Avoid recurrent microbial contamination using trending of historical data. El Azab Walid Technical Service Manager STERIS

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1 Avoid recurrent microbial contamination using trending of historical data El Azab Walid Technical Service Manager STERIS

2 Agenda Factors influencing the cleaning and disinfection performance Recurring microbial contamination observed on the field case studies Good practices for microbial contamination control Conclusion

3 Regulation Requirements: Cross-contamination Control Management for sterile NON EXHAUSTIVE LIST Contamination Sources : I. Biological Cleaning EU GMP: Annex 15 Chapter 3 and 5 EMA Health based US GMP CFR ISPE Risk MaPP PDA TR 29 and 49 PICS/S 006 II. Microorganism Endotoxin Chemical Crosscontamination control Product residue Cleaner residue Other residue Disinfection EU Annex 1 US FDA aseptic guidance and CFR PICS/S 009 JP Guidance for sterile manufacturing Who TRS961 Annex 6

4 Regulation Requirements: Cross-contamination Control Management for non sterile NON EXHAUSTIVE LIST Contamination Sources : I. Biological Cleaning EU GMP: Annex 15 Chapter 3 and 5 EMA Health based Eur. Ph. (5.1.4) US GMP CFR ISPE Risk MaPP PDA TR 29 USP <1111> & USP <1112> PICS/S 006 II. Microorganism Chemical Crosscontamination control Product residue Cleaner residue Other residue Disinfection Chapter 3 and 5 CFR PICS/S 009 WHO TRS961

5 Factors influencing microbial contamination

Parameters Affecting Cleaning and Disinfection Performance Equipment design Design is one of the key aspect for effective cleaning and disinfection. 100% recovery should always be reached.

6 Parameters Affecting Cleaning and Disinfection Performance Equipment design Design is one of the key aspect for effective cleaning and disinfection. 100% recovery should always be reached. Equipment design TACT Time, action, concentration and temperature are considered critical process parameter for effective cleaning Numbers Disinfectant is more effective against low number of microorganism than high number Expiry time TACT Type and resistance Sporicidal agent kills spore and vegetative microorganism. However, non oxidizing disinfectant kill vegetative microorganisms and could kill some spore microorganisms Residue ph & Temperature Numbers Water Hard water could reduce efficacy of many disinfectants Chemistry Type and resistance microorganism Chemistry Residue The choice of the chemistry should depend on the residue nature and aspect Residue should not interfere with the disinfectant efficacy. Rinse strategy should be put in place periodically. Water ph & temperature ph could influence the ionic biding of disinfectant, while temperature could affect the log kill over time (Q10). Expiry time Stability of the component ready to use or diluted need to be assessed. It can flexibility based on the shelf life

7 Agenda Factors influencing the cleaning and disinfection performance Recurring microbial contamination observed on the field case studies Good practices for microbial contamination control Conclusion

8 Case study #1: Recurrent microbial contamination of non sterile batches Recurrent deviation CAPA : CIP design dead leg removal Recurrent deviation CAPA : Increase rinsing step using PW for contact product Increase water system sanitization (from every 4 month 80 C for 30 min -> every 2 month 80 C for 30 min) Increase gloves sanitization (IPA) increase the cleaning/disinfection cleanroom frequency (from weekly to daily)

9 Case study #1: Recurrent microbial contamination of non sterile batches Equipment a. CIP system design: 1. dead leg 2. hoses connection and management b. Water system (PW) maintenance: 1. presence of rouge confirmed 2. recurrent microbial contamination Method f. Room cleaning and disinfection SOP: 1. disinfectant X efficacy vs EM data 2. absence of sporicidal vs EM data c. Water system (PW) sanitization: 1. temperature, time and frequency 2. periodic chemical sanitization d. Process equipment cleaning: 1. water / equipment microbial status 2. cleaner demonstrated not capable to to remove not remove product residueand remove microbial burden Environment Material e. Equipment/Material flows and control : 1. presence of cartons in the rooms 2. equipment flow were not adequate

Case Study #2: Non conform microbial level in final product QC testing Recurrent deviation : Root cause unidentified Specification change Action

10 Case Study #2: Non conform microbial level in final product QC testing Recurrent deviation : Root cause unidentified Specification change Action put in place : Increase the concentration: Double for the disinfectant X NaOCl from 1% to 2% Increase the contact time: From 15 min to 45 min 2015

11 Case Study #2: Non conform microbial level in final product QC testing Equipment b. Washing machine deisgn : 1. presence of rouge confirmed 2. recurrent microbial contamination a. Equipment design: 1. presence of rouge (high level) 2. high rugosity of the surfaces crevices & interstice Method d. Room cleaning and disinfection SOP: 1. Inadequate understanding of the disinfectant efficacy vs micro identified c. Process equipment cleaning: 1. Cleaner was inefficient the against microorganism found 2. cleaning cycle was inadequate to ensure effective cleaning visual check not achieved 3. Disinfection program for direct contact area with the product was inadequate Environment Material e. Personnel flow was inadequate f. Material status and maintenance was not enough for effective microbial contamination control

12 Case Study #3: Trend for microbial contamination deviation is increasing every year 45 Number of microbial contamination deviation

Case Study #3: Trend for microbial contamination deviation is increasing every year EM data from 2014-2016 Non conform EM

13 Case Study #3: Trend for microbial contamination deviation is increasing every year EM data from Non conform EM position from Air Contact plate contact product non contact product floor

14 Case study #3: Trend for microbial contamination deviation is increasing every year Equipment a. CIP system design: 1. dead leg 2. manual cleaning defective Method Environment Material b. Process equipment cleaning: 1. cleaner not capable to remove product residue 2. Manual cleaning leading to microbial contamination c. Cleaning of the equipment : 1. cleaning and disinfection method was ineffective (Spaghetti chart) 2. miss-used of the detergent vs efficacy 3. Disinfectant were not qualify for their use 4. cleaning simultaneously non contact and contact product using the same procedure d. Microbial specification is the same e. Non respect of the material flow and the number of equipment authorized in the area per validation protocol

15 Case study #3: Trend for microbial contamination deviation is increasing every year Short term corrective/preventive actions Actions list A C B D Material Man Method Equipment define adequate material flows clean/unclean increase awareness of microbial contamination factors. review the cleaning and disinfection procedure using a hard surface disinfectant and sporicide review the manual cleaning operation and the cleaning steps riboflavin test for automated equipment with spray ball E F Environment Measure

16 Case study #3: Trend for microbial contamination deviation is increasing every year Long term corrective/preventive actions Actions list A C B D E Material Man Method Equipment Environment reduce the number of detergent and disinfectant. qualify the disinfectant define adequate material flows clean/unclean update the cleaning validation SOP/protocol qualification and re-training review the cleaning and disinfection procedure based on the disinfectant qualification result knowledge transfer task force review the manual cleaning operation riboflavin test and technical upgrade automatic cleaning increase automation by using mobile skid reduce EM testing from intensive to normal F Measure

17 Case study #4: Recurrent Microbial Contamination of WFI Systems Position of the non-conformity Results per point of use (2 nd phase I PQ) Samples at start or return loop were conform

18 Case study #4: Recurrent Microbial Contamination of WFI Systems Source: see the source page

19 Case study #4: Recurrent Microbial Contamination of WFI Systems Source: see the source page

20 Case study #4: Recurrent Microbial Contamination of WFI Systems Short and long term corrective/preventive actions Actions list A C B D Material Man Method Equipment purchase more material and develop visual lean tools for material management update the SOP/protocol qualification and re-training design sampling instruction methods and check list knowledge transfer task force qualification and requalification requirement Purchase new valves E F Environment Measure

21 Case study #4: Recurrent Microbial Contamination of WFI Systems

22 Case Study #5: Non conform microbial level of tank vessel after cleaning hold time testing Description: Cleaning Revalidation: cleaning PW and rinse PW Recurrent contamination by gram - microorganism : P. aeruginosa and P. picketti Several final product with microbial results under USP <1111> specifications and the P. aeruginosa and R. picketti never identified Remedial action Root cause not found: Sanitization of the water system Water results were always conform Microbial analysis of the equipment after each cleaning Remove the clean hold time Identification of each CFU even under specification because consider as objectionable microorganism! After cleaning a 3 log reduction were achieved Cross functional investigation team / Fish bone and microbial screening risk assessment: Root cause: Equipment intra-design inducing water to stagnate Disinfection process was absent vs the equipment design Disassemble the equipment at the end of the week but not during routine testing Actions put in place but removed: Implement a disinfectant peroxide hydrogen impact on the product coloration

23 Case Study #6: The disinfectant is not working Description: Grade D and grade C: after application of the phenolic disinfectant the microbial testing is higher than prior application In vitro coupon testing were conform to the specifications with 5 minutes contact time micro identified: Staphylococcus epidermidis, Staphylococcus aureus and other human microorganism. Remedial action Root cause not found: Replace the current disinfectant with another phenolic disinfectant Review the procedure and increase the contact time

24 Case Study #6: The disinfectant is not working

25 Agenda Factors influencing the cleaning and disinfection performance Recurring microbial contamination observed on the field case studies Good practices for microbial contamination control Conclusion

Approach for Cleaning and Disinfection Process and non- Process Equipment A Soils and microbial Residue type and level A INDUSTRY PRACTICE Microbial residue: Is the

based assessment PDA TR13: it is recommended to periodically review challenge testing of the selected sanitizers, disinfectants and sporicide if representative new

26 Approach for Cleaning and Disinfection Process and non- Process Equipment A Soils and microbial Residue type and level A INDUSTRY PRACTICE 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

27 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

Microbial contamination reflect inadequate motion work Assess (Risk-based) and control factor(s) that influence microbial contamination during your manufacturing process Develop robust process,

28 Microbial contamination reflect inadequate motion work Assess (Risk-based) and control factor(s) that influence microbial contamination during your manufacturing process Develop robust process, cleaning and disinfection, preventive maintenance program Trend and control your data for preventive action and avoid deviation If a deviation the solution is on the shopfloor and the trending analysis!

29 Agenda Factors influencing the cleaning and disinfection performance Recurring microbial contamination observed on the field case studies Good practices for microbial contamination control Conclusion

30 Early collaboration between vendors and end-user will change the trend! : # : #5050 Center name: Drugs Actual Total # of 483's issued: 2014: # : # : # CFR Control of microbiological contamination: (a) 'Procedures designed to prevent objectionable microorganisms in drug products not required to be sterile are not [established] [written] [followed]. Specifically, (b) 'Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include [adequate] validation of the sterilization process. Specifically, CFR (a) 21 CFR (b) 21 CFR (a) 21 CFR (b) 21 CFR Source: 21 CFR Equipment cleaning and maintenance: (a) 'Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, (b) Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, and 'Written procedures for cleaning and maintenance fail to include [assignment of responsibility] [maintenance and cleaning schedules] [description in sufficient detail of methods, equipment and materials used] [description in sufficient detail of the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance] [instructions for removal or obliteration of previous batch identification] [instructions for protection of clean equipment from contamination prior to use] [parameters relevant to the operation]. Specifically, 21 CFR Equipment design, size, and location: Equipment used in the manufacture, processing, packing or holding of drug products is not [of appropriate design] [of adequate size] [suitably located] to facilitate operations for its [intended use] [cleaning and maintenance]. Specifically,

31 Thank You For your listening El Azab Walid Technical Service Manager STERIS

32 References Parenteral Drug Associations (2014) PDA Technical Report No. 67 : Exclusion of Objectionable Microorganism from Nonsterile Pharmaceuticals, Medical devices and cosmetics. Sutton S..(2012). What is an "Objectionable Organism"?, 2012, American Pharmaceutical Review 15(6): Sutton, S and L Jimenez. (2012). A Review of Reported Recalls Involving Microbiological Control with Emphasis on FDA Considerations of Objectionable Organisms, American Pharmaceutical Review 15(1):42-57 Tim Sandle, Assessment of the suitability of the R3A agar for the subculture of microorganisms isolated from pharmaceutical water systems. (2014). European Journal of Parenteral & Pharmaceutical Sciences 2014;19(3):85-93 Tim Sandle. (2011). A Review of Cleanroom Microflora: Types, Trends, and Patterns. PDA J Pharm Sci and Tech 2011, Lopolito, P. and Rivera, E. (2013) An Audit Approach to Address Microbial Contamination in Process Equipment, Volume 1, DHI/PDA, Chapter 15, El Azab W. (2016), Investigation of Microbiological Contamination in Water Systems: A Case Study, Contamination Control in Healthcare Product Manufacturing, Volume 4, DHI/PDA, Chapter 7 Sandle T., Understanding cleanroom flora, The Official Journal of The Institute of Science & Technology Journal, (2013) Sandle T., Peer Reviewed: Cleanroom Contamination, IVT network (people-cleanrooms-understanding-and-monitoring-personnelfactor), (2014). Madsen R., Moldenhauer J., Contamination Control in HealthCare Product Manufacturing, PDA and DHI, Vol. 3, 2013, p Lucia Stecchini M., Del Torre M., Sarais I., Saro O., Messina M., Maltini E., Influence of Structural Properties and Kinetic Constraints on Bacillus cereus Growth, Applied and Environmental Microbiology, 64 (3), (1997). Whyte W., and Eaton T., Microbiological contamination models for use in risk assessment during pharmaceutical production. European Journal of Parenteral and Pharmaceutical Sciences, 9 (1), pp (2004). Whyte W., and Eaton T., Microbial risk assessment in pharmaceutical cleanrooms. European Journal of Parenteral and Pharmaceutical Sciences, 9 (1), 16-23, (2004). Polarine J., Bartnett C., Smith T., Klein D., Karanja P., Peer Reviewed: Fungicidal Activity of Globally Acceptable Quaternary Ammonium Disinfectants, Journal of Validation Technology, 2013 Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.

Case study Microbiological excursion during a phase I PQ of a WFI system. Walid El Azab Technical Service Manager STERIS Life Science

Case study Microbiological excursion during a phase I PQ of a WFI system Walid El Azab Technical Service Manager STERIS Life Science Agenda Agenda Case study Microbiological excursion Description of the