1. Understanding cGMPs: What Attorneys Need to Know The Nuts & Bolts of cGMPs Statutory Overview and Basic Concepts James R. Johnson Hogan Lovells US LLP

2. Why is cGMP Important? Under the Federal Food, Drug, and Cosmetic Act (FDCA), all drugs are required to be manufactured in accordance with current good manufacturing practice (cGMP). See 21 USC 351(a)(2)(B) (a drug is adulterated if “the methods used in, or the facilities or controls used for, its manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice....”) (emphasis added).

3. Purpose of cGMP The purpose of cGMP is to prevent drug product defects by rigorously controlling the manner of production. If manufacturing processes are not compliant, the product is legally deemed to be adulterated.

4. Recent Expansion of the Statutory cGMP Definition Section 711 of the Food and Drug Administration Safety and Innovation Act (FDASIA) amended 21 USC 351(a)(2)(B) by adding that cGMP includes: Codified existing FDA’s policy that manufacturers implement quality oversight over their suppliers and gives FDA explicit authority to enforce requirements related to supply chain management. “the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.”

5. Drug cGMP Regulations Based on the statutory requirement for drug manufacturers to follow cGMP, FDA promulgated specific cGMP regulations for finished pharmaceutical products. See 21 CFR Parts 210 and 211. –The regulations contain the minimum cGMP for drug products for administration to humans or animals. See 21 C.F.R. § 211.1(a) (emphasis added). API manufacturers are expected to comply with the cGMP regulations, but because API is not a finished drug FDA will charge a violation of the statutory cGMP provision, 21 USC 351(a)(2)(B). Most Phase I investigational drug products are exempt from complying with the cGMP regulations.

6. Related cGMP RegulationsRelated cGMP Regulations Biological Products cGMP: 21 CFR Parts 600-680 –For therapeutic products that meet the definition of drug under the FDCA, they must comply with 21 CFR Parts 210-211 and 600-680 –cGMP for Blood and Blood Components: 21 CFR Part 606 –The regulations supplement the drug cGMP regulations, and are promulgated under authority of both the FDCA and the Public Health Service Act. See 21 CFR 210.2 and 211.1(b).

7. Fundamental Principles of cGMP Product quality cannot be adequately ensured only by inspecting and testing a finished product because finished-product testing cannot detect all defects Quality must be built into a product with processes that are well- controlled during design and manufacturing You can’t test quality into a product. If the processes were poor, no amount of testing will assure that the product meets all of its quality attributes

8. Fundamental Principles of cGMP, Continued Manufacturers are required to establish and follow quality systems that control each step of the manufacturing process The goal is to ensure that manufacturing processes consistently produce products that meet predetermined specifications

9. Fundamental Principles of cGMP, Continued cGMP covers all phases of product manufacturing and distribution and is flexible –Includes supply chain management –The requirements can be tailored to particular products and manufacturing processes –Goal of cGMP is to keep pace with technological advances in manufacturing processes –There are costs and benefits of the flexible approach

10. Fundamental Principles of cGMP, Continued cGMP is whatever practice is feasible and valuable in assuring drug quality. –National Association of Pharmaceutical Manufacturers v. Dep’t of HHS, 586 F. Supp. 740, 752 (S.D.N.Y. 1984) Finding “that ‘feasible and valuable’ is synonymous with, or at least consistent with, ‘current and good’”.

11. FDA’s Application of cGMP FDA has the authority to inspect cGMP records for prescription drugs and nonprescription (OTC) drugs intended for human use. 21 USC 374(a)(1). –Primary focus of FDA inspections is on determining whether a firm is in compliance with cGMP. Interstate shipments of adulterated drugs are subject to seizure, and responsible firms and individuals are subject to injunction and to criminal misdemeanor/felony charges. See 21 USC 331, 332, 333, and 334. Other consequences for cGMP noncompliance, as well

12. Evidence of Product Defect Is Not Required A cGMP violation does not require evidence that a product does not conform to its specifications, or any evidence of injuries from its use to be legally sufficient. –United States v. Bel-Mar Laboratories, Inc., 284 F. Supp. 875, 881-883 (E.D.N.Y. 1968) a drug manufactured in violation of cGMP is adulterated “regardless of whether the drug is actually shown to be deficient in some respect”. –United States v. 789 Cases of Latex Surgeons' Gloves, 799 F. Supp. 1275, 1286 (D.P.R. 1992) “A device that was not manufactured in compliance with GMP is adulterated, even if the device does not contain any actual defects.”

13. Maintain Compliance: Correction is Not Always a Defense United States v. Richlyn Laboratories, Inc., 827 F.Supp 1145 (E.D.Pa. 1992) –Preliminary injunction for cGMP violations is appropriate despite improvements made where firm has a history of cGMP violations and of promising and attempting to comply only upon receipt of FDA warnings and under threat of further legal action by FDA. United States v. Richlyn Laboratories, Inc., 822 F.Supp 268 (E.D.Pa. 1993) –Permanent injunction appropriate even though cGMP regulations did not specify exact conditions which would be acceptable to FDA investigator. United States v. Medwick Laboratories, Inc., 416 F.Supp 832 (N.D.Ill. E.D. 1976) –Not even complete cessation of alleged cGMP violations will, of itself, afford ground for denying injunctive relief.

14. FDA Must Prove cGMP Violations United States v. Barr Laboratories, Inc., 812 F.Supp. 458 (D.N.J. 1993) –Detailed probe into specific cGMP requirements and whether firm was in or out of compliance. United States v. Bioclinical Systems, Ind., et al., 666 F.Supp. 82 (D.MD. 1987) –Finding that a sterility assurance level of 0.1% was not cGMP in the tissue culture media industry just because FDA said it was. Had to be in the cGMP regulations or FDA had to support with adequate expert testimony at trial that it was in fact cGMP in the tissue culture media industry, which the court said FDA failed to do. Court found it was not economically feasible to attain such level and denied government's motion for an injunction.

15. FDA Must Prove cGMP Violations, Continued United States v. Utah Medical Inc., 404 F.Supp. 2d 1315 (D. Utah Oct. 21, 2005) –Denying a motion for preliminary injunction finding that government had not met its burden of showing that firm was not in compliance with the QSR and that the defendants were, in fact, in compliance with the QSR. United States v. Laerdal Manufacturing Corp., 853 F.Supp. 1219(D.Or. 1994) –Finding that government had not met its burden in showing that cGMP violations required court to order defendant to cease manufacturing and distribution of defibrillators.

16. When FDA Decides to Bring a cGMP Enforcement Actions For FDA, as well as industry, cGMP and supporting evidence can get rather esoteric and difficult to convey to a court. Thus, in most cGMP enforcement actions FDA believes it has the ability—and expert support—to convince a court of: –The reason for the cGMP requirement/regulation and its application to the particular product; –What responsible manufacturers do to comply with the cGMP requirement/regulation; –How the defendants failed to measure up; and –The consequences of the defendants failures.