A Quality Agreement Primer: Reviewing Regulations & Enforcement Activity

With many companies utilizing contract manufacturing and contract laboratories, quality agreements are extremely important. This is part two of a three-part article on quality agreements. Part one discussed identifying key risks in partnering with contract companies and working with vendors. This second part explores the regulations and enforcement activities that apply to quality agreements. In part three, we examine what to include in quality agreements and who should be responsible for the assigned tasks.

Regarding regulations and guidelines, there are many sources that mention the need for quality agreements. The following excerpts from the various sources is not intended to be an all-inclusive list, but rather is a sampling to stress the importance of developing and utilizing quality agreements.

• 21 CFR 211.22(a): “There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.”¹
• 21 CFR 211.22(d): “The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.”¹
• 21 CFR 200.10(b): “The Food and Drug Administration is aware that many manufacturers of pharmaceutical products utilize extramural independent contract facilities, such as testing laboratories, contract packers or labelers, and custom grinders, and regards extramural facilities as an extension of the manufacturer's own facility.”¹

• ICH Q7 (API): 16. Contract Manufacturers (Including Laboratories)
  • 16.10 All contract manufacturers (including laboratories) should comply with the GMP defined in this Guide. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.²
  • 16.11 Contract manufacturers (including laboratories) should be evaluated by the contract giver to ensure GMP compliance of the specific operations occurring at the contract sites.⁵
  • 16.12 There should be a written and approved contract or formal agreement between the contract giver and the contract acceptor that defines in detail the GMP responsibilities, including the quality measures, of each party.²
  • 16.13 The contract should permit the contract giver to audit the contract acceptor's facilities for compliance with GMP.²
  • 16.14 Where subcontracting is allowed, the contract acceptor should not pass to a third party any of the work entrusted to him under the contract without the contract giver's prior evaluation and approval of the arrangements.²
  • 16.15 Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.²
  • 16.16 Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes.²
• ICH Q9 (Quality Risk Management): II.5 Quality Risk Management as Part of Materials Management – Assessment and evaluation of suppliers and contract manufacturers “To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing, supplier quality agreements).”³
• ICH Q10 (Management Responsibility): 2.7 Management of Outsourced Activities and Purchased Materials – The pharmaceutical quality system, including the management responsibilities described in this section, extends to the control and review of any outsourced activities and quality of purchased materials. The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials. These processes should incorporate quality risk management and include:⁴
  • Assessing prior to outsourcing operations or selecting material suppliers, the suitability and competence of the other party to carry out the activity or provide the material using a defined supply chain (e.g., audits, material evaluations, qualification);⁴
  • Defining the responsibilities and communication processes for quality-related activities of the involved parties. For outsourced activities, this should be included in a written agreement between the contract giver and contract acceptor;⁴
  • Monitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and the identification and implementation of any needed improvements;⁴ and
  • Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain.⁴
• Food and Drug Administration (FDA) Guidance for Industry. Contract Manufacturing Arrangements for Drugs: Quality Agreements (November 2016): https://www.fda.gov/media/86193/download “Quality agreements should clearly describe the materials or services to be provided, quality specifications, responsibilities, and communication mechanisms between the owner and contract facility.”⁵

Warnings have been written for the use of quality agreements. An FDA warning letter dated Jan. 17, 2017 stated that “Firms acting as contract manufacturers must comply with cGMP. FDA is aware that many pharmaceutical product manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer. You and your customer, [redacted], have a quality agreement regarding the manufacture of [redacted]. Regardless of this agreement, you and [redacted] Pharmaceuticals are both responsible for the quality of drugs released and ultimately administered to patients. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm353925.pdf.”⁶

FDA Warning Letters Related To Quality Agreements

Another FDA warning letter dated May 12, 2017 stated “…our investigator observed the following violations of the FDA’s Current Good Manufacturing Practice (CGMP) requirements for dietary supplements, Title 21, Code of Federal Regulations (CFR), Part 111 (21 CFR Part 111), which would render your products adulterated dietary supplements under section 402(g)(1) of the Act [21 U.S.C. § 342(g)(1)] for the reasons described below. You receive finished, packaged, and labeled dietary supplements from a manufacturer that manufactures the dietary supplements on your behalf (your contract manufacturer). You state that you assume your contract manufacturer is responsible for preparing a master manufacturing record, exercising quality control functions, and verifying that the finished products meet specifications. You state that you assume your contract manufacturer is complying with 21 CFR Part 111 because you are unaware of any problems at the plant. You state that you do not have a written agreement with your contract manufacturer, and have not performed any audit or engaged in any other activity to determine the acceptability of the manufacturer to manufacture your dietary supplement products, or to ensure the quality of the dietary supplements received and that the products are packaged and labeled as specified in the master manufacturing record. As a distributor that contracts with a manufacturer to manufacture, package, and label dietary supplements on your behalf that your firm releases for distribution under your firm’s name, your firm has an obligation to know what and how manufacturing, packaging, and/or labeling activities are performed so that you can make decisions related to whether your dietary supplement products conform to established specifications and whether to approve and release the products for distribution. [72 Fed. Reg. 34752, 34790 (Jun. 25, 2007)]. Although a firm may contract out certain dietary supplement manufacturing, packaging, and/or labeling operations, it cannot contract out its ultimate responsibility to ensure that the dietary supplement it places into commerce (or causes to be placed into commerce) is not adulterated for failure to comply with dietary supplement CGMP requirements.”⁶

An FDA warning letter dated May 16, 2018 discusses the responsibilities of a contractor by stating “Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.”² “You and your customer, [REDACTED], have a quality agreement regarding the manufacture of [REDACTED] Gel OTC drug product. You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501[REDACTED] of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf.”⁶

Another FDA warning letter dated Feb. 25, 2019 states that “Lack of quality control over batch release – Your firm failed to establish adequate written responsibilities and procedures for reviewing batches made by your supplier. You also failed to review each batch produced for you to determine its appropriate disposition (i.e., reject or approve). Your firm used a contract manufacturer (also referred to as supplier), [REDACTED], to perform manufacturing, processing, and packaging activities for drug products on your behalf. In your quality agreement with [REACTED], you stated that both you and your supplier are responsible for complying with 21 CFR 211.22. However, the quality agreement further specified that your supplier is responsible for approval or rejection of all products. You are ultimately responsible for approving or rejecting drug product batches manufactured for you by a contract facility. Our inspection found that your firm was not performing final reviews of each batch to determine its disposition. Determining the suitability of each batch for release is an essential component of your quality unit responsibility.”⁶ This firm also lacked written procedures regarding critical quality control unit functions that were described in the quality agreement.⁶ The FDA continued on by saying, “Use of contract manufacturers – Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer. You are responsible for the quality of your drugs, regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.”⁶

Conclusions

There are multiple guidance documents and regulations that discuss quality agreements. When the regulations are not followed, warning letters are written. Warning letters can be viewed on the FDA’s website and can be used as a tool to correct potential observations at your own company before they occur.

Part three of this three-part series will explore what to include in quality agreements and who should be responsible for the assigned tasks.

References:

1. Code of Federal Regulations (CFR) Title 21: Food and Drugs. Accessed on September 17, 2020 at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm
2. International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients- Q7 (2000). Accessed on September 17, 2020 at https://database.ich.org/sites/default/files/Q7%20Guideline.pdf
3. International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline: Quality Risk Management- Q9 (2005). September 17, 2020 at https://database.ich.org/sites/default/files/Q9%20Guideline.pdf
4. International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline: Pharmaceutical Quality System- Q10 (2008). September 17, 2020 at https://database.ich.org/sites/default/files/Q10%20Guideline.pdf
5. Food and Drug Administration (FDA) Guidance for Industry. Contract Manufacturing Arrangements for Drugs: Quality Agreements (November 2016). Accessed on September 17, 2020 at https://www.fda.gov/media/86193/download
6. Food and Drug Administration (FDA) Warning Letters. Accessed on September 17, 2020 at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/

About The Author:

Crystal M. Booth, M.M., is a regional manager with PSC Biotech. She has over 20 years of experience in pharmaceutical microbiology, working in quality assurance, CDMOs, R&D, and quality control laboratories, including startup companies. During her career, she has developed and validated methods for antibiotics, otic products, topical creams, topical ointments, oral solid dose products, oral liquid dose products, veterinary products, human parenterals, vaccines, biologics, aseptically filled products, and terminally sterilized products. Those methods include microbial limits testing, bacterial endotoxins testing, particulate testing, sterility testing, pharmaceutical water system validations, environmental monitoring programs, surface recovery validations, disinfectant efficacy studies, minimum inhibitory concentration testing, antimicrobial effectiveness testing, hold time studies, and various equipment validations.