current and future guidance and standard · pdf fileneeds & necessities drivers &...

7th June 2016

Current and Future Guidance and

Standard Changes

Edward Tidswell

The views are solely the presenter's and do not reflect in any way the views or positions of any of the presenter’s affiliations.

Disclaimer

2

Current and Future Guidance and Standard Changes

Our world, who and how we provide live saving drugs and devices is rapidly altering

Economic forces, an explosion of new products, new technologies, new marketopportunities, under-served demographics and new diseases are encouraging commensurate change in guidance, standards and legislation

Review current, future and anticipated changes in guidance, regulations and standards representative of global markets relevant to sterility assurance in the manufacture of drugs and devices

Highlight key areas of change that will educate on new opportunities in expedient, efficient, economic and compliant sterile and non-sterile manufacturing

(will not cover recent changes to USP <797>, USP <1223>, ISO 14644 as these are covered within other presentations)

Introduction

3

Drivers and Headwinds

Standards, Guidance, RegulationsComplexity and diversityDefinitions

FDA GuidanceCombinatorial productsData Integrity

USPRecent changesAnticipated changes

EP/EMEA and PIC/SMutual inspectionsWFI

General Themes

4

Introduction

Local & Global Challenges

5

• SUPPLY• PROCESS & PORTFOLIO

DIVERSITY• REGULATIONS

Global

Regional

Complexity & diversity

Supply chain

Base costs

Linking lab to market

Personalized care

Therapies

Technologies

Drivers & Headwinds

6

• SUPPLY • REGULATIONS• PROCESS & PORTFOLIO

DIVERSITY

Effective QS integration

Flexible

Commensurate compliance

Flexible production

Increased agility

Minimal downtown

Self-detection, self-correction

Improved knowledge

Flexible processes

Systems

Needs & Necessities

Drivers & Headwinds

7

EU Annex 1 & PIC/sAnnex 1 Manufacture of Sterile Medical Products

ISO 14644 Cleanrooms and AssociatedControlled Environments

FDA 21 CFR 211 FDA Guidance for Industry Guide to Sterile Drug ProductsProduced by Aseptic Processing

Adjacent rooms of different grades should have a pressure differential of 10 – 15 Pa (guidance values)(Item 53)

The pressure…should lie typically in the range of 5 Pa to 20 Pa (Section A.5.3)

Aseptic processing, which includes as appropriate: (iii) An air supply filteredthrough high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or non laminar

For example, a positive pressure differential of at least 10-15 Pa should be maintained between adjacent rooms of differing classification (with doors closed)

Identical intent - Adjacent rooms of different grades should have a positive pressure differential

10-15 Pa 5–20 Pa None 10–15 Pa

Standards, Guidance, Regulations

Complexity & Diversity

8

Annex 1 Guidance

Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules andvials, making aseptic connections. Normally such conditions are provided by a laminar air flow workstation. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s(guidance value) at the working position in open clean room applications. The maintenance oflaminarity should be demonstrated and validated

Intent

Assure that air flow (first air) over and around high risk aseptic operations protects the product by preventing ingress and sweeping away contamination by proven (validated) mechanics and mechanism of HEPA filtered air


Complexity & Diversity

Regulations & LegislationRegulations are the general and permanent rules generated by governmental departments and agencies, statutory law/legislation.

e.g. Code of Federal Regulations,

9


StandardsA standard is a document that provides requirements, specifications, guidelines or characteristics that can be used consistently to ensure that materials, products, processes and services are fit for their purpose. Generated by experts within technical committees.

e.g. ISO, pharmacopeia

10


GuidanceInterpretation, information or expectation indicating how legislation is interpreted

‘FDA's guidance documents….., do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.

The use of the word should in FDA guidance means that something is suggested or recommended, but not required.’

e.g. FDA guidance Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, 2004

11


TechnicalContent

Diverse Technical Expert Contributors

Consensus Based

Global Scheduled Review

Potentially Impactful Changes

Legally Enforceable

Regulation No No No No Yes No Yes

Standards Yes Yes Yes Yes Yes Yes Yes

Guidance Yes No No No No Yes No

Italicized – general comment Scope• Microbiologically-related• Sterile and non-sterile manufacturing implications• Recent and anticipated

12


13

FDA Guidance

Regulatory Framework Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) requires that, with few exceptions, all drugs be manufactured in compliance with current good manufacturing practices (CGMPs). Drugs that are not in compliance with CGMPs are considered to be adulterated. Furthermore, finished pharmaceuticals are required to comply with the CGMP regulations at 21 CFR parts 210 and 211.

FDA“FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.”

Commissioner’s Office plus 6 Centers and the Field Operations– Center for Food Safety and Applied Nutrition (CFSAN)– Center for Veterinary Medicine (CVM)– Center for Devices and Radiological Health (CDRH)– Center for Biologics Evaluation and Research (CBER)– Center for Drug Evaluation and Research (CDER)– Center for Tobacco Products (CTP)– Office of Regulatory Affairs (ORA)

FDA Guidance Documents

• 1493 Guidance documents (final) spanning over 43 years

• 4 new ‘microbiology’ guidance documents 2015/14 all nucleic acid-based assays for disease organisms

• http://www.fda.gov/RegulatoryInformation/Guidances/default.htm

14

FDA Guidance

Regulatory Framework Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) requires that, with few exceptions, all drugs be manufactured in compliance with current good manufacturing practices (CGMPs). Drugs that are not in compliance with CGMPs are considered to be adulterated. Furthermore, finished pharmaceuticals are required to comply with the CGMP regulations at 21 CFR parts 210 and 211.

Current Good Manufacturing Practice Requirements for Combination ProductsDRAFT GUIDANCEJanuary 2015

Design controls (21 CFR 820.30) In addition, 21 CFR 820.30(g) requires that the manufacturer complete risk analysis, ……should begin early in the design process and continue throughout the lifecycle ...

Risk analysis influences other aspects of design control and additional activities including purchasing controls.

Risk analysis should be completed on the combination product as a whole ….design, manufacturing processes, and intended uses. Some risks may be identifiable during initial design development and addressed in design inputs, while others may become apparent based on postmarket experience (including adverse event reporting) and used to determine whether any aspect of the design should be adjusted or revised. Any unacceptable risk(s) should be reduced or mitigated.

15

FDA Guidance

Data Integrity and Compliance With CGMP Guidance for Industry DRAFT GUIDANCEApril 2016

Regulatory Framework The underlying premise in 210.1 and 212.2 is that CGMP sets forth minimum requirements to assure that drugs meet the standards of the Federal Food, Drug, and Cosmetic Act (FD&C Act) regarding safety, identity, strength, quality, and purity.

Requirements with respect to data integrity in parts 211 and 212 include, among other things:

• 211.68 (requiring that “backup data are exact and complete,” and “secure from alteration, inadvertent erasures, or loss”)

• 212.110(b) (requiring that data be “stored to prevent deterioration or loss”)• 211.100 and 211.160 (requiring that certain activities be “documented at the time of performance”

and that laboratory controls be “scientifically sound”)• 211.180 (requiring that records be retained as “original records,” “true copies,” or other “accurate

reproductions of the original records”)• 211.188, 211.194, and 212.60(g) (requiring “complete information,” “complete data derived from all

tests,” “complete record of all data,” and “complete records of all tests performed”)

16

FDA Guidance

Data Integrity and Compliance With CGMP Guidance for Industry DRAFT GUIDANCEApril 2016

Extensive questions and answers – consistent with MHRA guidance, definitions

Covers wide range of issues specifically - Access to systems, controlled logins (not shared), audit trails, control of blank forms

Significant focus on electronic systems

‘Control strategies must ensure that original laboratory records, including paper and electronic records, are subject to second-person review (211.194(a)(8)) to make certain that all test results are appropriately reported.’

‘How does FDA recommend data integrity problems identified during inspections, in warning letters, or in other regulatory actions be addressed?FDA encourages you to demonstrate that you have effectively remedied your problems by: hiring a third party auditor, determining the scope of the problem, implementing a corrective action plan (globally), and removing at all levels individuals responsible for problems from CGMP positions.’ 17

FDA Guidance

18

USP

A Private Pharmaceutical Standards-Setting Organization, established in 1820

“The value of the pharmacopeia depends upon the fidelity with which it conforms to the best state of medical knowledge of the day”

“To improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.”

19

USP

International RecognitionInternational regulatory authorities and governments have incorporated USP standards into their laws and regulatory provisions

Countries have taken different approaches to recognizing theUSP’s standards

Lyman Spalding

USP Convention

General NoticesRequirements applicable throughout USP−NF unless superseded by a chapter or monograph

General Chapters (Test and Informational)Required when monograph cites them; centralizing methods and procedures. Informational (numbered >1000). Supersede General Notice requirements in case of conflict

MonographsSpecifications for pharmaceutical articles – Tests, assays and acceptance criteria needed to demonstrate the article meets required quality standards. Supersede General Notice and General Chapter requirements in case of conflict

Physical Reference MaterialsProvide traceable standards to demonstrate broad-based acceptability of procedures

20

USP

USP Compendia

Compendium UpdatesAll new and revised standards are published for comment inPharmacopeial Forum (PF) or Food Chemicals Codex Forum(FCCF), with few exceptions

Comment period typically is 90 days

Each edition of PF/FCCF is destined for a specific final officialor effective publication, with few exceptions

PF End of Comment (3 months)

USP-NF Publish Date Official Date

Nov- Dec (6) 31 January ‘Book’ 1st November 1st May

Jan-Feb (1) 31 March

Mar-Apr (2) 31 May Supplement 1 1st February 1st August

May-Jun (3) 31 July

Jul-Aug (4) 30 September Supplement 2 1st June 1st December

Sep-Oct (5) 30 November

21

USP

22

USP

Sterility Assurance Changes

<1211> Sterility Assurance

Revised with additional new detail and a different structure

Emphasis on design, controls, risk and not testing

An initial ‘quick fix’ chapter will be issued before the entirely new chapter issued later

<1229> Sterilization

Expanded in to 15 additional new individual chapters developed for each sterilization method allowing greater clarity of content, flexibility and easier revision

Implementation ongoing

<1228> Depyrogenation

Expanded in to 7 additional new individual chapters developed for different modalities allowing greater clarity of content, flexibility and easier revision

Not a simple 3-log reduction in endotoxin

Implementation ongoing

<1211> Sterility Assurance

23

USP

24

USP

<1229x> Sterilization – Schedule of Change

# Title Status

1229 Sterilization Official S1, USP 36 - August 2013

1229.1 Steam Sterilization by Direct Contact Official S1, USP 36 - August 2013

1229.2 Steam Sterilization of Aqueous Liquids Official S1, USP 36 - August 2013

1229.3 Monitoring of Bioburden Official S2, USP 36 - December 2013

1229.4 Sterilizing Filtration of Liquids Official USP 37 – May 2014

1229.5 Biological Indicators for Sterilization Official S1,USP 39, August 2016

1229.6 Liquid Phasel Sterilization Official S2, USP 37 – December 2014

1229.7 Gaseous Sterilization Official USP 37 – May 2014

1229.8 Dry Heat Sterilization Official USP 37 – May 2014

1229.9 Radiation Sterilization Official USP 37 – May 2014

1229.10 Vapor Phase Sterilization Official S1, USP 37 – August 2015

1229.11 Physicochemical Integrators and Indicators Official S1,USP 39, August 2016

1229.12 New Sterilization Methods Official S1,USP 39, August 2016

1229.13 Sterilization-in-Place Official S2,USP 39, December 2016

1229.14 Sterilization Cycle Development PF September 2016

1229.15 Sterilizing Filtration of Gases PF September 2016

25

USP

<1228x> Depyrogenation – Schedule of Change

# Title Status

1228 Depyrogenation Official S1, USP 39 - August 2016

1228.1 Dry Heat Depyrogenation Official S1, USP 39 - August 2016

1228.2 Chemical Depyrogenation TBD

1228.3 Depyrogenation by Filtration Official S2, USP 39 – December 2016

1228.4 Depyrogenation by Physical Means TBD

1228.5 Endotoxin Indicators for Depyrogenation Official S2,USP 39, December 2016

1228.6 Endotoxin Control and Monitoring TBD

1228.7 Other Endotoxin Reduction Methods TBD

26

USP

<1229.5> Biological Indicators

Monographs6 Individual Monographs

<55> Biological Indicators—

Resistance Performance Tests

< 1035> Biological Indicators

For Sterilization

<1229.5> Sterilization Of

Compendial Items

General Description Total Viable Spore Count Types of Bioindicators

Packaging & Storage D-value Determination Methods Performance Evaluation

Expiration Date Use for In-process Validation

Labeling

Identification

D-value

Survival & Kill Window

Total Viable Spore Count

Purity

Shipment

Disposal

Some Portions Moved

Some Portions Moved

Revised

27

USP


Pharmacopeial/ Compendial Comparison of Biological IndicatorsUSP EP JP ISO

1229.5 5.1.2 G4 11138

Reference to ISO-11138 Yes No Yes

Moist Heat Species Direct contact: G. stearothermophilusAqueous liquds: C. sporogenes, B. subtilis, or B. atrophaeus

G. stearothermophilus G. stearothermophilus G. stearothermophilus

Resistance text "It must be established that the BI system provides a challenge to the sterilization process greater than the resistance of the bioburden."

"…or other strains of microorganisms having demonstrated equivalent performance are recommended."

"..other microorganisms with the greatest resistance to the sterilization procedure concerned, found in bioburden, can be used as the BI."

"Other microorganisms shall have D values supporting the application."

Moist Heat Spore Count NA Exceeds 5 x 105 NA >1 x 105

Moist Heat D-value NA At 121 0C, Not less than 1.5 min

NA > 1.5

Dry Heat Species B atrophaeus Bacillus atrophaeus Bacillus atrophaeus Bacillus atrophaeus

Dry Heat Spore Count NA Exceeds 1 x 106 NA > 1 x 106

Dry Heat D-value NA At 160 0C, Not less than 2.5 min

NA Not less than 2.5

28

USP


Pharmacopeial/ Compendial Comparison of Biological IndicatorsUSP EP JP ISO

1229.5 5.1.2 G4 11138Ethylene oxide Species Bacillus atrophaeus Bacillus atrophaeus Bacillus atrophaeus Bacillus atrophaeus or

Bacillus subtilisEthylene oxide Spore Count NA Exceeds 1 x 106 NA > 1 x 106

Ethylene oxide D-value NA Not less than 2.5 min for 600 mg/mL at 54C/60RH

NA Not less than 2.5 min for 600 mg/mL at 54C/60RH;

Not less than 12.5 min for 600 mg/mL at

300C/60RH

Radiation Indicator Dosimeters only Dosimeters; accelerated electron radiation- B. pumilus

Dosimeters only Ref. ISO 11137 Dosimeters only

Radiation Spore Count NA If used, exceeds 1 x 107 NA NA

Radiation D-value NA If used, not less than 1.9 kGy NA NA

Other gases species G. stearothermophilus or B. atrophaeus

B. atrophaeus NA Formaldehyde gas - G. stearothermophilus

Chemical species B. subtilis or B. atrophaeus NA NA

Vapor Phase species G. stearothermophilus or B. atrophaeus

NA NA

2016-2020: Commitment to USP up-to-date

USP will expand its commitment to harmonization of compendial standards by working with pharmacopoeias, the World Health Organization, and other stakeholders to determine optimal ways to advance and sustain globally harmonized standards

Pharmacopeial Harmonization & Objectives

29

USP

PHARMACEUTICAL INSPECTION CONVENTIONPHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

PROCEDURE TO INFORM FOREIGN REGULATORY AGENCIES OF FOREIGN INSPECTIONS TO BE CONDUCTED INTHEIR JURISDICTIONPI 039-1 November 2015

The purpose of this Standard Operating Procedure (SOP) is to guide communications between regulatory agencies when one PIC/S Participating Authority’s inspection is intended to be conducted in the jurisdiction of another regulatory agency

• Scope of the inspection (products, facilities, etc.)• Arrange joint inspection• Share previous inspection reports, legal prohibitions

30

EP/EMEA and PIC/S

17 March 2016, Strasbourg, France European Pharmacopoeia Commission adopts revised monograph on Water for Injections allowing production by non-distillation technologies • European Pharmacopeia (Ph. Eur.) Commission

adopted a revision of its monograph for Water for Injections (0169)

• The revision allows for production of WFI by a purification process equivalent to distillation (reverse osmosis, coupled with appropriate techniques)

• Change requires notice given to the supervisory authority before implementation

• EP more closely aligns with the USP and JP• Annex 1 will include new guidance on production

methods for WFI• The revised monograph for Water for Injections (0169)

will be published in the Ph. Eur. Supplement 9.1 and will become effective in April 2017

31

EP/EMEA and PIC/S

MHRA Guidance 2015 - Data Integrity

The data governance system should be integral to the pharmaceutical quality system described in EU GMP chapter 1

The effort and resource assigned to data governance should be commensurate with the risk to product quality, and should also be balanced with other quality assurance resource demands

As such, manufacturers and analytical laboratories are not expected to implement a forensic approach to data checking on a routine basis, but instead design and operate a system which provides an acceptable state of control based on the data integrity risk, and which is fully documented with supporting rationale

32

EP/EMEA and PIC/S


• Data integrity requirements apply equally to manual (paper) and electronic data

• Reverting from automated / computerised to manual / paper-based systems will not remove the need for data integrity controls

• This may also constitute a failure to comply with Article 23 of Directive 2001/83/EC, which requires an authorisationholder to take account of scientific and technical progress and enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods

33

EP/EMEA and PIC/S


Diagram to illustrate the spectrum of simple machine (left) to complex computerised system (right), and relevance of printouts as ‘original data’

34


Designing systems to assure data quality and integritySystems should be designed in a way that encourages compliance with the principles of data integrity. Examples include:

• Access to clocks for recording timed events • Accessibility of batch records at locations where activities take

place so that ad hoc data recording and later transcription to official records is not necessary

• Control over blank paper templates for data recording • User access rights which prevent (or audit trail) data

amendments • Automated data capture or printers attached to equipment such

as balances • Proximity of printers to relevant activities • Access to sampling points (e.g. for water systems) • Access to raw data for staff performing data checking activities

35

EP/EMEA and PIC/S


36

EP/EMEA and PIC/S

Term Definition Expectation / guidance (where relevant)

Data Information derived or obtained from raw data (e.g. a reported analytical result)

Data must be: A - attributable to the person generating the data L – legible and permanent C – contemporaneous

O – original record (or ‘true copy’) A - accurate

Data Integrity

The extent to which all data are complete, consistent and accurate throughout the data lifecycle.

Data integrity arrangements must ensure that the accuracy, completeness, content and meaning of data is retained throughout the data lifecycle

Data Lifecycle

All phases in the life of the data (including raw data)

The procedures for destruction of data should consider data criticality and legislative retention requirements. Archival arrangements should be in place for long term retention (in some cases, periods up to 30 years) Additionally, at least 2 years of data must be retrievable in a timely manner for the purposes of regulatory inspection.

• Improvement in the science-based content of guidance document and standards

• Increase in detail of standards and guidance documents• Standards and guidance documents generally more helpful• Increased reference to assessment of risk and linkage of controls to risk• Continued disparity between standards and guidance documents• Ongoing genuine harmonization efforts, however these will likely take 5-10

years• Regulatory authorities have formalized information sharing• Data integrity will be the continued focus of scrutiny

37

General Themes

38

Thank You