A Perspective on Oversight of API Manufacturing Sites

1. A Perspective on Oversight of API Manufacturing Sites Albinus D’Sa, Ph.D. Deputy Country Director India Office U.S. Food and Drug Administration Department of Health and Human Services

2. Current US Pharmaceutical Industry Landscape • Increased generic drug demand • Increase in median age of population • Innovator patents expiring • Downward cost pressure from payers • More outsourcing and globalization of finished dosage manufacturing • Specialization in facets of upstream manufacturing • API manufacturing is an example of a 40-year trend in outsourcing to specialists culminating by shift away from domestic (in this case specialty chemical) manufacturing base • Manufacturers will gain competitive edge through high quality and superior management of supply chains

3. Registration Statistics ”Manufacturers” exclude API manufacturers as well as contract sterilization, analytical labs, PET, repackaging/packaging, labeling/relabeling

4. Foreign GMP InspectionsAll Drugs

5. Drug Inspections in India 2008 2009 2010 2011 2012

6. Quality Problems Traced to Supply Chain are Driving a Heightened Focus on Ingredient Manufacturing • API – Highest Expectations for GMP • Excipients • Dietary supplement ingredients • Food ingredients • Cosmetic ingredients • Higher Quality Standards for Ingredients

7. Examples of Recalls Traced to ExcipientVariability or Low Levels of Impurities • Four recalls in 2010 due to dissolution failure were ascribed to excipients • Aldehyde impurity (OTC drug) • Properties of Zein (OTC drug) • Intra-batch variability in Ethylcellulose used in MR coating in capsule formulation (2 events involving the same product) • Acid value of Glyceryl Behenate matrix carrier in a microsphere formulation

8. FDA Detects High Levels of Peroxide in Imported Crospovidone and Issued a Drug Safety Advisory 10/21/2010http://www.fda.gov/drugs/drugsafety/ucm230492.htm • Peroxide levels found (1700 ppm) were 30-40x typical levels in this excipient • Peroxides can degrade APIs resulting in sub-potent drug • Impurity levels were not being monitored by the manufacturer of Crospovidone • Certificates of analysis were not indicating presence of such high levels of peroxide • USP to revise monograph to add limit of peroxide

9. Observation: Manufacturers are Applying High Standards for Ingredient Quality Assurance • More intensive supplier qualification by finished product manufacturers • Auditing of ingredient manufacturing sites • Expectations for direct communication between makers and user of ingredients • More rigor in standards of quality for ingredients • More frequent user confirmatory testing

10. FDA API CGMP Inspections • API - ingredient intended to furnish pharmacologic effect • The law defines API as a drug because it is a component of a drug • The law requires all drugs to be manufactured in conformance with CGMP • API not manufactured in conformance with CGMP is deemed adulterated • An import alert can be issued when an API appears to be adulterated as a result of inspection findings • ICH Q7 is a standard for FDA inspection of API establishment (see also CDER Compliance Program Guidance Manual section 7356.002F)

11. FDA API Pre-approval and CGMP Inspection Programs • CGMP inspections • Focused on six systems • Quality management system is always inspected • Facilities and equipment, Materials, Production, Packaging and Labeling, Laboratory • On a pre-approval inspection FDA will also be looking at the control of the API manufacturing process with greatest emphasis on critical process parameters and quality attributes • Biotechnologically derived APIs • Are usually going to be produced as “Sterile API” • Other more rigorous inspection programs which apply finished dosage form CGMP will generally apply

12. Facilities and Equipment Systems • Risks to address • Cross contamination risk • Contamination due to equipment or exposure of API process • Mix-ups ------------------------------------------------------------------------------ • Facility and equipment design • Flow of materials, people, activity • Cleaning during changeovers • Compatibility of materials with process stream • Identification of each piece of equipment and piping systems • Maintenance

13. Areas of High Contamination Risk • Dry processing such as drying or particle size reduction can generate airborne fine particles • Equipment which if not properly maintained or taken out of service when in irreversible disrepair can shed particles • Areas in which there is potential for API to accumulate and not be readily removed during cleaning

14. Materials Systems • Identification and purity specifications and testing of critical starting materials • Segregation in warehouse to avoid mix-ups • Tracking of inventory and traceability • traceability of API starting materials • FDA is particularly concerned about agriculturally derived starting materials • Water quality • Minimum standard is WHO drinking water quality • Water purification systems should be validated • Water quality should be monitored and controlled using action limits and procedures to describe actions taken when limits are exceeded

15. Suppliers of Critical Raw Materials for API Manufacturing • System for technical evaluation of suitability • System for approval of suppliers by the QU • Agreed upon purchasing specification • Name and address of the manufacturer of the critical raw material known • Written agreement to be notified about significant changes to manufacturing that might impact critical material quality

16. API Guidance Which Cover Starting Materials ICH Q7A: GMP Guidance for API http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073497.pdf ICH Q11: Draft Guidance on Development and Manufacture of Drug Substances http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM261078.pdf Draft Guidance on Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390.pdf

17. Total – deficiencies seen on API inspections 2007-2010, by region Source: DIDQ CO reviews of EIRs as reported in CMS Date of data pull: Sept 19, 2011

18. QA Systems Equipment design, Size, location Inadequate SOPS Buildings/Facilities Production/Process Control Equipment cleaning/ Maintenance System Qualifications Invalidated Lab Test Methods Raw Material Controls Inadequate Lab Controls

19. QA Systems Control Components, Intermediates, Raw Materials Buildings/Facilities Equipment design, Size, location Equipment cleaning/ Maintenance System Qualifications Production/Process Control Invalidated Lab Test Methods Inadequate SOPS

20. QA Systems Control Components, Intermediates, Raw Materials System Qualifications Production/Process Control Invalidated Lab Test Methods Inadequate SOPS Equipment cleaning/ Maintenance

21. Control Components, Intermediates, Raw Materials Equipment design, Size, location QA Systems Production/Process Control Invalidated Lab Test Methods Inadequate SOPS Equipment cleaning/ Maintenance System Qualifications

22. Lab Systems - Data Integrity • Accurate and reliable data and information • Ensuring data trustworthiness and reliability, as related to the security of the information/data • Quality • the degree to which a collection of data is complete, consistent, and accurate. • Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA) • FDA may look to see that the process of data creation at the site can be reconstructed and that it matches the information submitted to the agency. If problems are discovered, the integrity of the data is questionable.

23. Data Integrity – What We See • Not recording activities contemporaneously • Backdating • Fabricating data • Copying existing data as new data • Discarding data • Not saving electronic or hard copy data • Discarding data to release failing product • Repeat sampling or testing until compliance can be documented

24. Loss of Data Integrity - Observations • Batch production record • 7 instances involving 2 employees signing as having completed manufacturing steps; neither employee was on the premises at the time the steps were completed • Stability • Testing conducted late but recorded as having been tested on time • Testing data was generated without samples having been taken • Analytical Method Validation • Results from the method validation of one drug were used for the method validation of another drug

25. Loss of Data Integrity - Observations • Test Data for Batch Release • Test results for one batch were used to release other batches • Occurred for at least 3 batches • Happened at two unrelated firms • Employee used same sample for identity testing of multiple batches • Firm repackaged and released failing batch without performing an investigation

26. Data Integrity - References • FDA’s Guidance to Industry: Part 11, Electronic Records; Electronic Signatures — Scope and Application, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070295.pdf • Glossary of Computer Systems Software Development Terminology (8/95), available athttp://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074875.htm

27. Nine FDA Warning Letters Were Issued to Foreign API Manufacturers in 2011 • Failure to conduct adequate release testing • Failure to investigate failing lab results • Failure to validate analytical methods • Lab control issues and falsification of lab data • Failure to review data before release and failure to evaluate suppliers • Failure to implement procedures to prevent cross-contamination with penicillin products • Failure to document manufacturing operation records and inadequate facilities • Inadequate production records and laboratory controls • Failure to investigate deviations and inadequate maintenance

28. Validation • All API manufacturing processes should be validated • FDA recommends a lifecycle approach to validation • All test methods for release of API should be validated • All test methods should be suitable and scientifically sound for intended purpose • In process testing • Testing of starting materials, reagents, solvents, catalysts, etc.

29. Residual Solvents and Metallic Impurities • API manufacturers should be prepared to provide identity of potential residual solvents and metallic impurities to finished dosage form manufacturers • Requirements apply to finished drug products • See ICH Q3C for residual solvents (Option 2) • ICH Q3D (soon to be a Step 2 draft) and draft USP chapters <231> and <232> express impending expectations for metallic impurities • Instrumental methods to replace heavy metals test • Calculation of metallic impurities in drug products will usually be based on levels in APIs and excipients

30. Expect To See More… • Inspections of foreign API sites • Heightened focus on inspections related to generic drug manufacturing • More focus on management of suppliers • Consistent raw materials fit for purpose • Integrity of API supply chains • Sharing of information with trusted regulatory counterparts under confidentiality agreements • 3rd party involvement, especially in supplier audits normally conducted by finished drug manufacturers

31. References • Validation • FDA Guidance on Process Validation: General Principles and Practices http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070336.pdf • Residual Solvents • ICH Q3C http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073394.pdf • USP <467> • Elemental (Metallic) Impurities USP <232> • USP-PF 37(3)

32. Acknowledgements • Karan Takahashi • Grace McNally • Raphael Brykman • Steven Wolfgang • Elizabeth Philpy