Managing excipient variability in drug development: Our answers to important questions

You may have heard of Quality by Design, or QbD, but do you know how it can help manage excipient variability? In the pharmaceutical world, QbD is a scientific, risk-based, proactive approach to drug development that supports the creation of robust and safe medications from the start. QbD is based on thorough understanding of the drug manufacturing operations and ingredients used—including knowledge of variability in ingredient properties or processes that may impact the performance of the final drug product.

Excipients are one of the main ingredients that make up a drug product. In fact, they may represent up to 90% of a drug formulation!^i,ii Excipients must adhere to defined specifications outlined by pharmacopeia standards to ensure they are safe for drug development. But, like any other element of the drug formulation and manufacturing process, they exhibit inherent variability within those specifications*—whether that’s differences in particle size, moisture content or morphology. Understanding how excipient variability does (or does not) impact the performance of drug products is a fundamental aspect of QbD.

In this blog post, Mohammad Qadir, Lead Applications Scientist at IFF Pharma Solutions, addresses the most frequently asked questions his team receives on the topic of excipient variability. He even shares practical steps on how to consider excipient variability as part of the formulation design to safeguard the quality and effectiveness of drug products.

*In the context of this article, variability means fluctuation of the data set within specification limits set out by the excipient supplier or pharmacopoeia.

1. What is the impact of excipient variability on drug development?

First and foremost, excipient attributes must meet defined specifications before being included in a drug formulation. That said, some degree of variability is inherent—and unavoidable—within these parameters. The important thing is acknowledging this, then understanding how the variability might influence the drug’s therapeutic effectiveness, and finally, taking steps to manage it as part of the drug development process.

For example, we have helped pharma companies address issues both down the drug development cycle and even in marketed drug products when drug developers fail to understand the impact of key excipient attributes on their drug performance early in the development process. In some cases, the fix can be a simple change, like excipient grade to better control moisture content. However, some solutions require extensive work from both the excipient manufacturer and the drug manufacturer, delaying sales to the market. Conversely, by considering the potential effects of these attributes (and any potential variability) early on, manufacturers increase their chances of developing optimized formulations.

1. Is it possible to minimize excipient variability?

Although variability is inevitable, there are some key steps excipient manufacturers can take to minimize it.

1. Understand the raw material source: Raw materials used for excipient manufacturing can come from natural sources like tree pulp, minerals and seaweed, or they can be synthetically developed—each source bringing differing degrees of variability. An t excipient supplier experienced in QbD principles would be aware of potential variation and how to manage it.
2. Monitor the manufacturing process closely: Variability can arise if there are significant changes in processing conditions during the manufacturing of excipients. For example, different drying temperatures can impact moisture content of the excipient, while variations in milling or granulation can affect particle size. These differences can impact critical formulation processing parameters like flowability, compressibility and dissolution rates. Having robust manufacturing controls in place and real-time monitoring can improve excipient uniformity and the ability to meet required specifications.
3. Consider sensitivity of analytical instruments and test methods: Sometimes, analytical techniques will not capture variability accurately if they exhibit low sensitivity. For instance, instruments such as high-performance liquid chromatography (HPLC), commonly used for chromatography, offer higher sensitivity compared to tools like pycnometers used to measure density. Employing methods and instruments with high sensitivity allows for more precise detection of potential inconsistencies in excipients.

1. Are some excipients more susceptible to variation than others?

Excipient raw materials from natural origins are more susceptible to variability. This is mainly due to fluctuating environmental factors, such as soil type, climate change, use of fertilizers, and water conditions. While this variability in raw materials does not directly translate into finished excipient product variability, it is a factor that needs to be managed. Excipient producers can take proactive steps to minimize the variability of natural-origin excipients. Partnering with a reputable supplier can offer peace of mind here. A trusted supplier not only understands the critical attributes of their materials but also has robust systems in place to monitor and control variability to ensure consistent quality. This allows drug developers to focus on what really matters with confidence—innovation and product development.

1. Are there any regulations I need to be aware of—and changes in the future?

There are no regulations that specifically address excipient variability. However, pharmaceutical producers need to demonstrate a clear understanding of how raw materials and manufacturing processes affect drug product quality—and this must be formally documented in most major regulatory submissions. Regulators continue to place increasing emphasis on this type of risk assessment, and more advanced statistical techniques are being explored to support this. To assist with this expectation, QbD concepts are covered by guidelines from IPEC (International Pharmaceutical Excipients Council)ⁱⁱⁱ and ICH Q8.^iv

1. What are your top tips for developing a robust drug development strategy?

Effectively managing excipient variability is achievable through the application of QbD or Design of Experiment (DoE) principles. These frameworks consider critical excipient attribute variations up front in the drug development process, and aim to control or improve in real-time, rather than testing at the end. This leads to fewer unexpected problems during production, more reliable drug performance, and a greater chance of developing a robust and successful product.

Of course, excipient suppliers play a vital role in managing excipient variability too, because the level of variability largely depends on the control strategies they employ throughout the manufacturing and processing of the excipient. It’s important to be aware that not all suppliers are exclusively focused on the pharmaceutical industry though and, therefore, may not fully understand the regulatory requirements in pharma or customers’ complex needs in this space. My top tip for drug manufacturers is to source excipients from reliable suppliers with a history of providing materials with well-documented and understood variability.

1. How can IFF Pharma Solutions help me understand and minimize performance risks due to excipient variability?

IFF Pharma Solutions is a globally trusted excipient supplier with a deep understanding of excipient variability and the unique needs of pharma customers. We closely control the development of our excipients from raw material input to the finished product. Moreover, we have a dedicated team of process engineers, quality teams and R&D specialists who work diligently to ensure our excipients meet internal and pharmacopoeia specifications. For select product lines, we can also supply QbD samples that represent the highest and lowest limits within a defined specification range, enabling customers to produce in-house batches and evaluate any changes in their drug performance. As a standard, we provide our customers with informative variability data, allowing them to observe batch-to-batch variability as part of their own risk assessments. And we can offer additional qualification support for all our excipients.^v

Need further guidance on excipient variability and how to manage it via QbD? Explore more in-depth information or connect with one of our excipient experts here: answercenter.iff.com