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| Slide 1 of 43 29 - 30 March 2010, Beijing, China WHO GMP and API Inspections QUALITY OF PHARMACEUTICAL INGREDIENTS WHO Prequalification Programme: Priority.

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Presentation on theme: "| Slide 1 of 43 29 - 30 March 2010, Beijing, China WHO GMP and API Inspections QUALITY OF PHARMACEUTICAL INGREDIENTS WHO Prequalification Programme: Priority."— Presentation transcript:

1 | Slide 1 of March 2010, Beijing, China WHO GMP and API Inspections QUALITY OF PHARMACEUTICAL INGREDIENTS WHO Prequalification Programme: Priority Essential Medicines WHO GMP and API Inspections Presented by Mr. Deus K Mubangizi Technical Officer

2 | Slide 2 of March 2010, Beijing, China WHO GMP and API Inspections In this presentation: WHO-PQ: Inspection activities WHO-PQ: Norms and standards WHO-GMP for APIs versus ICH Q7A Key elements of ICH Q7A WHO-PQ API inspections: Observed trends and deficiencies Conclusions

3 | Slide 3 of March 2010, Beijing, China WHO GMP and API Inspections WHO Prequalification: Inspection activities *Stringent Regulatory Authority APIs, FPPs BE/CROs

4 | Slide 4 of March 2010, Beijing, China WHO GMP and API Inspections 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 and observe the inspection Observer from recipient/developing countries (nominated by DRA of the country)  Scope:  Compliance with guidelines: GMP (ICHQ7), GCP, GLP  Data verification – data manipulation, falsification, (validation, stability, clinical, bioanalytical)  Quality control (QC, BAL, NQCL, IQCL)

5 | Slide 5 of March 2010, Beijing, China WHO GMP and API Inspections 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

6 | Slide 6 of March 2010, Beijing, China WHO GMP and API Inspections 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

7 | Slide 7 of March 2010, Beijing, China WHO GMP and API Inspections 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/USFDA/Other) 12 Total Risk Score General remarks: Compliant OutcomeLast inspection date Not Compliant High Inspection prioritization Medium Low

8 | Slide 8 of March 2010, Beijing, China WHO GMP and API Inspections 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 (C) Determine on a case by case basis High (H) Determine on a case by case basis Medium (M) Determine on a case by case basis Low (L)

9 | Slide 9 of March 2010, Beijing, China WHO GMP and API Inspections Inspection Duration Guide ( on-site days ) Ref: SOP 401.1: Inspection Frequency and Scheduling RISK Manufacturer Size LMHCLMHC Re-inspectionInitial Inspection Large Major Standard

10 | Slide 10 of March 2010, Beijing, China WHO GMP and API Inspections Risk-based approach in: 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 – potential risk harm to the user –Major Observation – major deviation from GMP –Minor or Other Observation – departure from good practice

11 | Slide 11 of March 2010, Beijing, China WHO GMP and API Inspections Further considerations for classification 1.Classification of an observation is based on the assessed risk level and may vary depending on the nature of API 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.

12 | Slide 12 of March 2010, Beijing, China WHO GMP and API Inspections Risk-based approach in: Conclusion following an inspection When there are "other" observations only: –considered to be operating at an acceptable level of compliance with WHO GMP/ICHQ7. –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 GMP/ICHQ7 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/ICHQ7 guidelines. –Another inspection will be required

13 | Slide 13 of March 2010, Beijing, China WHO GMP and API Inspections Transparency: Information put in public domain - 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.

14 | Slide 14 of March 2010, Beijing, China WHO GMP and API Inspections Prequalification Programme: Use of Inspection reports from other NMRAs An inspection by the PQP may be omitted when other acceptable evidence of GMP compliance (Report + CAPAs) is provided by the FPP or API manufacturer. An inspection by another acceptable organization, such as a PIC/S member country, or US FDA or EU, 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 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 API manufacturer if considered necessary (specific product issues). 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 (also using update information from other NMRAs).

15 | Slide 15 of March 2010, Beijing, China WHO GMP and API Inspections Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide applicability Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol.2, GMP and inspection. WHO, Geneva, nce/production/en/index.html ICH Q7: GMP Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization. WHO GMP: water for pharmaceutical use. 39 th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3.

16 | Slide 16 of March 2010, Beijing, China WHO GMP and API Inspections Prequalification Programme: norms, standards and guidelines used… WHO guidelines for sampling of pharmaceutical products and related materials. 39 th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 4. Supplementary GMP guidelines for HVAC systems. 40 th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 2. Supplementary GMP guidelines: validation. 40 th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4. Good Practices for National Pharmaceutical Control Laboratories. 36 th Report. Geneva, WHO, 2002 (WHO TRS, No. 902), Annex 3. USP BP Ph. Eur. Ph. Int. Other guidelines e.g. ICH, ISO

17 | Slide 17 of March 2010, Beijing, China WHO GMP and API Inspections Prequalification Programme: norms, standards and guidelines used… WHO Expert Committee has revised WHO GMP for APIs at its meeting in October 2009 – adopted ICH Q7 principles. Final editing going on but numbering of sections essentially similar to ICH Q7: –ICH Q7 is used in the discussions that follow.

18 | Slide 18 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and ICH Q7 II. QUALITY MANAGEMENT III. PERSONNEL IV. BUILDINGS AND FACILITIES V. PROCESS EQUIPMENT VI. DOCUMENTATION AND RECORDS VII. MATERIALS MANAGEMENT VIII. PRODUCTION AND IN-PROCESS CONTROLS IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES X. STORAGE AND DISTRIBUTION XI. LABORATORY CONTROLS XII. VALIDATION XIII. CHANGE CONTROL XIV. REJECTION AND RE-USE OF MATERIALS XV. COMPLAINTS AND RECALLS XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS

19 | Slide 19 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP for APIs / ICH Q7 Key definitions: ICH Q7A –API starting material (API SM): a raw material, intermediate or an API used in the production of an API and incorporated as a significant structural fragment into the structure of the API. API SM can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API SM are normally of defined chemical properties and structure. –Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API.

20 | Slide 20 of March 2010, Beijing, China WHO GMP and API Inspections From what point does ICHQ7A start to be applied ? –“ICH Q7A applies from the point at which production of the API begins”. –Some indications are provided in Table 1 of ICH Q7A. For synthetic process, this corresponds to the introduction of the API starting material into the process; For other processes, on a case by case basis. ICH Q7A : Introduction

21 | Slide 21 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers Increasing GMP requirements

22 | Slide 22 of March 2010, Beijing, China WHO GMP and API Inspections Main issue : How to define the API SM ? Only flow chart GMPs do not apply Detailed description GMPs apply Competent Authorities Industry API SM Photo : Internet RM (solvent, catalyst, reagent, filtration aid, decolorizing agent, chromatography phase, etc.) C, H, O, N SM (Intermediates) n Active substance crude Active substance (pure)

23 | Slide 23 of March 2010, Beijing, China WHO GMP and API Inspections Application of ICHQ7 Companies should decide at which point ICH Q7A applies for their processes and should have documentation to support it. GMP applies from the declared and approved (API) SM in the registered file. Stringency of GMP in API manufacturing increases from early steps to final steps Advanced intermediates and crude APIs outsourced should be manufactured in compliance with GMP –This means that these “late intermediate and crude API” manufacturers should be considered as contract manufacturers (Q7A chapter 16 applicable). Sterilisation and aspetic processing should be performed according to GMP related to Sterile pharmaceutical products.

24 | Slide 24 of March 2010, Beijing, China WHO GMP and API Inspections Q7A does not apply to : –vaccines, whole cells, whole blood and plasma –blood and plasma derivatives (plasma fractionation) –gene therapy APIs –bulk-packaged medicinal products –medical gases and manufacturing/control aspects specific to radiopharmaceuticals. Q7A does not cover : –Safety aspects for the personnel engaged in the manufacture –and environmental issues. ICHQ7A: Scope

25 | Slide 25 of March 2010, Beijing, China WHO GMP and API Inspections Quality management (Chapter 2) –Responsibilities of the Quality Unit –Sections to –Tools for surveillance, monitoring and continuous improvement: –Internal audits/Self inspection (section 2.4) –Product Quality review (section 2.5) –Complaints, returns and recall (sections 14.5 and 15) –Change control (section 13) Review of some ICHQ7A’s concepts

26 | Slide 26 of March 2010, Beijing, China WHO GMP and API Inspections Change Change control –Raw materials, specifications, analytical methods, facilities, support systems, equipment (including computerized systems), processing steps, labelling and packaging materials –That can impact the quality of the API control Change control –Proposal drafted, reviewed and approved by the appropriate organisational unit –Change reviewed and approved by QU –Classification and impact assessment –Evaluation and monitoring + Notification Review of some ICHQ7A’s concepts

27 | Slide 27 of March 2010, Beijing, China WHO GMP and API Inspections –Documentation (section 6) Specifications for raw materials, intermediates, APIs, labelling and packaging materials (ICH 6.17) Retention period specified for production, control and distribution records (ICH 6.13) –Contract manufacturers (section 16) Contract manufacturers should comply with Annex 18 (ICH 16.10) A contract or a formal agreement should exist between the contract acceptor and the contract giver (ICH 16.12). Review of some ICHQ7A’s concepts –Personnel (section 3) Appropriate and regular GMP training periodically assessed (ICH 3.12)

28 | Slide 28 of March 2010, Beijing, China WHO GMP and API Inspections Facilities,equipment and utilities system –Facilities designed to prevent mix-ups and contamination –Precautions implemented based on a risk assessment –Equipment cleaning methodology and intervals appropriate to prevent build-up and carry-over of contaminants (degradants) Review of some ICHQ7A’s concepts Critical operation with prolonged exposure to the environment Non critical operation with prolonged exposure to the environment Non critical or critical operation in a closed equipment

29 | Slide 29 of March 2010, Beijing, China WHO GMP and API Inspections HVAC systems (section 4.2) –Adequate ventilation, air filtration and exhaust systems should be provided where appropriate (ICH 4.21, 4.22) –Qualification and appropriate monitoring and operating range limits in place (ICH 4.20) Water (section 4.3) –WHO potable water quality as a minimum (ICH 4.31) –Water for final isolation and purification steps for API for sterile products: test for microbial counts, objectionable counts and endotoxins. Review of some ICHQ7A’s concepts

30 | Slide 30 of March 2010, Beijing, China WHO GMP and API Inspections Material management (section 7.) –At least, identity testing of each batch on a sample representative of the batch (ICH 7.30) –Reduced testing for approved/validated suppliers (ICH 7.31) Past quality history Full analysis at least on three batches before starting reduced-testing Reliability of the CoA checked at regular intervals A documented supplier audit is not required but currently performed in the case of critical material by API manufacturers. –Precaution for bulk deliveries in non- dedicated tankers (ICH 7.22) Review of some ICHQ7A’s concepts

31 | Slide 31 of March 2010, Beijing, China WHO GMP and API Inspections Production (section 8) –Critical operations should be witnessed or subjected to an equivalent control (ICH 8.12) –Deviations should be documented, explained and/or investigated (ICH8.15) –Process time limits should be respected (ICH8.20) –Conditions and duration of storage of intermediates (ICH 8.21) –In-process sampling and controls (ICH 8.3) approved written procedures, avoid risk of cross contamination during sampling, sample integrity Review of some ICHQ7A’s concepts

32 | Slide 32 of March 2010, Beijing, China WHO GMP and API Inspections Review of some ICHQ7A’s concepts Production –Blending operations (section 8.4) Only batches meeting established specifications Expiry or retest date of the blended batch based on the manufacturing date of the oldest batch included. Should be controlled and documented – traceability Validation for homogeneity following blending OOS batches blended with others to meet specifications 1. Blending small batches to ↑se batch size 2. Blending tailings APIs for OSDs/ Suspensions 1. Particle size distribution 2. Bulk density 3. Tap density

33 | Slide 33 of March 2010, Beijing, China WHO GMP and API Inspections Reprocessing (s. 14.2) –Repeating a step of the established manufacturing process Crystallization, distillation, filtration, chromatography, milling, etc Continuation to completes process after IPQC in not reprocessing Introducing unreacted material into reaction is reprocessing –Included in the standard manufacturing process if reprocessing used for a majority batches Reworking (section 14.3) –Reason for non conformance determined prior to any reworking –Involves a “treatment” different from the established one Recrystallization with a a different solvent –Reworked batches to be subjected to appropriate evaluation, testing ± stability testing Concurrent validation Should have comparable impurity profile Review of some ICHQ7A’s concepts Reprocessing or reworking for intermediates or APIs which do not conform to standards or specifications

34 | Slide 34 of March 2010, Beijing, China WHO GMP and API Inspections Review of some ICHQ7A’s concepts Recovery of Materials and solvents –Reactants, intermediates or APIs may be recovered from mother liquor or filtrates. –Must use approved procedures and specifications. –Recovered solvents may be reused in same process or in different process if confirmed to meet appropriate standards. –Fresh and recovered solvents and reagents if confirmed their adequacy 1. Approved procedures 2. Suitable specs 3. Adequate testing 5. Use documented 1. No approved procedures 2. Specs – carry over impurities 3. Not adequately tested 4. Use not documented

35 | Slide 35 of March 2010, Beijing, China WHO GMP and API Inspections Validation (section 12) –Applies to Analytical methods Process Cleaning Computerized systems –Validate operations critical to the quality and purity of the API –Periodic review of validated systems Review of some ICHQ7A’s concepts 1.Prospective validation (≥3 consec batches) : complete before commercial distribution 2.Current validation (≥3 consec batches) : For API produced infrequently Batches may be released for commercial distribution after monitoring and testing 3.Retrospective Validation ( batches) : Only in exceptional cases For well established process All batches, including failed ones

36 | Slide 36 of March 2010, Beijing, China WHO GMP and API Inspections ICHQ7A : Conclusion –ICH Q7A is a “What to do document” –“How to do” is sometimes described –Flexibility –If necessary, when appropriate … –“Should” even if it could be interpreted mostly as “must” –Emphasis on the risks of –Contamination and cross contamination –Mix-ups, build-up and carry-over of degradants –Lack of traceability

37 | Slide 37 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers

38 | Slide 38 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers Vietnam (1) S. Korea (1) China (9) India (34) 2002 to 2009

39 | Slide 39 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers Most API inspections were conducted in India followed by China. The number of China API sites inspected has increased of recent

40 | Slide 40 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers API inspections have been increasing over time. Most API inspections were conducted in 2005, 2006, 2008 and Number of inspections per year

41 | Slide 41 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers Most observations were observed in sites for TB APIs and these were the sites with most of the major observations. Although sites for Malaria APIs had equally high number of observations, most of them were not major. The sites for HIV APIs were generally in a reasonable shape Inspections (disease areas) and number of observations

42 | Slide 42 of March 2010, Beijing, China WHO GMP and API Inspections WHO GMP and Inspection of API manufacturers The most frequently found deficiencies were: –Material management –SOPs –Cleaning Others included: –Batch records –Labelling –Cross contamination

43 | Slide 43 of March 2010, Beijing, China WHO GMP and API Inspections Summary and Conclusions Inspection of API sites is part of the WHO-PQ procedures International norms and standards are used during WHO-PQ inspections Risk management principles are applied when: –scheduling inspections –conducting inspections –closing out inspections Inspections of API sites has increased over time. Most of the API sites inspected by WHO-PQ are in India and China Deficiencies have been observed mainly in: –Material management, SOPs, Cleaning, Batch records, Labelling, Cross contamination Most deficiencies have been observed on sites for TB and Malaria APIs. 谢谢!


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