Regulatory Requirements, Expectations and Hot Topics

1. Regulatory Requirements, Expectations and Hot Topics Rachel Blount Global Validation Manager October 2014

2. Training Objectives To understand: • The regulatory requirements with regards to cleaning and disinfection • The regulatory expectations with regards to cleaning and disinfection • Examples of non-compliance (from FDA Warning Letters) • How to ensure compliance with the regulatory requirements and expectations

3. Cleaning and Disinfection – a critical process • Effective cleaning and disinfection is critical to contamination control • Often under-valued: • Performed at the end of the day • Maybe performed by contractors • Unlikely to be subject to comprehensive and objective review • Frequently a source of regulatory observations

4. US Inspection Trends FDA 2013 data, inspection of drug manufacturers 25% of all audit observations related to cleaning and disinfection (177 out of 690) • Cleaning/sanitisation/maintenance (71, 7th most common) • Deficiencies in procedures for cleaning/maintenance (26) • Deficient cleaning systems for aseptic processing rooms/equipment (20) • Building not clean/free of infestation (20) • Deficient sanitisationprocedures (15) • Cleaning/sanitisation records not kept (12)

5. US Inspection Trends FDA 2013 data, inspection of drug manufacturers Continued… • Written sanitisation procedures not followed (5) • SOP does not define responsibility for cleaning/sanitisation (2) • Floors/walls/ceilings in aseptic areas not easily cleanable (2) • Deficient cleaning schedules (1) • Deficient cleaning instructions (1)

6. GMP Guidelines • EU Guidelines to Good Manufacturing Practice – Medicinal Products for Human and Veterinary Use Part 1: Basic Requirements for Medicinal Products Annex 1: Manufacture of Sterile Medicinal Products • PIC/S – Pharmaceutical Inspection Co-operation Scheme A cooperative arrangement between health authorities of different nations intended to improve the GMP standards and facilitate international harmonisation of GMP standards PIC/S GMP Guide is harmonised with EU GMP Guide Plus additional non-mandatory guidance documents (cGMP)

7. EU GMP Guide – Chapter 4 Documentation 4.29. There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples: • Validation and qualification of processes, equipment and systems; • Maintenance, cleaning and sanitation; • Environmental monitoring

8. Example Audit Finding May 2013 “Written procedures are lacking for the use of fumigation agents and cleaning and sanitisation agents…” • The "Cleaning and Maintenance of the Clean Room Facility" document #3.020, version 2.0…requires the use of a variety of cleaning solutions e.g., 2% acidified bleach, Sterile 70% IPA, Vesphene and/or LpH, a "minimum contact time of 5 minutes is recommended for maximum disinfection efficacy when using bleach." However, there is no record to document the preparation and/or calculations that are performed when preparing the Vesphene and/or LpH sanitizing solutions and the Compounding Director and Pharmacy Technician confirmed that there is no record to document the "5 minutes recommended for maximum disinfection efficacy."

9. EU GMP Guide – Annex 1 Manufacture of Sterile Medicinal Products 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. 62. Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.

10. PIC/S Recommendation on the Validation of Aseptic Processes 9.4.1 There should be documented procedures describing the preparation and storage of disinfectants and detergents. These agents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being filled and have a short in-use shelf life.

11. Example Audit Finding May 2013 • There are no sterilisation records for the plastic squirt bottles that are used for sterile 70% isopropyl alcohol.

12. PIC/S Recommendation on the Validation of Aseptic Processes 9.4.2 Sporicidal agents should be used wherever possible but particularly for “spraying-in” components and equipment in aseptic areas.

13. Example Audit Finding 12 July 2012 • Your SOP entitled “Disinfection Program for Equipment and Manufacturing Areas in Building XXXX; BCG Department” is inadequate. Sporicidal disinfection of aseptic manufacturing areas using XXXXis only required to be performed XXXX. There have been no less than 58 documented non-conformances relating to the isolation of mould within the BCG aseptic processing areas…since August 2010.  • There is no documented evidence that corrective action in follow-up to non-conformances relating to the isolation of mould within the BCG aseptic manufacturing areas includes cleaning with a sporicidal agent. 

14. PIC/S Recommendation on the Validation of Aseptic Processes 9.4.3 The effectiveness of disinfectants and the minimum contact time on different surfaces should be validated.

15. Example Audit Finding 12 July 2012 “You failed to assure an adequate system for cleaning and disinfecting aseptic processing areas and equipment. For example: • Report C017795 entitled “Year 2010 Re-Evaluation of the Approved Disinfectants/Sporicidal Agents” used bacterial and mould spores to test the effectiveness of disinfectants and sporicidal agents used at your facility…The effectiveness study is inadequate in that it did not evaluate use of the disinfectants and sporicidal agents on surfaces other than XXXX.

16. Example Audit Finding May 2013 • Written procedures are lacking for the use of fumigating agents and cleaning and sanitizing agents designed to prevent the contamination of equipment, components, drug product containers, and drug products. The Manager of Quality Control and Clinical Trials confirmed that they do not have any records to document efficacy studies for the Vesphene, LpH, 70% Isopropyl alcohol, sodium hypochlorite 2% and/or for the sodium thiosulfate 0.9% with benzyl alcohol.

17. Directives and Guidance • FDA Guidance for Industry 2004 – Sterile Drug Products Produced by Aseptic Processing • “The suitability, efficacy and limitations of disinfecting agents and procedures should be assessed.” • “The effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces.” • “Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility.” • “… a sound disinfectant program also includes the use of a sporicidal agent, used according to a written schedule and when environmental data suggests the presence of sporeforming organisms.”

18. Directives and Guidance • USP36-NF31 Chapter <1072> • “The selection of suitable disinfectants and the verification of their effectiveness in surface challenge testing is critical in the development of a cleaning and sanitization program.” • “To demonstrate the efficacy of a disinfectant within a pharmaceutical manufacturing environment, it may be deemed necessary to conduct the following tests: • (1) use-dilution tests… • (2) surface challenge tests… • (3) a statistical comparison of the frequency of isolation and numbers of microorganisms isolated prior to and after the implementation of a new disinfectant.” • “It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent.”

19. Example Audit Findings • “…studies have not been completed to support the effectiveness of disinfectants used in the cleaning of manufacturing areas.” • “The study did not evaluate the effectiveness of the disinfectants in use on fungi and spore forming microorganisms. Spore forming microorganisms have been routinely isolated in your manufacturing facility” • ““…your firm’s disinfection program included insufficient use of sporicidal agents.”

20. Example Audit Findings • “You do not use an effective sporicidal disinfectant as part of your routine disinfection program for your clean rooms.” • The qualification of your disinfectant (b)(4) failed to demonstrate that it is suitable and effective to remove microorganisms from different surfaces. Specifically, this disinfectant failed to meet qualification criteria when challenged with multiple organisms.”

21. Regulatory Expectations - Training • Cleaning staff shall be provided with the same level of training as production staff • Training shall include not only the cleaning procedures, but also the basics of GMP and microbiology/hygiene • Training shall be documented • Ideally training should include a practical component (e.g. performance of techniques, visualisation of risks), not just reading the SOPs • NOTE: Training of contract cleaners is often overlooked and not given the same attention as training of company staff

22. Regulatory Expectations – Documents & Records • Written instructions shall include: • Responsibilities for the activities • A schedule of cleaning/disinfection • Description of materials approved for use • Details of techniques to be used • Instructions of maintenance and inspection of the cleaning equipment • Instructions for the preparation/disposal of disinfectant solutions

23. Regulatory Expectations – Documents & Records • Consider how the document will work in practice • Instructions should be clear and concise • Use tables and diagrams wherever possible rather than text • It may be useful to have a cleaning and disinfection policy document (what materials are approved for use and how they should be used) which is separate from the cleaning schedule (what areas are cleaned and at what frequency)

24. Regulatory Expectations – Documents & Records • Records shall be maintained and should include the following details: • Name and signature/initials of person performing the tasks • Preparation of disinfectants/cleaning agent • Batch number, expiry date of cleaning agent/disinfectant used • Records should be reviewed frequently by a supervisor to ensure compliance

25. Regulatory Expectations – Validation • Disinfectant efficacy shall be validated, including in-house isolates • EM contact media should be validated to confirm that it is able to neutralise any residual disinfectant • Contact media supplier for guidance on which neutralisers to use • Study should be performed to demonstrate that low levels of organisms can be recovered in the presence and absence of disinfectant surface residues

26. Regulatory Expectations – EM Trending • Trending of EM data shall be performed and acted upon. • EM trends can provide useful information with regards to the performance of the: • Room (e.g. surfaces) • Equipment (e.g. HVAC) • People (e.g. cleanroom behaviour) • Cleaning and disinfection process (e.g. appropriate agents used, appropriate frequencies etc.)

27. Regulatory Expectations – EM Trending • Points to consider for cleaning/disinfection related CAPAs: • Is cleaning being performed as well as disinfection? • Are the appropriate biocides being used (sterile vs. non-sterile, spectrum of activity)? • Is the correct rotational scheme in place? • Are the appropriate techniques being employed?

28. Summary • Cleaning and disinfection is a critical process, which is often over-looked • Many warning letters due to poor practice and lack of validation • Due to our customer contacts across the globe we can support you with information and guidance regarding industry best practice • We can provide customers with the appropriate materials, tools and training to enable them to work compliantly.

29. Questions? Thank you!