Presentation on theme: "QUALITY OF PHARMACEUTICAL INGREDIENTS"— Presentation transcript:
1QUALITY OF PHARMACEUTICAL INGREDIENTS WHO Prequalification Programme: Priority Essential MedicinesWHO GMP and API InspectionsPresented byMr. Deus K MubangiziTechnical Officer
2In this presentation: WHO-PQ: Inspection activities WHO-PQ: Norms and standardsWHO-GMP for APIs versus ICH Q7AKey elements of ICH Q7AWHO-PQ API inspections: Observed trends and deficienciesConclusions
4Prequalification: Inspection Processes By a team of qualified and experienced inspectorsWHO 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 inspectionObserver from recipient/developing countries (nominated by DRA of the country)Scope:Compliance with guidelines: GMP (ICHQ7), GCP, GLPData verification – data manipulation, falsification, (validation, stability, clinical, bioanalytical)Quality control (QC, BAL, NQCL, IQCL)
5RELATIVE RISK CATEGORY PRODUCT TYPE / ACTIVITY Guide to Manufacturer Risk Classification Ref: SOP 401.1: Inspection Frequency and SchedulingRELATIVE RISK CATEGORYPRODUCT TYPE / ACTIVITYLOWMEDIUMHIGHCRITICALFinished Products:Sterile finished productsNon-sterile finished productsAPIs:Sterile APIsNon-sterile APIs where there is a special risk (e.g. isomerism, polymorphism, special risk of harmful impurities, etc)Other non-sterile APIsQC LaboratoriesCROs
6RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME (1 of 2)APIManufacturerNumber of ProductsPresent in Product(Ref. Nos.)Risk ScoreRisk = 1Risk = 2ParameterNYPolymorphism1HighLowSolubility in water2Not complexComplexSynthesis3Low riskHigh RiskSolvents4Impurities5Sterile6Fermentation7
7RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME (2 of 2)Risk ScoreRisk = 1Risk = 2ParameterLowHighToxicity8Low riskHigh RiskActivity/potency9Particle size10Other property consideration11PositiveNegativeSite compliance information (WHO/EDQM/USFDA/Other)12Total Risk ScoreGeneral remarks:CompliantOutcomeLast inspection dateNot CompliantHighInspection prioritizationMediumLow
8GMP Compliance Rating: Guide To Inspection Frequency (in months) Ref: SOP 401.1: Inspection Frequency and SchedulingGMP Compliance Rating:RISKCATEGORY:UnacceptableAcceptable:BasicSatisfactoryGoodDetermine on a case by case basis121824Critical (C)152030High (H)36Medium (M)48Low (L)
10Risk-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 userMajor Observation – major deviation from GMPMinor or Other Observation – departure from good practice
11Further 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.
12Risk-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
13Transparency: 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 inspectionA 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.
14Prequalification 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, andThe scope of the inspection covered the specific API in question, andThe 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).
15Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide applicabilityQuality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol.2, GMP and inspection. WHO, Geneva, 2007.ICH Q7: GMP Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization.WHO GMP: water for pharmaceutical use. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3.
16Prequalification Programme: norms, standards and guidelines used… WHO guidelines for sampling of pharmaceutical products and related materials. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 4.Supplementary GMP guidelines for HVAC systems. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 2.Supplementary GMP guidelines: validation. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4.Good Practices for National Pharmaceutical Control Laboratories. 36th Report. Geneva, WHO, 2002 (WHO TRS, No. 902), Annex 3.USPBPPh. Eur.Ph. Int.Other guidelines e.g. ICH, ISO
17Prequalification 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.
18WHO GMP and ICH Q7 II. QUALITY MANAGEMENT III. PERSONNEL IV. BUILDINGS AND FACILITIESV. PROCESS EQUIPMENTVI. DOCUMENTATION AND RECORDSVII. MATERIALS MANAGEMENTVIII. PRODUCTION AND IN-PROCESS CONTROLSIX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATESX. STORAGE AND DISTRIBUTIONXI. LABORATORY CONTROLSXII. VALIDATIONXIII. CHANGE CONTROLXIV. REJECTION AND RE-USE OF MATERIALSXV. COMPLAINTS AND RECALLSXVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS
19WHO GMP for APIs / ICH Q7 Key definitions: ICH Q7AAPI 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.
20ICH Q7A : IntroductionFrom 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.
21WHO GMP and Inspection of API manufacturers Increasing GMP requirements
22Main issue : How to define the API SM ? World Health OrganizationMain issue : How to define the API SM ?6 April, 2017RM (solvent, catalyst, reagent, filtration aid, decolorizing agent, chromatography phase, etc.)C, H, O, NSM(Intermediates)nActive substance crudeActive substance (pure)Only flow chartGMPs do not applyDetailed descriptionGMPs applyAPI SMCompetentAuthoritiesIndustryPhoto : Internet
23Application of ICHQ7Companies 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 stepsAdvanced intermediates and crude APIs outsourced should be manufactured in compliance with GMPThis 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.
24World Health Organization 6 April, 2017ICHQ7A: ScopeQ7A does not apply to :vaccines, whole cells, whole blood and plasmablood and plasma derivatives (plasma fractionation)gene therapy APIsbulk-packaged medicinal productsmedical gases and manufacturing/control aspects specific to radiopharmaceuticals.Q7A does not cover :Safety aspects for the personnel engaged in the manufactureand environmental issues.vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs.medical gases, bulk-packaged drug (medicinal) products, and manufacturing/control aspects specific to radiopharmaceuticals.
25Review of some ICHQ7A’s concepts Quality management (Chapter 2)Responsibilities of the Quality UnitSections toTools 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)
26Review of some ICHQ7A’s concepts Change controlRaw materials, specifications, analytical methods, facilities, support systems, equipment (including computerized systems), processing steps, labelling and packaging materialsThat can impact the quality of the APIChange controlProposal drafted, reviewed and approved by the appropriate organisational unitChange reviewed and approved by QUClassification and impact assessmentEvaluation and monitoring + Notification
27Review of some ICHQ7A’s concepts Personnel (section 3)Appropriate and regular GMP training periodically assessed (ICH 3.12)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).
28Review of some ICHQ7A’s concepts Facilities,equipment and utilities systemFacilities designed to prevent mix-ups and contaminationPrecautions implemented based on a risk assessmentEquipment cleaning methodology and intervals appropriate to prevent build-up and carry-over of contaminants (degradants)Critical operation with prolonged exposure to the environmentNon critical operation with prolonged exposure to the environmentNon critical or critical operation in a closed equipment
29Review of some ICHQ7A’s concepts 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.
30Review of some ICHQ7A’s concepts 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 historyFull analysis at least on three batches before starting reduced-testingReliability of the CoA checked at regular intervalsA 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)
31Review of some ICHQ7A’s concepts 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
32Review of some ICHQ7A’s concepts ProductionBlending operations (section 8.4)Only batches meeting established specificationsExpiry or retest date of the blended batch based on the manufacturing date of the oldest batch included.Should be controlled and documented – traceabilityValidation for homogeneity following blendingOOS batches blended with others to meet specifications1. Blending small batches to ↑se batch size2. Blending tailingsAPIs for OSDs/ Suspensions1. Particle size distribution2. Bulk density3. Tap density
33Review of some ICHQ7A’s concepts Reprocessing or reworking for intermediates or APIs which do not conform to standards or specificationsReprocessing (s. 14.2)Repeating a step of the established manufacturing processCrystallization, distillation, filtration, chromatography, milling, etcContinuation to completes process after IPQC in not reprocessingIntroducing unreacted material into reaction is reprocessingIncluded in the standard manufacturing process if reprocessing used for a majority batchesReworking (section 14.3)Reason for non conformance determined prior to any reworkingInvolves a “treatment” different from the established oneRecrystallization with a a different solventReworked batches to be subjected to appropriate evaluation, testing ± stability testingConcurrent validationShould have comparable impurity profile
34Review of some ICHQ7A’s concepts Recovery of Materials and solventsReactants, 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 adequacy1. No approved procedures2. Specs – carry over impurities3. Not adequately tested4. Use not documented1. Approved procedures2. Suitable specs3. Adequate testing5. Use documented
35Review of some ICHQ7A’s concepts Prospective validation (≥3 consec batches):complete before commercial distributionCurrent validation (≥3 consec batches):For API produced infrequentlyBatches may be released for commercial distribution after monitoring and testingRetrospective Validation ( batches):Only in exceptional casesFor well established processAll batches, including failed onesValidation (section 12)Applies toAnalytical methodsProcessCleaningComputerized systemsValidate operations critical to the quality and purity of the APIPeriodic review of validated systems
36ICHQ7A : Conclusion ICH Q7A is a “What to do document” “How to do” is sometimes describedFlexibilityIf necessary, when appropriate …“Should” even if it could be interpreted mostly as “must”Emphasis on the risks ofContamination and cross contaminationMix-ups, build-up and carry-over of degradantsLack of traceability
37WHO GMP and Inspection of API manufacturers Trends . . .
38WHO GMP and Inspection of API manufacturers 2002 - 2009 2002 to 2009India (34)China (9)S. Korea (1)Vietnam (1)
39WHO 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
40WHO GMP and Inspection of API manufacturers Number of inspections per yearAPI inspections have been increasing over time.Most API inspections were conducted in 2005, 2006, and 2009.
41WHO GMP and Inspection of API manufacturers Inspections (disease areas) and number of observationsMost 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.
42WHO GMP and Inspection of API manufacturers The most frequently found deficiencies were:Material managementSOPsCleaningOthers included:Batch recordsLabellingCross contamination
43Summary and Conclusions Inspection of API sites is part of the WHO-PQ proceduresInternational norms and standards are used during WHO-PQ inspectionsRisk management principles are applied when:scheduling inspectionsconducting inspectionsclosing out inspectionsInspections of API sites has increased over time. Most of the API sites inspected by WHO-PQ are in India and ChinaDeficiencies have been observed mainly in:Material management, SOPs, Cleaning, Batch records, Labelling, Cross contaminationMost deficiencies have been observed on sites for TB and Malaria APIs.谢谢！