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Applying a QbD approach helps address excipient variability and other quality features.
A quality-by-design (QbD) approach to drug product development and manufacturing ensures that quality is considered from the earliest stages of the development process and thus built into both the drug product and process from the outset. Incorporation of excipients into QbD projects can be challenging, however. The innate variability of excipients must be factored into product design to ensure product robustness. In addition, many excipients are made by companies serving multiple markets, with pharmaceutical applications for their products often a minor portion of their businesses. Pharmaceutically aligned suppliers can support QbD projects, but some excipient manufacturers may need to be educated about the QbD process and how it can impact them.
Excipients account for a significant percentage of the material in most traditional drug products. It is therefore necessary to understand the properties of these excipients, how they can interact with the API and during processing, and how those interactions are impacted by excipient variability, according to Chris Moreton, vice-president of pharmaceutical sciences with FinnBrit Consulting.
Variability is particularly important. “Excipients,” explains Dejan Lamesic, scientific team leader at Catalent, “inherently have variable material properties and can show substantial polydispersity of their material attributes, which can be reflected in significant variability of drug product performance.”
Much of the information needed, Moreton notes, can be found in sources such as the pharmacopeias and the Handbook of Pharmaceutical Excipients (1), but if it isn’t available, the information should be generated. For instance, drug-excipient compatibility studies are carried out with the intent to identify, quantify, and predict potential interactions (physical or chemical) along with the impact of these interactions on the manufacturability, quality, and performance of the final drug product and processes, says Barry Gujral, senior manager of quality for Thermo Fisher Scientific’s Pharma Services business.
Categorization of the impact of excipient variability is essential, adds Brian A.C. Carlin, director of QbD/Regulatory for DFE Pharma. Performance of excipients will dominate design-of-experiment (DoE) studies with respect to determining the impact of the variability of excipients on the product and process. “Basic excipients may be found to have little or no impact in a DoE study but can have significant adverse impacts during the finished product lifecycle due to product or process drift,” he notes.
Characterization methods must adequately characterize material attribute distribution and its variability, and various multivariate tools should be applied to follow and monitor excipient variability over a set timeframe, adds Lamesic. “Even though individual attributes may still stay within their limits, certain interactions can lead to quality issues. The impact of material attribute variability may vary depending on the defined design space, and is highly drug product dependent,” he notes.
Strong emphasis also needs to be given to identifying all material attributes that may be critical to drug product performance, Lamesic asserts. “The attribute may not be recognized or included in pharmacopeial tests or may not be part of excipient supplier specification. It may also be a newly identified attribute in connection to a specific drug product,” he observes.
Applying a QbD approach to excipients could help address variability and other quality features. “Pharmaceutical excipients are no longer inert materials; excipients today are able to improve the characteristics of a product’s quality, stability, functionality, safety, solubility, and acceptance to patients,” Gujral explains. “They can interact with the active ingredients and alter the medicament characteristics. The QbD approach takes care of all of these factors by determining excipient impacts using various QbD tools including DoE and Monte Carlo simulations and optimizations.”
A QbD approach can further encourage and motivate excipient suppliers to build and enhance knowledge of their materials and their attributes and variability in relation to specific drug delivery routes or drug products, adds Lamesic. “In addition,” he states, “it may foster open communication and exchange of specific knowledge between the excipient supplier and pharmaceutical manufacturer, thus providing more clarity and understanding of the needs of both sides.”
A drug product’s quality target product profile (QTPP) documents the critical quality attributes (CQAs) of the product and is refined throughout development, informing the final drug product specification. The critical material attributes (CMAs) of the excipients and the critical process parameters (CPPs) of the manufacturing process are key factors in understanding and defining the design space, says Iain Davidson, senior manager, pharmaceutical development at Vectura.
“With fixed CPPs, variability in the input materials can result in variability in the output drug product, so understanding the relationship between the CQAs, CPPs, and CMAs is fundamental,” Davidson stresses. “An excipient control strategy needs to be inclusive of the specification and defines the wider criteria against which to evaluate and manage changes, ensuring consistent drug product performance is maintained throughout the product lifecycle. Ongoing monitoring of input CMAs—and mapping these to drug product performance CQAs—is important in determining process capability and maintaining consistent drug product performance,” he adds.
Lamesic believes that using a QbD approach may increase the frequency and effort required by the pharmaceutical manufacturer to monitor specific excipient-critical material attributes at defined time intervals if they are not controlled by the supplier specification. Moreton agrees that with a QbD approach, more time must be spent on development, but that time is recouped after commercial launch because there are fewer out-of-trend and out-of-specification investigations.
Excipients are chosen to add functionality to drug products but have batch-to-batch and supplier-to-supplier variability. A QbD approach, says Mara van Haandel, innovation manager at DFE Pharma, looks at the impact of excipient variability and thus allows the development of more robust processes and products.
QbD, Moreton agrees, requires drug manufacturers to better understand their excipients, APIs, and unit processes, because the more that is understood, the better likely traps and pitfalls (adverse effects) can be anticipated and proactively prevented.
“The purpose of QbD is to build quality into pharma products and processes. During the development stage, QbD incorporates the compatibility of the API with the excipients, thus enabling robustness of products and, in turn, robust processes,” asserts Gujral.
Incorporating excipients using a QbD approach sets the primary focus on determining and understanding the variability of their material attributes, such as particle size distribution, shape, molecular weight distribution, surface properties, substitution level, or chemical composition, adds Lamesic. “Using DoE studies and modeling to address excipient variability will increase the understanding of their impact on the manufacturing process and the drug product, minimizing process variability and disturbances and resulting in an increase in drug product robustness,” he says.
For inhalation products, Davidson comments, the excipients used in the formulation are critical to the product performance. Having a good understanding of the variability of the production processes, and therefore, the excipients produced—particularly over a prolonged timeframe or large number of batches—helps strengthen the understanding of the drug products throughout their development.
“Building this understanding from the early development stages will help accelerate product development and provide a wealth of information to support regulatory submission,” notes Davidson. He also points out that solving any problems and understanding the design space for the input materials and the process conditions at an earlier stage in the product development will save both time and cost as the products are scaled to commercial volumes.
In general, says Kristina Elena Steffens, principal formulation scientist for Catalent, excipients should be characterized thoroughly at the pre-formulation phase. “Gaining deep insight by focusing on the excipient at a molecular, particle, and bulk level is of great importance,” she observes.
All drug product quality attributes, including physical attributes, identification, assay, content uniformity, dissolution and drug release, degradation products, residual solvents, moisture, and microbial limits should be considered, according to Gujral.
Overall, characterization methods should be carefully chosen based on the needs of the final drug product. Specific methods for excipient characterization also depend on the attributes of those excipients and the context for control, according to Carlin. For example, Moreton notes that for oral solid dosage forms, particle size distribution, bulk and tapped densities, and flowability are important; for creams and ointments, the chemical composition may be important, along with physical properties such as viscosity and melting behavior.
Characterization methods can include classical solid-state characterization, such as X-ray powder diffraction (XRPD) and Fourier-transform infrared spectroscopy (FTIR), or methods related to surface characterization including wettability or specific surface area, and they should be carefully selected depending on the QTPP and the manufacturing process, according to Steffens.
In some cases, Steffens notes that the certificate of analysis (CoA) of the excipient manufacturer might not cover all analytical needs of the pharmaceutical industry. In addition, the acceptable variation for CMAs of the excipient given by the specification might not match the needs of the manufacturing process window of the final drug product.
Furthermore, batch-to-batch variations can also occur at the bulk level, with respect to excipient particle size distribution, bulk density, or flowability. By recording measurements in an internal database, Steffens comments that statistical evaluation of variations can be conducted, and a risk-based control strategy adopted.
Excipient variability is the biggest challenge to incorporating excipients into a QbD approach. “The need to balance cost and time against the appropriate and necessary QbD approach to understand the impact of excipient variability on product critical quality attributes is a constant issue,” asserts Ariana Low, principal formulation scientist with Catalent. “It is not always a straightforward process to incorporate the study of excipient variability impact without compromising project timelines,” she says.
Indeed, Gujral believes that incorporating excipients into a QbD approach to design quality in products and processes is a paradigm shift. “We need to consider API/excipient compatibility and develop the design space and control the variability of each input factor for all critical responses. To do so requires more time, money, and resources. At the end of the day, though, it will lead to more robust products and processes and avoid the cost of poor quality, thus transforming the so-called challenges into opportunities.”
Low agrees. She also expects these challenges will ease over time with increased concentrated effort to characterize and understand the impact of excipient variability on the development process.
There are other challenges as well. Differences in excipients of the same grade made at different manufacturing sites is one, according to Moreton. The existence of “unknown unknowns” also adds real uncertainty, says van Haandel. That uncertainty is magnified by the fact that many drug developers fail to involve excipient suppliers early enough in the development process, she notes.
QbD for inhalation product development can be even trickier. For these products, Davidson sees the QbD approach in excipient product development and lifecycle management as a bit of a double-edged sword from a material supplier perspective. “While a QbD approach offers advantages in terms of clearly defined specifications and a framework by which to manage and control changes throughout the product lifecycle, the inhalation product manufacturing demands are notorious in that the material volume requirements are relatively low, while the specification requirements are very specific, often bespoke and challenging to meet, making supply of these materials high effort,” he explains.
Similarly, the small scale of development batches creates issues for drug product developers because of the limited ability to fully evaluate excipient CMAs from a range of input batches the cost of purchasing and/or the logistics of storing the required quantity of material needed to support a QbD approach, according to Davidson. “The alternative is to use smaller-scale excipient batches that may not be fully representative of the final commercial-scale materials, with the resulting development drug product batches running the risk of not being representative of subsequent clinical and commercial materials,” he says.
On the positive side, however, Davidson believes that from the drug product manufacturing perspective, having a QbD approach in excipient product development and lifecycle management offers a more efficient product development pathway with greater assurance regarding manufacturing robustness, a reduction in product variability, a reduced risk of rejects and recalls, and a more efficient and proactive issue resolution and a structured change management framework.
Steffens agrees that knowledge of the critical influencing factors can help to implement manufacturing strategies that are not fixed to rigid formulations and process settings, making the pharmaceutical industry flexible in reacting to excipients’ batch-to-batch variations. QbD, adds Gujral, is an emerging idea that offers pharmaceutical manufacturers increased self-regulated flexibility while maintaining tight quality standards and real-time release of drug product.
Low notes that the multitude of choices of excipients from various suppliers using different processes confounds the application of QbD in product development. “Some of these variations may also be unknown to the formulator (i.e., not listed in the pharmacopeial specifications), and it is important to bridge the knowledge gap through intense discussions with excipient suppliers, which currently is often overlooked in the development process,” she says.
Moreton’s perspective is that no one knows it all. “Excipient manufacturers know far more about their excipients than appears in their promotional materials. However, some of this will not be disclosed unless there is a confidentiality agreement in place. It comes down to better two-way communication,” he states.
Davidson provides one example of successful collaboration. The most commonly used excipient in dry powder inhalers is lactose monohydrate. Lactose suppliers have worked closely with the regulatory authorities for many years to build a comprehensive specification for inhalation-grade lactose that goes well beyond the pharmacopeial testing, and includes impurities, protein content, and amorphous content.
“Because the particle size distribution remains the most critical parameter to control, drug developers work closely with excipient suppliers to understand the analytical procedures used for release testing and any offset in the results of analyses seen at the receiving facility due to differences in equipment, methods, or sites to in turn understand any analytical variability and ultimately the variability in the excipient itself,” Davidson observes. This collaboration, he concludes, allows the targets for the range of batches needed for a QbD approach to be set so that the batches are truly different, rather than within the scope of the variability.
In November 2020, the International Pharmaceutical Excipients Council Federation, (IPEC Federation) announced a new guide Incorporation of Pharmaceutical Excipients into Product Development using Quality-by-Design (2).
Gujral says the goals of the guide are to introduce quality by design (QbD) and pharmaceutical formulation development concepts to excipient manufacturers and suppliers; explain how changes in pharmaceutical formulation practices due to the introduction of QbD impact excipient manufacturers and suppliers; help excipient manufacturers and suppliers understand what excipient users will likely require when applying QbD principles during product development; and explain to excipient users and regulatory agencies what may or may not be possible when considering the impact of excipient variability in the application of QbD principles during product development.
The QbD guide provides, according to Carlin, a framework for addressing uncertainties and special cause variation, and also provides an improved definition of a critical material attribute (CMA), a frequently misunderstood concept. In conjunction with the 2016 IPEC QbD sampling guide (3), the new QbD guide will help bridge the understanding gap between excipient users and excipient makers/suppliers, adds Moreton.
The consistent framework and common understanding for suppliers and customers will link together drug substance understanding and the product development guidance from the International Council for Harmonisation and regulatory authorities, observes Davidson.
The IPEC QbD guide draws the attention of excipient users and suppliers/manufacturers to the importance of the incorporation of excipient variability into QbD and creates a platform for discussion, according to Low. “The advice brings excipient manufacturers/suppliers and formulators closer together to discuss and tackle excipient variability, which can only add robustness to current drug product development methods,” she says. It may also, Low adds, pave the way for regulatory body mindset change to lead to the re-classification of excipients as functional ingredients and not only as inactive ingredients.
One of the most important things the new IPEC QbD guide will do is build the close working relationship between the excipient suppliers and their customers that is essential to the successful development of robust pharmaceutical products, according to Davidson. “Collaboration between pharma companies and excipient suppliers to share data on excipient variability is crucial,” agrees van Haandel. Everyone needs to think beyond the certificate of analysis, she adds. DFE Pharma, for instance, provides stretch batches and historical data to support customer QbD studies.
1. P. Sheskey et. al., Handbook of Pharmaceutical Excipients (Pharmaceutical Press, 9th edition).
2. IPEC Federation, Incorporation of Pharmaceutical Excipients into Product Development using Quality-by-Design (Brussels, Belgium, November 2020).
3. IPEC Americas, Quality by Design Sampling Guide (Arlington, Va., May 2016).
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Vol. 45, No. 5
When referring to this article, please cite it as C. Challener, “QbD Helps Evaluate Excipient Variability,” Pharmaceutical Technology 45 (5) 2021.