baseline measurement be taken priorto work in the area begins. Any abnormal test resultand the resulting action taken should also bedocumented.

21.1.2 Exposure to cytotoxicsA log for all operators preparing cytotoxic drugsshould be maintained indefinitely. At a minimum, thislog should reflect the daily reconstituting activities ofall operators. If more than one cabinet/isolator isavailable, the actual cabinet/isolator used should benoted. In the event of any incident or accident,additional details should be recorded including thename of the operator, the name of each druginvolved, the number of products of each druginvolved, the estimated drug exposure (for example,mg) the duration of exposure, and the location. Thisinformation should be available for both past andpresent employees.

21.1.3 Education and trainingA record of all staff undergoing training in cytotoxicreconstitution should be maintained indefinitely.Similarly, a log should be kept of staff trained in theclean up of a cytotoxic spill. This will include anystaff working in a pharmacy store where cytotoxicsare kept, and any individual involved in the transportof cytotoxics around the hospital or outside theinstitution. A signature of the staff involved and thedate that the training was completed should berecorded.

21.1.4 ValidationDetails of validation of operators permitted to recon-stitute cytotoxic drugs should be maintained on anongoing basis.

21.2 Facilities

21.2.1 Microbiological monitoringThe results of any microbiological testing performedin the cytotoxic suite should be maintained for a

period of 3 years or other specified time dictated bylocal or institutional requirements. This may includesettle plates, finger dabs, broth inoculations, and anyend product testing that is performed.

21.2.2 Contamination monitoringThe results of any monitoring for chemical contam-ination that is performed should be maintained for aperiod of 10 years or other specified time dictated bylocal or institutional requirements.

21.2.3 Maintenance logAn equipment maintenance log should be main-tained. This will include the dates and results of allroutine maintenance and certification relating to thecytotoxic facilities and isolators/cabinets. If equip-ment fails any test, the follow-up action taken shouldbe detailed in this log. Details of any repairs, filterreplacements, and any technical problems withequipment should be recorded on an ongoing basis.

21.2.4 Pressure differentialsOn a daily basis, the pressure differentials within thecytotoxic suite should be checked and recorded ina log. This will include pressure differentials betweenany cleanrooms, airlock, and the external environ-ment. Any pressure readings on an isolator cabinetshould be checked daily and documented.

21.2.5 Temperature logsBoth a refrigeration temperature and a room temper-ature log should be maintained on a daily basis andkept for at least 3 years. Follow-up action taken as aresult of temperature excursion should bedocumented.

21.2.6 Particle countsThe results of any particle counts performed shouldbe documented.

21.2.7 Qualification and re-qualificationThe results of qualification and re-qualificationshould be maintained indefinitely.




21.3 Transport

21.3.1 Outside the institutionA record should be kept of any cytotoxic prepara-tions being transported out of the institution bycourier to either a second institution or to a patient’shome. The details should include the destination,contact details at destination, identity of personcollecting the item, contents of package, storageconditions for package, date and time of collection,and identity of person packing the items.

21.3.2 Within the institutionA record may be kept of any cytotoxic preparationsbeing transported. The details could include thedestination, contents of package, date and time ofdelivery, and identity of person transporting theitems.

21.4 Cytotoxic spillsA log of all cytotoxic spills occurring within theinstitution should be maintained for a period of 10years or other specified time dictated by local orinstitutional requirements. The information collec-tion should be that recorded on the spill report cardor incident form detailed in Section 20.4.1. Detailsshould also be recorded in the personal exposurerecord of employees involved in the spill and/orclean up.

21.5 ExtravasationA log of episodes of extravasation occurring withinthe institution should be maintained for a period of10 years or other specified time dictated by local orinstitutional requirements (see Section 20.3). Detailsof follow up action taken should be recorded. Thismay be either a pharmacy or nursing responsibility.

21.6 Cleaning

21.6.1 Cabinet/isolatorA written procedure must be maintained for thecleaning of the biohazard cabinet or isolator. Aninstitution may wish to have this routine cleaningdocumented on a daily basis. If any unusual event

occurs requiring the shut down of the appliance or ifa major spill occurs, this cleaning should bedocumented.

21.6.2 Sterile roomIf sterile areas are cleaned by a member of theinstitution’s cleaning staff, the date of the cleaningand the initials/signature of the cleaner should berecorded.

21.7 Workload statisticsEach institution should keep statistics which outlinethe workload of the cytotoxic preparation suite.These statistics should reflect not only the quantity ofitems prepared but include some measure of thecomplexity of the various items prepared.These figures should be reviewed on a regular basisin relation to the staffing level and mix of staffworking in the area.

21.8 Procedure manualEach institution should develop and maintain aprocedure manual which details the policies andprocedures for the appropriate manufacture ofcytotoxic agents. This should include a descriptionof aseptic technique, standard operating proceduresfor cytotoxic reconstitution, cleaning procedures,information on dealing with spills, transportingcytotoxics, and information on health monitoring. Itshould contain a full description of all personalprotective equipment and special containmentdevices to be used in the preparation of cytotoxics.This manual should be regularly updated and shouldbe available to staff at all times.

21.9 Material safety data sheets (MSDS)Each institution should retain a compilation of theseMaterial Safety Data Sheets, should ensure that theyare current and reflect the actual products usedwithin the institution, and should update the listwhenever purchased products change. These MSDSshould be readily available in all areas where hazard-ous drugs are stored or used.




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