「實驗室硬體相關訓練課程(三)」2009-09-24

設施之[正確]使用、維護及環境監控與確效Translating a Medical Finding to

a Pharmaceutical Practice

Yp wuypw@itri.org.tw 03-5912819

mailto:ypw@itri.org.tw

EffortEffort Invested in TherapyInvested in Therapy

Existing Models

IF Desirable, It is PossibleIF Desirable, It is Possible

Mission Statement of TotipotentTotipotentSCSC

WHENWHEN to Move from Lab to ‘Factory’?

Seeking the Greatest Interests for the BiggestMajority with the BEST Quality YOU can Achieve.

Principle / Mind Set CONTINUOUS

CONTINUOUSImprovement

WHAT IF there is a LAB space to be renovated into a Pharmaceutical process unit

NOT A [NEW] Building Project!!!

♦ Product driven architecture / construction♦ independent air handling system♦ specified group of personnel structure♦ designated equipment ♦ defined operations ♦ traceable documentation

Establishing a System not only put together a shield or set of tools

Maintaining a System not only rely on automation

But also [define specifications and purposes]

But also base on [noble humanity]

Safety, Purity, Potency/ Efficacy

Clean zone How clean is clean? Effort of removing “dust”…

Site particulate monitored (0.5µm particulates / cubic feet)

outer space ≦100

field (breeze) 100,000 to 300,000

residential area 100,000 to 200, 000

office (working hour) 200,000 to 400,000

industry area 400,000 to 1,000,000

smoker filled meeting room 600,000 to 1,000,000

Not generating► healthy, trained and specified personnel► no lingering or abrupt movement► lint free coverage or materials ► no unnecessary material brought in

No carry-over• avoid leakage of air-filtration apparatus• generate pressure difference• clean tools and materials brought in• clean garment & coverage

Segregation, and Containment

Principles of cleanroom management and maintenance

Biological Cleanroom maintenance

♦ Sufficient air change rate (>20/h air change rate)♦ exhausting set up on dust generating site♦ free flow air pattern

■ Smooth finishing and cleanable surface■ clean regularly■ no piling or dead space

Remove & No accumulation

AvoidAvoid Cross Contamination♦ Endotoxin Free, Sterile materials Used (at

least disinfected/cleaned)♦ Physically segregation

blockage with wall + ceilings, filtration, flow of air, wrapping, garment and etc…

♦ Aseptic training + practice♦ Risk assessment and simulating the accident

Early detection and early response closely monitoring

♦ Containment & Removal multilayer sealing and containerflow of air, filtrationcleaning, disinfection, sterilization and etc…

Material flow Personnel flow Waste flowProposed by Dr. David DiGiusto, 2008-07-18

Besides Gown and [Shining][Shining] Equipment

http://www.clarkson.edu/biology/facilities/cell.htmlX-cytehttp://www.oscell.enta.net/index.htm Culturing keratinocyte

http://www.clarkson.edu/biology/facilities/cell.htmlhttp://www.pharmaceutical-technology.com/projects/Serologicals/index.htmlhttp://www.oscell.enta.net/lab.htm

Air Quality warrants the baseline of [cleanliness]

risk-based approach monitoring

Zone ASupporting Area

ISO14644-1 Class 5USP USP. United States Pharmacopoeia General Chapter Pharmaceutical Compounding –Sterile Preparations.Food and Drug Administration’s (FDA) Guidance for Industry Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004

Air Flow, Air Exchanging Rate, Air Temperature+ Humidity

Laboratory vs Factory for Medicine

Characteristics Research Laboratory Factory/ Plant/ Diagnostic LabGeneral Purpose Test on small group, exploring

the innovative approaches

Procedure standardization Equipment and principle but not operation-wide

All procedures

Units of a specific product/service

+ ++++

Organization structure Simple Multi-level of quality assurance

Regulation + (mostly depends on self discipline)

+++ (actively involve, license might be required)

Traceability ++++ (in term of details/duration) +++++

From therapeutic purpose/ applicable guidance

GLP for pre-clinical or GMP for clinical trial

GMPGMP+ GTP + GCP + GRP + etc..

Operation/ management Mostly non-profit [biz] run for profit

Unit area for the same product + to ++ ++ to +++++

Mass production, protecting health for general public

Sign, Label & Poster - Graphic Guidance and SOP

Equipment supporting Operation and Production that also fostering Research• Cell separation/ Isolation/

EnrichmentDissecting vs. Homogenization Gradient centrifugationIPO isolation,

etc…• Cell Proliferation/ Incubation

3D vs. 2D culture bioreactor or other massive production apparatus

Materials + Containersnon xenogenous, sterile, endotoxin‘free’, pure, and functional (same quality as the quality of [products])

MediumReady to useLimited exposure

SupplementRemovable or dilute to ignorable amount

Ambient air filtered Gas purifiedPeople and waste [contained]

Methodology of Sterility Testing and Endotoxin Detection

• Sterility, a pass-or-fail testUSP 32 harmonized with EP 6.4 2.06.01 (Visual / Turbidity monitoring on 14 D culture; Soybean-Casein Digest Medium 20-25 °C Fluid Thioglycollate Medium 30-35 °C)Direct TransferMembrane Filtration

growth promotionbacteriostasis/ fungistasis testspecified area: isolator, sterility testing area

Limitations: Unable to detect and cultivate virus & mycoplasmaIrrecoverable & destructiveLow statistical valueNot intended as a sole product release test

Biological Indicators used in Growth Promotion and Bacteriostasis/Fungistasis Test

strains used with FTM; 30-35 °C typical strainClostridium sporogenes aerobic/ anaerobic ATCC 11437 / 19404

Bacteroides vulgatus ATCC 8482

Pseudomonas aeruginosa aerobic ATCC 9027Micrococcus leuteus ATCC 9341

Staphylococcus aureus aerobic ATCC 6538Bacillus subtilis ATCC 6633

strains used with SBCD; 20-25 °C typical strainAspergillus niger fungi ATCC 16404Bacillus subtilis aerobic ATCC 6633Candida albicans fungi ATCC 10231

Faster and quantitative method are recruiting and testing/ Rapid Microbiology Method

• Growth• ATP• PCR

Limitation No recovery and Destructive stillNo/less chance to be identified

http://www.microbiol.org/docs/sutton.pda.2004.pdfhttp://www.rapidmicrobiology.com/test-methods/index.php

http://www.microbiol.org/docs/sutton.pda.2004.pdf

Endotoxin Test

http://www.biomanufacturing.org/bioman/LAL_L_Rehfuss.ppt#19

Liquid and Moisture Handling• Limited in term of amount

and duration• Specified area (considering

high risk)• Frequent replacement• Avoid spill and aerosol

Contain and Dry Up

Maintenance – Clean, Replace and Check Scheduled / Routine Disinfection, Decontamination (Chemical, Fumigation and etc)

Monitored via particulate counting and microbial population examination

確效(Validation)to ensure/warrant the stable and qualifiedproduct and service in the long term.

the parameters/ results of test indicating the quality of product satisfy the acceptance criteria (允收標準).

user requirement specification

functional specification

design Specification

system build

installation qualification

operational qualification

performance qualification

verifies

verifies

verifies

Self Discipline vs. Stepwise Verification

• Daily check/ examination• In process verification• Internal auditing• Independent auditing• Inspection

http://nmdaweb.nmsu.edu/weights-and-measures/w-m-hidden-folder/egg1inspection.jpg

Continuous Improvement IISix Sigma at many organizations simply means a measure of quality that strives for near perfection. The statistical representation of Six Sigma describes quantitatively how a process is performing. To achieve Six Sigma, a process must not produce more than 3.4 defects per million opportunities. A Six Sigma defect is defined as anything outside of customer specifications. A Six Sigma opportunity is then the total quantity of chances for a defect.

http://en.wikipedia.org/wiki/Six_Sigma#Originhttp://en.wikipedia.org/wiki/Vilfredo_Pareto

DMAICDMAIC

http://en.wikipedia.org/wiki/Six_Sigma#Origin

Documentation + Execution

Background/ Purpose (why)Scope (who, where, when)Material and Equipment (how-1+ what)Procedure (Method; how-2)Note (link, risk assessment and etc…)

Installing the probesRelocating the content to

-80°C freezer

Power off

Clean up and resume power

Equivalent to long term,> 10 min, door opening

Re-shelving and continue monitoring

Generate pull down/up profile

Generate pull up profile

Simulate power failure

Equivalent to system recovery

Generate recovery profile

Generate long term maintenance profile in power failure condition

Generate long term maintenance profile; stability

18-20 hr

15-20 min

45-60 min

Flow Chart of Performance Verification + Annual Clean-up maintenance of -30C Freezer

1-2 day

Equipment Maintenance + Functional Verification

1. Commissioned agentVendors, specialist or engineerQualified Testing Laboratories

2. Self Examinationneed a. regularly calibrated testing equipmentb. reflecting the operation situationc. report documented, reviewedd. risk assessment

established

Automatic cell culture (ii)

http://www.automationpartnership.com

• SelecT ™is the automated cell culture system for multiple cell-lines and assay-ready plate production, with over 25 installations world-wide. Cell lines could be maintained and expanded in T-175 flasks (up to 182 in parallel).

Automation may lead to dismay just the same

Principle / Mind Set

Seeking the Greatest Interests for the Biggest Majority

with the BEST Quality YOU can Achieve.

Risk is not an opportunity for New Discovery or Self Satisfaction.Risk is an potential [ERROR][ERROR] or [LOST][LOST] and expected to be CONTROLLED!

THANK YOU FOR YOUR ATTENTION

討論/ 他山之石強化[管理]以[彌補]硬體設施之不足Bring up the BRIGHT SIDEBRIGHT SIDE of Humanity

• Limiting access• Scheduling + Coordination• Discipline and cultivating

the 2nd nature

Regulatory is not the ‘challenge’, Mother Nature and People themselves are the ‘TASK’ facing ‘DAILY’.

4 principles of cleanroom management and maintenance

Serlimik Fjord* What people could clean is insignificant.

Live with far from ideal

Make the BEST use of IT

困難 vs. 試煉►No terminal filter

limited and scheduled access, cover all gowning►Positive pressure

P2 level service, pre-selected client, small scale manipulation/ batch

►Not uni-direction flowscheduled access, contained and sealed materials, air lock installed for critical area

►Not standard factory construction+ human height < 180cm+ modify height of the equipment and machine+ access from airlock and scheduled maintenance

►No pass through autoclave or freezer for waste managementtriple layer containment and timely management

Personnel flow of gowned worker and visitor, the blue solid line ( )indicates the accessible area and directions of normal street clothed personnel; blue hollow line ( ), the white coated, masked/gloved/hair-covered personnel conducting specific assay; red hollow line ( ), the cover-all gowned, masked, and gloved worker/visitor.

Improvement with Limited Resource

Case 1: high bioburden of PU chairs in cleanroom

Case 2: tighten personnel flow or safety concern with interlock

Covering chairs with chair cover, class1000 gradeClean daily

Multi-entrance interlock accordingly3-door / entrance to culture suite3-door / main entrance/ gowning area/ QC room entrance

http://upload.wikimedia.org/wikipedia/commons/b/b2/Coins.jpg

Work Hard but Work with HIGH SPIRIT

「實驗室硬體相關訓練課程(三)」2009-09-24Effort Invested in TherapySeeking the Greatest Interests for the Biggest Majority with the BEST Quality YOU can Achieve.WHAT IF there is a LAB space to be renovated into a Pharmaceutical process unitClean zone How clean is clean? Effort of removing “dust”…Avoid Cross ContaminationLaboratory vs Factory for MedicineEquipment supporting Operation and Production that also fostering ResearchMaterials + Containers non xenogenous, sterile, endotoxin ‘free’, pure, and functional (same quality as the quality of [produMethodology of Sterility Testing and Endotoxin DetectionBiological Indicators used in Growth Promotion and Bacteriostasis/Fungistasis TestFaster and quantitative method are recruiting and testing/ Rapid Microbiology MethodEndotoxin TestLiquid and Moisture HandlingSelf Discipline vs. Stepwise VerificationDocumentation + ExecutionEquipment Maintenance + Functional VerificationAutomatic cell culture (ii)Seeking the Greatest Interests for the Biggest Majority with the BEST Quality YOU can Achieve.討論/ 他山之石4 principles of cleanroom management and maintenanceLive with far from ideal困難 vs. 試煉Improvement with Limited Resource