Understanding their functions benefits process control
By Lokesh Bhattacharyya, Ph.D.
Excipients interact with the actives in the final formulated dosage form and/or provide a matrix that affects the critical quality attributes of the actives, including stability and bioavailability.
Is compliance with compendial monographs sufficient for complete characterization of an excipient, particularly for understanding its processability?
Excipients are the materials (components)—other than the active ingredient(s)—intentionally incorporated into pharmaceutical dosage forms to play specific functional roles. Almost all pharmaceutical dosage forms include excipients. Indeed, in most dosage forms the amounts of one or more excipients are greater than the amounts of the active pharmaceutical ingredients (APIs) present in them. As with APIs, excipients are derived from natural sources, synthesized chemically, or prepared semisynthetically starting from a natural-sourced materials, and range from simple, usually well-characterized, organic or inorganic molecules to highly complex materials that are difficult to fully characterize.
Excipients play a wide variety of functional roles in pharmaceutical dosage forms, including:
• modulating solubility and bioavailability of APIs,
• increasing the stability of active ingredients in dosage forms,
• helping active ingredients maintain preferred polymorphic forms or conformations,
• maintaining the pH and/or osmolarity of liquid formulations,
• acting as antioxidants, emulsifying agents, aerosol propellants, tablet binders, and tablet disintegrants,
• preventing aggregation or dissociation (e.g., of protein and polysaccharide actives),
• modulating immunogenic responses of active ingredients (e.g., adjuvants), and more.
USP 29–NF 24 includes more than 40 functional categories of excipients in pharmaceuticals, and many more may be added over time to meet the needs of new drug delivery systems and biotechnology-derived products.1 The large number of functional categories represents the variety of applications of excipients in both pharmaceutical and biotechnological products.
More than 800 excipients are used currently in marketed pharmaceutical products in the U.S. This number is expected to grow rapidly as new drug delivery technologies are developed to address challenges of drug development such as poor solubility, permeability and bioavailability, along with the growth of the biotechnology industry, including gene and cell therapy products that have different drug delivery requirements compared to traditional small-molecule pharmaceuticals. Thus, there is a significant need to enhance awareness about new excipient development.
Excipient Selection and Use
An excipient is selected and used because it contributes one or more functional attributes to the product characteristics. The excipient interacts with the active in the final formulated dosage form and/or provides a matrix that affects the critical quality attributes of the actives, including stability and bioavailability. It follows logically that the quality of an excipient and its function play critical roles in the effectiveness, safety, potency, purity, and quality of a product. Thus, it is necessary to understand the function of an excipient in order to fully characterize, understand, and control the process as well as the product quality, particularly in the new era of Quality by Design.2 The lack of understanding of the function of an excipient may lead to a situation in which process control—and hence product quality—may be compromised, particularly when the impact of normal variation of the excipient quality on process control has not been established. The need for complete characterization of an excipient and understanding its functional role in the formulated product is far greater when the excipient is used in a more complex product, such as a monoclonal antibody, a vaccine, or a gene therapy/cell therapy product, or in a new/novel drug delivery system such as an inhalation product.
Excipients also influence the safety and effectiveness of drugs depending on the route of administration, so qualitative and quantitative understanding of the excipient’s composition is critically important to the understanding of a dosage form’s bioavailability and bio-equivalence. For orally administered dosage forms, excipients can affect safety and effectiveness outcomes by promoting or delaying gastrointestinal release. The same appears to be true also for certain injections, for which excipients can modify release patterns in much the same way they do for orally administered modified-release dosage forms. For locally acting products—topical applications, products for oral inhalation, nasal administrations, otic products, and ophthalmic dosage forms—excipients are also widely acknowledged to modify the effectiveness outcomes by influencing the pharmacodynamic properties of the actives. Adjuvants, which are excipients required for protein and conjugate vaccines, play a critical role in the immunologic characteristics of vaccines.
Because excipients can affect the safety and effectiveness of dosage forms, manufacturers should understand the functional contributions of the excipients, that is, their “processability.” Unless manufacturers have a good understanding of the processability of the excipients used in their products, it is difficult to see how the manufacturers can reliably demonstrate pharmaceutical equivalence among product(s) synthesized or perhaps formulated differently at different manufacturing sites, using excipients that possibly are sourced from different suppliers or vendors. Such excipients are likely to have been manufactured by different processes, with starting materials whose qualities may be different from and/or sourced differently than those referenced in the original New Drug Application (NDA). Thus, it is likely that the quality of the excipients used by different product manufacturers or at different manufacturing sites of the same product manufacturer may be different, particularly if the manufacturer engages in multisourcing. In the latter case, interchangeability of excipients cannot necessarily be taken for granted. These factors, together with the potential variation in equipment, processing operations, and personnel who may have different backgrounds, training, and levels of expertise, may present a complex multivariate situation that may render very difficult adequate control of the product quality. The variation could range from minor to significant depending upon the function of the excipient used in the product, excipient interaction with the actives(s), and the characteristics of the product, including its route of administration and other factors.
Legal Factors and Release Testing
The US Code of Federal Regulations (CFR) indicates the requirements for excipient (component) release testing in 21 CFR 211.84(6)(d)(2) as follows:
Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.
The second sentence of the CFR requirement above for release testing of excipients is clearly deficient in addressing excipient quality and processibility issues. The concept and the recognition of the need to understand the processability of an excipient and its relation to the quality of a product are relatively recent and require further discussion. In theory, an excipient manufacturer could perform suitable tests to demonstrate appropriate quality and processability of its excipients, provided the company knew the appropriate tests. However, it is not clear how excipient manufacturers would know what the appropriate tests should be, because the tests depend on the nature of the excipient, the characteristics of the active, nature of the product (e.g., solid, liquid, aerosol; therapeutic, prophylactic), the route of administration of the dosage form, and other factors.
In addition, it is conceivable that the same excipient may have different processabilities and functional contributions in different types of dosage forms. For example, the knowledge of the particle size distribution of lactose, a frequently used excipient, is critical for tablets but is unnecessary for an injectable product. Consequently, the tests that are appropriate for one type of product may not be appropriate for another type. For more common types of products (e.g., solid oral, parenteral), one solution to these quandaries is an excipient qualification agreement concluded between excipient vendors and manufacturers according to which vendors agree to make no process changes or other alterations that would affect the specifications of the finished excipient or its impurity profile, and/or to notify the manufacturer of such changes—or some variation of such agreements.
There is general agreement that if there is a pharmacopeial monograph (USP–NF, European Pharmacopoeia, and Japanese Pharmacopoeia) for an excipient, the tests described in the monograph should be performed. This is consistent with the CFR requirements mentioned above because the compendial monographs have written specifications for identity, purity, strength and quality. Therefore, it is critical to examine the roles and limitations of USP–NF (and other pharmacopeial) monographs in excipient testing. USP–NF standards are authoritative, science-based, and are established by a transparent and credible process with established integrity.3
The transparency and credibility of the monographs come from the open review and comment process that takes place when proposed monographs are published in Pharmacopeial Forum, USP’s bimonthly journal of standards development and compendial revision. Anyone interested can provide scientific and regulatory comments regarding the new monographs or revisions to existing monographs published in Pharmacopeial Forum. The quality standards and any public comments are evaluated by the members of the Expert Committees of the USP Council of Experts, who are unpaid volunteers and are recognized experts in their respective fields. Expert Committee members participate in the USP process as individual scientists and not as representatives of their employers or any trade association, thereby providing unbiased, authoritative, and science-based quality standards. Expert Committee members may agree with public comments regarding monographs published in Pharmacopeial Forum and may decide to revise and republish the monographs for further public review and comment. If the monograph is approved, it is published in and becomes official in USP–NF or in the next semiannual Supplement of USP–NF. Therefore, the quality values of monographs for excipients and other materials expressed in USP–NF are indisputable.
However, the question remains if compliance with compendial monographs is sufficient for complete characterization of an excipient, particularly for understanding its processability. This point is critical not only to their functionalities but also to the impurities that may be present in an excipient, which could under certain circumstances affect the quality, safety, and effectiveness of the dosage forms. An example may help clarify the point. A manufacturer changed the vendor of an excipient, and the product showed adverse reactions. However, the materials from both vendors complied with the USP–NF monograph of the excipient. Subsequent investigation showed that the impurity profiles of the excipients from two vendors were different.
Due considerations also need to be given to the concomitant components, i.e., the impurities that are necessary and desired components required to ensure the proper performance of an excipient in a drug formulation. The role and regulation of the concomitant components must be distinguished from other impurities, which are not intended to be present in the finished product, but are present because it is not possible, and often not necessary, in practice to remove them completely through the manufacturing process steps.
The previous example clearly illustrates the need for characterization and qualification of excipients, including evaluation of the processability. A USP–NF monograph, however authoritative and science-based, does not (and cannot) provide any information about the processability of an excipient. Processability depends on the nature of the active and its interaction with the excipient, the manufacturing process, and the route of administration of the dosage form. Neither USP–NF nor any other pharmacopeia has any knowledge of the manufacturing process used by a manufacturer. Furthermore, different manufacturers may use the same excipient to manufacture different dosage forms, so the processability of the excipient may be different.
Thus, the excipient user (product manufacturer) should develop a comprehensive and scientifically sound excipient characterization/qualification program to ensure purity, quality, strength, consistency, suitability, safety, traceability, and processability of the excipient. Although USP–NF monographs ensure purity, quality, strength, consistency, and freedom from bacteria, fungi, mycoplasma, and certain other adventitious agents, they do not ensure the processability and safety of the excipients, and their contributions to the effectiveness of drug products.
At present new excipients are allowed for use either as a part of an NDA process or via adoption of Generally Recognized as Safe (GRAS) status. Excipient standards are set by regional organizations such as USP, EP, and JP. The subtle differences in the requirements of the individual standards have resulted in added challenges for excipient manufacturers. Because the excipient supply chain is global and somewhat less regulated than that for finished pharmaceuticals, the increasing awareness of bioterrorism caused by product tampering has also enhanced the need for guidance for excipient manufacturing and supply chain control.
All these concerns have resulted in a strong need for additional information and guidelines (or guidances) about the development, characterization, and qualification of new excipients and new applications of current excipients. The importance of regulatory guidance for excipients is a concept that has emerged only in recent years. Hence very few standards (or guidances) are available that treat the subject in the manner outlined here. The pharmacopeias (USP, EP, and JP) and International Pharmaceutical Excipient Council (IPEC) have spearheaded some efforts to develop and harmonize the standards, as well as provide guidelines on good manufacturing and distribution practices for excipients.4 However, additional efforts are necessary to develop comprehensive and authoritative standards (or guidances) to promote innovation in the area of excipients, to improve understanding of the importance of excipients, and to forge new avenues for global regulatory review and approval. The pharmaceutical industry is globalizing. With the development of new concepts and new approaches to drugs and drug-delivery technologies, such standards (and guidances) are critical to the development of new excipients, sustaining excipient quality standards, and safe and optimum use of excipients in diverse types of drugs.
The author would like to thank Stefan Schuber, Ph.D., director of scientific reports at USP, for his editorial contributions to this paper.
1. United States Pharmacopeial Convention. USP 29–NF 24. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2006.
2. Hussain, AS. Engineering a proactive decision system for pharmaceutical quality: integrating science of design, process analytical technology, and quality system. Available at: www.fda.gov/cder/OPS/hussain_1_2005.pdf. Accessed March 29, 2006.
3. Bhattacharyya, L. et al. The value of USP public standards for therapeutic products. Pharm. Res. 2004;21:1725–1731.