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Environmental Control and Measurement
Mark J. Stannard
22
Presentation Outline
What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions
33
What is contamination?
Presence of any unwanted substance in the product
Two types of contaminants Viable Non-viable
44
Why prevent contamination?
Ensure product quality Protect our customers Comply with cGMP
regulations and laws– 21 CFR 211 and 600– EU GMP and Annex 1
55
Sources of Contamination?
WaterAirSurfacesPeople
66
Presentation Outline
What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions
77
How is contamination controlled?
Health and Hygiene Validated Sterilization of Equipment and Components Protective Apparel Aseptic Techniques Clean Room Conduct Cleaning and Disinfection Techniques Facility and Equipment Maintenance Open vs. Closed System Technology Air Flow, Filtration, and Pressurization
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Air Flow and Pressurization
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HEPA Filtration and Pressurization
HEPA Fact: HEPA filters are made of boron silicate microfibers formed into a flat sheet by a process similar to papermaking. The flat sheets are pleated to increase the overall surface area. A HEPA filter is able to trap 99.99% of particles of a diameter greater than or equal to 0.3 microns.
HEPA filtration and laminar flow serve as contamination control devices. HEPA (High Efficiency Particulate Air) filters are used to remove particulates and microorganisms from the air supply to the manufacturing/filling rooms, laminar flow hoods, biosafety cabinets, etc.
Cross-section of a HEPA Filter
1010
Open System Technology
1111
Closed System Technology
Bulk Closed Systems– Provide engineered solution to
achieve an advanced aseptic processing environment.
Benefits include– Separation of people and their
contaminants from the aseptic process by enclosing the filling area, thus requiring that personnel interventions, work, and handling of materials be conducted remotely.
– Use of contiguous piping to improve the maintenance culture purity/asepsis in the process.
– Use of clean in place and sterilize in place systems for vessel/piping decontamination
1212
Closed System Technology Barrier Isolator Technology
– Provides engineered solution to achieve an advanced aseptic processing environment.
Benefits include– Separation of people and their
contaminants from the aseptic process by enclosing the filling area, thus requiring that personnel interventions, work, and handling of materials be conducted remotely.
– Use of validated pass-through device designs to improve the maintenance of asepsis in the isolator.
– Use of gas/vapor decontamination agents with validated decontamination cycles
The Mini Aseptic Filling System (MAFS) from Bosch-TL Systems
1313
Presentation Outline
What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions
1414
Environmental Monitoring Program for Classified Areas
HEPA filter certification Qualification of Classified Areas Air Flow Visualization Studies Process Simulation Testing Routine Monitoring of Classified Areas and
Utilities Personnel Monitoring Test Processing and Result Analysis Investigations for Excursions Closed System Technology
1515
HEPA Filter Certification
Equipment utilizing HEPA filter technology must be certified initially and periodically.
Certification tests include: – a velocity profile – induction leak test – particle counts– airflow pattern test– a HEPA filter leak test HEPA Filter
1616
Area Classification for Style-ogen® Process Steps
•Tank Fermentation•Non Sterile Purification •Buffer/Media Hold
•Solution Prep•Equipment Assembly•Sterile Purification
• Open Sterile Sampling• Open Sterile Transfers
Lighter shading signifies more stringent area classification
• Open Aseptic TransfersO
pen
Proc
essi
ng
Unclassified Space
Clo
sed
Equi
pmen
t
Classified Space
Grade A
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Classified and Aseptic Areas
Classified and Aseptic Areas – Maximum allowable number of viable and non
viable particles per volume of air sampled– Defined by regulatory agencies
Gowning Room
Air Lock
ProcessingRoom
LFH
Hall
Class 100,000/Grade C
Class 10,000/Grade BClass 100/Grade A
Gowning Room
Air Lock
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FDA/ISO Particulate and Microbial Air Classificationsa and Levels
Clean Area Classification (0.5 um particles/ft3)
ISO Designation b
> 0.5 µm particles/m3
Microbiological Active Air Action Levels c
(cfu/m3 )
Microbiological Settling Plates Action Levels c,d
(diam. 90mm; cfu/4 hours)
100 5 3,520 1e 1e
1000 6 35,200 7 3 10,000 7 352,000 10 5 100,000 8 3,520,000 100 50 a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity. b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A. c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. d- The additional use of settling plates is optional. e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.
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Qualification of Classified Areas
Initial Qualification– Ensure HVAC systems are performing to specifications and
meeting regulatory levels for environmental control– Select test sites based upon area of room (i.e., ISO
formula) and risk of contamination to product– Air and Surface testing conducted for multiple days to
ensure satisfactory performance Periodic Re-Qualification
– Demonstrate continued satisfactory HVAC performance and continued compliance with regulatory specified levels.
– At periodic intervals (e.g., semi-annually for Class 100/10,000; annually for Class 100,000)
– Following area modifications and/or breaches of room integrity
2020
Air Flow Visualization Studies
Verify – Airflow pattern characteristics and unidirectional nature of
airflow in the Grade A zone under static and dynamic conditions – LFH’s ability to limit dispersion of viable/non-viable particles
Assess – Appropriate work flow and personnel aseptic technique specific
to the equipment design and airflow patterns – Non-unidirectional occurrences, such as back-flow, ‘pulsing’ of
air, or dead spots.– Optimal environmental monitoring test site locations for
qualification and routine testing.
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Air Flow Visualization Studies
2222
Process Simulation (Media Challenges)
Simulates aseptic process using growth promoting media in the place of actual product.
Simulates process as closely as possible while incorporating selected worst case conditions
Assures that aseptic process conditions and associated controls are sufficiently rigorous to ensure the manufacture of pure culture or sterile product.
Serves as a continuing assessment of the processes, equipment, procedures, and personnel associated with aseptic manufacturing.
Conducted on predefined frequency as specified by regulations
Conducted following modifications/shutdowns Incubate media, examine for presence of
contamination (e.g., flocculation or turbidity)
2323
Process Simulations (Cont.)
Aseptic Filling– Twice per year per line per
shift– Min 5,000 vials filled– Target 0 contaminated vials– Perform all representative
interventions– Aseptic PQ of Personnel
2424
Routine Monitoring: Air and Compressed Gas Testing
2525
Routine Monitoring: Air and Compressed Gas Testing (Cont.)
2626
Routine Monitoring: Surface Testing
RODAC (Replicate Organism Detection and Count) plates contain growth promoting mediumDirect contact (by pressing the
plate to the specified surface)
OR Swabbing the surface and subsequently swabbing the plate with the sample or inserting swab into broth filled tube
2727
Routine Monitoring of Classified Areas
Frequency and extent of testing is commensurate with proximity to product and level of risk of contamination to product
– Class 100,000 Areas Weekly Air and Selected Surfaces
– Class 10,000 Areas Once per use day during processing Air and Surface
– Class 100 Areas Per Process for each operating shift Air, Surface, Personnel Product Contact Surfaces (end of process)
2828
Utility Monitoring
Conducted for – Initial qualification – Routine monitoring – Following incursions into the utility system
Testing is commensurate with type of system and usage– e.g., Water for Injection (WFI) vs. Potable Water
Water (WFI)– Microbe, Particle, and Endotoxin Testing per use day or weekly– Chemical/Physical test weekly
Clean Steam– Endotoxin and Chemical/Physical test once per month
Compressed Gases– Microbes and Particles– Particles weekly and microbes monthly
2929
Personnel Monitoring
Personnel greatest vehicle for contamination into cleanrooms
Cleanroom clothing required to protect product from people
Four test site locations– Fingertips of both hands– Forearm and Chest
Avoid unnecessary movements and touching of surfaces
Follow Aseptic Technique Disinfect hands frequently Practice “First Air Rule”
3030
Test Processing
1. How many CFUs?2. Are they mold or bacteria?
•Record immediate particle air count
• Incubate microbial test plates per procedures
•Count colonies on plate• Identify representative colonies
•Record all test results
3131
Result Analysis
Action Level: Test result above maximum allowable level.
Alert Level:Possible indication of adverse trend in area/utility performance
Passing Level: Satisfactory results 0
20
40
60
80
100
120
140
Test#1
Test#2
Test#3
Test#4
Test#5
Test#6
Test#7
Alert Level
Action Level
3232
Investigations for Alert/Levels
Regulatory Requirement Investigation Method
– Trend– Describe Event– Identify Affected Materials and Lot(s)– Identify Root Cause/Corrective Actions– Trend for Same Root Cause Previously– Conclusion and Impact Statement
3333
Presentation Outline
What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions
3434
Environmental Monitoring Issues
Aseptic versus Sterile Concepts– Cleanrooms are clean to allowable levels and not sterile– Personnel are the predominant source of cleanroom
contamination EM is not equivalent to a quantitative analytical test
– Accuracy is limited at low level concentrations – Results vary with equipment used– Adventitious contamination of the test plate occurs– Therefore, EM levels are not product specifications
EM most appropriate as trending tool to demonstrate continued control and/or changes in area performance
– Continued “snap shots” in time provide picture of overall level of control
– Occasional elevated results do not indicate a loss of control
3535
Presentation Outline
What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions
3636
Regulations and Guidance
Incr
easi
ng R
equi
rem
ents
3737
Risk Based Approach
Regulatory Guidance often non prescriptive for EM– Majority of guidance addresses aseptic filling– Identify process steps with highest risk to product
quality– Design program to address the risk(s)– Document rationale for program design
3838
Example Regulatory Citations (483s)
Air returns within aseptic filling rooms were obstructed by shelves, tables, and disposal cans.
Pressure differentials are not monitored between the filling room xx and the adjacent construction area. There is no documentation to show the physical integrity of the seal surrounding door between filling room xx and the adjacent construction area.
Procedures for the recording of pressure differentials in the fermentation area were not followed mm/dd/yy.
The fermentor in room XXX had a defective “leaking” valve. A pool of water was also observed XXX tank.
A system should be implemented in the airlock to prevent the opening of both doors at the same time.
3939
Example Regulatory Citations (483s) (Cont. )
Qualification of the method used to detect contamination in the fermentor was incomplete in that raw data did not include counts of the test organisms.
Aseptic personnel practices observed during the fill of XXXXX on mm/dd/yy were inappropriate in that operators did not routinely disinfect gloves between manufacturing operations.
The EM program does not include the use of microbial growth media that is optimum for the propagation of yeast or mold.
The rationale and justification of environmental monitoring samples for all locations is not documented.
The firm has not conducted recovery studies to qualify the ….method and material utilized…..
4040
Presentation Outline
What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions
4141
References and Reading Suggestions
Title 21 Code of Federal Regulations (CFR) Parts 210, 211 and 600
FDA 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing
Q7A GMP Guidance for API Rules Governing Medicinal Products in the European Union
Volume IV – ‘Good Manufacturing Practice for Medicinal Products’ (EudraLex) –
– Annex 1 ‘Manufacture of Sterile Medicinal Products’– Annex 2 Manufacture of Biological Medicinal Products– Annex 18 GMP for APIs
US Pharmacopoeia– General Chapter <1116> Microbiological Evaluation of Cleanrooms
and Other Controlled Environments ISPE
– Baseline Pharmaceutical Engineering Guide, A Guide for New Facilities. Volume 6 Pharmaceuticals, 2004.
4242
References and Reading Suggestions(Cont.)
International Standards Organization (ISO)– Cleanrooms and Associated Controlled Environments – Part 1:
14644-1: Classification of Air Cleanliness1.– Cleanrooms and Associated Controlled Environments – Part 2:
14644-2: Specification for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1.
PDA – Technical Report (TR) 13 Fundamentals of Environmental
Monitoring Program– TR 22 Process Simulation Testing for Aseptically Filled Products – TR 28 Process simulation Testing for Sterile Bulk Pharmaceuticals
Books– Microbiology in Pharmaceutical Manufacturing. Editor R. Prince,
PDA and Davis Horwood International Publishing, Ltd. 2001.