General Introduction To GMP, History, ICH, PIC/S, EU, FDA - DCVMN
General Introduction toGMP, History, ICH, PIC/S,EU, FDA Pharmaceutical Consultancy Services, All rights reserved.
LAW: REGULATORY BODIESA regulatory body is like a professional body but it is not a membership organisationand its primary activity is to protect the public. Unlike professional bodies, it isestablished on the basis of legal mandate.Regulatory bodies exercise a regulatory function, that is: imposing requirements,restrictions and conditions, setting standards in relation to any activity, and securingcompliance, or enforcementExamples:ANVISA: BrazilianIGZ: DutchNRA’s (National Regulatory Angencies)US-FDA: United States of AmericaEU: Guidelines and Directives to be implemented by individual memberstates. Pharmaceutical Consultancy Services, All rights reserved.2
WHY BY LAW?Risks have increased: 1800:Effect of Medicines: Administered to (already)sick persons User has no capability todetermine quality,effectiveness or safety Neither does the prescriber Molecules not part ofregular metabolic system. Globally distributed (scale) Natural medicines “Home made” Herbs etc 1800 - 1900: Physics / Small Scale 1900:– Medicinal Production Local National European Globally Existing Situation:– Complex Distribution System Pharmaceutical Consultancy Services, All rights reserved.3
EU LEGISLATION Assurance of Quality (Medicinal Products) Registration GMP Release by Company (QP vs RP) Tracebility of Medicinal Products Across the Entire Supply Chain Preventing introduction into the Supply Chain of non-approvedMedicinal Products: Counterfeit Over due’s and/or Recall Pharmaceutical Consultancy Services, All rights reserved.4
PURPOSE OF LAWFit for their intended use,Comply with the requirements of the dossierDo not place patients at risk due toinadequate:safety,qualityefficacy.during the entire period being in the SupplyChainProtected against Falsification/Counterfeit Pharmaceutical Consultancy Services, All rights reserved.5
DEVELOPMENT OF MEDICINESGLPFindingProofofPrinciple Pharmaceutical Consultancy Services, All rights PhaseClin.PhaseIIIIIIMarket
EU “LAW” DIRECTIVES for Medicinal Products Formerly: 65/65/EEC, 75/319/EEC, 75/318/EEC– Combined in: 2001/83/EC Counterfeit Directive: 2011/62/EU GMP: 2003/94/EC GDP: 2013/C 68/01 Pharmaceutical Consultancy Services, All rights reserved.7
PRINCIPLE OF LICENCED SUPPLY CHAIN SYSTEMManufactured Outside EUImporter (EU)Manufacturedinside Wholesaler Pharmaceutical Consultancy Services, All rights reserved.8
GDP-GUIDELINES (2013/C 68/01) Wholesale distribution– Control of the Distribution Chain (maintaining Quality)– Prevent entering Falsified Medicines into the chain. Current Insights (compared with 1994 version)– Quality Systems– Risk Management– Warehouse-facilities– Qualification and Validation– Outsourcing– Falsified Medicines Pharmaceutical Consultancy Services, All rights reserved.9
GDP VERSUS GMP CHAPTERS (EUDRALEX VOL 4)GDP Chapters (OtherDocuments)GMP Chapters (Part I)1.2.3.4.5.6.Quality ManagementPersonnelPremises and EquipmentDocumentationOperationsComplaints, Returns, SuspectedFalsified Medicinal Products andMedicinal Product Recalls7. Outsourced Activities8. Self-Inspections9. Transportation10. Specific Provisions for Brokers Pharmaceutical Consultancy Services, All rights reserved.101.2.3.4.5.6.Pharmaceutical Quality SystemPersonnelPremise and EquipmentDocumentationProductionQuality Control7.8.9.Outsourced ActivitiesComplaints and RecallSelf Inspection
EU GMP-GUIDELINE CONTENTAnnexes: (1-19) amongst others:1-Manufacture of Sterile Medicinal Products2-Manufacture of Biological active substances and MedicinalProducts for Human Use3-Manufacture of Radiopharmaceuticals4-Manufacture of Veterinary Medicinal Products other thanImmunological Veterinary Medicinal Products6-Manufacture of Medicinal Gases9-Manufacture of Liquids, Creams and Ointments11-Computerised Systems15-Qualification and Validation17-Parametric Release19-Reference and Retention Samples Pharmaceutical Consultancy Services, All rights reserved.11
EU GMP-GUIDELINE CONTENT Part II: Basic Requirements for Active Substances used asStarting MaterialsText of old Annex 18 Pharmaceutical Consultancy Services, All rights reserved.12
EU GMP-GUIDELINE CONTENT Part III - GMP related documents Amongst others;Site Master FileQ9 Quality Risk ManagementQ10 Guidance on Pharmaceutical Quality SystemMRA Batch Certificate Pharmaceutical Consultancy Services, All rights reserved.13
U.S. FDA Pharmaceutical Consultancy Services, All rights reserved.14
US-FDA OFFICESStrategic locations around the world, including China, Europe, India and Latin America.Work closely with foreign governments, industry, and other stakeholders Pharmaceutical Consultancy Services, All rights reserved.15
US-FDA 21CFR’SUS FDA Title 21 CFR Parts Part 11 - regulations on electronic records and electronic signatures Part 210 – CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERALPart 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHEDPHARMACEUTICALS Part 600 - Biological Products:GeneralPart 601 - Licensing BiologicsPart 610 - General Biological Products Standards Pharmaceutical Consultancy Services, All rights reserved.16
MODERNIZATION OF FDAThis guidance is intended to help manufacturers implementing modern quality systemsand risk management approaches to meet the requirements of the FDA s current goodmanufacturing practice (CGMP) regulations (2l CFR parts 210 and s/UCM070337.pdf Pharmaceutical Consultancy Services, All rights reserved.17
MODERNIZATION OF FDAOctober 2014 Guidance (US) for Industry: Circumstances that ConstituteDelaying, Denying, Limiting, or Refusing a Drug Inspection Pharmaceutical Consultancy Services, All rights reserved.18
MODERNIZATION OF FDABACKGROUND AND PURPOSE- August 2002, the FDA announced the Pharmaceutical CGMPs for the 21st Century Initiative- Intent to integrate quality systems and risk management approachesGOAL OF THE GUIDANCE- Describes a comprehensive quality systems model- Demonstrates how/where the elements of this comprehensive model can fit within therequirements of the CGMP regulations- Bridge between the 1978 regulations and current understanding of quality systemsSCOPE OF THE GUIDANCE- NOT intended to create new requirements for pharmaceutical manufacturing- NOT intended to be a guide for the conduct of FDA inspections- Explains how implementing comprehensive quality systems can help manufacturers achievecompliance with 21 CFR parts 210 and 211ORGANIZATION OF THE GUIDANCE- Major sections:Management Responsibilities, Resources, Man. Operations & EvaluationActivities Pharmaceutical Consultancy Services, All rights reserved.19
Pharmaceutical Consultancy Services, All rights reserved.20
WHAT IS 483An FDA 483 is a form used by an FDA investigator following an inspectionof your plant. It lists deficiencies in your quality system and potential noncompliance issues with GMP's. These observations are based on theinvestigators interpretation of the GMP regulations as they apply to yourspecific situation. During the investigator's closing meeting withmanagement, you may be given a Form 483. The Form 483 is officiallyknown as the "Notice of Inspection Observations." Pharmaceutical Consultancy Services, All rights reserved.21
WHAT IS 483The content of a 483 may be handwritten, typed, completed in a PDF fileand printed, or completed via the FDA's computer system called Turbo EIR Header information Observations Annotation Signatures Converse side Addenda/amendments Pharmaceutical Consultancy Services, All rights reserved.22
USP Pharmaceutical Consultancy Services, All rights reserved.23
USPUSP ChaptersGeneral chapters numbered above 1000 in USP–NF typically areinformational and contain no mandatory requirements, unlessspecifically referenced in a monographGeneral chapters designated as below 1000 contain tests andprocedures that are intended to apply to items recognized in USP or NFwhen called out in a monographExample: General Chapter 1116 Microbiological Control and Monitoringof Aseptic Processing Environments Pharmaceutical Consultancy Services, All rights reserved.24
USP 1229 Sterilization of Compendial Articles 1229.1 Steam Sterilization by Direct Contact 1229.2 Moist Heat Sterilization of Aqueous Liquids 1229.3 Monitoring of Bioburden 1229.4 Sterilizing Filtration of Liquids 1229.5 Biological Indicators for Sterilization 1229.6 Liquid Phase Sterilization 1229.7 Gaseous Sterilization 1229.8 Dry Heat Sterilization 1229.9 Physicochemical Integrators and Indicators for Sterilization 1229.10 Radiation Sterilization 1229.11 Vapor Phase Sterilization Pharmaceutical Consultancy Services, All rights reserved.25
WHO (WORLD HEALTH ORGANIZATION) Pharmaceutical Consultancy Services, All rights reserved.26
WHO GUIDELINES FOR VACCINESThe World Health Organization brings together international experts inspecific fields through its biological standardization programme to developand revise specific recommendations for the production and quality controlof vaccines of major international public health en/TRS 822, Annex 1 Biological products, GMP; Pharmaceutical Consultancy Services, All rights reserved.27
WHO GENERAL GMP GUIDELINESTRS 986, Annex 2 WHO good manufacturing practices for pharmaceuticalproducts: main ty safety/quality assurance/production/en/ Pharmaceutical Consultancy Services, All rights reserved.28
WHO GENERAL GMP GUIDELINESTRS 961 - Forty-fifth Report (Geneva, 18–22 October 2010)WHO Expert Committee on Specifications for Pharmaceutical Js18652en/ Pharmaceutical Consultancy Services, All rights reserved.29
(ICH) INTERNATIONAL CONFERENCEON HARMONIZATION Pharmaceutical Consultancy Services, All rights reserved.30
ICH ICH – International Conference on Harmonization of technicalrequirements for registration of pharmaceuticals for human use Pioneered by EU in 1980s to facilitate the move towardssingle market for Pharmaceuticals Bilateral discussions between Europe, Japan and USA onpossibility of harmonisation WHO Conference 1989 in Paris, agreement was reached toinitiate a joint regulatory-industry initiative for internationalharmonisation ICH was borne in April 1990 (Brussels) Pharmaceutical Consultancy Services, All rights reserved.31
ICHICH Work Products (Quality Section) Stability – Q1 A – Q1 F Analytical Validation – Q2 A – Q2B Impurities – Q3 A – Q3 C Pharmacopoeias – Q4 – Q4 B Quality of Biotechnological Products – Q5 A – Q5 E Specifications – Q6 A – Q6 Good Manufacturing Practice (APIs) – Q7 A Pharmaceutical Development – Q8 Risk Assessment – Q9 Pharmaceutical Quality Systems – Q10 Development and Manufacturing –drug substances–Q11 (draft) Pharmaceutical Consultancy Services, All rights reserved.32
BRUSSELS 2003 (ICH)The RegulatoryQuality SystemQuality RiskManagement(Q9)Quality ent(Quality byDesign) Pharmaceutical Consultancy Services, All rights ms(Q10)For companies with :1. Good design andcontrol strategies2. Good RiskManagement strategies3. Good Quality SystemsReduced intensity ofRegulatory Oversight:1. Reduction of submissionson changes/variations2. Inspection of qualitysystems
ICHInternational Harmonisation on Legislatory Quality Vision:Develop a harmonized pharmaceutical quality systemapplicable across the life cycle of the product emphasizingan integrated approach to quality risk management andscience (ICH Brussels 2003)ISOTop management shall provide evidence of its commitment tothe development and implementation of the qualitymanagement system and continually improve itseffectiveness (ISO9000-2008) Pharmaceutical Consultancy Services, All rights reserved.34
ISO “CIRCLE”ISO “CIRCLE”Clauses are references to the ISO-chapters Pharmaceutical Consultancy Services, All rights reserved.35
Q10; PQS Pharmaceutical Consultancy Services, All rights reserved.36
STANDARD QMS (QUALITY MANAGEMENT SYSTEM)ELEMENTSChange entsPQR/APRRecallDestructionVendor ManagementQuality ControlOn-going ationExternal InspectionsFacilities / Utilities / Equipment Pharmaceutical Consultancy Services, All rights reserved.TrainingDistributionArtworkAudit System (Internal/External)DocumentationCMC maintenanceTechnical TransferPharmacovigilanceClinical StudiesMarketing MaterialRegulatory AffairsData ManagementInvestigationsDevelopment Studies37
Q10; QUALITY MANAGEMENTQ10: Pharmaceutical Quality System (PQS) ISO GMP ICH-Q8 and ICH-Q9Concept of Q10 is broader than GMPQ10 objectives Achieve product realization Establish and maintain a state of control Facilitate continual improvementLife-cycle approach Pharmaceutical Consultancy Services, All rights reserved.38
Q10; QUALITY MANAGEMENTBased on (enablers) KnowledgeSubject Matter Experts –SME introduced byASTM2500 Risk ManagementBased on ICH-Q9A more science based approach as underlying theme.MANAGEMENT IS HELD RESPONSIBLE Pharmaceutical Consultancy Services, All rights reserved.39
Q10; QUALITY MANAGEMENTControls (1) Process Performance Product Quality MonitoringControls (2) Change Management CAPA Correction (direct related to specific batch/event) Corrective Action (broader concept to avoid re-occurrence) Preventative Action (concept of avoiding –future- risks)Controls (3) MANAGEMENT REVIEW Pharmaceutical Consultancy Services, All rights reserved.40
Q10; QUALITY MANAGEMENTManagement Review Senior Management should be responsible for: Pharmaceutical Quality System Governance PQS, to be suitable and effective Assessing the Conclusions on periodic review;1.2.process/productPharmaceutical Quality System (PQS)Compared with GMP Part 1 - Old Chapter 2 section 3Key Personnel includes the head of Production, the head of Quality Control,and if at least one of these persons is not responsible for the release ofproducts the authorised person(s) designated for the purpose. Normally keyposts should be occupied by full-time personnel. The heads of Production andQuality Control must be independent from each other Pharmaceutical Consultancy Services, All rights reserved.41
EUDRALEX VOL. 4 CH. 1 - PQS 1.5 Senior management has the ultimate responsibility to ensure an effectivePharmaceutical Quality System is in place, adequately resourced and that roles,responsibilities, and authorities are defined, communicated and implementedthroughout the organisation. Senior management’s leadership and activeparticipation in the Pharmaceutical Quality System is essential. This leadershipshould ensure the support and commitment of staff at all levels and sites withinthe organisation to the Pharmaceutical Quality System. 1.6 There should be periodic management review, with the involvement of seniormanagement, of the operation of the Pharmaceutical Quality System to identifyopportunities for continual improvement of products, processes and the systemitself. Pharmaceutical Consultancy Services, All rights reserved.42
Q10; QUALITY MANAGEMENT Pharmaceutical Consultancy Services, All rights reserved.43
Q9; QRM Pharmaceutical Consultancy Services, All rights reserved.44
Q9; QUALITY RISK MANAGEMENTRisk (ICH-Q9 definition) Probability of occurrence of harm Severity of that harmPrime importance: protection of the patientNote: included within term “patient” is: the to be vaccinated recipient.Systematics: Formal / Informal Multi-disciplinary Examples in Q9: at least works as agenda(s) Pharmaceutical Consultancy Services, All rights reserved.45
Q9; QUALITY RISK MANAGEMENTIntegrated throughout Quality Management System: DocumentationTraining and educationQuality defectsAuditing / InspectionPeriodic reviewChange management / change controlContinual improvement Inspectorates / PIC/S: Develop training programme on QRM for inspectors Develop guidance for assessment of QRM implementation inindustry Update PIC/S Site Master File format with QRM Pharmaceutical Consultancy Services, All rights reserved.46
Q9; QUALITY RISK MANAGEMENTConcept includes (not limited) Risk: Identification Analysis Evaluation Control FMEA – studies (as an example) Impact Assessments Change Management Deviations / NCMR CAPA DATA gathering Pharmaceutical Consultancy Services, All rights reserved.47
Q9; QUALITY RISK MANAGEMENTNotes: Risk to quality is just one component of theoverall risk! Product quality should be maintainedthroughout the product life cycle Risk management in pharma industry meansprotection of the patients by managing the riskto quality Pharmaceutical Consultancy Services, All rights reserved.48
(PIC/S) PHARMACEUTICAL INSPECTIONCONVENTION Pharmaceutical Consultancy Services, All rights reserved.49
PIC/SPIC (Pharmaceutical Inspection Convention) was founded inOctober 1970 by EFTA (European Free Trade Association)under the title of “The Convention for the MutualRecognition of Inspections in Respect of the Manufacture ofPharmaceutical Products”.Started with 10 members (European), followed by others (8),including Australia, until 1993.PIC Scheme (Cooperation) was formed on 2 November 1995.PIC and the PIC Scheme, which operate together in parallel,are jointly referred to as PIC/S. USA is a member since 2011 Pharmaceutical Consultancy Services, All rights reserved.50
PIC/S PIC/S' mission is "to lead the internationaldevelopment, implementation andmaintenance of harmonised GoodManufacturing Practice (GMP) standards andquality systems of inspectorates in the field ofmedicinal products46 CountriesEMA, WHO and UNICEF are Partnering withPIC/s Pharmaceutical Consultancy Services, All rights reserved.51
PIC/SThe need to form the PIC Scheme became necessary when it was realisedthat an incompatibility between PIC and European law did not permitindividual EU countries that were members of PIC to sign agreements withother countries seeking to join PIC.PIC/S provides an active and constructive co-operation in the field of GMP(Good Manufacturing Practice). The purpose of PIC/S is to facilitate thenetworking between participating authorities and the maintenance of mutualconfidence, the exchange of information and experience in the field of GMPand related areas, and the mutual training of GMP inspectors.Interesting publications: PI 032-2 PI 012-3 PI 007-6 PI 014-3 Pharmaceutical Consultancy Services, All rights reserved.Where to find them!http://www.picscheme.org/publication.php52
PIC/S GUIDANCEThe need to form the PIC Scheme became necessary when it was realisedthat an incompatibility between PIC and European law did not permitindividual EU countries that were members of PIC to sign agreements withother countries seeking to join PIC.PIC/S provides an active and constructive co-operation in the field of GMP(Good Manufacturing Practice). The purpose of PIC/S is to facilitate thenetworking between participating authorities and the maintenance of mutualconfidence, the exchange of information and experience in the field of GMPand related areas, and the mutual training of GMP inspectors. Pharmaceutical Consultancy Services, All rights reserved.53
PDA Pharmaceutical Consultancy Services, All rights reserved.54
OVERVIEW PDA TR S 2013/2014/20152013: TR 60 – 64 TR 54 – 3, TR 54 – 2 Review TR 43, TR 33, TR 32014: TR 65 – 68 TR 54 – 4 Review TR 132015: Points to consider for Aseptic Processing Task Force; Part 1: January Pharmaceutical Consultancy Services, All rights reserved.55
OVERVIEW PDA TR S 2013/2014/20152013: TR 60 – Process Validation: A lifecycle approach TR 61 – Steam in place TR 62 – Recommended practices for manual aseptic processes TR 63 – Quality requirements for the extemporaneous preparation ofclinical trial materials TR 64 – Active temperature-controlled systems TR 54 – 2 (Annex 1), TR 54 – 3 (Annex 2) Review TR 43, TR 33, TR 3 Pharmaceutical Consultancy Services, All rights reserved.56
OVERVIEW PDA TR S 2013/2014/20152014/15: TR 65 – Technology Transfer TR 66 – Application of Single-Use Systems in pharmaceutical manufacturing TR 67 – Exclusion of objectionable microorganisms from nonsterilepharmaceuticals, medical devices and cosmetics TR 68 – Risk-Based approach for prevention and management of drug shortage TR 69 - Bioburden and Biofilm Management in Pharmaceutical Drug SubstanceManufacturing (very recent) TR 54 – 4 (Annex 3) Review TR 13 - Fundamentals of an Environmental Monitoring Program Pharmaceutical Consultancy Services, All rights reserved.57
TESTING Pharmaceutical Consultancy Services, All rights reserved.58
BY HAND RAISINGSenior Management responsibilities were in thepast NOT clearly defined/emphasized:OPTIONS:1. TRUE2. NOT-TRUE3. DON’T KNOW Pharmaceutical Consultancy Services, All rights reserved.59
BY HAND RAISINGICH guidelines, are only mandatory onceincorporated into “local” laws/guidelines:OPTIONS:1. TRUE2. NOT-TRUE3. DON’T KNOW Pharmaceutical Consultancy Services, All rights reserved.60
BY HAND RAISINGPIC/s and PDA are NOT regulatory bodies:OPTIONS:1. TRUE2. NOT-TRUE3. DON’T KNOW Pharmaceutical Consultancy Services, All rights reserved.61
THANK YOU FORYOUR ATTENTION Pharmaceutical Consultancy Services, All rights reserved.
Development (Quality by Design) Quality Risk Management The Regulatory Quality System Quality Systems Quality Systems (Q10) For companies with : 1. Good design and control strategies 2. Good Risk Management strategies 3. Good Quality Systems Quality Risk Management (Q9) Pharmaceutical Development (Q8) Reduced intensity of Regulatory Oversight: 1.
EU GMP Guide-Annex 15 Qualification & Validation draft released In February 2014, a draft of the revised Annex 15 was released by the European Commission (EC) for public comment. The draft version is based on an EMA Concept Paper, published in November 2012 which outlined various reasons for the revision of Annex 15.File Size: 553KBPage Count: 17Explore furtherEU GMP Annex 15: Qualification and Validation - ECA Acad www.gmp-compliance.orgEU GMP Annex 15 Revisions: Improving Qualification and .www.cleanroomtechnology.c GUIDELINES ON VALIDATION APPENDIX 6 VALIDATION O www.who.intGuideline on Process Validationwww.ema.europa.euEudraLex - Volume 4 - Good Manufacturing Practice (GMP .ec.europa.euRecommended to you b
Therapeutic Goods Administration GMP clearance guidance V18.3 July 2019 Page 9 of 84 GMP clearance basics What GMP clearance is GMP Clearance is a non-statutory mechanism used to verify that overseas manufacturing sites
3. Good Manufacturing Practices (GMP) guidelines GMP is a production and testing practice that helps to ensure a quality product. Many countries have legislated that pharmaceutical and medical device companies must follow GMP procedures, and have created their own GM P
GMP GMP is the part of QA that ensures products are consistently manufactured to a standard appropriate to their intended use. It is concerned with both manufacturing and Quality Control procedures. QC Quality Control is the part of GMP which is concerned with sampling, specification and testing and also organization, documentation and release. 17
changing filters or adding lubricant can dramatically impact product quality. The GMP regulations require all contractors to be trained appropriately before they enter GMP areas. Developing tight, long term relationships with your contracting suppliers is critical. Their HR systems should trigger GMP training for every new hire.
GMP guidance - EU and PIC/S Introduction Part I Part II Part III Annexes Part IV PQS, personnel, premises, documents, production, QC, outsourcing, complaints, audits An 1 –17, 19, 21 Self-standing GMP for ATMPs API
symbiotica speciality ingredients sdn. bhd. malaysia pic/s - ich q7a gmp certification - npra, malaysia us fda - inspected and accepted facility cofepris, mexico - gmp certification edqm certificate of suitability - 8 products, 2 under evaluation us dmf - 8 filed, 10 more being filed rephine, uk pharmasses gmp mnc - approved suppliers to gsk, sanofi, takeda, mylan, stada, teva
GMP & GDP FORUM 2021 22-24 June 2021 Heidelberg, Germany & Live Online EU GMP Annex 21: Import of Medicinal Products Dr. Ulrich Kissel, Chairman European QP Association e meaning of importation within scope of Annex 21 What is new in Annex 21 (dra )? What do we miss in Annex 21 (dra )? Conclusions and comments on the document
