Environmental Control and Measurement

1. Environmental Control and Measurement Mark J. Stannard

2. Presentation Outline • What is contamination? • How is contamination controlled? • Environmental Monitoring Program • Environmental Monitoring Issues • Regulatory Overview and Citations • References and Reading Suggestions 2

3. What is contamination? • Presence of any unwanted substance in the product • Two types of contaminants • Viable • Non-viable 3

4. Ensure product quality Protect our customers Comply with cGMP regulations and laws 21 CFR 211 and 600 EU GMP and Annex 1 Why prevent contamination? 4

5. Sources of Contamination? • Water • Air • Surfaces • People 5

6. Presentation Outline • What is contamination? • How is contamination controlled? • Environmental Monitoring Program • Environmental Monitoring Issues • Regulatory Overview and Citations • References and Reading Suggestions 6

7. 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 7

8. Air Flow and Pressurization 8

9. HEPA Filtration and Pressurization 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. 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. Cross-section of a HEPA Filter 9

10. Open System Technology 10

11. 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 Closed System Technology 11

12. 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 Closed System Technology The Mini Aseptic Filling System (MAFS) from Bosch-TL Systems 12

13. Presentation Outline • What is contamination? • How is contamination controlled? • Environmental Monitoring Program • Environmental Monitoring Issues • Regulatory Overview and Citations • References and Reading Suggestions 13

14. 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 14

15. 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 15

16. Area Classification for Style-ogen® Process Steps • Tank Fermentation • Non Sterile Purification • Buffer/Media Hold Unclassified Space Open Processing Closed Equipment Grade A • Solution Prep • Equipment Assembly • Sterile Purification Classified Space • Open Sterile Sampling • Open Sterile Transfers • Open Aseptic Transfers 16 Lighter shading signifies more stringent area classification

17. 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 Class 100,000/Grade C Class 10,000/Grade B Class 100/Grade A Gowning Room ProcessingRoom Gowning Room Hall Air Lock LFH Air Lock 17

18. FDA/ISO Particulate and Microbial Air Classificationsa and Levels 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. 18

19. 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 19

20. 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. 20

21. Air Flow Visualization Studies 21

22. 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) Process Simulation (Media Challenges) 22

23. 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 Process Simulations (Cont.) 23

24. Routine Monitoring: Air and Compressed Gas Testing 24

25. Routine Monitoring: Air and Compressed Gas Testing (Cont.) 25

26. Routine Monitoring: Surface Testing • RODAC (Replicate Organism Detection and Count) plates contain growth promoting medium 26

27. 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) 27

28. 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 28

29. 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” Personnel Monitoring 29

30. Test Processing • Record immediate particle air count • Incubate microbial test plates per procedures • Count colonies on plate • Identify representative colonies • Record all test results 1. How many CFUs? 2. Are they mold or bacteria? 30

31. 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 Action Level Alert Level 31

32. 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 32

33. Presentation Outline • What is contamination? • How is contamination controlled? • Environmental Monitoring Program • Environmental Monitoring Issues • Regulatory Overview and Citations • References and Reading Suggestions 33

34. 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 34

35. Presentation Outline • What is contamination? • How is contamination controlled? • Environmental Monitoring Program • Environmental Monitoring Issues • Regulatory Overview and Citations • References and Reading Suggestions 35

36. Regulations and Guidance Increasing Requirements 36

37. 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 37

38. 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. 38

39. 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….. 39

40. Presentation Outline • What is contamination? • How is contamination controlled? • Environmental Monitoring Program • Environmental Monitoring Issues • Regulatory Overview and Citations • References and Reading Suggestions 40

41. 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. 41

42. 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. 42