1. New York Washington Seattle Charles J. Raubicheck, Partner (craubicheck@flhlaw.com) and craubicheck@flhlaw.com Brian J. Malkin, Partner (bmalkin@flhlaw.com) Brian J. Malkin, Partner (bmalkin@flhlaw.com)bmalkin@flhlaw.com Frommer Lawrence & Haug LLP FDA Lawyers Blog (http://www.fdalawyersblog.com) THE ROLE OF CURRENT GOOD MANUFACTURING PRACTICES (cGMPS) IN REGULATORY DRUG QUALITY Korea-Maryland, USA Bio Expo 2013 November 8, 2013

2. © 2013 Frommer Lawrence & Haug LLP OVERVIEW  Guidelines for Manufacturing and Quality Control Charles J. Raubicheck  Generic Pharmaceutical Manufacturing Brian J. Malkin 2

3. © 2013 Frommer Lawrence & Haug LLP Guidelines for Manufacturing and Quality Control 3

4. © 2013 Frommer Lawrence & Haug LLP Regulatory Authority  1) Drug Adulterated Unless It Complies With Current Good Manufacturing Practices (cGMPs) to Assure Identity, Strength, Quality, and Purity [Federal Food, Drug, and Cosmetic Act, Section 501]  2) FDA GMP Regulations for Finished Pharmaceuticals [21 CFR Part 210]  3) Courts Upheld cGMP Regulations as Sufficiently Specific 4

5. © 2013 Frommer Lawrence & Haug LLP FDA’S DRUG cGMP REGULATIONS  1) Control of Drug Components Sampling and Testing of Incoming Raw Materials (Specifications) Retesting Rejections  2) Control of Containers and Closures (Specifications, Physical Examination) 5

6. © 2013 Frommer Lawrence & Haug LLP FDA’S DRUG cGMP REGULATIONS (cont’d)  3) Records Equipment Cleaning and Use Log Components, Container/Closures and Labeling Master Production Records Batch Production Records Laboratory Records Distribution Records Complaint Files 6

7. © 2013 Frommer Lawrence & Haug LLP FDA’S DRUG cGMP REGULATIONS (cont’d)  4) Production and Process Controls Written Procedures for Manufacturing Sampling and Testing of In-Process Materials and Finished Products Control of Microbiological Contamination Reprocessing to Meet Specifications 7

8. © 2013 Frommer Lawrence & Haug LLP FDA’S DRUG cGMP REGULATIONS (cont’d) 5)Laboratory Controls  Incoming Raw Materials 6)Stability (Potency) 7)Reserve Samples 8)Finished Product Release 9)Distribution Procedures 8

9. © 2013 Frommer Lawrence & Haug LLP FDA’S DRUG cGMP REGULATIONS (cont’d) MANUFACTURING PROCESS VALIDATION ─ 3 Production Batches ─ FDA: Prior to Shipment 9

10. © 2013 Frommer Lawrence & Haug LLP  FDA Pre-Approval Inspection  Post-Approval Inspection Every 2 Years  Court Injunctions  Criminal Prosecutions (Park case)  Product Seizures 10 cGMP COMPLIANCE

11. © 2013 Frommer Lawrence & Haug LLP Generic Pharmaceutical Development Manufacturing 11

12. © 2013 Frommer Lawrence & Haug LLP Purpose of cGMPs  Quality is a centerpiece of FDA’s cGMP regulations (effective March 28, 1979): Under the Federal Food, Drug, and Cosmetic Act, a drug is deemed to be adulterated unless the methods used in its manufacture, processing, packing, and holding, and the facilities and controls used therefore, conform to current good manufacturing practice so the drug meets the safety requirements of the act and has the identity and strength and meets the quality and purity characteristics that is represented to have. 12

13. © 2013 Frommer Lawrence & Haug LLP Purpose of cGMPs  Identity is the identification specification.  Strength is the potency specification.  Purity includes the impurity specifications.  Quality is more than just conformance to specifications Means it is what it says it is, not adulterated Means it does what it supposed to do Means it is made under cGMP Means it is pure and not contaminated. 13

14. © 2013 Frommer Lawrence & Haug LLP  Quality is everything under FDASIA: Section 501 (21 U.S.C. 351) amended to add:  “For the purposes of paragraph (a)(2)(B), the term ‘current good manufacturing practice’ includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.” 14 Quality under FDASIA

15. © 2013 Frommer Lawrence & Haug LLP  Shift towards innovation and continuous improvement  Guidance includes: ICH Q1 through Q11 Q8(R2) Pharmaceutical Development Q9 Quality Risk Management Q10 Pharmaceutical Quality System. 15 Quality Documents

16. © 2013 Frommer Lawrence & Haug LLP  Concept of quality includes Robust quality system Quality risk management Corrective and Preventive Actions (CAPA) Change control Separate quality management of product, system, and process quality Leadership needs to be committed to quality. 16 Quality Documents

17. © 2013 Frommer Lawrence & Haug LLP  Account for 70-75% U.S. Prescriptions  Therapeutically Equivalent means: Has the same clinical effect and safety profile when administered to patients under the labeled conditions Pharmaceutically Equivalent + Bioequivalent. 17 Generic Drugs

18. © 2013 Frommer Lawrence & Haug LLP  Pharmaceutical equivalence means: Same active ingredient Same dosage form Same route of administration Identical in strength or concentration Meet compendial or applicable standards of strength, quality, purity, and identity May differ in shape, excipients, packaging. 18 Generic Drugs (cont’d)

19. © 2013 Frommer Lawrence & Haug LLP  Bioequivalence Generally demonstrated by in vivo blood plasma levels (90% confidence interval, log transformed to 80-125% parameters compared to innovator’s product). In vitro dissolution is often a quality measure but may also be required for more complex dosage forms (e.g., simulated gastrointestinal tract pH levels). May involve multiple active ingredients or prodrug and metabolite. All bioequivalence studies must be included in an ANDA. 19 Generic Drugs (cont’d)

20. © 2013 Frommer Lawrence & Haug LLP Generic cGMP Toolbox  Quality by Design (QbD) initiatives  Question-Based Review (QbR) and FDA MaPPs  Auditing and due diligence controls  Remaining current with GMPs Industry meetings and seminars Monitor trends via FDA 483s and Warning Letters Industry publications External consulting Delivery of quality message 20

21. © 2013 Frommer Lawrence & Haug LLP Quality by Design (QbD)  Common to innovator and generic products “[M]eans that product and process performance characteristics are scientifically designed to meet specific objectives... To achieve QbD objectives, product and process characteristics important to desired performance must be derived from a combination of prior knowledge and experimental assessment during product development.” Function of drug substance, excipients, manufacturing, and packaging Goal to develop a Quality Target Product Profile (QTPP) 21

22. © 2013 Frommer Lawrence & Haug LLP Quality Metrics  Metrics must be quantitative and objective.  Metrics must be clinically relevant to patient safety and health.  Main metrics (consensus development) Batch/lot failure rate (rejected, reworked) Right first time Laboratory failure investigation rates  Standards for sampling/acceptance plans.  For generics, sponsors must explain how they systematically arrived at a bioequivalent drug product (not just passed bioequivalence studies) & demonstrate stability and other critical metrics for a consistent drug product. 22

23. © 2013 Frommer Lawrence & Haug LLP Examples of Generic Drug Quality Metrics  Efforts to optimize formulation for “stability by design”  Demonstrate active pharmaceutical ingredient/excipient compatibility  Demonstrate stability of dispersion (API/binder) on pharmaceutical core (i.e., compare different binders and relative amounts on final product)  Consider plasticizers/coatings to minimize curing and consistent coating issues (i.e., to prevent changes in drug release by the curing process)  Consider effect of compression on coatings (cushioning excipients needed?)  Scale-up issues addressed prior to approval. 23

24. © 2013 Frommer Lawrence & Haug LLP Audits and Due Diligence  Dive deep into ALL systems for baseline.  Understand site processes and people.  Harmonize gaps between sites.  Regularly assess cGMP compliance and measure progress toward harmonization goals.  Train stakeholders to develop workflows to constantly assess programs and improve based on experiences and regulatory requirements.  Consider post-approval changes (lifecycle). 24

25. © 2013 Frommer Lawrence & Haug LLP Quality Deficiencies Lead to …  Increased regulatory oversight  Inspections for cause  Warning Letters  Recalls and field alerts  Shortages  Reduced acceptance of generic drugs. 25

26. © 2013 Frommer Lawrence & Haug LLP Perception of Generic Drugs  Immediate release/solutions generally viewed as good.  Complex dosage forms potentially problematic: Modified release drugs may have different release mechanisms but bioequivalent blood levels Greater chance for chemistry, manufacturing, and control issues, particularly with selection of API and excipients.  More modified release generic products are leading to more consumer complaints – actual or real problems?  Complexities or variability of innovator drug may be missed in rush to be first-to-file generic (180-day exclusivity). 26

27. © 2013 Frommer Lawrence & Haug LLP  Quality agreements define role of product owners and contract facilities in terms of responsibilities, cGMPs, and ability for product owners to evaluate contracted facilities as well as mechanisms for timely notifications and communications.  Owners have ultimate responsibility for final product including rejected lots/batches.  Contracted facility has responsibility for meeting cGMPS including identification and responses to quality issues. 27 New Contract Manufacturing Draft Guidance

28. © 2013 Frommer Lawrence & Haug LLP  Fees to pay for backlog review (3000 unapproved ANDAs; trend was 1000 new ANDAs/year with 600 approvals/year), permit hiring additional review employees, and implement efficiency improvements.  Fee structure for ANDAs, DMFs / Facility self-identification.  ANDA Complete Response Letters (except easily correctible).  Focus on drug supply chain including active pharmaceutical ingredients AND excipients.  Requires maintaining records for inspections (prioritized).  ANDA median review times up (35 months) during new staff training and efficacy changes – will FDA meet 10-month ANDA reviews (2-month controlled correspondence)? 28 GDUFA Considerations

29. © 2013 Frommer Lawrence & Haug LLP QUESTIONS? 29 Brian J. Malkin Partner, Frommer Lawrence & Haug LLP Editor, FDA Lawyers Blog 202-292-1530 bmalkin@flhlaw.com bmalkin@flhlaw.com Charles J. Raubicheck Partner, Frommer Lawrence & Haug LLP 212-588-0800 craubicheck@flhlaw.com craubicheck@flhlaw.com http://www.fdalawyersblog.com