Webinar Expert Module 3: GMP Inspections Dupont

Transcription

1 Webinar Expert Module 3: GMP Inspections Dupont 26 January & 9 February 2018 GOP-Innovations your Partner for Practical Training and e-learning

2 Milenko Pavičić Pharmaceutical microbiologist, trainer, coach 10 years of research experience Vrije Universiteit Amsterdam (Medical and Oral Microbiology) Intervet International B.V. (Antibiotics R&D) 19 years of production and QC experience Pharmaceutical companies (NL, B, D, F) Hospital pharmacies (NL, B) Member of the NVZA (Dutch Society of Hospital Pharmacists) work group Microbiology and Hygiene

3 Pavičić Pharmaceutical Microbiology (PPM) and GOP-Innovations Consultancy Courses Practical Training E-learning Aseptic production, Sterilisation, Cleaning, Cleanrooms, Disinfection, Microbiology, GMP, Annex 1, Annex 17, QC, Validation, Qualification, Behavior, SOPs, Media fills, Environmental monitoring, Water systems, Sampling, Hygienic Design, EU-GMP, FDA-GMP, EP, USP, Contamination Risk

4 Subjects for today Introduction to GMP inspections Inspection topics related to cleanroom garments and gowning Examples of garment and gowning related inspection observations

5 Good Manufacturing Practice (GMP) guidelines European GMP Example: Annex 1: Manufacture of Sterile Medicinal Products United States GMP Example: Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing cgmp Japanese GMP Example: Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing World Health Organization (WHO) GMP Example: Annex 6. WHO good manufacturing practices for sterile pharmaceutical products

6 European GMP guidelines Eudralex Volume 4 of The rules governing medicinal products in the European Union Eudralex Volume 4 contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively.

7 GMP guidelines Minimum standard for production processes for medicines Medicines must have a consistent high quality be appropriate for their intended use meet the requirements of the marketing authorization

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9 The 10 golden rules of GMP 1. Get the facility design right from the start 2. Validate processes 3. Write good procedures and follow them 4. Identify who does what 5. Keep good records 6. Train and develop staff 7. Practice good hygiene 8. Maintain facilities and equipment 9. Build quality into the whole product lifecycle 10. Perform regular audits

10 GMP inspections general Check if manufacturers and distributors comply with GMP Initial inspection takes place at organizations that apply for a manufacturer or wholesaler dealer license Periodic inspections take place based on risk assessments

11 European Medicines Agency (EMA) role in GMP inspections Coordination of GMP inspections of manufacturers with EU marketing authorizations Coordination and harmonization of GMP activities coordination of the preparation of new/revised guidance ensure common interpretation of guidance development of EU-wide procedures on GMP inspections

12 Execution of inspections EU EU: national authorities responsible for inspections located within their own territories Outside EU: inspected by national authority of Member State where the EU importer is located, unless a mutual recognition agreement (MRA) is in place (= rely on each other s inspections)

13 Types of GMP inspections EU Initial inspection: New applications Periodic inspection: Assessment of GMP compliance For cause inspection: Finding of possible noncompliance Follow-up inspection Variation inspection: After an application to vary the manufacturing license is received

14 Food & Drug Administration (FDA) responsibilities Protecting public health by ensuring that human and veterinary drugs, and vaccines and other biological products and medical devices intended for human use are safe and effective Advancing the public health by helping to speed product innovations

15 Types of GMP inspections FDA Pre-Approval Inspection Post-Approval Inspection Full Inspection (new facility, history of noncompliance, doubts about quality system) Abbreviated Inspection (surveillance, satisfactory compliance record)

16 Form 483 FDA Used by FDA Investigators to document deficiencies Issued at the end of the inspection Official response within 15 working days Only then it is guaranteed that the company s statement will be taken into account in a possible Warning Letter

17 Establishment Investigation Report (EIR) FDA Document from the FDA Investigator in addition to form 483 within 30 working days Responsible Center or District Office of the FDA determines GMP status

18 GMP status FDA No Action Indicated (NAI): no objectionable items found during the inspection Voluntary Action Indicated (VAI): objectionable items were found, but no action is required on the part of the authority. All of the company's actions are on a voluntary basis. Official Action Indicated (OAI): objectionable items were found and further regulatory measures will be derived (e.g. Warning Letter)

19 Warning letter FDA When serious defects were identified Answer to the Form 483 is classified as inadequate Response within 15 working days Response shall include a detailed explanation how deficiencies will be resolved and how recurrence will be prevented

20 Consequences FDA Influence on the approval: Authorization for products will not be granted. Applications will not be processed. Import Stop: The company's product may no longer be imported into the US. Debarment List: All persons who are not allowed to produce pharmaceutical products for the American market. Court - Consent Decree: for several months to years a consulting company will check the company and streamline systems and processes. A final inspection is carried out at the end.

21 GMP Inspections WHO Routine inspection Concise inspection Follow-up inspection Special inspection Quality systems review

22 Quality Systems Review Assessment of quality assurance (QA) system Quality Systems Manual (QSM) Quality systems and standards Operational process Quality management policy Quality assurance approach The QSM reflects the process of implementation of the quality policy, keeping of records, quality control and other quality assurance activities

23 Frequency of Inspections Type of inspection Risk based Validity of manufacturing license or GMP certificate History Inspectorate resources

24 Duration of Inspections Days to weeks Depends on Type of inspection Purpose of the visit/reason for inspection Size of the company Number of inspectors Inspectorate resources

25 Announced and unannounced inspections Announced: comprehensive inspection Unannounced routine inspection (depending on country policy) concise inspection follow-up inspection special inspection

26 Consequences/Regulatory Actions Correction of unsatisfactory situations Closing down of a factory Withholding of authorizations Product recall

27 Cleanroom garments (1) GMP inspections Qualification of manufacturer and supplier Qualification of cleanroom laundry service Validation of sterilization of garments Qualification of garment (URS, DQ, IQ, OQ, PQ)

28 Cleanroom garments (2) GMP inspections Quality Control Transport, storage Policy for damaged garments and repairs Garments replacement policy

29 Gowning training Gowning GMP inspections Gowning qualification Monitoring Actions after deviations Follow-up actions after deviations

30 Inspection observations (1) examples Five of 10 garments released for use in aseptic production areas had loose fibers or other damage. No assessment of washing, drying, ironing, sterilizing, or other operations that may contribute to sterile garment damage. No limit mentioned for the number of sterilizations.

31 Inspection observations (2) examples Correct your visual inspection procedures for sterile garments to improve detection and rejection of defective garments. Conduct a risk assessment of the effects of damaged garments on your drugs. Your firm demonstrated poor aseptic technique in gowning.

32 Inspection observations (3) examples Investigators observed poor aseptic practices, including, but not limited to, excessive touching of the outside of hood and gown. Your firm fails to perform personnel (gowning) monitoring. Your firm fails to perform gowning qualification for operators and all operators are not requalified for gowning on an annual basis.

33 Inspection observations (4) examples Water sprayed directly onto an operator, which wet his gown. The operator continued line setup activities without re-gowning. FDA investigators observed incorrect donning of protective clothing. Our expectation is that gowning components, including goggles, be sterilized before use in an aseptic processing area.

34 Inspection observations (5) examples You have not validated your aseptic gowning process and routine personnel monitoring is not performed. Your firm has failed to establish a program to qualify the operators ability to gown in an aseptic manner. Your firm does not perform fingertip sampling and gowning assessments as part of either an initial competency evaluation or a routine monitoring program to assess the aseptic practices of compounding personnel.

35 Inspection observations (6) examples Our investigator observed employees working in gowns that had unraveled stitching extending from hoods, zippers, and pants. Your firm approved these gowns for operations. Our investigator noted that you sterilize gowns numerous times. These excessive sterilizations lead to breakdown of gown fibers. An operator sitting on the clean room floor during set-up of the filling line and not changing the gown after standing up.

36 Inspection observations (7) examples Select appropriate gown suppliers. Include the role of the quality unit in making supplier selection and ongoing qualification decisions. Reduce your maximum number of gown sterilizations to ensure that gowns are discarded before they show signs of breakdown. Provide the maximum number of resterilizations you will allow, and describe how you will document and validate this procedure.

37 Inspection observations (8) examples Correct your visual inspection procedures for sterile garments to improve detection and rejection of defective garments. Ensure that the quality unit makes final decisions relating to release of raw materials and supplies (e.g., garments) you use in production. Conduct a risk assessment of the effects of damaged garments on your drugs.

38 Inspection observations (9) examples Your facility was inadequately designed to prevent contamination. Specifically, components and gowning items are brought into the ISO 7 anteroom and placed on top of the potable water sink with no additional disinfection step prior to being transferred to the ISO 5 area.