Setting The Bar For Drug Product Quality, Part 1: How Best Practices Prevail
By Fran DeGrazio, executive editor, Drug Delivery Leader
What is the expectation for quality when developing and commercializing a drug product?
The minimum expectation is to be compliant with the laws and standards that have been formally defined and documented by regulatory agencies and other governing bodies. Often, however, industry itself develops and adopts best practices that quite often become de facto “expectations.”
These best practices typically develop over time and can often be attributed to two common reasons. The first results from industry responding to various real-life issues that occur and could negatively impact patient safety. These industry responses are often triggered by interactions with a regulatory agency – for example, by questions asked during CMC review or from issues raised during a pre-approval inspection. The second driver is industry itself. Quite often, organizations with depth of experience will apply more rigorous, science-based approaches that lead to the development of new methodologies and evolve beyond minimum regulatory standards.
So, biopharma companies have a choice to make as they address product quality: a) meet the current minimum requirements, or b) strive for a deeper understanding of product and process based on science and on minimizing risks. Frankly, some less experienced organizations may feel that meeting minimum requirements is all that is necessary. However, such an approach can lead to challenges resulting in longer approval times when regulatory submissions are reviewed. In those scenarios, organizations that have already gone beyond the minimum requirements or are supplementing them with best practices may fare much better on their regulatory journeys.
Over time the official regulations, guidances, and standards do tend to evolve and ultimately reflect these emerging best practices; however, that evolution may take years. Meanwhile, de facto expectations are likely to have been cemented into practice long before the formal documents catch up in the form of new or revised versions.
Extract an Example from Extractables
An illustrative case in point is the evolution of regulatory guidance for extractables and leachables (E&L) testing. As far back as 25 or so years ago, testing of drug product for E&L was becoming an expectation for industry. The official driver for this was the FDA 1999 guideline Container Closure Systems for Packaging Human Drugs and Biologics. As we now know, the kind of testing that became required is quite different from USP compendial testing. At the time, however, some in the industry felt that doing compendial testing such as that outlined in USP 381Elastomeric Closures for Injection would suffice as extractables testing of elastomeric components. It was not until August 1, 2015, that USP 1663 & 1664, documents that provide background and outline studies for extractables and leachables, became official. However, long before 2015, it was an industry expectation and best practice to perform E&L testing.
For Combination Products, Factor in Human Factors
A similar evolution of best practices and regulatory guidance can be seen in the arena of combination product quality. The FDA formed a human factors (HF) group within CDER in 2006. In 2011 the agency published a draft guidance entitled Applying Human Factors and Usability Engineering to Optimize Medical Device Design. This document references various AAMI and ISO documents and was applied to the device portion of a combination product.
As considerations around human factors continued to evolve, FDA published a final guidance in 2023 replacing a draft guidance on combination products that was issued in 2016. Entitled Application of Human Factors Engineering Principles for Combination Products: Questions and Answers, the guidance asserts, “The goal of applying HFE principles during development is to ensure that the user interface supports the safety and effectiveness of the combination product as a whole.”
Even with the availability of these guidance documents, the actual user experience suggests that additional advances toward best practices are still in order. Such experiences appear in the form of medical device adverse events that have been reported – for example, certain autoinjector failures that caused spontaneous activation.
One of the main reasons for insufficient attention to the patient perspective is that official guidance typically provides only high-level, general direction on a topic of concern. HF concepts should be applied with the intent to achieve a scientifically sound, patient-centered product and not just meet minimum compliance criteria. As an example, a combination product must meet a range of physical attributes while addressing cognitive and physiological HF performance variables. If a combination product and the HF work completed during development address only the “typical “patient group, the product may meet the needs of the majority but not those of all potential user groups, such as patients who may be in an extreme range of a disease state or may be lower in cognitive ability.
These kinds of factors are not highlighted in current FDA guidance; nevertheless, they may be challenged during the regulatory process or, if not then, when the commercially available product leads to adverse events.
Frankly, applying best practices over and above minimum regulatory requirements makes sense not only in terms of product quality and patient safety. It also makes good business sense for biopharma companies, who will find it to be much more cost effective to make product adjustments during development rather than after a product has been marketed commercially.
In Part 2 of this article series, I take a deeper dive into the question of whether to simply meet minimum requirements or to apply best practices, illustrating my points with the scenario of product quality challenges related to particles in injectable drug products and injectable combination products: “Setting the Bar for Drug Product Quality, Part 2: The Evolving Practice of Particle Testing”