1. Regulation of Drug Manufacturing Neil P. Di Spirito, Esq. Rumberger, Kirk & Caldwell ndispirito@rumberger.com

2. Define Small/Midsize Drug Companies Sales of $25million to $200million 75 to 150 employees 10,000 to 1000,000 sq. ft. of plant space 3 to 6 products on average Privately or Publicly held Specialty or underserved markets From topicals to very high-tech biopharms (produced in smaller quantities) and Orphan Drugs

3. Define Small/Midsize Drug Companies Usually no or general (non- regulatory/compliance) in-house counsel Newer less experienced Quality Units Diversity of Issues Capable of handling their regulatory/compliance, business (i.e. licensing, contracts,etc.), litigation and enforcement Need background in science, business and law (undergrad science with MBA and Law Degree)

4. When FDA Knocks Hi, I’m from the Government… and I’m here to help… It is a crime to refuse an authorized FDA Inspection Got it?!

5. Challenges to Small/Midsize Drug Companies Understanding drug current Good Manufacturing Practices (cGMPs), and defining "adulteration" and "misbranding" Review the different types of inspections Explore the elements of a 483 observation and the components involved with closing out an inspection

6. Two Major Challenges to Small/Midsize Drug Companies Adulteration---methods or processes used are not in conformance with good manufacturing practices –(FDCA §501 (a)(2), 21 U.S.C. §351 (a)(2)(b), 21 CFR Part 210 & 211); Misbranding--- provisions can pertain to materials that are physically distant from the product or its container (ads making improper claims run in journals). labeling is false or misleading –(FDCA §502 a), 21 U.S.C. §352(a));

7. Good Manufacturing Practice (GMP) Good manufacturing Practices were implemented by the FDA to ensure that Drug Products are manufactured in an appropriate and safe way –(21 CFR 210 & 211) FDCA grants FDA authority to ensure compliance with current GMP –(cGMP) (§ § 301(a), 501(a)(2)(b); 21 USC § § 331(a); 351(a)(2)(b) A Drug is adulterated if found not to be manufactured according to cGMP’s –(§ § 301(a), 501(a)(2)(b);

8. Good Manufacturing Practice (GMP) A drug can meet its specifications, contain no detectable impurities, be both safe and effective and still be considered adulterated if the manufacturing was not in compliance with cGMP’s. –(FDCA §501 (a)(2), 21 U.S.C. §351 (a)(2)(b), 21 CFR Part 210 & 211); Quality should be built into the product and testing alone cannot be relied upon to ensure product quality” –(FDA Guidance for Industry, Sept. 2006)

9. Good Manufacturing Practice (GMP) The role of the FDA is to determine which practices in use are “good” and enforce those. FDA does not prescribe “how to make products”, but requires manufacturers to do so. Must establish: Procedures which assure the drug is manufactured in a way to consistently meet specifications.

10. GMP: Current not Static Reference point not FDA imposed In use by various manufacturers FDA assess practices as “Good” and enforces those practices Advance state of the art Need not be widely prevalent to become “standard”

11. SOP’s Source of Issues for Small/Midsize Companies Production Process and Controls Requires written procedures (SOP’s and validation) to conduct batch production and processing in a way ensuring the accuracy of: –Identity –Strength –Purity –Quality (21 CFR 211(f)) Attorney review to ensure compliance with latest Policy/Regulations of FDA (Consultants not always up to date)

12. Laboratory Controls Laboratory Controls: Requires the design and continued use of Lab procedures to maintain continuous control of lab processes. –(21 CFR Part 211(i)) These are the standards, specifications, and test procedures that ensure the tested drugs are of the appropriate identity, strength, quality and purity. –(21 CFR Part 211(i))

13. Challenges (OOS) No or inadequate procedures for handling “out of specification” (“OOS”) situations, failure investigations and “corrective and preventive actions” (CAPA) are amongst the most frequently found deviations in FDA warning letters. Most companies have procedures but either they are not adequate or are not followed.

14. Challenges Process Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)) Method process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug

15. Validation Processes The foundation for process validation is provided in § 211.100(a), which states that “there shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess...”

16. Validation Processes The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. The regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes.

17. Validation Processes The goal of validation is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal.

18. Inspection Parameters FDA Entitled to: Relevant information concerning whether drugs (for human consumption) are: – Manufactured – Transported – Processed – Packed In accordance with the Act [FDCA] –(704(a)(1); 21 USC 374(a)(1)

19. Inspection Parameters NOT Entitled to: Financial Data Sales Data (other than shipping amounts) Pricing data Personnel data (other than the qualifications of professional personnel) Research data (except for data required to be disclosed under 21 USC 374 ‘approval data’) Internal audit, supplier audit, mgmt reviews)

20. Inspection Parameters May Attempt to Obtain: Not statutorily or regulation authorized –Affidavits from individuals (NEVER sign) –Interview of employees (only those you select) –FDCA does not authorize investigators to interview a company’s employees; (if so, with counsel present) Managerial or non-managerial employees

21. Inspection Conclusions Post inspection discussion with investigators (optional) Usually helpful to figure out FDA next steps Corrective actions disclosed Review of Form 483

22. Response to Form 483 FDA expects a response from manufacturer on each observation –15 business days Explain problem identified Proposed action or plan to prevent reoccurrence of observation Use system preventative answers.

23. Establishment Inspection Report More detail description of 483 observations Generally tracks and expands on 483 Classifies as “Voluntary Action Indicated” or “VAI” or “Official Action Indicated” or “OAI” OAI usually indicates enforcement action of some type (Warning Letter, etc.)

24. Establishment Inspection Report “RTS” Referred to State, local, or other federal office. –no federal jurisdiction over violation –state action is the least involved and fastest “RTC” or Referred to Center –No clear policy –technical issues require Center review

25. Use of cGMP Violations in Litigation Finding of adulteration based on failure to comply with GMP’s even if product quality is fine –Title 21 S. 351(a)(2)(B) Even if final product is “pharmaceutically perfect,” manufacturing non-compliance will deem product adulterated. Not only “Good” but “Current”

26. GMP: Current not Static Reference point not FDA imposed In use by various manufacturers FDA assess practices as “Good” and enforces those practices Advance state of the art Need not be widely prevalent to become “standard”

27. GMP: Proof in Litigation FDA must only prove : –Manufacturer did not follow a particular practice –Practice was deemed “Good” by FDA Cases: –Provide flexibility…specific enough to assure drug is safe and relaible… »U.S. v. Bel Mar Labs, 284 F. Supp. 875

28. GMP: Proof in Litigation Non-USP mehtods used must be validated to FDA satisfaction –U.S. v. Barr Labs, 812 F. Supp. 458 Enforced without expert testimony on the currency or goodness of the practice –Nat’l Ass’n PhARM. Manufacturers v. FDA, 637 F.2d 877 FDA has authority to issue binding cGMP regulations –Nat’l Ass’n PhARM. Manufacturers v. FDA, 637 F.2d 877

29. Other Issues Establishment Registration And Drug Listing –§510(c), 21 U.S.C. §360(c); 21 C.F.R. §207.21 Drug Product Listing (Form FDA 2657) –21 C.F.R. §207.25 Field Alert Reports (FAR) –21 CFR 314.81(b)(1)(i)

30. 21 CFR 314.81(b)(1)(i) and (ii) Notify the district office within 3 working days Information may be provided by telephone, Fax, E-mail or other rapid communication means prompt written follow-up (Form FDA 333) Internet Availability of Form 3331 Field Alert Reports (FAR)

31. When to engage a consultant/ Field Alert Reports (FAR) Bacterial contamination Stability Issues: –Product deterioration –Out-of-specification –Chemical changes in composition –Physical changes (i.e. pills crumble) –FAR’s on drug products foreign or domestic

32. Regulation of Drug Manufacturing Thank You Neil P. Di Spirito, Esq. Rumberger, Kirk & Caldwell ndispirito@rumberger.com