Tara Lin Couch EAS Consulting Group
Many dietary supplement products are manufactured by a contract manufacturer, packaged by a contract packager, tested by a contract laboratory, and distributed by a contract distributor. To ensure product quality and safety, each facility involved must comply with the applicable good manufacturing practices (GMPs) dictated in 21 CFR Part 11. This can be a challenge for a dietary supplement product owner, or own label distributor (OLD), because according to the FDA, the OLD is responsible for adhering to GMPs regardless of who actually carries out the individual operations1.
A central tenet of these GMPs is that a quality unit (QU)—collectively quality assurance (QA) and quality control (QC)—must have oversight responsibilities over all operations. The QU must also have the authority to approve or reject materials and products based on whether they meet specified quality requirements such as identity, purity, strength, quality, and limits of potential contaminants2.
A quality agreement is the best means for an OLD to ensure GMP compliance. While there is no regulatory requirement for a quality agreement when manufacturing dietary supplements, the FDA frequently requests this document during facility inspections to verify quality responsibilities for all aspects of the manufacturing process.
Quality Agreements
A quality agreement is a comprehensive, formal document that defines the individual and shared responsibilities of the QUs for the OLD and each contracting party for all GMP activities and potential regulatory matters. It is not a commercial, financial, or business agreement and should be an entirely separate document that includes:
- a statement of the scope and purpose of the agreement;
- the terms of the agreement such as an effective date and termination clause;
- a detailed assignment of QU responsibilities;
- a dispute resolution discussion;
- revision and amendment allowances;
- confidentiality and non-disclosure requirements for both parties; and
- the signatures from key personnel and QU representatives from both parties.
The agreement may also use appendices to list specific contractor materials, products, or services as well as mutually agreed upon and/or approved suppliers or acceptable third parties. A standard operating procedure (SOP) should be established by the OLD to govern the preparation and use of a quality agreement for all potential contractors. The SOP should describe the quality agreement’s purpose and content as well as provide a quality agreement template. The OLD’s QU must monitor contractor compliance with the quality agreement SOP and with the agreement itself.
Assigning Responsibilities
The principal purpose of the quality agreement is to assign QU responsibilities, which is best accomplished by incorporating a responsibilities table into the document. The table outlines the topics and designates the party—OLD or contractor—responsible for each. Some topics will require that both parties share responsibility, while others will primarily be the responsibility of one party but necessitate the other party’s cooperation. The document should also include a description of responsibilities that correlates with the responsibilities table and details each party’s obligations.
Regulatory matters
The quality agreement should include a regulatory matters section to ensure that both the OLD and the contractor hold all the necessary licenses, registrations, claim files, submission reports, preapprovals, notifications, filings, and other authorizations to manufacture the dietary supplement product. The parties must agree upon and sustain compliance with the applicable GMPs and other statutory requirements. The contractor should then conduct routine internal audits to verify compliance, but the OLD should also have the right to audit the contractor. In the event of a government agency inspection, the parties must notify each other and cooperate with the inspection and share any subsequent communications—including the issuance of an FDA Form 483, a list of observations, or warning letters. It’s also vital to delegate responsibilities for product complaints, serious adverse events and reporting, and product recall situations.
Quality systems
Both parties must develop and implement appropriate SOPs for the processes and controls necessary for GMP compliance. This includes a document control and management of change procedure to govern facility, equipment, materials, manufacturing/ packaging processes, records, labels, specifications, test methods, and release requirements. All records must be kept in accordance with GMP requirements.
The contractor should also implement a quality incident reporting system encompassing deviations, out-of-spec investigations, material reviews, non-conformances, product complaints, product returns, and corrective and preventative actions (CAPA) to address trending quality issues, audit findings, and regulatory authority observations. The contractor must notify the OLD of any incident impacting its material, product, or service. This section of the quality agreement should also delineate requirements for the acquisition and retention of reserve samples.
The assignment of a product expiration date must be supported by scientific data. Also, the quality agreement should indicate the party responsible for generating, compiling, and reviewing that data in accordance with a stability program.
Facilities and equipment
The contractor’s facilities must be of suitable size, construction, and state of repair to facilitate cleaning and sanitizing operations and allow for the orderly placement of equipment and holding of materials and/or product. This is necessary for maintenance, cleaning, and sanitizing operations as well as to prevent contamination and mix-ups. All equipment should be of an appropriate design and construction and be evaluated through a procedural equipment qualification and calibration program that is reviewed by the contractor QU. The state of the contracting facility will be verified through an initial audit, but the contractor must notify the OLD of any significant changes to the facility so the OLD can assess if a follow-up audit is warranted.
Both parties will perform and maintain an environmental monitoring program that includes the use of swabs for microbiological contaminants and allergens as well as point- of- use water testing. The parties must also establish procedures and controls for storing and handling allergenic materials to prevent cross-contamination and a pest control program that incorporates facility inspections, extermination, or other means to limit pest contamination sources.
The OLD and contractor will each have a documented personnel training program to ensure that all personnel have the education and experience to perform their assigned job functions. Initial and annual follow-up GMP training must be part of the program. When changes in key personnel occur, each party should be notified.
Production control
The quality agreement should include a master manufacturing record (MMR)—reviewed and approved by both the OLD and the contractor— dictating each step of the manufacturing and packaging process to ensure GMP compliance and adherence to the approved product formulation. The MMR should also include in-process specifications to guarantee quality. The contractor should prepare a batch production record (BPR) every time a unique batch of the product is manufactured and packaged, and the OLD QU should periodically review completed BPRs to ensure execution of the MMR. BPRs must also contain the results of tests and examinations that demonstrate the finished product quality.
No rework, reprocessing, or other manipulation of the product outside of the defined process noted in the MMR should be conducted without the review and approval of both parties’ QUs.
Materials, components, and product labels
The contractor must also establish and maintain a physical location and procedures for storing and securing materials, components, and product labels to prevent mix-ups or cross-contamination. Items must be quarantined until they have been appropriately released by the QU. The quality agreement should designate supplier selection and qualification and the corresponding specifications. The document should also indicate the authority to release materials, components, and product labels.
Laboratory operations
Whether a contractor uses an in-house or third-party contract laboratory for testing, the laboratory must be qualified before use, and the OLD must receive prior written notice. The laboratory must establish and follow written procedures for laboratory operations; demonstrate that all equipment is of appropriate design and construction and is suitable for its intended use per the laboratory equipment qualification, calibration, and preventive maintenance program; use only test methods that have been determined to be scientifically valid; and document the performance of all testing and laboratory control processes at the time of performance.
Finished products
The OLD must establish a finished product specification for the contractor to use, and a representative, statistical sample of the product must be tested in-house by the contractor or by a third-party contract lab to determine if the specification has been met. The quality agreement must define the authority to release the product based on the completed BPR and test results. If the contractor is responsible for the disposition of product, a certificate of analysis (COA) should be kept on file and/or provided to the OLD upon request.
Shipping and distribution
The distribution date as well as the distributor’s name and address must be available and traceable to the exact product batch. Records of all product shipments must be prepared and maintained in accordance to contractor procedures and made available to the OLD as necessary.
References
1. 21 CFR § 111.1
2. 21 CFR § 111.105
Tara Lin Couch, PhD, is senior director of dietary supplements and tobacco services at EAS Consulting Group, Alexandria, VA (571 447 5500, www.easconsultinggroup.com).