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Excipients: Background/Introduction

Article · January 2006

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Excipients: Background/Introduction

Lokesh Bhattacharyya, Stefan Schuber, Catherine Sheehan,

and Roger William
Department of Standards Development, United States Pharmacopeia,
Rockville, Maryland, U.S.A.

Almost all therapeutic products, including therapeutic products for human and
veterinary use, include excipients—indeed, the total amount of excipients frequently
used is greater than the amount of the active drug substance(s) in a dosage form. As
with drug substances, excipients are derived from natural sources or are synthesized
either chemically or by other means. They range from simple, usually highly charac-
terized, organic, or inorganic molecules to highly complex materials that are difficult
to fully characterize.
In earlier days, excipients were considered inactive ingredients. Over time,
pharmaceutical scientists learned that excipients are not inactive and frequently have
substantial impact on the manufacture and quality, safety, and efficacy of the drug
substance(s) in a dosage form. Further, variability in the performance of an excip-
ient—both batch to batch within a single manufacturer as well as between batches
from different manufacturers—came to be understood as a key determinant of
dosage form performance. Excipients are now known to have defined functional
roles in pharmaceutical dosage forms. These include (i) modulating solubility and
bioavailability of the active ingredient(s); (ii) enhancing stability of the active ingre-
dient(s) in finished dosage forms; (iii) helping active ingredients maintain a preferred
polymorphic form or conformation; (iv) maintaining pH and osmolarity of liquid
formulations; (v) acting as antioxidants, emulsifying agents, aerosol propellants,
tablet binders, and tablet disintegrants; (vi) preventing aggregation or dissociation;
and (vii) modulating the immunogenic response of active ingredients (e.g., adju-
vants) and many others. United States Pharmacopeia 28–National Formulary 23 lists
40 functional categories of excipients for pharmaceuticals, and many more are
expected as new—and usually increasingly complex—drug-delivery systems emerge
and evolve. Approximately 800 excipients are currently used in the marketed phar-
maceutical products in the United States. This number is also expected to grow with
new therapeutic categories, such as gene therapy and cell therapy, and new drug-
delivery technologies.
In these various contexts, excipients and issues associated with them can be
considered in the following different areas. ‘‘Functionality’’: An excipient interacts
with the active in the formulated dosage form and/or provides a matrix that
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can affect critical quality attributes of the drug substance, including stability and
bioavailability. Given an excipient’s potential influence on the finished dosage form,
manufacturers will execute careful characterization studies, with due attention to
final specifications and change control, in order to ensure consistent performance of
the dosage form. Many examples have demonstrated that limited understanding
of excipient functionality can compromise process control and product quality. As
a general rule, the more complex the dosage form and/or its ingredients, the greater
is the impact of excipient functionality. ‘‘Safety and efficacy’’: Excipients can them-
selves affect safety and efficacy outcomes. Excipients, or their impurities, can be
associated with adverse events, either by direct action or by formation of undesirable
adducts. By modifying absorption and, for parenteral products, distribution, excip-
ients can change exposure patterns and thus influence both safety and efficacy
outcomes. Excipients are well known to affect the safety and efficacy profiles of
locally acting products. As adjuvants, excipients required for protein and conjugate
vaccines play a crucial role in the immunogenic properties of vaccines. ‘‘New excip-
ients’’: These may require careful and, not uncommonly, extensive safety studies,
with corresponding careful attention to characterization and specification setting.
At present, new excipients in the United States do not undergo separate approval
but attain market access frequently via a regulatory process in association with
the new drug application process for a dosage form. ‘‘Processability’’: Manufacturers
increasingly rely on a good understanding of the characteristics and functional con-
tributions of excipients to aid in the day-to-day manufacture of a dosage form.
‘‘Evolving regulatory and compendial approaches and harmonization’’: Regulatory
agencies and compendia now fully realize the value of careful attention to the safety
and quality attributes of excipients and their impact on dosage form performance and
safety/efficacy outcomes. This has led to an increasing number of regulatory and com-
pendial documents, many of which are in active harmonization. ‘‘Excipients and
food additives’’: The relationship between excipients and food additives, in their
manufacture, and regulatory control, is complex and evolving. They are frequently
identical in character, yet are controlled according to different regulatory requirements
and compendial standards. In the United States, food additives are the ‘‘excipients’’
used in a dietary supplement. Many excipients arise in the manufacture of food-grade
material, a point that poses special challenges in terms of achieving pharmaceutical-
grade material and regulatory control.
In the rapidly evolving world of excipient manufacture, with attendant chal-
lenges of regulatory control and compendial standards-setting, the need for a timely,
comprehensive, and thoughtful publication is clear. This need is filled by the follow-
ing text, prepared with talented editorial oversight from Dr. Ashok Katdare and
Dr. Mahesh Chaubal. The author list developed by these editors is composed of
distinguished experts with a broad range of skills, experience, and geographical
representation. The topics covered are broad and challenging. The text fulfills a cri-
tical need for up-to-date and comprehensive information about a rapidly evolving
topic for which regulatory guidance is only now emerging. We encourage readers
to learn from this text and to consider themselves challenged in helping pharmaceu-
tical scientists, excipient and dosage form manufacturers, and regulatory and
compendial experts understand how to advance the field. Careful consideration of
the many issues discussed in this book will help talented experts advance to the next
stage of understanding of the importance of excipients and food additives in the
manufacture of therapeutic products. The need is clear—and the benefit to patients
and practitioners is unquestionable.

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