From The Editor | July 29, 2024

Setting The Bar For Drug Product Quality, Part 2: The Evolving Practice Of Particle Testing

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By Fran DeGrazio, executive editor, Drug Delivery Leader

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In Part 1 of this two-part article series, “Setting the Bar for Drug Product Quality, Part 1: How Best Practices Prevail,” I introduced and discussed common scenarios in which established best practices for addressing product quality often exceed the minimum, documented regulatory guidance and standards at any point in time. A current challenge area for industry – particulate analysis of sterile drugs and biologics – is worthy of an even deeper dive consideration of the potential variances between, on the one hand, official industry guidance and, on the other, expectations around best practices. Since the early 2010s, there has been growing sensitivity in the US about this challenge area, as indicated by the number of FDA recalls occurring due to particles in sterile products. A recent, notable example is Sagent Pharmaceuticals’ announcement of a voluntary recall.

Frankly, achieving a best practices approach to minimizing particle contamination will require a multi-factor set of practices that go well beyond running standard compendial tests. Environmental features, analytical capabilities, and the maintenance of processing equipment are just a few of the factors in play.

Know These Five Particulate Testing Challenges

Below I have listed five key challenges or obstacles that should become well-understood and addressed along the way to building a particle minimization program that demonstrates best practices in operation. I will then comment on each:

  1. Standards/guidances are neither up-to-date nor well-aligned with each other
  2. Test methods assumed to be equivalent and, therefore, sufficient may not be
  3. Visible particulate garners inordinately more attention than does subvisible particulate
  4. Genuinely risk-based approaches are inconsistently applied
  5. Particle characterization of a drug when combined with a device may not be given enough focus compared to characterization in its primary package

Go Beyond Compendial Standards

Regarding particulate analysis, there exists a current series of USP test standards and specifications. These specific USP compendia are:

USP<787> Subvisible Particulate Matter in Therapeutic Protein Injections

USP<788>Particulate Matter in Injections

USP<789>Particulate Matter in Ophthalmic Solutions

USP<790> Visible Particulates in Injections

USP<1790>Visual Inspection of Injections

However, an FDA industry guidance published in draft in 2021 and entitled Inspection of Injectable Products for Visible Particulates makes clear that organizations must go beyond simply meeting USP compendial standards. As stated in the introduction, “This guidance also clarifies that meeting an applicable United States Pharmacopeia ( USP) compendial standard alone is not generally sufficient for meeting the current good manufacturing practice (CGMP) requirements for the manufacture of injectable products.” This statement in the guidance confirms that building a best practice that is science-based and risk-driven is a must.

Avoid Test Method Mismatches

Because of specific characteristics of the drug product being tested, it is imperative to understand differences in the testing methods being used, including any limitations of the instrumentation. Such attention to the methods and limitations helps ensure thorough understanding of the product and its processing from a particulate perspective.

For example, two common analytical methods are light-obscuration (LO) and microscopy. However, several more are often used to supplement them, including micro-flow imaging (MFI) and background membrane imaging (BMI), among others.

So, the correct – that is, specific and applicable – methods must be chosen for the drug substance at hand. For instance, a protein solution will respond differently than will a non-protein product. Similarly, detecting subvisible particulate will require a different methodology from that used to confirm the presence of visible particulate.

To drug delivery professionals not close to particle testing, it could seem that simple, standardized testing would suffice; however, the reality is quite different. Complex factors potentially impacting product results and, therefore, being factors in need of attention during testing include sample acquisition, sample preparation, and the testing environment itself.

All of these should be well understood and considered in meeting best practice expectations.

Do Not Ignore Subvisible Particulate

From a regulatory perspective, there is much focus on visible particulate. This attention seems to stem from a belief that the presence of even one visible particle may indicate a process that is out of control or that the visible particle could be a sign of biological contamination. These concerns are valid; however, unless there has been a significant breakdown in the manufacturing process, visible particulate will likely be limited to just one or two vials and, therefore, can simply be removed from the much larger lot of product.

The presence of subvisible particulate, on the other hand, is of much greater concern. First, there is much less industry guidance on how to deal with this category of particulate. Moreover, subvisible particles are typically discovered across an entire lot of products. This broader distribution presents a significantly increased safety concern because of the potential for adverse immunogenicity in patients, especially when subvisible particles are under 10 microns.

Minimize Risk with Risk-Based Approaches

Frankly, the common practice of having standardized compendia provide a test method and a spec that are deployed in the same way for every drug/biologic product runs contrary to any attempts to be genuinely risk-based. The identity, shape, and quantity of particles are just a few aspects to be understood as inputs into evaluating risk by way of approaches that go beyond those outlined in standardized compendia. For instance, fibers have been shown to give a different biological response compared to round particulate of a similar size. These kinds of differences have the potential to lead to harm to patients based on variable factors such as user groups and drug therapies. Therefore, best practices in overall risk analysis should take all of these differences and factors into consideration.

Considerations for Combination Products

From the perspective of industry, there is typically a better understanding of and characterization of particles around a drug/biologic and its primary package than there is for many of the delivery systems that may be used to bring the product to the patient. This lesser attention given to particles in devices includes those components that may form part of a combination product or combined use system.

As an example, ISO standard 8536-4:20105 describes a test process and acceptance criteria for single use gravity feed infusion sets and intravenous equipment. The specifications fall into three categories, with the smallest size being 25-50 microns. If subvisible particles at less than 10 microns are a concern for protein drug products, would there not be a similar concern about the delivery system used to get the drug into the patient?

Finally, although many look for the simplicity of a compendial test method with a spec, frankly, that approach is contrary to understanding patient needs, therapy requirements, and other unique considerations when working from a best practices mindset.