GMP Manufacturing for Worldwide Clinical Trials

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This presentation describes the complex process of manufacturing clinical trial materials using examples from the InstantGMP manufacturing execution system. InstantGMP is an electronic batch record system for small pharmaceutical operations and is ideal for manufacturing CTM or tracking inventory worldwide.

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GMP Manufacturing for Worldwide Clinical Trials

  1. 1. GMP Manufacturing for Worldwide Clinical Trials Richard Soltero, Ph.D. Founder InstantGMPInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
  2. 2. Discussions  Flow of GMP Manufacturing processes  Approaches to GMP compliance throughout the world  Impact on clinical trial suppliesInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 2
  3. 3. ICH Q7A Good Manufacturing Practice  International Conference on Harmonization  ICH Member Countries –  European Union (EU) - 27 countries  Japan  United States  Australia  Canada  NorwayInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 3
  4. 4. Basic of GMPs according to ICH  Instructions and procedures are clear and unambiguous  Manufacturing processes are clearly defined and controlled  Facilities designed to minimize cross- contamination and mix-ups  Operators are trained  Records demonstrate that all required steps were taken  Distribution minimizes any riskInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 4
  5. 5. Different approaches to GMPs compliance depending on country  There is a global disequilibrium – quality and compliance are different  A nation’s relative development dictates the level of compliance they can afford  ICH signatories have the best quality  BRIC nations generally are struggling with the cost of compliance, even while they recognize the value for international commerceInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 5
  6. 6. GMP starts with the Quality System Structure First step of compliance is the quality system structure Next is facility design that prevents cross contamination and mix- ups Then control of materials Finally documentation of manufacturing informationInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 6
  7. 7. Manufacturing Facility  Facility and flow designed to minimize potential contamination and mix-ups  Defined areas for:  Receipt  Quarantine  Storage  Production  Packaging  WashingInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 7
  8. 8. Small Scale CTM Manufacturing Facility Material flowInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 8
  9. 9. GMP Facility Inspections  FDA conducts facility inspections for products to be sold in the US  Doesn’t include CTM facilities  Doesn’t include clinical stage products  UK and EU use UK’s “Orange Guide” to check compliance  China, Japan, India et al rely on local inspectorsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 9
  10. 10. Typical GMP Facilities in US and UKInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 10
  11. 11. GMP in India Pharma companies in India don’t pay taxes for their first ten years They don’t go through complex certification procedures Over 20,000 pharma companies in India Only 100 have been FDA inspectedInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 11
  12. 12. GMP Facilities in India Schedule M regulations were harmful to the small players in the pharmaceutical industryInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 12
  13. 13. GMP Facilities in India So the government is cutting them some slackInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 13
  14. 14. Materials Only QA approved materials can be used in CTM manufacturing Excipients Containers/Closures Components Work in ProcessInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 14
  15. 15. Getting ready for manufacturing – Control of Materials API, excipients Assign Part #s, and components tests, methods, identified Specs PM Initiates Vendors Specs Yes Yes Project Qualified? Approved? Quality Quality No Manager Manager Project Vendor Project Manager Select Personnel Qualification Definition and Roles CompletedInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 15
  16. 16. GMP in Russia  90% of materials used in Russia are from unknown origins  Only one out of every five drugs purchased in Russia is produced domestically  19 of the top 20 producers of drugs sold in Russia are foreign owned  Only 50 of Russia’s 528 drug factories meet international GMP standards  Before 1991 the state was the only supplier, customer and authority to create standards  Compliance to plan was more important than compliance with GMP standardsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 16
  17. 17. GMP in Russia  In 2004 the EU GMP Guideline was approved as Russian national standard GOST R 52249-2004  National standards are not mandatory documents according to Russian Law  There are multiple challenges to meeting GMP in Russia including bureaucracy and corruption  Pharma 2020 is the governments intended fix  $6 billion in industry-wide investment in training and infrastructure development, GMP practice development and R&D  In the meantime, producing or distributing CTM through CMOs in Russia carries some riskInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 17
  18. 18. Vendors QA shall qualify vendors for materials used in CTM  Phase 1 CTM  Paper based quality survey  Phase 2 CTM  Either a paper based quality survey or an on-site audit  Phase 3 CTM  On-site auditInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 18
  19. 19. Specifications QA shall approve specifications of materials and components  Test - A measurement of a quality attribute such as potency or water content  Method - The procedure by which the quality attribute is measured  Limit - The acceptable range for the attribute  Other Requirements  Sampling Instructions  Safety and HandlingInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 19
  20. 20. Specifications Specifications have version control to keep track of changes Most recent specs apply, but old specs must be kept available for reviewInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 20
  21. 21. Specifications Specifications can have Safety, Handling and Sampling instructionsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 21
  22. 22. Specifications Specifications include Test, Methods and Limits that will go on Certificate of AnalysisInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 22
  23. 23. GMP in Japan  Japan has meticulous, detailed and strategic local GMP rules  You may not know if a Japanese supplier or distributer is in compliance; you just have to trust them  Most GMP texts are in Japanese, rare to see local pharmaceutical guidelines in English  Japan is a signatory of ICH, but there are differences between Japan’s and International GMP  Japan applies a more thorough interpretation of GMPs than ICH requires  The Local Government and Certification Bodies administer GMP in JapanInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 23
  24. 24. Process Flow – Material Management Receipt at Available for Bill Warehouse Record into Released Yes of Materials & Inventory Production No Quarantine, Quality Facility Test & Manager Manager ReleaseInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 24
  25. 25. ReceivingInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 25
  26. 26. Quality Testing and ReleaseInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 26
  27. 27. GMP in China  Regulations issued in the 1980’s and 1990’s were supposed to strengthen China’s pharmaceutical manufacturing  GMP 2010 has become law  Nearly 4,000 pharmaceutical companies in China are small to medium size who will need significant capital to meet new standardsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 27
  28. 28. GMP in China  Nearly impossible to verify if Chinese produced product is in compliance  GMP guidelines in Chinese  Locally inspected  One standard for export and another for localInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 28
  29. 29. GMP in China Only a small % of Chinese factories have FDA inspectionsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 29
  30. 30. GMP in China The rest are inspected locally where corruption remains a possibilityInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 30
  31. 31. Process Flow - Production Manufacturing Instructions Bill of Master Batch Approve Materials Production Production Batch Record In Process Equipment Tests Quality Facility Sponsor Manager ManagerInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 31
  32. 32. Master Production RecordInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 32
  33. 33. Master Production Record - BOMInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 33
  34. 34. Master Production Record – Manufacturing InstructionsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 34
  35. 35. Batch Production Record – Manufacturing InstructionsInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 35
  36. 36. Testing and Release  Samples pulled from production batch  QC will test according to methods in specifications  In US, QA will disposition batch after final product in made in the US  in the UK and Europe, QP (Qualified Person) is used for batch releaseInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 36
  37. 37. GMP in the UK  GMP in the UK is based on is the 1968 Medicines Act  “Guide to Good Pharmaceutical Manufacturing Practice” issued in 1971  Basis for US GMP regulations  Now known as the “Orange Guide”  Essential reference for all pharmaceutical manufacturing and distributing in the European continent.  GMP Inspectorate uses this document as their reference for checking the compliance of companies to EU GMP/GDP standards.InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 37
  38. 38. GMP in Brazil  In the 70s and 80s, steep price control, high inflation, weak intellectual property rights and absence of quality assurance affected drugs  ANIVSA (National Health Surveillance Agency like our FDA) started regulating generics in the 90s  ANIVSA revised its GMP in 2000s to be in line with WHO GMP standards  Now RDC 25 requires quality control and compliance of pharmaceuticals made or imported into BrazilInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 38
  39. 39. GMP in Brazil  Despite the benefits of RDC 25 some manufacturers opposed it due to the cost of compliance  RDC eventually was narrowed down and bases the certification or approval to “risks” of the product  Risk levels 1 and 2 are considered low level while levels 3 and 4 are high  The determination of the product risks will be made by ANIVSA  Only high risks pharmaceutical products require certifications  Level 1 and 2 products are not subjected for registration proceduresInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 39
  40. 40. InventoryInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 40
  41. 41. Tracking of CTM DistributionInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 41
  42. 42. GMP in Taiwan  Regulated by Taiwan’s DOH (Department of Health)  1988, DOH’s required manufacturing plant to provide PMFs (Plant Master File) as mandated by the international GMP  1998, Taiwan applied for PIC/S Pharmaceutical Inspection Co-Operation Scheme membership  In 2001, it expanded and updated its guidelines to include product distribution and recall, plant inspection, auditing and complaints.  Focused on export and international acceptanceInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 42
  43. 43. GMP Inspections World Wide  PIC/S (Pharmaceutical Inspection Cooperation Scheme)  PIC/S references “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” (ICH Q7A)  Participants include Australia, Canada, Eastern Europe, EU, Malaysia, SA, Singapore, UK, US , Taiwan  Not participating: Brazil, Russia, India, ChinaInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 43
  44. 44. Messages  No one GMP compliance system exists even in countries that are signatories to ICH  BRIC countries want to become compliant, but they have a long way to go  Most countries outside of Europe, Japan and US have little control over quality or compliance  If you are manufacturing, packaging or distributing CTM world wide, you have to understand both local regulations and how they are (or are not) enforcedInstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations

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