While CMP regulations do not explicitly require owners and procuring entities to document their respective responsibilities in contract manufacturing agreements, the regulations require that the responsibilities and procedures of the quality unit be in writing (21 CFR 211.22(d)). The FDA believes that implementing a written quality agreement facilitates compliance with Section 211.22(d). Therefore, the FDA recommends that owners and contract entities enter into a written quality agreement to document their respective responsibilities in contract manufacturing agreements. The new guidelines highlight the need to define who is responsible for plant and equipment activities that affect manufacturing operations. This also includes defining who is responsible for the qualification of installations and devices and the validation of processes. It should also cover systems that support manufacturing operations, including information technology and automated control systems, environmental monitoring and room classification, utilities and any other equipment and facilities that need to be maintained to perform contract manufacturing operations in accordance with GMP. In the draft directive, the FDA defined an owner as any party that “introduces a drug into interstate commerce (or causes the introduction of a drug). As we noted in our previous article, this definition was so broad that it seemed highly unlikely that the FDA actually wanted the guidelines to apply to all companies that would meet this definition (e.B. Distributors). Not only did it seem illogical to require distributors or other downstream “owners” to be responsible for certain non-delegable GMP requirements, such as product release, but it would also have resulted in the destruction of section 303(c) of the Act, which allows downstream companies to rely on written warranties from downstream manufacturers.
To avoid misunderstandings, a glossary that defines keywords, acronyms and abbreviations is essential. It is important for everyone to know what is meant by each term used in the quality agreement. This is especially true for contracts with non-U.S. citizens. Parts, as terminology can vary greatly. Be sure to define all referenced documents. The guidelines address the relationship between “owners” and “contractual entities” and define owners as manufacturers of APIs, drug substances, process materials, finished drugs (including biologics) and combination products. The term “owner” does not apply to retail pharmacies, pharmacies, supermarkets, discount stores or other retailers who purchase finished drugs for sale over the counter as a store brand.
The Guidelines define `contracting entities` as parties carrying out one or more manufacturing operations on behalf of one or more owners. In November 2016, the FDA issued new industry guidelines titled Contract Manufacturing Arrangements for Drugs: Quality Agreements. This forecast is timely given the rise of the virtual biotech company in the development landscape. Most development programs now include support from at least one contract service provider (CSP) for services ranging from early development contract research to commercial manufacturing and analytical support. There are four types of quality agreements: manufacturing, supplier, supplier and service quality agreements, each tailored to the relevant aspects of each type of relationship. Quality assurance with input from manufacturing and laboratory personnel from both parties should prepare the agreement. The quality assurance functions of both parties should review and approve the quality agreement. Nothing should be taken for granted. Each party must review the quality agreement to ensure that its requirements are taken into account. Quality agreements are not only good business practices, there are also regulatory requirements for them. ICH Industry Guide Q7 Good Manufacturing Practices Guide for Active Pharmaceutical Ingredients recommends that owners evaluate contract facilities to ensure contractors` sites are GMP compliant for specific operations. Written agreements should also set out subcontracting considerations.
They should describe how changes to processes, equipment, methodologies and specifications are managed, and allow the owner to verify compliance with the PMCCs of their contractor`s facilities. A standard operating procedure should be in place to indicate which types of suppliers and services require a quality agreement. At the very least, an agreement must be reached every time a CMO is used, as well as with all suppliers of critical materials. They are recommended for suppliers of large quantities of raw materials or components. To be clear to our readers, the original FDA statement and the statement implicit in the final guidelines are correct: there are no legal or regulatory requirements for a quality agreement between owners and contractual entities. That being said, we have seen a significant increase in the number of clients seeking help in drafting and negotiating quality agreements between many types of parties – it is clear that the use of quality agreements is becoming both industry standard practice and useful for clarifying specific roles and responsibilities between parties. Such agreements can have both tangible and intangible benefits for all parties throughout the duration of the relationship. A quality agreement must include at least the following sections: You may submit comments on the guidelines online or in writing at any time (see 21 CFR 10.115(g)(5)) This guide describes the FDA`s current considerations for defining, defining, and documenting the manufacturing activities of parties involved in the contract manufacturing of drugs, subject to current Good Manufacturing Practices (GMPC) requirements. In particular, we describe how parties involved in the contract manufacturing of pharmaceuticals can use quality agreements to delineate their manufacturing activities to ensure GMP compliance. Companies should be aware that the FDA intends to review quality agreements during facility inspections, so the FDA (and we) recommend that quality agreements be separated from other contracts between owners and contracting entities. The implementation of a written quality agreement can facilitate compliance with GMP and in particular 21 CFR 211.22(d), according to which the activities and procedures of the quality unit must be in writing. The FDA recommends that owners and contracting entities enter into a written quality agreement to describe their respective roles, responsibilities, and activities related to GMP in drug manufacturing.
Deviations and corrective and preventive measures (CAPA) are other potential areas of discord. Deviations require the CMO and sponsor to understand the cause and impact of a QMS process or excursion. The primary responsibility for root cause investigations must be clearly stated in the quality agreement, as well as the question of when and how a drug sponsor may participate in an investigation. Often, large pharmaceutical and biotech companies have formalized investigative frameworks that must be applied to gaps, while the CMO can enable other approaches. The ability to reconcile two different sets of requirements is essential to avoid unnecessary disruption downstream of the commercial supply chain. This is another example where limiting the scope of advice to trade programs is a missed opportunity for the Agency. It is also important to note that, as the FDA confirmed in the draft guideline, the FDA`s cGMP regulations “do not explicitly require owners and contracting entities to document their respective responsibilities in contract manufacturing agreements.” The full citation in the draft guideline reads as follows: A quality agreement is a comprehensive document that describes both the specific quality parameters of a project and the party responsible for executing those parameters. .