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This article reviews sources of excipient variability, including raw materials and processing, both of which may vary from supplier to supplier and from plant to plant for a single manufacturer.
Excipients are substances other than the API, which have been appropriately evaluated for safety and are intentionally included in drug delivery systems. Excipients are typically more complex than APIs, because they are frequently multi-component and less well-defined. In addition, excipient variability can present itself in various forms, compositionally, physically, or functionally.
Most excipients are not pure substances. Other residual and trace components present in excipients can impact key excipient functional characteristics when used in pharmaceutical formulations (1). The International Pharmaceutical Excipients Council (IPEC) refers to these other unavoidable substances in excipients as concomitant components (2). Performance of many excipients in a drug formulation may rely on the presence of such substances in the excipient. These excipient components are not considered impurities and could vary due to changes in raw materials, process variability, and from supplier to supplier. Excipients are not controlled at an individual parameter level. There are many degrees of freedom associated with polydispersity of particle size, molecular weight, and chemical composition, all of which may be process or supplier dependent. Particle size is usually controlled as an average or distribution, and dilute solution viscosities are often used for routine analysis to monitor batch-to-batch consistency of polymer molecular weight. The composition profile of a complex mixture may not be well defined, and the performance impact of the many components may not be well understood.
Silverstein contrasted the control of API quality versus that of excipients (3):
“API quality is improved by reducing the presence of all materials other than the desired chemical. […] Extraneous substances may be harmful to the patient in that they may lead to side effects, or they are inert, thus reducing API purity and thereby compromising efficacy.”
“Excipient quality is described quite differently. While one would again refer to compliance with the compendial monograph (if there is one) or the manufacturer’s specification, a higher assay is not always better. While this may seem counterintuitive, excipients are often complex mixtures that include constituents arising from raw materials, catalyst, solvent, initiator residue, or side reactions” (3).
Excipients are often mixtures of materials with major and minor components, and the minor components may contribute to the overall excipient performance in a particular application (4). For example, the compactibility of coarse grade dibasic calcium phosphate dihydrate is influenced by the presence of “impurities” in the crystal lattice, which cause dislocations and weakness, allowing brittle fracture to occur. Very pure coarse-grade dibasic calcium phosphate dihydrate does not compact as well. However, in general, the exact
relationship between excipient composition and excipient performance is not often well understood and will vary with each application (5).
Many excipients possess some inherent variability. Variability in the finished excipient attributes can arise from many sources such as, but not limited to those in Table I (6).
Excipient variability for some excipients can also be influenced by degradation, which also can be impacted by packaging and/or environmental conditions during storage and distribution.
As described in the IPEC quality-by-design (QbD) guide (6), “excipient manufacturers can control excipient variability only within the limits of their process capability and for which the processing equipment was designed and constructed.” Process capability is a general statistical concept based on the ratio of the specification limits to the process variability. If the variability is the same as the specification range the process capability is one, with no room for error. The higher the process capability the lower the risk of failure. Less than one means that not all batches will meet specification. Therefore, arbitrary narrowing of a specification by users may adversely impact sustainable excipient supply. Robust formulations are not critically impacted by typical excipient variabilities, not all of which may be reflected in the specification.
“In addition, the equipment train used in the process and the type of processing and unit operations included may all influence variability. Various excipients are continuously manufactured in many metric tons per annum. Results reported on a certificate of analysis (CoA) will often be a composite or average, potentially underestimating variability. Not all excipients will have the crystallization or precipitation steps typically used to purify fine chemicals. Users should discuss inherent variability with the supplier and their capability to supply product as it relates to the user’s needs (7). It is the responsibility of the user to identify potential critical material attributes (CMAs) for the excipients used in their formulations but the suppliers may be able to assist. A risk-based approach will probably be appropriate” (6).
Different excipient manufacturers are likely to use different raw material sources as well as different manufacturing processes. Therefore, variability introduced by alternate sources encompasses variability of both raw materials and processing.
Excipients from alternate sources (additional sites within a manufacturer and/or alternate supplier(s)) may not be compositionally, physically, or functionally identical, but may still demonstrate equivalent performance within the drug product depending on application. Excipient users should define functional performance requirements for alternate excipient sources (8).
When evaluating alternate excipient sources, users should not assume that all sources conforming with the same compendial requirements are interchangeable in all drug product formulations. Variability in excipient composition and other attributes among excipient sources could impact performance. To gain an understanding of the potential origin for various components that may be found in excipients from different sources, see Figure 1.
Confirmation of equivalent performance is necessary to support interchangeability. The critical quality attributes (CQAs), including stability, of the drug product manufactured with the alternate source must be demonstrated.
Distributors should not substitute an alternate excipient source without prior notification to the excipient user to allow evaluation of the interchangeability of the alternate source in their specific drug applications.
In a 2008 article on “Comparative Tableting Properties of Sixteen Microcrystalline Celluloses” (9), Doelker et al. noted that, “Great differences in packing and tableting properties and in sensitivity to the addition of a lubricant were generally observed between
products from the various manufacturers. In contrast, lot-to-lot variability was quite acceptable.”
Moreton defined a robust formulation as being “able to accommodate the typical variability seen in API, excipients, and processes without compromising the manufacture, stability, performance, or any other attribute of the product critical to the patient’s care or well-being” (5).
Qualifying multiple sources should be considered when establishing the design space to reduce the time required to switch to an alternative supply after launch (10). If the impact of an excipient variability on finished product CQAs is unacceptable, then additional controls (CMAs) should be considered. Both limits and methods for CMAs must be agreed between user and excipient manufacturer.
It may be necessary for excipient manufacturers to make changes to their processes for various reasons that have the potential to impact excipient performance and thus finished product performance. Excipient manufacturers should consult the IPEC Significant Change Guide for Pharmaceutical Excipients (11) whenever a change is to be made to excipient raw materials, manufacturing process, and/or finished excipient testing and assess the need for customer notification. Based on a risk assessment, the excipient manufacturer should apply the same reasoning (as far as is practicable) to their own suppliers of starting materials, reagent, solvents, processing aids, and additives used in the manufacture of the excipient.
When investigating potential impacts of notified changes, it is strongly recommended that a risk assessment be undertaken by the excipient user. Based on the results of the risk assessment, the excipient user should determine their need for further action.
It may be necessary for the excipient user to build product inventory, thus requiring pre-change excipient supply, because regulatory filings may be subject to extended review times. This may, in turn, require coordination between excipient manufacturer and user.
It should also be remembered that not all changes to an excipient will be detrimental to the performance of the excipient or pharmaceutical finished product. All changes should be considered as significant unless it can be scientifically justified as not a significant change. Significant changes should be notified to the excipient user (11).
Factoring excipient variability into design of experiments, control strategy, and lifecycle management will increase finished product robustness (12),
which will improve the overall product quality and performance, leading to better patient outcomes.
Excipient variability should always be a concern unless proven otherwise. Relying only on the excipient sales specification or the compendial monograph is not enough to account for potential variation(s) because many CMAs may not be part of these requirements. Drug product manufacturers should have a robust dialogue with their excipient suppliers to understand the variability of material attributes.
Brian Carlin is owner Carlin Pharma Consulting LLC. George Collins is the Vice-President for Excipient Mineral Manufacturing, RT Vanderbilt Company. Chris Moreton is partner at FinnBrit Consulting. David R. Schoneker is the President/Owner of Black Diamond Regulatory Consulting, LLC. Jennifer Putnam is a Senior Supervisor, Analytical R&D at Perrigo.Joseph Zeleznik is Technical Director, North America for IMCD US Pharma. Katherine Ulman is the owner and Primary for KLU Consulting, LLC. Stacey Bremer, Director, Product Stewardship Medical at Celanese.
Vol. 46, No. 8
When referring to this article, please cite it as B. Carlin et al., “Mitigating the Risk from Excipient Variability,” Pharmaceutical Technology 46 (8) 2022.