A Quality Agreement Primer: What To Include & Who To Assign It To

With many companies utilizing contract manufacturing and contract laboratories, quality agreements are extremely important. Part one of this three-part series on quality agreements discussed identifying key risks in partnering with contract companies and working with vendors. Part two explored the regulations and enforcement activities associated with quality agreements. In this final part, we examine what to include in quality agreements and who should be responsible for the assigned tasks.

There should be a quality agreement any time a contract company is used. When developing a quality agreement, keep in mind that “quality agreements should clearly describe the materials or services to be provided, quality specifications, and communication mechanisms between the owner and contractor.”¹ The most critical pieces of a quality agreement are quality and change control. If a product is going to be manufactured, manufacturing activities are going to be the most important element in the quality agreement.¹

The following items are best practices and potential items to include in a quality agreement:

• Use clear language.¹
• Include all activities for ensuring compliance with cGMP,¹
  • cGMP compliance is mandatory and should be stated.¹
• Describe the materials and services.¹
  • List all applicable sites with addresses.¹
• List the audit expectations (supplier, regulatory, routine, and for-cause).¹
  • List the expectations for inspections, communications of findings, and responses.¹
  • Explain how documents are available for inspections.¹
• Be clear in terms of roles and responsibilities.¹
  • Include key contacts for all parties.¹
  • Include quality assurance unit representatives.¹
• Be clear regarding quality expectations.¹
• Include subcontracting expectations (i.e., fourth-party vendors).¹
  • Who will audit, qualify, and monitor other suppliers and fourth-party vendors?
• Include quality specifications.¹
• Describe details of how QA parties work together to ensure cGMP compliance.¹
  • Communication: How often, when, and how (verbally or in writing)?¹
    • Describe how product quality information gained throughout the product life cycle will be shared.¹
  • Deviations, out of specification (OOS), out of trend (OOT): How are they communicated, investigated, documented, and resolved?¹
  • Change controls: How are they communicated and documented? What items require permission or notification?¹
    • Changes made to documents, manufacturing records, specifications, laboratory controls, validation documents, investigation records, annual reports, establishment locations, suppliers, equipment, manufacturing processes, components, shipping methods, etc.¹
    • Both parties need to be aware of changes that need to be submitted to the FDA.¹
  • Validation: Who will validate processes, maintain systems or equipment, or approve activities?¹
    • Include process validation, design, qualification, verification, and monitoring.¹
• Be clear with respect to product release.¹
  • Contract facilities approve or reject the data they generate.¹
  • Owners approve or reject the data the contract facilities generate AND determine final release disposition.¹
• Be clear regarding manufacturing expectations.¹
  • Defined manufacturing operations¹
  • Cross contamination prevention and traceability¹
  • Batch numbering process¹
  • Expiration/retest dating¹
  • Storage and shipment¹
  • Lot disposition¹
• Be clear regarding inventory management expectations.¹
  • Define physical control of materials (storing, transporting, and shipping conditions).¹
• Documentation expectations¹
  • Be clear regarding expectations for reviewing and approving documents.¹
  • Describe making and maintaining original documents or true copies.¹
  • Electronic records should be stored in accordance with cGMPs and be retrievable.¹
• Laboratory expectations¹
  • Owner and contract facility should have access to labs for quality control testing.¹
  • There should be procedures discussing controls of sampling and testing.¹
    • Who will conduct sampling and testing?
  • There should be procedures for communicating all laboratory testing results.¹
  • There should be validated laboratory testing methods.¹
    • Both the owner and contract facilities need to accurately transfer, develop, and validate the testing methods.¹
  • There should be procedures for routine auditing.¹

In contrast, quality agreements do not include business terms and conditions, confidentiality obligations, pricing and costs, delivery terms, limits or liability damage, or forecasting.⁵

Assigning Responsibilities

Define the expectations, roles, and responsibilities up front between the stakeholders to streamline the validation activities and quality management.¹ Be clear about who does what. Who is responsible? What is the expected outcome? Also, be sure to include the details of communication pathways and expectations. Remember to always be clear and concise.¹

Everyone is responsible for quality.² Responsibilities for cGMP cannot be contracted out to a vendor.¹

Separate operation agreements may need to be written to define who does what, when, and how. To be successful, audits and inspections should be planned before they are conducted. Ensure that the right stakeholders and subject matter experts are available and track all activities to completion.

Most of the responsibilities come directly from the regulations and guidance documents, and they are required to be in writing and be followed.¹ Both parties (i.e., owner and contractor) are responsible for the cGMP activities they perform.¹ GMP activities include controls to ensure quality, safety of raw materials, safety of drug products, and that risks are managed.¹

The following responsibilities are required of both the owner and the contract company:

• cGMP compliance²
• Product quality and patient safety²
• Share relevant information to ensure compliance with cGMP and the FD&C Act¹
• Have access to adequate laboratory facilities for product testing¹
• Be aware of the changes that need to be submitted to the FDA in a supplement or annual report¹
• Agree upon responsibilities in the quality agreement

The owner is ultimately responsible for the following items:

• Approve or reject drugs, including final release^1,2
• Review and approve executed batch records ¹
• Audit and evaluate contract facilities^1,3
• Approve changes that may impact product (change control)⁴
• Approve subcontractors (i.e., fourth-party suppliers)⁴
• Define and approve excipient and drug product specifications¹
• Approve method and specification changes⁴
• Define responsibilities and communication processes for quality-related activities of all parties^1,7
• Responsible for analytical and manufacturing technology transfer¹
• Monitor incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain^1,3
• Responsible for determining whether to initiate communications or filings with regulators
• Notify contractor of formal responses of complaints or product recalls
• Approve stability protocol, review stability data, and establish retests and expiration dates
• Approve all artwork, inserts, labeling, packaging, printed labels, and text
• Approve reprocessing or rework
• Responsible for filing the regulatory application, maintenance, updates, and approvals to filings
• Be aware of applications and approval requirements that could affect manufacturing activities¹

The third-party contractors are typically responsible for the following items:

• Review and approve batch records and data, issue certificates of analysis, and perform manufacturer’s batch release²
  • Provide copies of completed batch record and analytical results
• Evaluate and address manufacturing and quality problems²
• Notify owners of changes to process, equipment, methods, or specifications and obtain approval if needed¹
• Self-inspections, employee training, and document control
• Storage, handling, sampling, testing, preparing product for shipment, and approving/rejecting materials¹
• Preventing contamination, cross-contamination, and mix-ups¹
• Controlled access to facility¹
• Share knowledge of analytical technology transfer, perform manufacturing process technology transfer, and develop methods¹
• Ensure data integrity -- ALCOA (accurate, legible, contemporaneous, original, and accurate)
• Need procedures for sampling and testing products¹
• Manufacturing, packaging, and labeling¹
• Procedures for receiving, reviewing, and investigating complaints
• Investigates and approves of any deviations, OOS, complaint, or unexpected event¹
  • Forwards owner a copy of completed deviation or OOS investigation
• Notifies owner of changes, use of subcontractors, deviations, batch contamination, OOS results, or unexpected events¹
• Communicates laboratory test results to owner¹
• Creates stability protocol, tests stability samples, creates data tables
• Notify owner of FDA or regulatory inspection related to the owner’s product¹
• Notify owner of regulatory requests for samples or batch records¹
• Provide copies of 483s, requests for information, notices of violations, and warning letters to owner¹
• Maintain licenses, registrations, and other authorizations for cGMP work
• Review and approve documents¹
• Maintain data and provide copies when needed¹
• Maintain electronic data and have it easily accessible¹
• Archive data and batch records when required

Responsibility for the following items tends to vary between the owner and the contract company. They should be agreed upon by both parties.

• Batch numbering process¹
• Validates the processes and equipment¹
  • Qualification, calibration, and maintenance of the facility and equipment
  • Cleaning verification of non-dedicated equipment
  • EM, room classifications, utilities, etc.
• Approve excipient suppliers or subcontractors (i.e., fourth-party suppliers)
• Approve equipment validation, qualification, and maintenance activities¹
• Establish processes for auditing, qualifying, and monitoring component suppliers¹
• Inventory management¹
• Tests drug substances, excipients, in-process testing, and drug product¹
• Maintaining traceability¹
• Monitoring or validating shipping conditions¹
• Preparing artwork, inserts, labeling, label printing, inventory reconciliation, product status identification, and packaging as described by owner¹
• Expiration/retest dating (e.g., stability testing)¹
• Approve major or critical deviations, batch contamination, OOS, or unexpected events¹
• Approve master batch records
• Establish specifications for components¹
• Notify other party of regulatory investigation of the product, product sample requests, or product batch records¹
• Notify other party of regulatory information requests or notices of violations related to the product¹

Key Takeaways

It is the owner’s quality unit that is legally responsible for approving or rejecting results, including the final release disposition. The quality unit’s responsibilities and procedures must be in writing and followed.¹ Quality agreements may be reviewed during regulatory inspections. Each party is responsible for ensuring compliance with cGMP.¹ Quality agreements cannot be used to delegate cGMP responsibilities.¹

Conclusion

“A quality agreement is a document that defines both specific quality parameters for a project and which party is responsible for the execution of those parameters.”⁵ Most of the responsibilities come directly from the regulations and guidance documents.¹ Keep in mind that both parties (i.e., owner and contractor) are responsible for the cGMP activities they perform and that the owner is ultimately responsible for approving or rejecting drug product batches manufactured for it by a contract facility.¹ Quality agreements should include all aspects that impact:

• A product’s identity⁵
• Quality⁵
• Product safety⁵
• Product potency⁵
• Product purity⁵
• Compliance status⁵

There are regulations and guidance documents that speak to quality agreements, and quality agreements may be reviewed during regulatory inspections.¹ A well-written, comprehensive quality agreement that covers all the items and responsibilities outlined in this article is key to facilitating compliance with cGMP requirements and other regulatory requirements when engaging a contractor.

References:

1. 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
2. Katz, Paula (2016) Putting the ‘Quality’ in Quality Agreements for Contract Manufacturing Operations. Food and Drug Administration (FDA) Downloads. Accessed on September 17, 2020 at https://www.coursehero.com/file/35542857/Quality-Agreements-Contract-Manufacturing-Operations-11-03-2016-Katz-S508pdf/
3. 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
4. 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
5. Trag, Arvilla (2017) The 5 ‘W’s of Quality Agreements. MasterControl. Accessed on September 17, 2020 at https://www.mastercontrol.com/gxp-lifeline/quality_agreements_1209/

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.