Does FDA Consistently Assess Product Quality Risk and Control in Applications?

January 15, 2020

Early in 2018, the Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) published a “white paper” which contained recommendations that drug companies could consider when preparing a Quality Overall Summary (QOS) as part of marketing or licensing applications for human drugs (see a copy of the paper here).

The paper includes a discussion of using the QOS to effectively summarize the overall control strategy for the product.  The paper describes a control strategy as a planned set of controls derived from current product and process understanding that assures product quality and process performance. 

These controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

As part of the Integrated Quality Assessment (IQA) of marketing applications, FDA now develops a formal risk assessment for individual applications (see comments from FDA on slide 37 here).  To learn whether these risk assessments are consistent with the complexity of the product and its potential risk to a consumer, if they evaluate a product’s total control strategy, and what industry can learn from FDA’s perspectives on evaluating product risk, a sample of 11 redacted IQA documents developed as part of the review of marketing applications approved in 2018 and 2019 and subsequently published by FDA were reviewed. 

Four examples were chosen from the sample that use different dosage forms that present different levels of increasing complexity and risk to a consumer – two types of solid oral tablets, a suspension for inhalation and an intravenous injection.

The first example is taken from an immediate release oral capsule that was approved in 2019 (see page 3 of the review here).  The drug was granted orphan designation in 2009 but was denied fast track designation for the review of the marketing application.  The risk assessment’s evaluation of the control strategy is almost entirely dependent on meeting final product specifications even though factors that FDA indicated could affect the product’s quality attributes included formulation design, materials, container-closure, process parameters, equipment, and site.

The second example is taken from the product quality review of an orally disintegrating sub-lingual tablet approved in 2018 (see page 10 of the review here).   Based on the unredacted comments in the risk assessment, the FDA analysis of the product’s risk included aspects of a more comprehensive control strategy such as material attributes, process parameters, container-closure system properties and CGMP-related controls than the approach used in the first example.  

The third example is taken from the product quality review of a liposomal inhalation suspension approved in 2018 (see page 60 of the review here).   

The approved drug product was part of a co-packaged kit that also contained a device for administering the drug.   This product was arguably more complex than the oral tablets in the first and second example.   Yet the final risk assessment in the IQA was heavily dependent on a much less comprehensive control strategy that placed increased reliance on adherence to approved specifications and testing methods while less emphasis was placed on formulation design, manufacturing process controls and CGMP-related and facility controls.

The fourth and final example is taken from the product quality review of an intravenous injection of an antibacterial approved in 2018 (see page 34-35 of the review here). 

This is the most comprehensive risk assessment of the four examples. Elements of the control strategy that included reproducibility and acceptability of the impurity profile, storage conditions, manufacturing in-process controls, sterilization process validation, container-closure, material attributes, stability monitoring and CGMP status of facilities were all considered in addition to adherence to specifications. This approach seems to be congruent with the higher risk to consumers when an intravenously administered product is manufactured and used.

Here are three points that industry can learn from this brief examination of how FDA is using formal product quality risk assessments for individual applications.

  • Firms are advised to consider including their own risk assessments and the derivative control strategies in suitable locations in the application.  Since the applicant cannot be present to participate in the review of the application, this is an opportunity to inform and persuade the agency that the risks related to product quality have been adequately identified and controlled.  If there is a difference of opinion, then the firm has laid the foundation to understand any reasonable basis on which the agency disagrees with its assessment and control of risk.
  • Despite the apparent contradiction of using a risk assessment that relies heavily on control by conformance to specifications with long-held FDA policy that quality cannot be tested into a product, this small sample size does provide clear evidence that manufacturers can expect the agency to use more complex risk assessments and confirm more comprehensive control strategies for products that pose a greater risk to consumers.  In this case, the risk assessments for both the liposomal inhalation suspension and intravenous injection were far more comprehensive that the ones for the solid oral tablets.  For a risk-ranking of product complexity that was developed by the FDA, see this article.
  • Risk assessments will become more prominent. Even though FDA has acknowledged that risk assessments can be subjective and may lead to inconsistent regulatory actions, the agency intends to refine their use as part of the knowledge aided assessment and structured applications (KASA) initiative.  By evaluating risk control, KASA is intended to capture and convey residual product, manufacturing, and facility risk for each regulatory submission. For more information about KASA, see the agency’s most recent article here.


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