The recently issued FDA guidance for industry titled, “Contract Manufacturing Arrangements for Drugs: Quality Agreements,” (the “Quality Agreements Guidance”) states that the FDA considers that the owner’s—those who own and control a pharmaceutical material and engage the services of the contract facilities—Quality Unit responsibility includes approving or rejecting the contract facility’s product or service —parties that provide services on behalf of an owner. The services that can be outsourced to a contract facility can be varied: formulation, fill and finish, chemical synthesis, analytical testing, packaging and labeling etc.

However, all such activities are critical to the quality and efficacy of the final product and the owner, when approving a contract facility, must ensure that the contract facility adheres to cGMP requirements. Indeed, within the Quality Agreements Guidance, it states that it is both the owner’s and contract facility’s responsibility to ensure compliance with cGMP for a drug product manufacturing operation, otherwise, a drug product may be considered to be adulterated.

With the FDA issuing the Quality Agreement Guidance, there is recognition by the FDA that owners routinely utilize the services of contract facilities for various critical activities of drug manufacturing and that a critical tool to ensure a successful relationship between the owner and the contract facility is the Quality Agreement. As part of a comprehensive quality systems model, the owner should utilize a written quality agreement whenever engaging the services of a contract facility so that it is clear the respective cGMP related roles/responsibilities between the owner and contract facility for the services to be provided.

The quality agreement should clearly describe the materials or services to be provided, quality specifications and define the communication mechanisms between owner and contract facility. The quality agreement should address items that have a potential to impact the quality of the contract facilities deliverable, such as: subcontracting by the contract facility; and addressing change to processes, equipment, methods, specification, records/data, etc. The FDA considers the quality agreement to be key in facilitating compliance with cGMP to those matters relating to 21 CFR 211.22, which states that quality unit activities and procedures should be in writing.

The Quality Agreements Guidance builds upon ICH guidance titled, “Q10 Pharmaceutical Quality System,” which states that the owner is ultimately responsible for ensuring that “processes are in place to assure the control of outsourced activities and the quality of purchased material.” Risk management should be considered by the owner when approving a contract facility and when compiling the quality agreement. The FDA encourages both parties to utilize the concepts described in ICH guidance titled, “Q9 Quality Risk Management,” to ensure the most critical areas with the greatest potential impact to the drug product or active pharmaceutical ingredient are considered during contract facility approval and quality agreement implementation. When qualifying a potential contract facility, the owner must assess the suitability and competence via on-site audits—or other pre-defined qualification criteria—and continually assess the performance of “approved” contract facilities against pre-defined criteria, which, in turn, is driven by the quality needs of the outsourced activities.

The primary goal of the quality agreement is to define between the owner or contract facility who has what cGMP responsibility in relation to those applicable CFR requirements such as 21 CFR parts 210, 211, 600-680, 820 and 1271. The Quality Agreements Guidance defines the elements of a quality agreement within the following sections: purpose/scope; definitions; resolution of disagreements; manufacturing activities and document lifecycle. The bulk of the quality agreement will specify the roles and responsibilities for the manufacturing and testing activities—the owner outsourced services—which is the most critical element of the quality agreement. It is imperative that the quality agreement clearly specifies which party is responsible for the specific activity and depending upon the nature of the outsourced activity will cover the following topics.

Quality unit activities
Within the quality agreement relating to quality activities, it should be clear how the owner and contract facility’s individual quality operations will collaborate to ensure the manufactured products that are impacted by the outsourced activity will be compliant with cGMP. It should be stressed within the quality agreement that the contract facility quality unit is responsible for rejecting or approving the deliverable from the contract facility, such as test results, in-process materials, etc., but the owner quality operations are ultimately responsible for approving or rejecting drugs, including final release, which have been impacted by the outsourced activity. The agreement should cover audits and the expectations relating to the communication of findings and the classification of findings that the owner needs to be aware of, such as, critical vs. major vs. minor. There should be provision to allow the owner to inspect the contract facility to ensure compliance with cGMP as part of routine verification of owner qualification of the contract facility.

Facilities and equipment
This will address the specifics of the contracted operations in relation to the actual sites and equipment that will be utilized by the contract facility and who has the responsibility for qualifying and maintaining the equipment and applicable systems along with validating the processes. This is to include all equipment and facilities that are needed to ensure the cGMP operations of the contracted operations, such as, information technology and automated control systems, environmental monitoring, utilities and room classification. A critical component for this section of the quality agreement is ensuring the defining of controls to prevent cross contamination when the contract facility processes drugs for multiple owners.

Materials management
This section of the quality agreement will define responsibility for the establishment of specifications for components and the qualification of component suppliers. In addition, it will address ownership for the sampling and testing of the components and inventory management and the necessary segregation and status control of materials. It should be clear within the agreement who has responsibility for physical control of materials at different points in the manufacturing process and ensuring proper conditions for storing and transporting materials.

Product-specific considerations
The agreement may include specific requirements relating to the product such as: product specifications; and product details relating to manufacturing operations, etc. Provisions should be included for knowledge transfer such as the transfer of development information from the owner to the contract facility and how the contract facility will keep the owner appraised of information gained through the outsourced activities.

Laboratory controls 
It is recommended that the quality agreement for contract testing references the procedures/processes by which all test results conducted by the contract facility are communicated to the owner for evaluation. The owner should have clear procedures on the review and approval of testing that is conducted by the contract facility and the mechanism for accessing the contract facilities raw data—hardcopies and e-records—as part of routine review by the owner.

The agreement should also cover the mechanism for the transfer of analytical test procedures between the owner and contract facility. It is paramount that the quality agreement defines the procedures for the routine owner audit of the contract facility laboratory controls to provide assurance that the laboratory operates in a controlled state and in accordance with cGMP. Such auditing should include confirmation by the owner that the contract facility has a data integrity governance system. There should also be clear delineation of responsibility within the quality agreement for investigating deviations, discrepancies, and OOS/OOT results between the owner and contract facility.

Documentation
There should be clear delineation within the agreement for responsibility between the owner and contract facility for the review and approval of documents. This includes the review and approval of changes to contract facility procedures that will have an impact on the outsourced activities performed by the contract facility and the accessibility of all critical documentation for inspections/audits.

It is imperative that change control is discussed within the quality agreement and the Quality Agreements Guidance provides direction for how owners and contract facilities should address changes to processes, facilities, equipment, test methods, etc. It should be explicitly stated within the quality agreement, what changes the owners need to review and approve and, correspondingly, what changes the contract facility must approve and a description of the notification process and timing. Depending upon the nature of the change it should be defined within the agreement how change controls are managed and who has what responsibility, such as conducting validation, updating the FDA, and the vehicle by which the agency is notified of changes to validated processes—supplement, annual report, etc. 

Conclusion
As more activities relating to drug product and active pharmaceutical ingredient (API) manufacturing are outsourced, the FDA recognizes the criticality of the quality agreement in ensuring the outsourced activity complies to cGMP requirements and ultimately meets the quality requirements of the impacted final drug product. Within the recently issued Quality Agreements Guidance, the FDA outlines clear expectations on what should be contained within the agreement to ensure responsibilities are defined between the owner and contract facility. 

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Paul Mason is a director in the science and technology practice at Lachman Consultants. With over 17 years of experience in the pharmaceutical industry, he is a quality control chemist experienced in sterile parenteral, API, and solid oral dosage forms. His experience spans finished dosage form, CMOs, and API intermediates manufacture support in both a quality control and analytical development setting. For further information relating to quality agreements please contact the author at p.mason@lachmanconsultants.com, or James Davidson at j.davidson@lachmanconsultants.com.