Presentation on theme: "World Bank Training Program on HIV/AIDS Drugs Training Module 4 Quality Assurance Ben K Botwe April 2005."— Presentation transcript:
1 World Bank Training Program on HIV/AIDS Drugs Training Module 4 Quality Assurance Ben K Botwe April 2005
2 Learning ObjectivesUpon completion of this module, you will be able toExplain the need for a systematic quality assurance process for pharmaceutical productsDescribe key elements of the quality assurance process for pharmaceuticalsDiscuss the procedures and standards for prequalification of suppliers of pharmaceuticalsApply quality assurance and supplier selection principles to case discussions
3 Rationale for this Module Quality medicines are safe, effective and efficient tools for treatment of HIV/AIDSPoor quality (sub-standard) medicines may not produce desired effects, may cause harmErrors in production can lead to sub-standard medicinesQuality Assurance principles can be used to detect errors or problems in production and ensure suppliers conform to standards and expectationsBattling HIV/AIDS: A decision maker’s guide to the procurement of medicines and related supplies provides framework for quality assurance
4 Outline of the Presentation Introduction, Definitions and Quality AssuranceGood Manufacturing PracticesProduct SelectionSuppliers and ManufacturersSelection and SourcingProcedures for Prequalification of SuppliersStability and EquivalenceConclusionCase Study
5 Quality Assurance A process, not an end-point Must be independent of financial pressuresMust ensure that quality policies are followedMust have final authority in product acceptance, rejection and release to publicIntegral to production, not an add-onResponsible for day-to-day operations and for longer term goal settingsQuantitative discipline with specified parameters
6 DEFINITIONS QUALITY QUALITY ASSURANCE The totality of features and characteristics of a medicinal product and its ability to satisfy stated and/or implied needsQUALITY ASSURANCEThe sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use.
7 DEFINITIONS GOOD MANUFACTURING PRACTICE (GMP) QUALITY CONTROL That part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use.QUALITY CONTROLThat part of GMP which is concerned with sampling, specifications and testing.
9 Quality relationships Quality ManagementQuality AssuranceGMPQuality Control
10 FACTORS IN DRUG QUALITY ASSURANCE IMPORT& EXPORTCONTROLLEGISLATIVEFRAMEWORK-REGULATIONSPACKAGINGHUMANRESOURCES-PROFESSIONALSLABELLING &PRODUCTINFROMATIONDRUGPRODUCTQUALITYRAWMATERIALS-ACTIVE &INACTIVEQC &ANALYSISTRANSPORTDISTRIBUTIONDISPENSING& USEMANUFACURINGPROCESSES& PROCEDURESSTORAGE
11 Quality Assurance Primary Functions Quality Control Analytical testing of productsActive and Non active material controlSampling, inspecting and testing of incoming raw materialsPackaging and labeling componentsBottles, caps, foils, labels, measures, cartonsPhysical inspection of product and operations at critical intermediate stagesIn-process controls, HHACCPControl of product through its distributionGSP, GDP ETC
12 Quality Must Be Designed Into A Product Quality is not an add-on: it begins with research and developmentProduct quality criteria must be establishedDetailed specifications provide quantitative parameters for measurementWritten procedures document how quality is attained and maintainedContinuous monitoring (sampling, testing) to confirm quality is being built-into product
14 Elements of the Quality Assurance Cycle in Pharmaceutical Manufacturing ResearchDevelopmentPrototypingDocumentationRaw MaterialsFacilitiesEquipmentPersonnel and SupervisionMonitoring, Feedback, Follow-up
15 Analytical Control Laboratory Heart of Quality Management in PharmaceuticalsAcademically trained and certified staffExperienced supervision/managementCapable of performing complex analysesAble to report honestly and in a timely mannerEquipment and instrumentation must be suitable for performing testingAccess to reliable power, water and other stable infrastructure
16 Quality Control & Analysis QualificationDesign, Installation, Process and OperationalCalibrationDaily and periodicValidationEquipment, Method and processSOPsAuthorized, used and updatedDocumentationSystematic and well keptQuality ManualQuality manager, staff trained and motivated to comply.Safety measures
17 Quality Assurance Throughout the Manufacturing Process Monitoring environmental conditions under which products are manufactured/storedMonitoring of air and water systems to prevent contamination– Air Handling UnitsMonitoring of humidityMonitoring of personnelFeedback and follow-up
18 Manufacturing Process and Procedures Dispensing / WeighingMixing / Granulation / PreparationCompression / Encapsulation / FillingEquipment, Operational & Process QualificationValidation & calibrationDocumentation and record keepingYield Reconciliation
19 A Guiding Philosophy for Quality Assurance in the Pharmaceutical Industry Poor Quality Medicines:Are a health hazardWaste money for governments and consumersMay contain toxic substances that have unpredictable, unintended consequencesWill not have a desired therapeutic effectDoes not save anyone any money in the long termHurt everyone – patients, health care workers, policy makers, regulators, manufacturers
20 CONSEQUENCES OF QA BREACHES Poor Treatment outcomesHigh Health BillsTreatment Failures & DeathsLoss of Confidence in the Health ServicesEnormous Economic LossesNational Security Issue
21 What is GMP? (WHO)Comprehensive system for ensuring products are consistently produced and controlled according to quality standardsDesigned to minimize risks involved in any pharmaceutical production that cannot be eliminated through testing of final product aloneCross-contamination
22 Major Risks in Pharmaceutical Production Contamination of products (microbial, particulate or other)Incorrect labels on containersInsufficient active ingredientExcess active ingredientPoor quality raw materialsPoor formulation practices
23 Analysis of Substandard Medicines Source: (WHO)
24 The Breadth of GMP Covers all aspects of production including Raw or starting materialsFinished productsPremises and environmentEquipmentpersonnelTrainingHygiene
25 GMP Principles Must be built into manufacturing process Prevents errors that cannot be eliminated through quality control of finished productEnsures all units of a medicine are of the same (within specified parameters) qualityPoor medicines leads to loss of credibility for everyone: manufacturers, health care workers and governmentsWHO Guidelines for GMP
26 WHO Technical Guide to GMP First prepared in 1967Updated and revised regularly“Quality Management in the Drug Industry” outlines general concepts and principle components of GMP“Good practices in production and quality control” describes implementation
27 WHO Technical Guide to GMP General Consideration“Licensed pharmaceutical products should be manufactured only by licensed manufacturers whose activities are regularly inspected by competent national authorities”
28 WHO Technical Guide to GMP Key ConceptsValidationAction of proving (in accordance with principles of GMP) that any procedure, process, equipment, material, activity, or system actually leads to expected results
29 WHO Technical Guide to GMP Key ConceptsQualificationAction of proving that any premises, system, and items of equipment work correctly and actually lead to expected results
30 Associated Concepts Good Laboratory Practice (GLP) Good Clinical Practice (GCP)Clear language useEffective record keepingDesign, installation, operational and process qualification (DQ, IQ, OQ and PQ)Self-inspection and self-regulationGood Distribution Practice (GDP)
31 Key Elements of GMP (WHO Technical Guide) Sanitation and hygieneQualification and validationComplaintsProduct recallsContract Production and AnalysisSelf-Inspection and Quality Audits
32 Key Elements of GMP (WHO Technical Guide) Personnel(Training, Hygiene)Documentation Premises(Equipment)Materials(Supplies, Ingredients)
33 Product Selection Issues Unique nature of medicines heightens need for effective quality assuranceAll medicines used must be safe, effective, and of consistent qualityFailure to select proper products will lead to treatment failure, drug resistance, wasted resources and human suffering
34 Product Selection Issues (Cont.) Selection of product and goal of treatment may vary depending upon patient groupInfected adultsInfected women (who may be/may become pregnant)Infected children (blood-borne or sexual transmission)Emergency workersVictims of sexual assault
35 Demographic Profile of HIV Patients Source: (Zaheer et al., 2003)
36 Demographic Profile of HIV Patients (Cont.) Source: (Zaheer et al., 2003)
37 Clinical OutcomesSuccessful treatment for HIV with quality medicines will:Improve general health status/well-beingReduce viral load to <20 cells/mLMaintain CD4 within normal range ( cells/mL)Prevent/reduce drug resistanceManage and minimize drug-related side-effectsReduce need for medical intervention
39 Combination ProductsMore convenient, improve adherence, reduce pill burden for patientE.g. Triomune (NRTI-NNRTI triple combination therapy consisting of stavudine, lamivudine, and nevirapine)Product formulations to allow twice daily (or even once daily) dosing
40 Use of Medicines in Women Who are Pregnant Acceptable combination treatmentsd4T + 3TC + NVPZDV + 3TC + NVPCombination treatments to avoidd4T + 3TC +EFZZDV + 3TC + EFZ
41 Suppliers/Manufacturers “Many reliable manufacturers, both innovator and generic companies, can offer quality products…the aim…is sustained, consistent and acceptable quality rather than high or better quality, terms that are impossible to quantify”Battling HIV/AIDS, World Bank 2004
42 Sources of Pharmaceutical Products Multi-sourceWell-established products, long history of use, no longer subject to patent protection (e.g. Rifampin)Single sourceNewer products still subject to patent protection in many countries (e.g. Saquinavir)Limited sourceMore than single source/supply possible (e.g. AZT); may be difficult to manufacture (e.g. amphotericin); may be unprofitable drug with limited market potential
44 Identifying Product Suppliers Systematic ApproachPre-qualification of suppliers and productsSpecifying supplier conditions in contractMonitoring quality of product and processesContinuous evaluation of supplier performance and product performance in clinical practice
46 Selecting and Sourcing Multi-Source Products Innovator vs. generic issuesPrequalification systemsSpecific issues related to interchangeability of products - stability, bioavailability, bioequivalence, etc.
47 Selecting and Sourcing Multi-Source Products Innovator vs. generic issuesPrequalification systemsSpecific issues related to interchangeability of products - stability, bioavailability, bioequivalence, etc.
48 Procedures for Prequalification of Suppliers RationaleMore meaningful, effective, efficient and less expensive to eliminate sub-standard manufacturers and products at the opening of bidding/tendering than during the processPurposeTo ensure that products are manufactured in compliance with GMP and products meet established quality standards
49 Procedures for Prequalification of Manufacturers Local Procurement Committee comprising managerial, technical, and professional staffManufacturers submit dossiers for review; must be reviewed/re-inspected every 3-5 years to ensure adherence to policiesReview/re-inspection also performed if product changes occur that may impact on safety, efficacy, quality, manufacturing method, or location of manufacturing
50 Procedures for Prequalification of Manufacturers (Cont.) Evaluation of Product DossierRandom testing of samplesVerification of compliance with GMPVerification of compliance with good distribution practicesRole of national drug regulatory organizations (in compliance with WHO standards)
51 Prequalification: Evaluation of Product Dossier Specifications in WHO guidelinesMust include details regarding:Regulatory statusPharmaceutically active ingredient(s)Manufacturing processesFinished product specifications (stability, bioavailability, interchangeability etc.)Packaging/labeling/storage detailsProduct/patient information
52 Prequalification: Evaluation of Product Dossier- Multi-source Products For products manufactured and registered in countries with a stringent regulatory authority, the product dossier presented may be the same as that presented to the regulatory authorityAppropriate documentation/certification provided if product differs in any way from product registered in original country (e.g. packaging, formulation, strength, manufacturing site, etc.)
53 Prequalification: Evaluation of Product Dossier- Single/Limited Source Products Include specifications of in-house quality-control and quality management practices in sufficient detail to allow replication by another laboratoryValidation of in-house methods must be provided by manufacturerQuality assessment of products to be undertaken by external laboratory
54 Prequalification: Random Testing of Samples Undertaken to verify compliance with standards and references provided in dossierTest samples should be from supplies, not from pre-supply batchesOn-going random sampling and quality control analysis post-supply
55 Prequalification Verifications Compliance with GMPCompliance with good distribution practicesInspections and certification of facilities or reliance on national regulatory authoritiesQuality assurance methods for selection of raw material suppliers, storage of products, transportation delivery of final product, etc.
56 Summary of Prequalification Processes: WHO Perspective IssueGuidelinesReceiveSubmissionsEvaluateSubmissionsPerformInspectionsCommunicateDecision
57 Summary of Prequalification Processes: Manufacturer’s Perspective SubmitEOISubmitProduct DossierSubmit SiteMaster FileSubmit AdditionalData if neededSubmit CorrectiveAction Plan if needed
58 Options for Prequalification WHO PrequalificationRegional PrequalificationInternational Low-cost SuppliersDevelopment of international consolidated prequalification system
59 Pharmaceutical Stability GMP state there must be a written testing program designed to assess stability characteristics of drugs. Results of stability testing are used to determine appropriate storage conditions and expiration dating
60 Stability Definitions (1) Capability of a particular formulation of a pharmaceutical in a specified container/closure system to remain within specified physical, chemical, microbiological, therapeutic and toxicological specifications
61 Stability Definitions (2) The time from the date of manufacture and packaging of the formulation until its chemical or biological activity is not less than a predetermined level (generally, 90%) of labeled potency and its physical characteristics have not changed appreciably
62 Stability Issues Time-related harmful events include Deterioration of therapeutic activity below specified thresholdPotentiation of therapeutic activity above specified thresholdc) Appearance of toxic substance forming as a degradation by-product
63 Factors Affecting Stability of a Pharmaceutical Product Stability of active ingredientInteraction between active/inactive ingredientsManufacturing processDosage formulationContainer/Liner/Closure SystemEnvironment during storage, handlingLength of time between manufacturing and usage
64 Evaluation of Therapeutic Equivalence of Generic Products Basic AssumptionDrug quality is a function of consistent and optimal release, dissolution, and absorption of active ingredient from a dosage form: this impacts upon chemical equivalence, lot-to-lot uniformity in manufacturing, stability, etc.
65 BioavailabilityMeasurement of both the rate of drug absorption and total amount (extent) of drug that reaches the general systemic circulation from an administered dosage form
66 EquivalenceMore general, relative term indicating a comparison of one drug with another along a set of established standards/criteriaBio-equivalenceClinical equivalenceTherapeutic equivalencePharmaceutical equivalence
67 Therapeutic Equivalence Two different brands of a drug product are expected to yield the same clinical resultFor therapeutic equivalencePharmaceutical, chemical and bio-equivalence must be demonstratedProduct must be appropriately labeledProduct must be manufactured in compliance with GMP
68 Factors Affecting Equivalences Properties of the DrugProperties of the Dosage FormProperties of Inactive Ingredients (e.g. binders, fillers, disintegrants, lubricants)
69 Bio-EquivalenceIndicates that a drug in two or more similar dosage forms reaches the general circulation at the same relative rate and the same relative extentDoes not necessarily demonstrate clinical or therapeutic equivalence (but does not necessarily rule it out either!)
70 Evaluation of Equivalence Products frequently tested in small samples, not whole populationsIndividual variations may emergeMust adhere to GMPAppropriate and accurate labeling (e.g. generic or brand-name product)
71 Conclusions GMP as a quality management system Ensure appropriate infrastructure encompassing organizational structure, procedures, processes, and resourcesEnsure systematic actions necessary to provide adequate confidence that product will meet quality standards and expectations
72 Conclusions Good Manufacturing Practices are Pivotal to quality assuranceEveryone’s responsibility (manufacturers, purchasers, distributors, consumers)Clear, transparent, documented, readily observableOn-going, consistent, reproducible
73 ConclusionsGMP are aimed at reducing risks inherent in pharmaceutical productionQualification and validation provides confidence in manufacturers’ processesPrequalification provides greatest assurance regarding quality of pharmaceutical products, based on GMP and product dossier
74 Case StudyIn your small groups, review the case study which you have already read. As a group, identify critical issues raised by this case study. Use the guided discovery questions to prompt discussion.
75 Case Discussion Question How should the government of Fatakia prioritize elements of Good Manufacturing Practices, given the unique situation it faces in procurement, storage, and distribution of anti-retrovirals? What if Fatakia does not have the capacity to pre-qualify suppliers?
76 Case Discussion Question Given the unique factors of the drug distribution system in Fatakia, what particular issues related to stability must be considered? How can the drug distribution be modified to optimize pharmaceutical stability?
77 Case Discussion Question In evaluating claims and documents made by different manufacturers of the same drug, what principles must be weighed to ensure optimal health outcomes?How would you advise the government of Fatakia to develop an evaluation scheme for multiple, competing providers of the same medicine?
78 Case Study Summary Key Issues Health System Infrastructure (e.g. laboratory testing facilities, medics, etc.)Drug Distribution System (e.g. transport/storage logistics, deterioration in quality of products, drug diversion issues)Financial Pressures (e.g. use of generic products)
79 Case Study Summary Prequalification of suppliers In accordance with GMPProvision of dossierRandom testing of samples (not pre-supply)Changes/variances must be qualified/validatedDemonstrated on-going commitment to standardsOptions in case there is insufficient capacity to pre-qualify suppliers
80 Case Study SummaryWHO Certification Scheme on the Quality of Pharmaceutical Products Moving In International CommerceManufacturing authorizationsMarketing authorizations
81 Case Study Summary Equivalency Decisions Linked directly to GMP Additional burden of proof based on pharmacopeial/compendial standardsDifferentiate bio-equivalence, therapeutic equivalence, and clinical equivalence
82 Case Study Summary Stability Issues Drug specific issues Drug-formulation specific issuesContainer issuesStorage/handling/transportation issuesDrug Distribution System considerationsHealth Care System considerations