Is it true, Annex 1 revision will have no impact on resources or cost? Walid El Azab Technical Service Manager STERIS

Agenda Annex 1 revision why? Impact of the change on the field Conclusion

The Revision of the Annex 1 - aligned with previous EU GMP updates and be harmonized Joint WG PIC/S PI007 (2011) Eur. Ph. WFI US FDA Guide on ASP (2004) USP <1116> PDA TR22 PDA TR13 SITUATION OCT 2016 NON EXHAUSTIVE PIC/S Annex 1 WHO TRS691 Annex 6 (2011) WHO EM for vaccine (2012) JP guide on ASP (2005) EMA guidance on Sterilization (draft) EC annex 15 (2015) EC Annex 1 EC Chapter 3 (2015) EMA guidance on Health based limit (2015) EC Chapter 5 (2015) Structure of the document Revision of the topics: Environmental Monitoring: viable and nonviable Media-simulation Risk assessment and risk management Enforce root cause and product impact Cleaning and disinfection Clean utilities and other Sterilization Cross contamination control Risk Management Monitoring trending New technology

The Revision of the Annex 1 - aligned with previous EU GMP updates and be harmonized SITUATION OCT 2016 NON EXHAUSTIVE ISO/TC 209 Clean room and associated controlled environment EN 285 ISO/TC 198 Sterilization of health care products ISO 14644-1 and -2 (2015) IS0 14698 (2015) AAMI TR52 ISO 17665-1 (2006) ISO 13408 (2005-2013) Particle specification Sample number using table NL Risk Assessment: Location Frequency Monitoring Trending Alert and Action limit must be based on trending EC Annex 1 Impact of ISO documents: Environmental Monitoring: viable and nonviable Sterilization management Risk assessment and risk management Cleaning and disinfection Life cycle approach ICH Q9 ICH Q10 ICH Q12

Agenda Annex 1 revision why? Future changes and impact on the field Conclusion

Impact of ISO 14644-1 and -2: 2015 on non-viable monitoring and control Key changes: Part 1 : Classification specification ISO class 5 Number of sampling and locations Part 2 : Risk Assessment and Management Monitoring plan Frequency Trending (control) Alert and Action Limit based on CpK and assess the frequency for monitoring Guidance about critical parameter monitoring EU and PIC/S annex 1 JP guidance ASP FDA guidance ASP Europe 1 year to implement USA -??

Impact of ISO 14644-1 and -2: 2015 on non-viable monitoring and control ISO 14644-1:1999 ISO 14644-1:2015 Current EU and PIC/S annex 1; WHO Annex 6 and JP guidance on ASP are not aligned with the ISO 14644 Future Annex 1: remove the 5.0 µm for qualification and initial classification but still need to monitor in operation (in routine production) Why still monitor the > 5.0 µm particle: Provide early warning of a potential problem occur In operation is different than at-rest ISO Annex C allow macro-particles monitoring use the terminology e.g.: ISO M (20; 5.0); LSAPC

Impact of ISO 14644-1 and -2: 2015 on non-viable monitoring and control ISO 14644-1:1999 ISO 14644-1:2015 Table A.1 Sample location related to cleanroom area Surface square of the clean room Important changes on classification and requalification: Impact on the sampling plan Impact on the position and the frequency (Yearly but can be extended if real time monitoring) Scientific approach - based on a risk assessment: Personnel and equipment flow, Operation or position criticality, Smoke studies (grade A, UDF), historical data, etc.

Environmental Monitoring and control must be riskbased and scientifically justified The goal of EM is to confirm at-rest and in operation : The environment cleanliness: Air, Surface, People, water, gazes The cleaning and disinfection procedure effectiveness EM plan include : Risk assessment Position Frequency Smoke study Duration QC (media, recovery, incubation) Acceptance Criteria 1 2 DESIGN IMPLEMENT EM Lifecycle approach Implement and Monitor : Measure Gathering data Review and adapt: Acceptance criteria In-house isolate EM plan Cleaning and disinfection People behavior Facility and Process design ACTIONS 4 3 CONTROL Trend and confirm the effectiveness of : EM plan in place Cleaning and Disinfection SOP Define process capability: Upper and Lower contamination Level Atypical results and why?

Average for microbial limit would be no more acceptable in Europe, PIC/S and WHO requirements Same microbial limits: EU annex 1 PIC/S annex 1 JP guidance on aseptic processing WHO TR691 annex 6 WHO guidance for vaccine manufacturing Annex 1 (2008) Annex 1 (201X)

Microbial recovery rate and incubation program is a key factor for effective monitoring and control plan Recovery and Incubation program may vary depending on the manufacturers process, suppliers, regulatory requirements > Must be scientifically justified! Environmental Monitoring Media simulation Sterility Testing EU PIC/S EU and PIC/S annex 1: N/A PIC/S 007-6 (2011)**: 1. 20-25 C min. 7 days 2. 30-35 C min 7 days US JP WHO Aseptic manufacturing Shopfloor FDA guidance ASP (2004): 30-35 C for 48-72h 20-25 C for 5-7 days USP <1116>: 20-35 C min.72h N/A WHO EM cleanroom in Vaccine Manufacturing (2012)*: 1. 20-25 C for 3-5 days 2. 30-35 C for 2-3 days it is a mix depending on several parameters***: - Recovery rate on TSA, SCDA - Environment specificity - Market release FDA guidance ASP (2004) and JP guidance ASP (2006): 20-35 C at least 14 days (Target+:-2.5 C) If two temperature then min. 7 day each starting with the lower temperature WHO TR691 Annex 6 (2011): N/A it is a mix depending on several parameters***: - Recovery rate on TSA, SCDA - process specificity - Market release EU Ph. 2.6.1; USP <71>; JP <4.0.6> are harmonized: - Temp.: 20-25 C SCD and 30-35 C TSA - Time: 14 days incubation *Alternative methods are acceptable when high recoveries (>90%) of microorganisms of interest can be consistently demonstrated. ** Other incubation schedules should be based on supporting validation data. *** different manufacturer has tested at different temperature vs one temperature and shown no difference in recovery rate. This statement is true for some and not for other therefore scientific data must be shown to justify the incubation program [author benchmark]

Incubation strategy must be justified based on scientific data and rational for EM and aseptic simulation Gordon O. and all (2014) Roland GM. and all (2016) Sandle T. (2014) Environmental Microorganism Environmental microorganism: Highest recovery: TAC (personnel flow) using TSA and SDA incubated at 30-35 C Reasonable recovery: TAC (personnel flow) using TSA and SDA incubated at at 25-35 C Two temperature incubation Environmental Microorganism with TSA SP and CP Highest recovery: 97.7% recovery on SP at 32.5 C 65.4% recovery on CP at 32.5 C Cocci Gram +, non-spore-forming, Grampositive rods > 95% growth and recovery at 32.5 C Environmental Microorganism with TSA recovery: Regime A: 30-35 C followed by 20-25 C Regime B: 20-25 C followed by 30-35 C No significant difference for TMC between regime A and B Environmental Moulds and yeast Highest recovery: Moulds using TSA and SDA incubated at 20-25 C Reasonable recovery: Moulds using TSA and SDA incubated at 25-35 C Two temperature incubation Inneffective recovery: Moulds using TSA and SDA incubated at 30-35 C Highest recovery: Moulds at 22.5 C alone or as a first temperature incubation No recovery: Strict anaerobes Environmental fungi with TSA recovery: Regime A: 30-35 C followed by 20-25 C Regime B: 20-25 C followed by 30-35 C Higher indients and number of fungi with the regime B Conclusion 2 samples - 20-25 C aerobic count (in routine) - 30-35 C Moulds (in routine) 2 samples - 32.5 C aerobic count (in routine) - 22.5 C Moulds (periodically) 1 sample - 20-25 C followed by 30-35 C Source: Gordon O., Berchtold M., Staerk A., Roesti D., Comparison of different incubation conditions for microbiological environmental monitoring, PDA J Pharm Sci Technol.

Approach for Cleaning and Disinfection Process and non- Process Equipment INDUSTRY PRACTICE A Soils and microbial Residue type and level A Microbial residue: Is the cleaner agent used efficient B Surface And Equipment Design B Material substrate, area classification, design C C Cleaning and disinfection program based on risk based assessment PDA TR13: it is recommended to periodically review challenge testing of the selected sanitizers, disinfectants and sporicide if representative new isolate are routinely recovered in the EM program Source: Image from McDonnell, Antisepsis, Disinfection, and Sterilization: Types, Action, and Resistance 2007, ASM Press

Cleaning and disinfection strategy must be based on the sampling risk level Step 1: Risk Factor determination EXAMPLE Step 2: Risk Factor determination Duration Proximity # People Risk Class Step 3: Design the cleaning and disinfection SOP

Disinfectant rotation definition evolution? Eudralex annex 1 (2008) 61. The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains.» FDA guidance on aseptic manufacturing (2004). Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility.. and Therefore, a sound disinfectant program also includes a sporicidal agent, used according to a written schedule and when environmental data suggest the presence of sporeforming organisms. PIC/S WHO JP guidance on aseptic manufacturing (2006) Cleaning and disinfection of facilities and equipment A program for cleaning and (3) If selected disinfectants might have inferior disinfecting facilities and equipment should be efficacy against microorganisms isolated from established taking into account the potential the environment, the efficacy should be development of drug-resistant microorganisms. reevaluated and the replacement with or The program should contain procedures for alternate use of different disinfectants should be screening and classifying bacterial isolates in each considered and implemented, as appropriate. manufacturing environment.» (4) If environmental monitoring data indicate or suggest the presence of spore-forming bacteria or fungi, suitable sporicides or fungicides should be selected for disinfection. PDA TR70 cleaning and disinfection (2015) USP 39 <1072> disinfectant and antiseptics The rotation of an effective disinfectant with a sporicide is encouraged. It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent. The daily application of sporicidal agents is not generally favored because of their tendency to corrode equipment and because of the potential safety issues with chronic operator exposure. Other disinfection rotation schemes may be supported on the basis of a review of the historical environmental monitoring data. However, the most frequently isolated microorganisms from an environmental monitoring program may be periodically subjected to use-dilution testing with the agents used in the disinfection program to confirm their susceptibility, as there are real differences among different species in resistance to the lethal effects of different sanitizers.

EU annex 1 and EMA guidance on sterilization (draft) and ISO document aligned or not? Proposed change: EU Annex 1 does not reference the EN 285 or other ISO related to Sterilization processes. However, it is clear that Steam quality and air removal must be performed to demonstrate sterilization process suitability Proposed change: demonstrate sterile integrity of sterilize or RTU packaging before use, e.g. by vacuumed packaged Current Annex 1 and EMA guidance on sterilization require: 113. The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test. PUPSIT = Post Use Post Sterilization Integrity Test is it mandatory?

PUPSIT is it mandatory? Yes, except if the process does not allow a PUPSIT but robust data and adequate risk assessment must demonstrated it. The objective of each filter is important to assess the impact of a failure

The goal is to tend to zero contaminated unit during media simulation regardless the number filled. The future annex 1 will ask to tend to zero unit failed during media simulation. Process design must be well developed to avoid non-plus value intervention during aseptic production and simulation. Risk assessment model must be used to assess design effective aseptic manipulation, intervention and assess the risk of failure Intervention with no plus-value must be removed Intervention with high risk of contamination must be avoided Step 1: Risk Factor determination Step 3: Intervention Risk analysis Source Table: Baseman H., Hardiman M., Henkels W., Long M.,2014, Contamination control in Healthcare Product Manufacturing, In: Madsen R. and Moldenhauer J., Contamination Control in Health Care Product Manufacturing, PDA and DHI,Vol.3, p. 341-404

Other changes Structure of the document will change Title will not change and the scope is for aseptic manufacturing Emphasis on EU Dir. 2003/94 article 5 and 2001/83 article 23 Enforce root cause investigation and product impact assessment Process risk assessment and process risk management Personnel training and knowledge Emphasis on keeping the operators away from the product: LABS, RABS, Isolators. Isolators are not mandatory to avoid site closing

Other changes Revision WFI monograph: allow the production of WFI by a purification process equivalent to distillation such as reverse osmosis, coupled with appropriate techniques. The revised monograph will be published in the Ph. Eur. Supplement 9.1 and will become effective in April 2017. New Section will be added in the Annex 1: Utilities: Compressed air WFI production Biofilms Maybe a possibility for a new document called utilities

Factor influencing biofilm generation Biofilm is generally composed of multiple microorganism encased in matrix extracellular polymetric susbstance (EPS): Factor influencing biofilm generation Biofilm generation Conceptual drawing: Biofilm generation

Combination of Cleaning Approaches show Effectiveness against Microbial and Biofilm Contamination Combination strategy will be effective against microbial contamination: INDUSTRY BEST PRACTICE 1. Use of alkaline cleaning chemistry: Increase the chemical action Increase the mechanical action 2. Use of the sporicidal chemistry or thermal to disinfect or sterilize the system Fluorescently labeled P. aeruginosa exposed to 5% concentration at 60⁰C: Before exposure biocide (3min) alkaline detergent (6min) P. Aeruginosa Source : STERIS Technical tip 410-200-3088

Agenda Annex 1 revision why? Future changes and impact on the field Conclusion

All processes, program and strategy must be based on effective Risk assessment and design development Environmental monitoring Cleaning and disinfection Cleaning process equipment Media simulation Sterilization Process design People gowning and behavior Etc. 1 2 DESIGN IMPLEMENT Implement and Monitor : Measure Gathering data Lifecycle approach Review and adapt: avoid failure Real time is better ACTIONS 4 3 CONTROL Trend and confirm the effectiveness of : Process capability and performance Assess Alert and Action Limit Define and condirm STV

The revision of the annex 1 should reflect the current aseptic practices Are we as good as we think? Number of 483s Issued from the System FY center name Drugs 21.CFR211.113 (b) procedure for sterile drug product 21 CFR211.113 (b) validation lacking for sterile drug product 21 CFR211.42 (c)(10)(iv) Environmental monitoring 21 CFR211.42 (c)(10)(v) Cleaning systems 21 CFR211.42 (c)(10)(vi) equipment control condition 21 CFR211.67 (a) cleaning/sanitization/maintenance 21 CFR211.67 (b) written not establish and not followed/followed 21 CFR211.67 (b) written procedure failed to include 21 CFR211.167 (a) Sterility/pyrogen-free testing 6 21 25 23 24 37 42 35 33 53 53 72 60 68 63 72 83 104 0 20 40 60 80 100 120 FY1015 FY2014 Source: http://www.fda.gov/iceci/inspections/ucm424098.htm http://www.fda.gov/iceci/inspections/ucm481432.htm#drugs

the results of a Belgium Pharmacist Association workshop and questionnaire around the revision of the Annex 1 will be shared during the presentation Participant: 19 pharmaceutical industries Slides will be provided during the presentation.

Thank You For your listening El Azab Walid Technical Service Manager STERIS Walid_elazab@steris.com +32479790273

References Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial. European GMP guide to good manufacturing practice for medicinal products annex 1 FDA guidance for industry sterile drug products produced by aseptic processing - current good manufacturing practice WHO annex 6 good manufacturing practices for sterile pharmaceutical products ICH Q9 Quality Risk Management ISO 14644 : 2015 Cleanrooms and associated controlled environments -- Part 1: Classification of air cleanliness by particle concentration Gordon O., Berchtold M., Staerk A., Roesti D., Comparison of different incubation conditions for microbiological environmental monitoring, PDA J Pharm Sci Technol. 2014;68(5):394-406 Roland GM., Nicole B., Philippe D., Julien T., Mehdi R., Michel T., Philippe B., Christophe A., Edith M., Florine G., Marjorie L., Catherine A., MULTICENTRE STUDY ON INCUBATION PROGRAM FOR ENVIRONMENTAL MONITORING AND ASEPTIC PROCESS SIMULATION, PDA J Pharm Sci Technol. 2016 Sandle T., Examination of the order of incubation for the recovery of bacteria and fungi from pharmaceutical-grade cleanrooms, Int J Pharm Compd. 2014 May-Jun;18(3):242-7. Baseman H., Hardiman M., Henkels W., Long M.,2014, Contamination control in Healthcare Product Manufacturing, In: Madsen R. and Moldenhauer J., Contamination Control in Health Care Product Manufacturing, PDA and DHI,Vol.3, p. 341-404 USP 39 <1072> disinfectant and antiseptics JP guidance on aseptic manufacturing (2006) PDA TR70 cleaning and disinfection (2015) Baseman H., Hardiman M., Henkels W., Long M.,2014, Contamination control in Healthcare Product Manufacturing, In: Madsen R. and Moldenhauer J., Contamination Control in Health Care Product Manufacturing, PDA and DHI,Vol.3, p. 341-404