1. GMP issues for Quality Assessment of Dossiers Rutendo Kuwana Technical Officer Prequalification of Medicines Program WHO

2. Dossier for FPP pre-qualification ScreeningApplicant Quality Part of Dossier API FPP Efficacy/Safety Part of Dossier Biowaivers Bioequivalence studies Clinical trials GMP API manufacturing sites FPP manufacturing sites Clinical research sites. Review of GMP Certification, Inspection reports, Site Master Files (SMF). Information requested Applicant Dossier accepted for assessment Assessment APIMF Accepted Information requested Applicant Manufacturers Inspection Corrective and preventive actions Final decision on prequalification Listing on WHO website Requalification (5 years after listing) Variations Complaints Random sampling Information requested Information requested APIMF holder Information requested Optional

3. PQ Assessors training, Jan 2011 Overview Aims of inspection and link to assessment Types of inspections and what they focus on Some examples How deep should you go during assessment in case the same is assessed during inspection? Challenges faced

4. PQ Assessors training, Jan 20114 General aims of inspection Evaluate commercial manufacturing capability, adequacy of production and control procedures, suitability of equipment and facilities, and effectiveness of the quality system in assuring the overall state of control Use principles of risk assessment Observe claims/activities/practices in-situ

5. PQ Assessors training, Jan 2011 Link to Assessment Assessment provides essential input on product/process design, and feeds into the inspection to evaluate commercial process implementation Assessors should, as much as possible, state any need (with reasons) for GMP, GLP and GCP concerns

6. PQ Assessors training, Jan 2011 Inspectors Assure a Safe Landing for Assessors?

7. PQ Assessors training, Jan 2011 ICH Q10 "Monitoring during scale-up activities can provide a preliminary indication of process performance and the successful integration into manufacturing. Knowledge obtained during transfer and scale-up activities can be useful in further developing the control strategy"

8. PQ Assessors training, Jan 2011 The ICH Q8, 9 and 10 - inspection focus Is the manufacturer implementing the process parameters (both CPPs and non-critical) How is change control performed in the design space? In the manufacturer inside / outside the Design Space? How does the manufacturer manage an event ‘out of design space’? Is the manufacturing site capable of implementing the control strategy

9. PQ Assessors training, Jan 20119 Pre-Approval Inspections (PAI) Evaluation of authenticity of submitted data and link to dossier Assessors generally should trust attestations provided in dossiers by applicants/manufacturers The inspectors role is to provide further assurance that the trust is not misplaced Remember assessors are generally shown the "compliant" data. Inspectors will also see "failed" studies and evaluate lessons learnt

10. PQ Assessors training, Jan 2011 Focus of post approval inspection Assess whether manufacturer maintains State of Control by assessing: Review of process performance and product quality monitoring system Corrective action and preventive action (CAPA) system Assessment commitments e.g. commitment that three consecutive, production-scale batches of the FPP will be subjected to prospective validation in accordance with submitted protocol; The applicant commits that information from these studies will be available for verification after prequalification by the WHO inspection team. Also for ongoing stability testing

11. PQ Assessors training, Jan 2011 Pre Approval Inspections (PAI) - General Technology transfer from development site to manufacturing site: evaluation of protocols and acceptance criteria Provide the possibility to review batches in addition to those submitted in the application Review Process Validation plan and Master Validation plan (or equivalent) So does the assessor need SOPs to be submitted for assessment or simply statements of confirmation that it is done?

12. PQ Assessors training, Jan 2011 How is Pharmaceutical Quality System (PQS) operating? Evaluate if Systems in place support new product and to if they can detect any potentially non-compliant product to prevent its distribution on the market Clarify if PQS is product or site specific or global How PQS is integrating “outsourced” activities e.g. contracting of testing when relevant equipment/technology not available on site Process improvements - Is process knowledge used for improvement? How? When? Self inspection Product release and Annual Product Quality review

13. PQ Assessors training, Jan 2011 General issues on API manufacturing Outsourcing of API or intermediate supply Supplier Management of Starting Materials, intermediates, etc. under PQS – Supplier/Vendor Qualification

14. PQ Assessors training, Jan 2011 PAI for API Review of API process (DMF, batch records, receipt/handling or storage of starting materials, any holding or storage of the API during the process,) Equipment/ facility capability, production SOPs, scale-up Control of starting materials and intermediates Control for potential degradation Control of particle size during crystallization Focus is on critical parameters e.g. degradation and crystallization. Or any other critical parameters

15. PQ Assessors training, Jan 2011 PAI - FPP Review the development report, if available Evaluation of Potential variables and associated risks (e.g. raw materials, sites, equipment, personnel…) Does the operation support the intended volume of production? i.e. Resources and Equipment (including support equipment e.g. HVAC)

16. PQ Assessors training, Jan 2011 Control of materials Inspectors will look at aspects of the Raw Material Control Program e.g. Supplier selection and qualification program and Incoming raw material testing program Focus on critical quality attributes (CQA) e.g. specific surface area (SSA) for magnesium stearate Adequacy of the sampling plan (number of containers, part of container, sample size, pooling of sample etc) and testing (Skip testing, reliance on supplier CoA)

17. PQ Assessors training, Jan 2011 PAI - FPP Evaluation of aspects of unit operations focusing on manual or semi-automated aspects such as Blender loading and discharge Transport and storage of blend Charging of the compression machine Training adequacy (risk based training?) Evaluation of mechanical aspects of unit operations e.g. Special equipment performance and capability to deliver the desired output

18. PQ Assessors training, Jan 2011 PAI - testing Can the test method described in the application be implemented (Whether pharmacopoeial or in-house)? Verification of method development and/or validation data – review of raw data, chromatograms, calculations, security of data from loss or manipulation of source data Generation, control and use of reference standards – primary, secondary etc equipment calibration and qualification Sample handling and records

19. PQ Assessors training, Jan 2011 Example: Evaluation of viability of blend homogeneity Evaluation of equipment IQ, OQ, PQ reports and instruments e.g. type of transmittance probe for IPC How post-blend hold time was determined – results of study demonstrating absence of segregation / aggregation during discharge, transport and charging API assay in blend: sampling tool, number of samples, sampling plan Stability to moisture risks

20. PQ Assessors training, Jan 2011 Example: Control of Compression operation e.g. Evaluation of details of the control strategy for tablet hardness established within quality system How is this parameter controlled on line, at line or in line? Sampling plan Total number of tablets tested Acceptance criteria SOPs for handling deviations

21. PQ Assessors training, Jan 2011 Assessors Should Be Aware of The inspection process including criteria for when to inspect and specifically when in terms of the progress of the dossier the site is deemed ready for inspection How the assessment report is used by inspectors (including "Recommendations for inspection") The critical information which should be in the assessment reports (addresses, document references, versions, effective dates, errors/omissions, critical statements or claims that need verification) Known inspection-related issues to be flagged by assessors e.g. site-specific and general issues which should result in a closer assessment of related dossiers, importance of unit/block information, PQS, validation, recurrent omissions, data contradictions/inconsistencies

22. PQ Assessors training, Jan 2011 Some manufacturer's Challenges for Inspectors Suppliers of excipients not consistent or varied/"too big" for manufacturer to effectively control Manual vs. automated equipment e.g. hand filling of tablets, hoppers filled by constant pouring blend from bins Old equipment that cannot be calibrated or controlled using assessment expectations e.g. amperage for granulation end point Manual integration of chromatograms electronically/graphically Most documents/records generated during period of "poor regulation"

23. PQ Assessors training, Jan 2011 So how relevant is local GMP certificate? For PQP we recognise only SRA and PICs inspectorate certificates + our own WHO inspections Local GMP confirms that the facility is authorised to carry out the activities we intend to or have approved What is a WHO GMP certificate? This does not exist. However WHO has published a recommended (WHO – type) format of presenting certification of compliance with GMP Certification of compliance with any GMP guidance is as good as the inspectorate issuing it and not necessarily the guidance referred to

24. PQ Assessors training, Jan 2011 Concluding Messages Assessment and inspection are complementary but different activities Collaboration between assessors and inspectors in pre-approval inspections is critical For efficiency it is important to respect the distinct roles of assessors and inspectors Inspection determines manufacturing capability and evaluates whether the manufacturer remains in control of the products quality at a point in time