Beyond The FDA Guidance: Practical Considerations For Quality Agreements

By Brian Clark, principal, GMP Operations Consulting LLC

Much has been written in recent months about the FDA’s final guidance for industry, Contract Manufacturing Arrangement for Drugs:  Quality Agreements, issued in November 2016.  Recently, a thorough assessment of the guidance requirements and gaps was published on this website. (See FDA's New Quality Agreement Guidance — What It Says (And What It Fails To Say) and Examining FDA's New Quality Agreement Guidance.)

The guidance covers key elements of 21 CFR Parts 210, 211, 600-680, 820, and 1271 that should be included in quality agreements at a high level.  It also briefly touches upon ICH Q7, Q9, and Q10 and their recommendations for contract manufacturing agreements.  This provides a framework for ensuring compliance with, and assigning ownership for, each element of the regulations and standards.  The focus on compliance is necessary, but not sufficient, for developing an effective quality agreement.  It is critical for both sponsor companies and contract manufacturing organizations (CMOs) to consider the practical application of these requirements and to develop a clear guide for how their organizations will work together effectively.

Many sponsors, particularly small to midsize organizations, opt to use their CMO’s boilerplate quality agreement.  These agreements in many cases are compliant with the standards, but they usually lack many of the practical details to ensure an effective relationship with clear expectations.  These practical considerations can cover multiple elements of the quality agreement but can be summed up in the following three categories:

• Timing
• Access
• Language

Timing Considerations

The quality agreement guidance notes that the agreement “should describe how and when the owner and contract facility will communicate with each other.”  Many boilerplate agreements address the communication method (the “how”) and the trigger (the “when”), but they do not specify actual timing.  There are several situations where such timing may be critical to the sponsor to manage supply and risk.  Specifying turnaround times for batch review and release, preferably from the completion of manufacturing, provides for more predictable supply.  Some agreements provide a duration for batch release based on completion of testing but do not specify the testing duration.  This results in unnecessary uncertainty regarding the actual release date.

Timing should also be considered for key quality system triggers.  Time limits for notification of major and critical deviations and confirmed out-of-specification (OOS) results should be set based on the date of discovery of the deviation or OOS.  If these limits are not set, or are tied to investigation completion, the notification may be delayed.  This may not be as critical to a commercial product with significant safety stock, but it could seriously impact the limited supply that is often maintained during clinical development.

Conversely, some sponsors seek real-time notification of minor deviations.  This extra information may bog down communications unnecessarily, assuming both parties have clear agreement on what constitutes a minor deviation.  It may be more efficient to summarize and/or include minor deviations with the batch release packet.

Time limits should also be considered for notification of pending or surprise health authority inspections that include, or are likely to include or impact, the sponsor’s product.

Access Considerations

There are several points in the quality agreement where access level should be considered.  These include sponsor access to the facility, access to inspections, and access to documentation.

The FDA guidance document requires “Provisions to allow owner personnel access to the contract facility when appropriate.”  Consequently, most quality agreement templates provide for access by “person-in-plant.”  However, many agreements do not specify what areas the person-in-plant may access.  Some companies allow access to parts of the manufacturing floor and QC labs, with certain restrictions.  Others may limit access to a viewing window or a visitor office/conference room, sometimes with video monitoring capability.  Clarification of person-in-plant access level in the quality agreement will help prevent misunderstandings once the relationship is underway.

The quality agreement guidance discusses the need to set expectations regarding FDA inspections and focuses on communication of inspection observations from the contract facility to the sponsor.  Simple notification of relevant observations and follow-up may be appropriate for some contract arrangements.  Other situations, such as those in which manufacturing space is dedicated to a sponsor company, may benefit from inclusion of the sponsor in client-specific portions of the inspection.  Access to health authority inspections should be evaluated and clarified in the quality agreement, as should each party’s role in generating or reviewing product-specific observation responses.

Documentation access is also important to consider and spell out in detail in the quality agreement. It is standard for contract companies to provide client-specific documents and records to the sponsor.  However, access to referenced documents that may be critical to the product varies across contract organizations.  Some may provide such documents upon request or allow viewing on a controlled shared drive or portal.  Some companies limit ancillary document access to sponsor staff while they are on-site or during an audit.  This should be clarified in the quality agreement. 

Finally, access to all relevant data in the manufacturer batch release packets may vary from company to company.  Some include all QC raw data, while others just provide QC summaries.  Ancillary documents, such as environmental monitoring results and temperature charts, may not be routinely provided in a batch release packet.  The list of documents provided with the batch release package should be detailed in the quality agreement.

Language Considerations

Language is the final area that should be considered carefully in developing effective quality agreements.  First, it is critical to ensure that key definitions are reconciled between the sponsor’s and the contractor’s quality systems.  This is especially important for terms such as minor, major, and critical deviations; divergent understanding of deviation classifications can prove challenging, especially if minor deviations are not reviewed in real time.  Similarly, all definitions should be reconciled between the quality agreement and the supply agreement or master services agreement to avoid conflicting terms.

It is also important to consider language when dealing with international suppliers.  Quality agreements should specify whether SOPs, batch records, deviations, and other documents are written in English, the local language, or bilingual.   Alternatively, batch records may be written in the local language and a template provided in English.  This detail should be captured in the quality agreement.  Timing for these items should also be considered and captured in the quality agreement or associated supply/services agreement.  Otherwise, while agreement on language may be reached, impact on timelines for availability of the translated documents may not be clear up front and could result in unnecessary conflict later.

Finding Alignment With Your Contract Partner

In summary, the new FDA guidance document has provided much-needed structure for quality agreements and can be used to generate a checklist of quality agreement elements to ensure compliance.  However, it is incumbent on both parties to assess where additional details are required.  Together, the sponsor and contractor can align explicitly on these practical aspects to ensure clearer expectations across the partnership.

About the Author:

Brian Clark is principal at GMP Operations Consulting LLC, a CMC consulting firm founded in 2006. He has more than 25 years’ experience in the development, manufacturing, and quality management of biologics, drugs, and medical devices, with specific expertise in advanced technology medicinal products such as cell therapies and gene therapies, and antibody drug conjugates.  Previously, he served in executive and senior leadership roles at ImmunoGen Inc., Altus Pharmaceuticals, Alkermes, Therion Biologics, Antigenics (now Agenus), and Genzyme Tissue Repair.  Brian has a BS in Biology from the University of Massachusetts, Boston, and an MBA in General Management from Boston University. You can connect with Brian on LinkedIn.