FDA guidance on Quality Agreements for drug manufacturing has been somewhat scattered, with companies left to glean FDA expectations from interpretations of the regulations, portions of a number of different cGMP-related guidance documents, 483s and Warning Letters, and informal statements of FDA policy. 

In late May, FDA issued a new draft guidance for industry, “Contract Manufacturing Arrangements for Drugs: Quality Agreements.” 

The draft guidance addresses – in one place – methods of defining, establishing and documenting the responsibilities of each party involved in the contract manufacturing of drugs subject to current Good Manufacturing Practice (cGMP), with special emphasis on Quality Agreements.  Although FDA’s expectation of Quality Agreements has been evident in recent years, the issuance of this draft guidance is still significant; due to some differences in the underlying regulations, the basis of FDA’s expectation of a Quality Agreement has historically been more clear on the device side, due to “purchasing controls” requirements in 21 C.F.R. § 820.50.

While the draft guidance is new, concern around cGMP compliance is not.  In recent years, industry has seen the potential for significant consequences of alleged non-compliance with FDA quality requirements.  See our prior discussion on the topic here.  Because the agency considers contractors an “extension of the manufacturer’s own facility,” both the owner (i.e., the party that introduces a drug into interstate commerce) and contracted facilities are responsible for ensuring that their products are not adulterated or misbranded.  21 C.F.R. § 210.10.  Although the drug cGMP regulations do not explicitly require owners and contracted facilities to document their respective responsibilities in contract manufacturing arrangements, the regulations do require that Quality Unit responsibilities and procedures be in writing.  Id. § 211.22(d).  Accordingly, the agency encourages all parties involved to work together to ensure that the drug is neither adulterated nor misbranded as a result of its contract manufacturing operations and recommends the use of Quality Agreements to facilitate compliance with cGMP requirements

In the draft guidance, FDA suggests that a Quality Agreement clarify which of the cGMP activities are to be carried out by each party and track the basic subparts of the cGMP regulations or guidelines (e.g., for APIs, ICH Q7 guidance).  At a minimum, a Quality Agreement should contain the following basic sections: 

  • Purpose/scope
  • Terms (including effective date and termination clause)
  • Dispute resolution
  • Responsibilities, including communication mechanisms and contacts, and
  • Change control and revisions (including subcontractors).

Areas of responsibility include Quality Unit, facilities and equipment, materials management, product-specific requirements and responsibilities, laboratory controls and documentation.

FDA has issued various guidelines addressing quality management principles related to contract manufacturing operations and recommended the use of Quality Agreements in the past, but the new draft guidance is significant for its focus on the importance and the details of written Quality Agreements.  Although, as the agency notes, written Quality Agreements do not relieve either party of their respective cGMP responsibilities under the regulations (you can’t contract away regulatory responsibility), parties can draw on quality management principles to carry out the complicated process of contract drug manufacturing by utilizing Quality Agreements.  In other words, a Quality Agreements is an important tool that  can be used to achieve compliance, to the benefit of all involved.

The draft guidance would apply to human drugs, veterinary drugs, certain combination products, biological and biotechnology products, finished products, active pharmaceutical ingredients (APIs or drug substances, or their intermediates) and drug constituents of combination drug/device products.