Guest Column | June 20, 2022

FDA Proposes Benefit-Risk Considerations For Product Quality Assessments

By Mark Durivage, Quality Systems Compliance LLC

Expert NetworkOn May 10, 2022, the FDA’s Center for Drug Evaluation and Research (CDER) released for public comment Benefit-Risk Considerations for Product Quality Assessments: Guidance for Industry. The purpose of this guidance is to describe the benefit-risk principles applied by the FDA when conducting product quality-related assessments of chemistry, manufacturing, and controls (CMCs) when information is submitted to the FDA for an assessment as part of original new drug applications (NDAs), original biologics license applications (BLAs), or supplements to NDAs or BLAs, in addition to other information available (enforcement actions, adverse reactions, recalls, etc.).

This guidance discusses how the FDA considers and assesses risks, sources of uncertainty, and possible mitigation strategies for product quality-related issues and how unresolved product quality issues may be addressed. The FDA uses product quality assessments to determine whether an applicant’s product development studies, manufacturing process, and process control strategy will consistently result in finished product of acceptable quality. The FDA considers the overall benefit(s) and risk(s) identified for the product, including any residual risk related to unresolved product quality issues, regarding the regulatory approval of an NDA or BLA.

Background On Product Quality-Related Statutory & Regulatory Requirements

The FDA must determine whether the drug product is both safe and effective for use under the conditions prescribed, corresponding to the product labeling and instructions, prior to granting regulatory approval of an NDA or BLA. The FDA requires a new drug applicant to submit a full statement of the drug’s composition as well as a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packaging of such drug. Manufacturers must demonstrate in the NDA their ability to ensure and preserve a drug product’s identity, strength, quality, and purity or, for a BLA, the biological product’s safety, purity, and potency. The FDA will only provide regulatory approval for an NDA, BLA, or supplement to an NDA or BLA after it determines the product meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling. The agency uses scientific judgment to determine the type and quantity of data and information an applicant is required to provide to the FDA due to the variety of drugs and the varied processes used for manufacturing. The FDA utilizes this information to determine if the applicant can ensure the identity, strength, quality, and purity of the drug substance and drug product.

The foundation for FDA’s regulatory evaluation of human drugs and biological products are benefit-risk assessments. The FDA considers regulatory approval of BLAs based on a demonstration that the biological product and the facility in which the biological product is manufactured, processed, packed, or held is designed to ensure the biological product is safe, pure, and potent.

How The Product Quality Assessment Contributes To The Premarketing Benefit-Risk Assessment

Product quality assessments consider every aspect of a drug’s components and formulation, including manufacturing, process control strategy, packaging components, end product or release testing, microbial, and, as applicable, sterility assurance, to determine overall quality. A product quality assessment is used by the FDA to identify product quality issues and evaluate the risk of harm posed by the issues and the uncertainties associated with those issues and risks.

Product quality-related uncertainty may include gaps in current knowledge, including stability and shelf life, new technologies, new dosage forms, frequency of observed issues, limited commercial manufacturing experience, packaging components, gaps in process understanding, sources of variability, and the ability to detect problems. The FDA’s product quality assessment to determine whether the product meets the requirements for the identity, strength, quality, and purity for a drug, or safety, purity, and potency for a biological product is generally supported by the International Council for Harmonisation (ICH) guidance for industry Q9 Quality Risk Management (June 2006).

As part of a product quality assessment, the FDA identifies potential risks and control strategies for mitigating risks associated with the formulation, manufacturing process, and packaging components utilizing an iterative approach to allow applicants to gain a better understanding of issues and explore possible mitigation strategies. The FDA’s decision is weighted heavily on its confidence in the manufacturer’s ability to identify and control risks and residual risks posed by unresolved product quality issues.

Interdisciplinary teams, including clinical, product quality, nonclinical, pharmacology, and biostatistics, may be used by product quality assessors to gain an understanding of the therapeutic context (patient population, disease or condition, and benefits compared to the products currently available to medical practitioners).

When determining whether a drug or biological product meets the standard for approval, the FDA conducts an overall benefit-risk assessment that “takes into account the extensive evidence of safety and effectiveness submitted by a sponsor ... as well as many other factors affecting the benefit-risk assessment.”  The FDA’s benefit-risk assessment involves making a judgment regarding whether the product’s benefits outweigh the potential risks under the conditions of use defined in labeling using the draft guidance Benefit-Risk Assessment for New Drug and Biological Products.

Responsibilities For Product Quality Assessments

The FDA considers these guiding principles during product quality assessments of marketing applications, including the interrelationship among therapeutic context, potential benefits, product quality-related risk considerations, and assessment of risks posed by a product quality issues.

Product assessors may use the interdisciplinary team’s understanding of the therapeutic context and the assessment of benefit to gain a greater understanding of the patient population and disease for which the product will be used; identify whether the drug addresses an unmet medical need; and identify potential sources of product quality risk that, if unmitigated, could result in patient risk.

Product assessment teams use the therapeutic context to identify additional potential sources of product quality risk that arise from the patient population using the product or how it is intended to be used. Products failing to perform as intended due to product quality defects and pharmacological activity pose a risk to patients. As the FDA better understands the efficacy and safety profile of a product, identified benefits may influence how a product quality issue is evaluated and addressed during the product quality assessment.

The product quality assessment team provides its recommendation to approve or not approve a marketing application from the product quality perspective based on a drug’s (NDA) ability to meet the regulatory requirements for identity, strength, and quality or a biologic’s (BLA) safety, purity, and potency. The determination reflects whether an applicant has developed a product, manufacturing process, and control strategy that will consistently provide the quality attributes necessary to meet the intended product performance throughout the product’s shelf-life.

FDA Evaluation Of Product Quality Assessments For Marketing Applications

The FDA evaluates each application’s unique information on CMC strategies and applies the following principles when assessing quality issues: the risk-based considerations related to therapeutic context; the extent of impact on safety and/or effectiveness; the totality of product quality information; inspectional findings; possible mitigation strategies; development of or revisions to applicable compendial standards; and possible mitigation strategies. These principles are not a comprehensive list of considerations due to advances in pharmaceutical sciences but provide a framework for the FDA when evaluating product quality issues in light of the benefit(s) and therapeutic context.

The FDA will generally not approve a product with unresolved quality issues unless the residual risk posed by the unresolved quality issue is outweighed by the benefits of the product and of having the product on the market more quickly.

The FDA may allow certain information to be submitted post-approval, including when it is not feasible for the product quality issue to be resolved before approval and the issue can be addressed post-approval without an unacceptable level of risk and when the residual risk, in the context of the overall benefit of the drug product, is found to be acceptable to allow certain confirmatory information to be provided in an agreed-upon post-approval time frame.

When the FDA allows certain information to be submitted post-approval, the FDA may use a quality post-marketing agreement (QPA). A QPA is an agreement between the FDA and the manufacturer specifying the timeline for submitting supporting data post-approval. A QPA is not a substitute for the manufacturer satisfying statutory and regulatory requirements for approval.

How Applicable Is This Guidance To Generic Drug Products?

Given the FDA’s knowledge and experience with the reference listed drug (RLD) at the time an abbreviated new drug application (ANDA) is received, many of the considerations discussed in this guidance for new drug and biological product assessments are generally not applicable to the assessment of a generic drug product, including the use of QPAs. The FDA may require a QPA if the generic drug product being submitted in the ANDA addresses a public health emergency or pervasive drug shortage A QPA is not a substitute for the manufacturer satisfying statutory and regulatory requirements for approval.

Generic drug products seeking FDA approval in an ANDA utilize an RLD that has already been determined as safe and effective. The FDA will approve generic drug products that have the same active ingredient(s), conditions of use, route of administration, dosage form, strength, labeling, and bioequivalence as the RLD. However, if the facilities and controls used for the manufacture, processing, and packing of the drug are inadequate to ensure and preserve the drug’s identity, strength, quality, and purity, the FDA will not approve an ANDA.

Generic drug products that are therapeutically equivalent to their RLD can be substituted with the expectation that the generic drug product will produce the same clinical effect and safety profile as the RLD under the conditions specified in the labeling.


Benefit-risk assessments are used by the FDA when conducting product quality-related assessments for drug products seeking approval using a NDA, ANDA, or BLA to determine if the drug product is safe and effective for use under the conditions prescribed, according to the product labeling and instructions for use.

Please submit written comments by July 10, 2022, to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852 or electronic comments to Please reference docket number FDA-2022-D-0168 with all comments. For questions regarding this draft document, contact Natalia Comella at 301-796-6226.

About The Author:

Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC and is an ASQ Fellow and SRE Fellow. Durivage primarily works with companies in the FDA-regulated industries (medical devices, human tissue, animal tissue, and pharmaceuticals) focusing on quality management system implementation, integration, updates, and training. Additionally, he assists companies by providing internal and external audit support as well as FDA 483 and warning letter response and remediation services. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. You can reach him at with any questions or comments.