FDA recommends that owners and contract manufacturers implement written quality agreements to define each party’s manufacturing activities/roles to ensure compliance with current good manufacturing practices.
The U.S. Food and Drug Administration (FDA) has released a final guidance, entitled “Contract Manufacturing Arrangements for Drugs: Quality Agreements,” which includes the agency’s non-binding recommendations regarding quality agreements establishing responsibilities of each entity involved in the manufacture of a pharmaceutical product (e.g., an owner[1] and a contract manufacturer[2]) in adherence to current good manufacturing practices (cGMPs).
This guidance covers commercial manufacturing of the following categories of drugs: human drugs, veterinary drugs, certain combination products, biological and biotechnology products, finished products, active pharmaceutical ingredients (APIs), drug substances, in-process materials and drug constituents of combination drug/device products. It does not, however, cover Type A medicated articles and medicated feed; medical devices; dietary supplements; or human cells, tissues or cellular or tissue-based products.
The Guidance
FDA recommends that owners and contract manufacturers implement written quality agreements to define each party’s manufacturing activities/roles to ensure compliance with cGMP. In drafting the quality agreement, the parties may rely on quality management principles and engage in “defining, establishing, and documenting their activities in drug manufacturing operations, including processing, packing, holding, labeling operations, testing, and quality control operations.”
The Agency notes that each party engaged in manufacturing is responsible for ensuring cGMP compliance, both statutory and regulatory, for manufacturing activities that it performs. The quality agreement cannot be used as a means to delegate/assign responsibility to comply with cGMP. For instance, even when the owner uses a contract manufacturing facility, the owner’s quality control unit is responsible for approving and rejecting drug products manufactured by the contract facility, including the final release of the drug product.
From the agency’s guidance, it is apparent that FDA considers contract facilities to be an extension of the owner’s facility and recommends both the owner and contract facility to work together to establish and maintain quality oversight of contract manufacturing operations and materials produced under the contracted manufacturing agreements.
FDA’s Recommendations Regarding Contents of the Quality Agreement
A quality agreement defines the owner’s and the contract facility’s roles and manufacturing activities under cGMP. The FDA recommends including, at least, the following sections in the quality agreement: (1) purpose/scope – to cover the nature of the contract manufacturing services to be provided; (2) definitions – to ensure that the parties agree on precise meaning of terms; (3) a resolution of disagreements section describing how the parties will resolve disagreements regarding issues, such as quality; (4) manufacturing activities – to document quality unit and other activities associated with manufacturing processes, as well as control of changes to manufacturing processes; and (5) life cycles of, and revisions to, the quality agreement.
The FDA suggests that “[f]rom a CGMP perspective, manufacturing activities are the most important element in a quality agreement” and “[t]he most critical pieces are quality control and change control.” As to the manufacturing activities, the FDA recommends defining the responsibilities of each party, including addressing the role of each party’s quality unit and its role in ensuring that products are manufactured in compliance with cGMP; identifying facilities, materials and equipment that may be used in the manufacture; product-specific consideration; laboratory controls; documentation of production; and change controls. An owner or contract manufacturer may initiate a change to processes, equipment, test methods, specifications and other contractual requirements; however, both parties should discuss such changes and outline them in the quality agreement, including allocation of responsibilities for validation needed before implementing the changes. Both parties should be aware of the changes that need to be submitted and approved by the FDA and by each party’s quality control unit.
The agency added that the quality agreements may be reviewed during inspections, and they should not cover general business terms and conditions. Preferably, the quality agreement should be separate or at least severable from other business documents.
For Further Information
If you have any questions about this Alert or would like more information, please contact Frederick (Rick) R. Ball, Neelaabh Shankar, Ph.D., any of the attorneys in our Pharmaceutical, Medical Device, Pharmacy and Food industry group or the attorney in the firm with whom you are regularly in contact.
Notes
[1] The term “owner” refers to manufacturers of APIs; drug substances; in-process materials; finished drug products, including biological products; and combination products. The term “owner” does not include retail pharmacies, drug stores, supermarkets, discount warehouse stores and other such retailers who purchase finished drug products to sell over the counter.
[2] Parties that perform one or more manufacturing operations on behalf of an owner or owners.
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