| Slide 1 of November 2009 Prequalification: Inspection Activities Prequalification Programme: Priority Essential Medicines WHO Prequalification of Generic Medicines approved by Stringent Regulatory Authorities Presented by Mr. Deus K Mubangizi Technical Officer Organization of prequalification inspections and applied standards

| Slide 2 of November 2009 Prequalification: Inspection Activities In this presentation: Inspection activities wrt WHO-PQ Mission, Strategy and Process Scope of inspection activities: FPPs, APIs, BE/CROs, QCLs Norms and standards used Risk-based approach to inspections Use of inspection reports from other NMRAs Inspection frequency, duration and scheduling Inspection process Classification of deficiencies Conclusions following an inspection: –Acceptable level of compliance –Conclusion on level of compliance awaits CAPAs –Unacceptable level of compliance Results and transparency: WHOPIRs and NOCs on website

| Slide 3 of November 2009 Prequalification: Inspection Activities Inspection Activities and scope wrt PQ Mission & Strategy Prequalification Programme aims to make quality priority medicines available for the benefit of those in need through: –Evaluation of a dossier of product quality, safety and efficacy information –inspection of manufacturing sites for FPPs and APIs, BE studies/CROs, QCL (National or independent) –building national capacity for sustainable manufacturing and monitoring of quality medicines.

| Slide 4 of November 2009 Prequalification: Inspection Activities USP BP Ph. Eur. Ph. Int. Prequalification Programme: International norms, standards and guidelines used in inspection activities Other guidelines e.g. ICH, ISO

| Slide 5 of November 2009 Prequalification: Inspection Activities Risk based approach to inspections Ref: SOP 401.1: Inspection Frequency and Scheduling Inspections are scheduled on a risk basis, taking into account all known factors that could affect quality, safety and efficacy, including the following: –results of previous WHO inspections  results of inspections by other National Regulators –type of APIs, products and dosage form manufactured or - activities performed  recalls or complaints since last inspection  results of product testing –significant changes within the manufacturer, e.g. changes to key personnel, buildings, equipment, products etc. –any other relevant information (e.g. variations)

| Slide 6 of November 2009 Prequalification: Inspection Activities Prequalification Programme: Use of Inspection reports from other NMRAs An inspection by the PQP may be omitted when other acceptable evidence of GMP compliance is provided by the FPP or API manufacturer. An inspection by another acceptable organization, such as a PIC/S member country, or the US FDA, may be considered in lieu of a PQP inspection when: –The inspection was conducted within the last 2 years, and  The scope of the inspection covered the specific FPP or API in question, and  The FPP or API manufacturer submits a copy of the last inspection report for review by the PQP. (During the review, the inspectors will determine whether the inspection was comprehensive, covered the relevant areas appropriate to the product in question and that the inspection report supports the final outcome in accordance with WHO GMP). –Irrespective of the above, the PQP reserves the right to inspect any FPP or API manufacturer if considered necessary. Whether inspected by the PQP or GMP compliance is based on an inspection by another acceptable organization, on-going GMP compliance will be confirmed by WHO.

| Slide 7 of November 2009 Prequalification: Inspection Activities Guide to Manufacturer Risk Classification Ref: SOP 401.1: Inspection Frequency and Scheduling RELATIVE RISK CATEGORY PRODUCT TYPE / ACTIVITY LOWMEDIUMHIGHCRITICAL Finished Products: Sterile finished products Non-sterile finished products APIs: Sterile APIs Non-sterile APIs where there is a special risk (e.g. isomerism, polymorphism, special risk of harmful impurities, etc) Other non-sterile APIs QC Laboratories CROs

| Slide 8 of November 2009 Prequalification: Inspection Activities RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME (1 of 2) API Manufacturer Number of ProductsPresent in Product (Ref. Nos.) Risk ScoreRisk = 1Risk = 2Parameter NYPolymorphism1 HighLowSolubility in water2 Not complexComplexSynthesis3 Low riskHigh RiskSolvents4 Low riskHigh RiskImpurities5 NYSterile6 NYFermentation7

| Slide 9 of November 2009 Prequalification: Inspection Activities RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME (2 of 2) Risk ScoreRisk = 1Risk = 2Parameter LowHighToxicity8 Low riskHigh RiskActivity/potency9 Low riskHigh RiskParticle size10 Other property consideration11 PositiveNegative Site compliance information (WHO/EDQM/Other) 12 Total Risk Score General remarks: Compliant OutcomeLast inspection date Not Compliant High Inspection prioritization Medium Low

| Slide 10 of November 2009 Prequalification: Inspection Activities Guide To Inspection Frequency ( in months ) Ref: SOP 401.1: Inspection Frequency and Scheduling GMP Compliance Rating: RISK CATEGORY : Unacceptable Acceptable: BasicSatisfactoryGood Determine on a case by case basis Critical Determine on a case by case basis High Determine on a case by case basis Medium Determine on a case by case basis Low

| Slide 11 of November 2009 Prequalification: Inspection Activities Inspection Duration Guide ( on-site days ) Ref: SOP 401.1: Inspection Frequency and Scheduling RISK Manufacturer Size LMHCLMHC Re-inspectionInitial Inspection Large Major Standard

| Slide 12 of November 2009 Prequalification: Inspection Activities Inspection Scheduling Initial inspections: are scheduled at a suitable time to avoid delaying product prequalification (max 180 days after dossier accepted). Routine re-inspections: are scheduled so that the inspection is conducted within the period 3 months before and 3 months after, the due date. –The due date for re-inspection is determined immediately after each inspection based on manufacturer risk classification and GMP compliance rating. –Maximum validity of compliance status – 3 years Special inspections: (e.g. to investigate a complaint or reasons for product failure) may be conducted at any time. Follow-up inspections: (to close out deficiencies from the last inspection) may be conducted if deemed necessary. –If a special or follow-up inspection is conducted, the timing of the next routine re-inspection is re-determined on a case by case basis.

| Slide 13 of November 2009 Prequalification: Inspection Activities Prequalification: Inspection Processes  By a team of qualified and experienced inspectors WHO representative (qualified inspector) Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S) National inspector/s invited to be part of the team but have NO decision making power (different GMP standards, potential conflict of interest) Observer from recipient/developing countries (nominated by DRA of the country)  Scope:  Compliance with guidelines: GMP, GCP, GLP  Data verification – data manipulation, falsification, (validation, stability, clinical, bioanalytical)  Quality control (QC, BAL, NQCL, IQCL)

| Slide 14 of November 2009 Prequalification: Inspection Activities Definition and classification of deficiencies Deficiencies are descriptions of non-compliance with GMP requirements. A distinction is made between deficiencies as a result of: - –a defective system or, –failure to comply with the system. Deficiencies may be classified as: –Critical Observation –Major Observation –Minor or Other Observation

| Slide 15 of November 2009 Prequalification: Inspection Activities Further considerations for classification 1.Classification of an observation is based on the assessed risk level and may vary depending on the nature of products manufactured, e.g. in some circumstances an example of an "other" deficiency may be categorized as "major". 2.A deficiency that was reported at a previous inspection and not corrected may be reported in a higher classification. 3.One-off minor lapses or less significant issues are usually not formally reported, but are brought to the attention of the manufacturer during the inspection.

| Slide 16 of November 2009 Prequalification: Inspection Activities Conclusion following an inspection: When there are "other" observations only: –considered to be operating at an acceptable level of compliance with WHO GxP. –The manufacturer is expected to provide CAPAs. –CAPAs are evaluation and followed up during the next routine inspection. When the are "other" and a few "major" observations: –compliance with WHO GxP is made after the CAPAs have been assessed. –CAPAs for majors to include documented evidence of completion. –CAPAs paper evaluated ± an on-site follow up inspection. When there are "critical" or several "major" observations: –considered to be operating at an unacceptable level of compliance with WHO GMP, GCP, GLP guidelines. –Another inspection will be required

| Slide 17 of November 2009 Prequalification: Inspection Activities Prequalification Programme: Transparency - WHOPIRs and NOCs These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO, among other actions: –"3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;" A WHO Public Inspection Report (WHOPIR) reflects a positive outcome after an inspection A Notice of Concern (NOC) is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or research organization.

| Slide 18 of November 2009 Prequalification: Inspection Activities Conclusions For PQP of generics approved by SRA, we shall largely rely on positive inspection outcome by SRAs - but reserve the right to inspect Risk management principles are applied when: –scheduling inspections –conducting inspections –closing out inspections Inspections are conducted according to written SOPs: –No bias or subjectivity – each deficiency is referenced to a guideline, standard or norm. –No surprises in the report - Feedback is given every day and at the end of the inspection. Participation of NRAs in providing co-inspectors and observers is good for: –Tapping into international skills –Ensuring transparency  Facilitating ownership – possible faster national penetration –Contributing to capacity building