Understanding cGMPS – What Attorneys Need to Know The Nuts + Bolts of cGMPS July 10, CFR Parts 210 and 211 cGMP case law Andrew D. Bos Senior Director – Legal Services Caraco Pharmaceutical Laboratories, Ltd.

cGMPs Found in CFR Title 21 Parts 210 and 211 History goes back to the 1962 amendments to the Federal Food, Drug, and Cosmetic Act

Objectives Standards for methods to be used for the: –Manufacture –Processing –Packing –Holding So that that the drug meets the requirements for: –Safety –Identity –Strength –Quality –Purity

“Minimum” Standards The CFR regulations which make up the cGMPs contain the “minimum” current good manufacturing practice CFR § 210.1(a).

Flexible “The cGMP requirements were established to be flexible in order to allow each manufacturer to decide individually how to best implement the necessary controls by using scientifically sound design, processing methods, and testing procedures.” - FDA website, June 27, 2013, /ucm htm

But yet still definite cGMP regulations have survived challenges on the grounds that they are vague, indefinite and uncertain. –United States v. The Kendall Co., 324 F. Supp. 628 –United States v. Bel-Mar Laboratories, Inc., 284 F. Supp. 875 –United States v. An Article of Drug, 484 F. 2d 748

Binding Regulations cGMPS are binding regulations, not merely interpretive. –Nat’l Ass’n of Pharmaceutical Mfrs. v. Food and Drug Admin., 487 F. Supp. 412, affirmed, 637 F.2d 877

Violations of cGMP Result in the drug product being adulterated. 21 CFR § 210.1(b); 21 U.S.C. § 351(a)(2)(B). Even if “pharmaceutically perfect in content”, a drug is adulterated if made in violation of cGMP. United States v. Lit Drug Co., 338 F. Supp. 990

Part 211 Subparts of cGMP Organization and Personnel Buildings and Facilities Equipment Control of Components and Drug Product Containers and Closures Production and Process Controls Packaging and Labeling Control Holding and Distribution Laboratory Controls Records and Reports Returned and Salvaged Drug Products

Organization and Personnel The quality department is responsible for approving or rejecting drug components, containers, packaging, labeling and production records. Adequate laboratory facilities Personnel qualifications

Buildings and Facilities Suitable size, construction and location Adequate space Operations to be performed within specifically defined areas

Equipment Shall be of appropriate design, adequate size, and suitably located Equipment construction Equipment cleaning and maintenance Filters

Components and Containers For components and drug product containers need to have written procedures regarding: –Receipt –Identification –Storage –Handling –Sampling –Testing –Approval or rejection

Production and Process Control To assure that the drugs have the identity, strength, quality, and purity they represent to have. Weighing, measuring and calculation of yield Equipment Identification Sampling and testing of in-process materials Time limits for production

Packaging and Labeling Control Receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials.

Holding and Distribution Warehousing Procedures –Quarantine procedures –Storage Temperature Humidity Light Distribution Procedures –Oldest approved stock first –Ability to facilitate a recall if necessary

Laboratory Controls Testing and release for distribution Stability testing Special testing requirements Reserve samples

Records and Reports Any production, control or distribution record associated with a drug batch –1 year after expiration of the batch –3 years after distribution for OTC –Applies to drug components, containers, closures and labeling Must be “readily available” for an FDA inspection

Records and Reports, cont’d Complaint files –Written and oral complaints –Determine the need for an investigation –Unexpected ADE that needs to be reported? –Written record of each complaint

Returned Product Storing, handling and disposition (and possible salvaging) of returned product.

United States v. Barr Laboratories, Inc. Most significant case dealing with cGMPs 812 F. Supp. 458 (1993) A court battle involving the need for manufacturing standards, and how specific those standards would be. Case arose out of FDA inspectors issuing 483 observations to Barr

U.S. v. Barr, cont’d Key FDA criticisms of Barr –Manufacturing process are invalid / not validated –Failure investigations are inadequate –Release of drug products that fail specifications –Cleaning validation deficiencies –Record-keeping deficiencies –Failure to validate testing methods FDA sought an injunction against Barr to have it suspend, recall or revamp numerous products

United States v. Barr, cont’d Court recognized the regulations can sometimes lead to “conflicting, but plausible” interpretations. To the extent that there are ambiguities, companies can turn to FDA guidance or scientific judgment. –Industry practice cannot be a basis to determine compliance.

United States v. Barr, cont’d Court concluded Barr violated cGMP –Did not conduct failure investigations –Released batches on the basis of selective data –Refused to validate cleaning processes Court did acknowledge Barr made improvements during the course of the litigation

United States v. Barr, cont’d No shutdown –“In light of Barr’s recent makeover….the Court is unwilling to order a temporary shutdown. While Barr’s transformation from an ugly duckling to a swan is neither natural nor complete, the Court cannot ignore Barr’s remedial efforts.”

United States v. Barr, cont’d Court’s ruling –Helped clear up uncertainty in the regulations –Helped define parameters for drug testing –Prompted the FDA to issue guidance to assist companies to reach better cGMP compliance

Questions ? Andrew D. Bos Senior Director - Legal Services Caraco Pharmaceutical Laboratories, Ltd Extension 4318