The expectations between a sponsor company and contract service provider define not only the nature of the outsourced relationship but also dictate the quality of the material being supplied or service provided. Quality agreements between contract manufacturers and their pharmaceutical customers are a well-established practice. Recent draft guidance by FDA brings quality agreements into greater focus by applying the science- and risk-based approach inherent in quality risk-management principles and practices. Industry groups and pharmaceutical companies have offered their input of the draft guidance
FDA issued its draft guidance, Contract Manufacturing Arrangements for Drugs: Quality Agreements, in May 2013 to describe the agency’s current thinking on defining, establishing, and documenting the responsibilities of parties involved in contract cGMP manufacturing of drugs (1). The draft guidance describes how parties involved in contract manufacturing of drugs can use quality agreements to delineate their responsibilities and ensure drug quality, safety, and efficacy. The guidance applies to the commercial manufacturing of APIs (drug substances or their intermediates), finished drug products, combination products, and biological drug products (1). Moreover, the quality agreements described under the draft guidance fit within the larger scheme of pharmaceutical quality systems and provisions of ICH guidelines, including ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients , ICH Q9 Quality Risk Management , and ICH Q10 Pharmaceutical Quality Systems (1–4). In the draft guidance, FDA specifies that the principles of quality management extend to contract manufacturing, and that the agency FDA expects parties engaged in contract manufacturing to implement quality-management practices. The draft guidance is intended to build upon the quality-management principles in ICH guidelines in developing and executing contracted-manufacturing arrangements (1-4). Public comment on the draft guidance ended at the end of July 2013, and the pharmaceutical industry weighed in on the guidance with several major pharmaceutical companies and industry groups offering comments.
Issues with scope
One concern raised by several companies and industry groups was that the draft guidance did not adequately address developmental activities. The Biotechnology Industry Organization (BIO) offered the following comment: “The Draft Guidance applies to commercial manufacturing of product. However, BIO notes that quality agreements are equally important during the development phase. They are a useful tool to provide both thoughtful consideration of reasonable quality expectations based on the item being procured and to provide standards during development and manufacturing. Limiting the guidance to commercial manufacturing may lead contract manufacturers to conclude that such agreements are unnecessary during drug development.”
BIO suggested that the guidance be further applied to investigational products. “We ask FDA to consider expanding the scope of the guidance to include quality agreements for investigational product during the development phase. Contract manufacturing of drugs may also be subject to good laboratory practices (GLPs) as applicable. While the Draft Guidance is appropriately focused on good manufacturing practices (GMPs), it does not appear to allow for a contract laboratory to perform certain tests in accordance with GLPs. BIO asks that the Guidance recognize that manufacturing of drugs may also be subject to GLPs and therefore, are also included in the scope of the Guidance.” AstraZeneca also concurred that the guidance and related provisions on quality agreements should include GLPs.
The Parenteral Drug Association (PDA) further suggested that the scope of the guidance include developmental activity. “Since it is common for virtual companies to use contracted parties in all phases of development, it would be valuable if the guidance could be extended to include manufacture of clinical trial materials.” To this end, PDA suggested a clarification to the language in the draft guidance. “For purposes of this guidance, while the term commercial manufacturing does not include research and development activities or the manufacture of material for clinical trials or treatment Investigational New Drugs (INDs), or for veterinary investigational files (INADs or JINADs), the principles and concepts outline herein could be applied and it would be a best practice to have a quality agreement in place for these drugs prior to start of manufacture of any drug intended for human or animal use.”
The Active Pharmaceutical Ingredient Committee (APIC) of the European Chemical Industry Council (CEFIC) also suggested the inclusion of clinical trial materials with respect to the guidance. “As such trials [clinical trials,], especially Phase III could eventually be used in commercial production plus the level of GMP needs to increase through the different stages of clinical trials, we feel the guidelines should give guidance on the requirements for a quality agreement for such activities.”
Further refinements of quality agreements
Other groups and pharmaceutical companies suggested further refinements to the draft guidance. PDA suggested further emphasis on the collaborative relationship between CMOs and owners. “PDA commends FDA on writing this guidance which highlights common gaps which have occurred in the past between CMOs and Owners and clearly points out many elements of current best industry practic. PDA suggests that FDA further emphasize in this guidance, the importance of establishing a collaborative relationship between the parties in addition to clearly assigning and defining the appropriate responsibilities.”
PDA also made suggestions as to the quality agreement itself. “In some instances the guidance appears to be asking that the Quality Agreement include listings of parts of the CMO’s quality system. We recommend clarifying that the intent is for the Quality Agreement to assign responsibilities to parties by general categories rather than a restatement of individual GMP elements. PDA also recommends against requiring specific procedures to be included in the Quality Agreement since such an approach might inhibit the effective functioning of either party’s quality system with respect to continual improvement.”
PDA also suggested the guidance include measures relating to audits in a quality agreement. “A initial quality system audit of the Contract Acceptor should precede the signing of a Quality Agreement. During this audit, the Contract Giver is responsible for verifying and accepting (or rejecting) the Contract Acceptor’s quality system and the ability of the Contract Acceptor to meet GMPs. With this approach, the purpose of the Quality Agreement should then be limited to defining the roles and responsibilities for the specific product(s) processes and activities covered by the agreement. The Quality Agreement should also address responsibilities of each party in subsequent audits such as how to schedule, notice, response and corrective actions.”
The International Society for Pharmaceutical Engineering (ISPE) recommended that additional key quality elements be included in the scope of the guidance, including a subsection for exception-related events and outcomes and the involvement of the “Owner” in the decision to rework, reprocess, re-inspect product, and product acceptance as these issues are critical aspects as part of the “Owner’s” management oversight of the Contract Facility. ISPE also suggested additional items to be considered for scope inclusion: a subsection for Complaints and Safety Events that includes direction around timeliness, responsibilities and communication; a subsection for field action/recall roles and responsibilities; and a definition section to clearly define specific terms.
Bristol Myers Squibb (BMS) noted that the quality agreement should also indicate how the parties will communicate information about presenting cross-contamination and maintaining traceability when a contracted facility processes or tests drugs for multiple product owners. “The product Owner and Contracted Facility might opt to refer to existing documentation or procedures or the presence of such documents verified during the qualification of the facility,” noted BMS.
Industry comments also focused on definitions used in the draft guidance. For purposes of the draft guidance, the “owner” is defined as the party that introduces the drug into interstate commerce, whether the drug is covered by a marketing application/license or not. The “contracted facilities” are the outside entities performing manufacturing operations for the product owner. Some of the manufacturing operations performed by contracted facilities include: formulation, fill–finish, chemical synthesis, cell-culture manufacturing and fermentation for biological products, analytical testing, other laboratory services, and packaging and labeling. The draft guidance specifies that the owner is responsible for ensuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected contracted facilities. In turn, all contracted facilities must ensure compliance with applicable cGMP for all manufacturing, testing, or other support operations performed to make a drug(s) for the owner (1).
Merck & Co. noted that draft guidance covers only pure CMO arrangements, but that pharmaceutical companies are involved in many hybrid forms of contracts, such as in-licensing, comarketing, reciprocal CMO, joint ventures, public-private partnerships, and clinical supply partnerships It noted that the current definition of “owner” in the draft guidance “is ambiguous in contracts that are not pure CMO arrangements. A less ambiguous approach would be to define “Owner” as equal to the Marketing Authorization Holder. In reality, this references the party that is “the lead,” has the principle pharmaceutical liability, and is responsible for all interactions with the Health Authorities.
The Consumer Healthcare Product Association, which represents manufacturers of over-the-counter products, also noted issues with the definition of “owner.” “The term owner and its definition do not address the complex license agreements that can arise is today’s pharmaceutical supply chain. Due to the complexities of licensing agreements, there are situations where the ‘ownership” of the application or of the intellectual property rights for the product is different from the contract given, “said CPHA. “For example, a company may license from the application holder the distribution rights and may also take responsibility for the supply of the product. In such as case, the distributor would contract with the contract manufacturer and would enter into a quality agreement. However, such a distributor would own neither the application nor the intellectual property. It is not clear who would be the ‘owner in such an arrangement. If the holder of the application in such an arrangement is a small business that discovered the product, it might not have the expertise or resources to oversee a manufacturer.”
The Bulk Pharmaceuticals Task Force of the Society of Chemical Manufacturers and Affiliates suggested clarification that the term “contract manufacturing” apply to those activities for a specific customer. “API manufacturing and its associated activities is composed of custom businesses that are exclusive for specific customers and non-custom businesses that are nonexclusive for a range of customers. A high level of oversight of change control and deviations is appropriate for the former. In the latter case, such a level of oversight and approval is unmanageable....This guidance is appropriate for a custom business but not for a noncustom business.”
Pfizer noted the work of ICH in addressing measures in the guidance and to ensure that there is alignment between the draft guidance and specific ICH measures. “The ICH Q7 IWG (Implementation Working Group) is preparing a Q&A that will address much of the same concerns as outlined in this guidance (the first round of questions are loaded with expectations of contract manufacturing quality units, etc.). Suggest holding this guidance as draft to assure alignment and minimize confusion/implementation.”
1. FDA, Draft Guidance for Industry–Contract Manufacturing–Arrangements for Drugs Quality Agreements (Rockville, MD, May 2013).
2. ICH, Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Geneva, 2000).
3. ICH, Q9 Qualified Risk Management (Geneva, 2005).
4. ICH, Q10 Pharmaceutical Quality Systems (Geneva, 2008).