Flexible Approaches to Accommodate Excipient Variability Using the Principles of QbD

The authors review new regulatory expectations and describe potential approaches to accommodate excipient variability. This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."
Apr 30, 2010

This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."

Pharmaceutical formulations generally comprise the active pharmaceutical ingredient (API) and excipients, which are then combined using specific processing. Quality by design (QbD) requires understanding the raw-material variabilities and their effect on finished-product quality. Traditionally, excipient-supplier involvement in the formulation-development process has been limited, with the supplier often unaware of the application or functionality, and the user unaware of supplier's process capabilities. This lack of mutual understanding must change in order for QbD to succeed.

Excipients are a potential source of product variability, and they are generally less well characterized than APIs. QbD, therefore, has emphasized the role of excipients—once referred to as "inert" ingredients—and they are now properly recognized as enabling the API to be converted to a medicinal product that can be administered safely and efficaciously to the patient. Excipients are also now subject to increasing scrutiny from users, regulators, pharmacopeias, and other standard-setting and educational bodies such as the International Pharmaceutical Excipients Council (IPEC), the International Society of Pharmaceutical Engineering (ISPE), the American Society for Testing and Materials (ASTM), and the National Institute for Pharmaceutical Technology and Education (NIPTE).

This paper will discuss several topics related to excipients in a QbD context (1, 2), including: excipient functionality; approaches to raw-material variability; excipient manufacture and quality control; functionality versus composition; and the building of flexibility into the development process (2).

Excipient functionality

Traditionally, pharmacopoeias have emphasized safety and purity of raw materials and focused on chemical composition. Excipient monograhs do not address efficacy or functionality, and typically include identification tests, possibly assays, tests related to minor components, and occasionally, a limited series of physical tests intended to further characterize the material. Specification of pharmaceutical excipients has thus generally emphasized consistency of composition rather than consistency of functionality. Although such chemical and physical testing may be insufficient to guarantee functionality, it is useful for grade specification. This difference may be due in part to the fact that the use and performance of an excipient in a given process and formulation may not be an entirely intrinsic raw-material property.

For example, biopolymers such as carrageenan are sold "pure" for pharmaceutical use, whereas for food use, the same materials are diluted with other food-grade materials to provide a consistent or standardized functionality. This functionality is usually defined, along with agreed-upon methods, in the purchase agreement. The pharmaceutical industry has been somewhat unique in the past in that it has promoted consistency of composition at the expense of consistent performance.

Another example of consistency is control of color. Because of the visual impact, even pharmaceutical users will prefer constant color to constant composition when offered the choice. For example, a supplier producing an orange film-coating may formulate the product using not only an orange pigment, but also small amounts of red and yellow pigments. This way, if there is batch-to-batch variability in the orange pigment, adjustment of the proportions of red and yellow can be used to guarantee a consistent orange color. Slightly different quantitative formulations would be necessary for each batch of constant-color excipient.

Pharmacopeial compliance has often been erroneously perceived as a guarantee of performance for excipients, when in fact, compliance only establishes minimum safety and purity standards. Functionality transcends the molecular composition of the excipient or its particle form, and may depend on the application (reason for use), the formulation (effect of other ingredients), and the process (the details of how the API and excipients are combined together in a particular application). There is often a trade-off between competing formulation objectives, and a given excipient may be multifunctional in a particular application.

Because excipient functionality or performance is application-specific, it can only be properly assessed in the particular application. However, manufacturing a test batch of product for every excipient lot received is not an economical option. Thus, surrogate tests are necessary whereby some type of test—often physical, but sometimes chemical—that correlates with performance in the medicinal product can be used to assess the suitability of a particular lot of an excipient or API.

Most in industry agree that surrogate testing may be necessary and appropriate. Opinion is divided, however, as to the best approach to use. Two approaches to such testing have been proposed. The European Pharmacopoeia (Ph. Eur.) has introduced a nonmandatory Functionality Related Characteristics (FRCs) section to some individual monographs. FRCs, however, as advocated by the pharmacopeia may not be relevant to functionalities in all cases, and they run the risk of overspecification beyond what is required for use in a particular application.

For example, lactose is included in hundreds of dry-powder systems for film coating. The dry powder formulation is reconstituted in water to form the film coating suspension that is then sprayed onto the tablets. One FRC for lactose is particle-size distribution. In this film-coating application, the lactose is used to help disperse the other components and promote the hydration of the powder mix. Particle-size distribution is not particularly relevant in this application because the lactose is dissolving. Obviously, lactose particle size may have an influence on the rate of dissolution of the lactose, but in the context of the application, the effect is not relevant because the hydration of the polymer takes considerably longer than even the coarsest grade of pharmaceutical lactose would take to dissolve. Unfortunately, even though the FRC section of the Ph. Eur. clearly states that the test is nonmandatory, customers frequently demand the information. Many customers consider the monograph specification to be mandatory, even if the particular test is included in the FRC section.

The United States Pharmacopeial Convention (USP) is proposing a new general chapter on excipient performance, General Chapter <1059>. A first draft was published as a "Stimuli to Revision" article in 2007 (3). Based on received comments, USP revised and published a second version of the chapter as an in-process revision in 2009 (4). USP's general-chapter approach is considered more useful because it addresses the relevant attributes pertinent to an excipient application rather than trying to arrive at a set of tests for FRCs that will be applicable for all the typical uses of a particular excipient.

For example, microcrystalline cellulose (mcc) is frequently used in solid dose forms as a filler/binder and disintegrant, and also to improve the rheological properties of the wet mass in wet granulation and extrusion-spheronization. Mcc can also be used, however, in aqueous suspensions as a suspension stabilizer (auxiliary suspending agent) to provide a sufficient disperse phase to make the suspension more stable. The FRCs for Microcrystalline Cellulose Ph.Eur. are particle-size distribution and powder flow. Powder flow is irrelevant to the ingredient's use as a rheology modifier or suspending aid. However, because powder flow is included in the monograph, customers will often request it, despite the fact that the fine-particle grade used in aqueous suspensions does not flow like a powder because it is very fine and cohesive.