Today, around two-thirds of pharmaceutical manufacturing is outsourced, with the worldwide pharmaceutical contract manufacturing market valued at $92.3 billion in 2017, and forecast to rise by a compound annual growth rate (CAGR) of 8.1% to $146.4 billion by 2023. Contract facilities offer a range of services including: formulation, fill and finish, chemical synthesis, cell culture and fermentation, analytical testing, packaging and labeling, and sterilization or terminal sterilization. Market drivers include the increasing demand for generic medicines and biologics, the capital-intensive nature and complexity of manufacturing, and the trend for pharma companies to focus resources on their core areas of competency.
Companies considering outsourcing pharmaceutical manufacturing should keep in mind the fact that they remain fully accountable for product quality and for meeting current good manufacturing practices (CGMPs). Outsourcing to contract manufacturers can increase risks to quality, because full-time oversight is no longer possible. Quality agreements offer a route to manage suppliers as an extension of in-house facilities in order to manage risk appropriately. Such agreements are becoming standard industry practice, and are useful in clarifying specific roles and responsibilities.
While final FDA guidance on quality agreements with contract manufacturers has been in place since November 2016, the agency has recently been highlighting the guidance at public conferences. Examples include two presentations at the Parenteral Drug Association/Food and Drug Administration (PDA/FDA) Joint Regulatory Conference (December 6, 2017). One was by Paula Katz, Director, Manufacturing Quality Guidance and Policy, at FDA’s Center for Drug Evaluation and Research (CDER). Ms. Katz described current FDA thinking on quality agreements, pointing out that ‘You can’t ‘contract around’ CGMP!’
A second was given by Donald Ashley, JD, Director of the CDER Office of Compliance. Ashley’s presentation included a slide titled, ‘Contract Manufacturing: From Bad to Worse.’ Ashley quoted a 2017 warning letter saying, ‘You have engaged Firm B to manufacture Firm A Perox-A-Mint… Among other things, Firm B manufactured your oral solution drugs using the same equipment in which Firm B manufactured toxic industrial-grade car washes and waxes. You are responsible for ensuring that all of your products are manufactured in accordance with CGMP…Contractors are extensions of the manufacturer, and you are required to ensure that your drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity…”
In addition, as the FDA Law Blog notes, “companies should be aware that FDA intends to review quality agreements during facility inspections, so FDA (and we) recommend that quality agreements be separate from other contracts between owners and contract facilities.”
FDA defines a quality agreement as ‘a comprehensive written agreement between parties involved in the contract manufacturing of drugs that defines and establishes each party’s manufacturing activities in terms of how each will comply with CGMP.’ The quality agreement should clearly state which party carries out specific CGMP activities, and ‘should cover activities mentioned in section 501(a)(2)(B) of the Federal Food, Drug & Cosmetic Act and, as applicable, those in 21 CFR parts 210, 211, 600-680, 820, and 1271, as well as all other applicable statutory or regulatory requirements.’
The FDA guidance notes that a well-written quality agreement uses clear language, defines key manufacturing roles and responsibilities, and establishes expectations for communication. Most contract manufacturing quality agreements include:
- Purpose and scope, covering the nature of the services to be provided
- Definitions to ensure that all parties agree on the exact meaning of terms used
- Resolution of disagreements about product quality issues or other problems
- Manufacturing activities, with documentation of quality and other activities, as well as control of any changes to manufacturing processes
- Life cycle of the quality agreement and any revisions to the document.
According to the guidance, the quality agreement should address expectations for reporting and approving changes to: components and/or their suppliers; establishment locations; manufacturing processes; products or product types that use the same production line, equipment train, or facility; testing procedures; major manufacturing equipment; shipping methods; the lot numbering scheme; container closure systems; and tamper evidence features.
As the use of contract manufacturers continues to increase, this use of quality management principles to define, establish and document all manufacturing operations will continue to be an essential step in minimizing regulatory risk and ensuring compliance with CGMP.
Contact us for more information on how Validant can help you successfully navigate working with a contract manufacturer.
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