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Although not easy to do, it is essential because excipients can affect drug-product safety and efficacy.
Drug products must be produced in a manner that ensures both their safety and efficacy. That requires consideration of the quality of all ingredients in a final formulation, including all excipients, whether they are functional or inert.
“Excipients are critical to the safety and efficacy of nearly every drug product, if not all drug products, regardless of route of administration,” says Joseph Zeleznik, technical director, North America at IMCD Pharma. They can impact drug substance solubility and permeability, stability, release rate, and absorption. Variability in excipients therefore needs to be part of the formulation risk assessment.
Evaluating how excipients affect performance is essential to ensuring drug product performance and achieving therapeutic success. Leveraging excipient supplier expertise facilitates pharmaceutical development processes. Good two-way communication contributes to the risk assessment and experimental design to obtain the enhanced understanding of formulation components and processing required quality-by-design (QbD) approaches.
Excipients are complex materials typically made up of multiple components, which vary from batch to batch and supplier to supplier, according to a International Pharmaceutical Excipients Council (IPEC)-Americas panel comprising Brian Carlin (owner of Carlin Pharma Consulting), Chris Moreton (principal consultant at FinnBrit Consulting), David Schoneker (president/owner/consultant of Black Diamond Regulatory Consulting), Katherine Ulman (primary at KLU Consulting), and Joseph Zeleznik. In addition, residual and trace materials can change between excipient manufacturers, says Krizia M. Karry, head of global technical marketing for BASF Pharma Solutions.
“Due to the multi-component nature of excipients, what drives excipient performance depends on its intended application,” Karry observes. For example, she notes that a co-processed excipient may enable direct compression of fast-dissolving tablets, but if its chemical composition or physical properties change within the allowed ranges, there could be an effect on tabletability or disintegration.
“QbD,” the IPEC-Americas panel states, “requires a more in-depth understanding of the excipient beyond the traditional compliance with (sales) specifications.” That includes the impacts of excipient lot-to-lot variability and changing excipient suppliers, adds Zeleznik. Therefore, he contends, if excipients are not included as part of a QbD approach, their impact on the API and, more importantly, drug product performance cannot be properly assessed.
There are no specific regulatory requirements for excipients relating to QbD, and QbD is not compulsory in the United States. QbD guidelines for drug product development have been documented by the International Council for Harmonisation (ICH) and only include excipients in as much as excipients are a part of the drug product composition, notes Zeleznik. However, that does not change the fact that excipient variability will be important for all users to understand who may want to submit a QbD-related drug application, according to Schoneker.
QbD is a science-based approach that is complementary to traditional regulatory compliance approaches, says Carlin. Compliance does not ensure fitness for purpose in a finished product: additional product-specific specifications may be required, most notably critical material attributes (CMAs). “It is good practice to understand excipient variability and its impact on drug product performance to minimize any impact to patient safety and/or drug product efficacy,” he comments.
Moreton adds that excipients intended for human use, either in clinical trials or after commercial launch, should be manufactured to appropriate good manufacturing practice (GMP) standards per the United States Pharmacopeia (USP)–National Formulary (NF) General Notices (even if they do not have a USP or NF monograph) or another pharmacopeia depending on the jurisdiction. For topical products, Karry notes that using GMP-grade raw materials is not a requirement, and many companies use cosmetic-grade raw materials because they are less expensive, which has other consequences from a supplier accessibility and regulatory perspective.
Annual product quality reviews (APRs) may also be valuable for addressing the needs of QbD programs at drug manufacturers, Karry comments. BASF performs APRs to verify that its processes remain in a validated state and assess if there are systematic process or quality defects. The data-trending component of APRs helps the excipient supplier work with the drug product formulator to analyze the distribution of certificate of analysis (CoA) parameters, information she says can potentially be used to expand the design space and make it less susceptible to intrinsic material and process variability, thereby increasing robustness.
The challenges to incorporating excipients into QbD programs are numerous and diverse. Communication can be a major hurdle to incorporating excipients into QbD programs, according to Zeleznik. “Drug product manufacturers may not fully understand or appreciate excipient composition complexity and/or variability as well as the potential impact to drug product performance. It is important that pharmaceutical product manufacturers have open dialogue with excipient suppliers regarding excipient choice and application in a drug product. Relying on ingredient specifications and monograph requirements and CoA data is often not enough.Asking whether there [are] any data or information related to a particular application very well could help with product development and consistent drug product manufacture and, more importantly, performance,” he remarks.
Karry points to a lack of sufficient historical data to understand the impact of intrinsic excipient variability throughout its retest period on drug product safety and efficacy. She also notes that many drug manufacturers, rather than work with excipient manufacturers to jointly evaluate the data and understand risks, resort to adding more variables to their design of experiment (DoE) studies. “It is a common misconception that a QbD approach to pharmaceutical development will always result in more experiments and test batches,” she observes.
In a similar vein, Zeleznik observes that there is a misconception regarding “QbD samples,” which in fact don’t exist, at least, he says, not in the way that pharmaceutical companies desire—“manufactured at the edge of specification.” “This ill-conceived notion that excipient manufacturers can or would be willing to manufacture to edge of specification is impractical.There are too many interdependencies among some acceptance criteria making it impossible as well as the number of permutations that would need to be created,” he states.The more practical approach, Zeleznik says, is to secure samples that are at the boundaries within normal variation, if available.
For Moreton, the fact that most excipients are produced in large volume using continuous manufacturing is a challenge to providing samples at extremes of specification. “These processes operate in a form of balanced equilibrium and changing one processing parameter may mean that another parameter has to be changed to compensate. In some cases, it may not be possible to make the change. The result is most often that the production of excipients with properties at the limits of specification cannot be achieved,” he explains. He adds that the IPEC-Americas QbD Sampling Guide for Excipient Makers, Users, and Distributors (2016) was developed to explain ways in which it may be possible to simulate excipients at the limits of specification.
Other challenges noted by Carlin include:
The growing recognition of the value of the QbD approach and the need to thoroughly understand all aspects of a manufacturing process are leading to the development of solutions for many of these challenges. “Pharmaceutical companies are starting to ask more questions about excipients.This is a significant step towards overcoming challenges related to product development and the impact associated with excipients,” Zeleznik notes.
For instance, Karry observes that some drug companies are working with excipient manufacturers to “open the books,” enabling joint evaluation of relevant data and exploration of the potential impacts of variability in both CoA and non-specified parameters. As an example, she points to a recent project in which BASF worked with a customer that was using fine crospovidone for its binding disintegrant functionality.
It was found in this joint project that large changes in particle-size distribution (PSD) affected tablet hardness and friability. While particle-size distribution (PSD) is not a monograph specification, it is an FRC that depends on the excipient use. It is not included in the crospovidone CoA, but BASF measures it internally. Analysis of historical data on the variability of crospovidone PSD revealed low variability. BASF also conducted a quick study in the compaction simulator using a crospovidone lot with higher PSD values to confirm the assessment that the material was low risk. “This is one example of how drug manufacturers, working with the excipient producers, can expedite and de-risk drug development,” Karry believes.
Other practices that help to overcome challenges associated with incorporated excipients into QbD programs are the adoption of a model compound approach, the use of methods outlined in the IPEC QbD Sampling Guide, and leveraging statistically driven DoE studies to get maximum benefit from a minimum number of experiments, according to Moreton.
DoE studies, according to Zeleznik, can help drug manufacturers understand the impact of variability in drug substances, excipients, and manufacturing processes on drug-product performance. A full-factorial design, adds Moreton, can be very inefficient and wasteful of materials, time, and resources. There are other better designs that can be statistically analyzed to provide clearer results and conclusions using fewer experiments.
QbD is not a new concept. The principles have been used by the semiconductor and microelectronics industries for decades, Zeleznik observes. There have been many names by which the principles have been known; however, the principles have changed little from one naming convention to another.
The fine chemicals industry, of which excipients are a part, has also been using these same principles for decades, Zeleznik says.“The heart of the concept is understanding those parameters that impact product quality such as process and raw material fluctuations and designing a robust process that minimizes finished-product variation, ensuring lot-to-lot consistency,” he states. In essence, Zeleznik concludes, the excipients industry predates the pharmaceutical industry by many years in “QbD” use.
Moreton agrees that excipient manufacturers using continuous manufacturing have probably already undertaken something analogous to QbD to develop their manufacturing process(es), although it would not have been called QbD. “Once the excipient and process have been developed and the excipient launched into the market place, then statistical process control methods would be used to ensure that the excipient continues to meet the manufacturer’s specification,” he comments.
The high degree of process and material understanding that comes with statistical process control enables high-volume continuous manufacturing, which provides cost-effective availability of high-quality common excipients, adds the IPEC-Americas panel. “Raw materials and processes will vary from supplier to supplier, however, and are subject to the demand and economics of the major markets. In addition, reliance on pharmacopeial compliance may hide changes by a supplier or differences between suppliers and change control is ineffective against force majeure when pharmaceutical consumption is relatively small,” the group believes.
Despite these issues, excipient suppliers can play a very important role in increasing formulation knowledge and experience, adds Karry. “Wider design spaces can be created by thorough evaluation of historical data and with selected raw material lots that offer flexibility in drug development to accelerate scale-up and establish appropriate control strategies for commercial manufacturing,” she notes.
Providing advice on which parameters may be useful in which applications (formulations) is another way in which excipient suppliers can help drug developers with their QbD initiatives, particularly if manufacturers provide information on the impact of excipient manufacturing variability raw material/feedstock seasonal variations, etc.
“Excipient suppliers may be able to supply excipient samples and information pertaining to excipient variability (including both physical properties and composition), but only if they understand what the drug product developer is trying to achieve,” agrees the IPEC-Americas panel. That again requires two-way communication between excipient suppliers and drug-product developers.
The COVID-19 pandemic has impacted supply chains across all industries. Pharmaceutical and excipient manufacturers have not been excluded. Drug-product developers with robust products and effective risk-management and multi-sourcing strategies (i.e., QbD) most likely fared better, according to the IPEC-Americas panel.
“Drug manufacturers that have implemented QbD are battling supply challenges, but their upper hand is at the time of qualifying new vendors (excipient manufacturers). A risk assessment that lists and ranks CMAs and their impact on drug-product critical quality attributes is an essential part of a QbD application. With this documented knowledge on the impact of excipient and API variability, procurement and technical service departments can work together to accelerate material evaluation and new vendor qualification, thus minimizing disruptions,” Karry explains.
Those drug makers that implemented a QbD approach during product development that included the identification of multiple ingredient sources as part of the development program have fared better, according to Zeleznik. “This fact is truly a measurement of the positive impact QbD can have. Knowing how changing excipient suppliers (when feasible) can potentially impact drug product quality and performance during product development greatly minimizes risk during supply chain disruptions,” he concludes.
The IPEC Incorporation of Pharmaceutical Excipients into Product Development Using Quality-by-Design (QbD Guide) (1) was issued at the end of 2020 to complement the IPEC-Americas QbD Sampling Guide for Pharmaceutical Excipient Makers, Users, and Distributors (2), which was published in 2016. The guide, notes Karry, informs on user/regulatory expectations when incorporating excipient variability into formulation development and why to look past specifications. There is a lot of useful information for both excipient suppliers and users, according to Moreton.
One of the key messages in both of the IPEC guides and expressed repeatedly by industry experts is that communication is critical if QbD is to work as intended.This key takeaway applies to both drug-product developers and excipient manufacturers. “Drug-product manufacturers must be willing to share how an excipient will be used so that excipient suppliers can provide pertinent information that could
help understand the excipient’s impact on formulation performance,” Moreton emphasizes.
1. IPEC Federation, “New IPEC Guide: Incorporation of Pharmaceutical Excipients into Product Development using Quality-by-Design,” Press Release, November 30, 2020.
2. IPEC-Americas, “IPEC-Americas Publishes Quality by Design Sampling Guide for Excipient Makers, Users, and Distributors,” Press Release, May 2, 2016.
Volume 46, Number 4
When referring to this article, please cite it as C. Challener, “Bringing Excipients into the Quality-by-Design Paradigm,” Pharmaceutical Technology 46 (4) (2022).