Why do you need to get one? You may be one inspection away from a misbranding or adulteration claim.

On May 28, 2013 FDA issued its Draft Guidance entitled Contract Manufacturing Arrangements for Drugs. The Draft Guidance concerns active pharmaceutical ingredients (APIs) and finished products that result in a "drug that is intended to be marketed, distributed, and sold." The term "manufacturing" is defined to include "processing, packing, holding, labeling operations, testing, and operations of the Quality Unit."

As with all guidance documents, FDA states it is merely describing its "current thinking on a topic and should be viewed only as recommendations" but the agency will be looking for these Contract Manufacturing and Quality Management Agreement in its routine inspections.

The draft guidance cites International Conference on Harmonization quality guidelines Q7, Q9 and Q10, highlighting an assessment of the "suitability and competence of the potential Contracted Facility" and the need for a formal Contract Manufacturing and Quality Management Agreement to detail quality management practices.

FDA regulations already require that manufacturing procedures be written. According to the Draft Guidance implementing a written Quality Agreement will facilitate compliance with the regulations." FDA expects comprehensive written agreements that define and establish "the obligations and responsibilities of the Quality Units of each of the parties involved in the contract manufacturing of drugs." FDA further recommends that the representatives from each party's quality control group participate in drafting the Agreement and that it be separate from Master Services Agreements, Supply Agreements, and other documents that FDA does not routinely review. FDA is looking for these Agreements to be among the documents "routinely requested and reviewed."

Contract Manufacturing And Quality Management Agreements Should Contain The Following:

  • Purpose/Scope;
  • Terms (including effective date and termination clause);
  • Dispute Resolution; Responsibilities (including communication mechanisms & contacts); and
  • Change control and revisions.

In establishing the responsibilities the Agreement should detail:

  • Quality Unit Responsibilities: According to FDA, this is "perhaps the most critical element of a Quality Agreement, should define in detail the CGMP responsibilities of each party, including the quality activities and measures."
  • Facilities and equipment: Identify the specific site(s) at which manufacturing operations will be performed.
  • Materials management: "The parties should indicate who is responsible for setting specifications for raw materials; auditing, qualifying, and monitoring suppliers of those materials; and conducting required sampling and testing."
  • Product-specific terms: product/component specifications and manufacturing operations."
  • Laboratory controls: The Agreement should specify that the Owner and Contract Laboratory are responsible for ensuring that methods validated, equipment is calibrated, and maintained. While the primary responsibility rests on the Contract Laboratory; the Owner must ensure compliance with CGMP through routine auditing.
  • Documentation: The Agreement should include procedures for the review of documents such as Standard Operating Procedures, manufacturing records, specifications, laboratory records, validation documentation, investigation records, annual reports, and any other documents/records related to the product manufactured or services provided by the Contracted Facility. The parties should also specify methods of records management and storage.

Missbranding and Adulteration can be a Misde

While "[i]n all cases, the Owner is responsible for assuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected Contracted Facilities," the FDA considers contractors an "extension of the manufacturer's own facility" who are also responsible for product adulteration and misbranding under 21 CFR 200.10. "Owners" are defined as the parties that introduce a drug into interstate commerce and "Contracted Facilities" are entities performing manufacturing operations. Both Owners and Contracted Facilities are liable under 21 U.S.C. 301(a) for introducing or causing the introduction of adulterated or misbranded drugs into interstate commerce and, pursuant to 21 U.S.C. 351(a)(2)(B), a drug is adulterated unless there is compliance with current good manufacturing practice.

It cannot be overstated that introducing or causing the introduction of adulterated or misbranded drugs into interstate commerce is a crime and, according to FDA the "requirements of foresight and vigilance imposed on responsible corporate agents are ... demanding, and perhaps onerous, but ... no more stringent than the public has a right to expect of those who voluntarily assume positions of authority in ... enterprises whose services and products affect the health and well-being of the public ..." United States v. Park, 421 U.S. 658, 672 (1975). The Supreme Court in Park did state that a defendant charged with misbranding an FDA-regulated product could assert a defense that he or she was "powerless" to prevent the violation. But, in practice, the defense is difficult, at best, to pursue, and violations are effectively strict liability crimes.

Adding urgency to compliance, in January 2011 FDA published internal guidelines titled "Special Procedures and Considerations for Park Doctrine prosecutions" stating:

The Park Doctrine, as established by Supreme Court case law, provides that a responsible corporate official can be held liable for a first time misdemeanor (and possible subsequent felony) under the Federal Food, Drug, and Cosmetic Act ("the Act") without proof that the corporate official acted with intent or even negligence, and even if such corporate official did not have any actual knowledge of, or participation in, the specific offense. A Park Doctrine prosecution, for the purposes of this section, refers to a recommended prosecution of a responsible corporate official for a misdemeanor violation of the Act.

The comment period is open until July 29, 2013. The Docket is located at Regulations.gov FDA-2013-D-0558-0001.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.