Frequently Asked Questions

1. What are pharmaceutical excipients?

2. How are pharmaceutical excipients classified?

3. Why are excipients important in a drug product?

4. What are the most common pharmaceutical excipients used in U.S.-manufactured drug products?

5. Who sets standards for the quality, etc., of pharmaceutical excipients?

6. What information is contained in these compendia and what status do they have?

7. How are excipients "approved" for use in pharmaceutical products?

8. How are new excipients permitted for use in U.S. drug products? Would the procedure be similar in the case of a previously allowed (GRAS) excipient for a new pharmaceutical use?

9. What is a Type IV Drug Master File (DMF) and what information is contained in this type of DMF?

10. How can one assure that excipients used in the formulation of a new drug undergoing clinical trials will continue to be available for purchase when the product reaches the market ­ three to five years later?

11.Can USP/NF grade excipients be used in drug applications in other countries?

12. If it is so difficult to qualify a new excipient for pharmaceutical use, doesn't that have a chilling effect on the ability of finished drug manufacturers to develop better delivery systems for new, improved drug therapy for heart disease, cancer, and other serious conditions?

1. What are pharmaceutical excipients?
Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form. [Top]

2. How are pharmaceutical excipients classified?
They are classified by the functions they perform in a pharmaceutical dosage form. Principal excipient classifications (functions) are the following:

• Binders
• Disintegrants
• Fillers (diluents)
• Lubricants
• Glidants (flow enhancers)
• Compression aids
• Colors
• Sweeteners
• Preservatives
• Suspensing/dispersing agents
• Film formers/coatings
• Flavors
• Printing inks

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3. Why are excipients important in a drug product?
For many reasons. Some, for example, comprise the product's delivery system. These transport the active drug to the site in the body where the drug is intended to exert its action. Others will keep the drug from being released too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset. Others help the drug to disintegrate into particles small enough to reach the blood stream more quickly and still others protect the product's stability so it will be at maximum effectiveness at time of use. In addition, some excipients are used to aid the identification of a drug product. Last, but not least, some excipients are used simply to make the product taste and look better. This improves patient compliance, especially in children. Although technically "inactive" from a therapeutic sense, pharmaceutical excipients are critical and essential components of a modern drug product. In many products, excipients make up the bulk of the total dosage form. [Top]

4. What are the most common pharmaceutical excipients used in U.S.-manufactured drug products?

The following are the most commonly used excipients in U.S.-manufactured drug products:

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5. Who sets standards for the quality, etc., of pharmaceutical excipients?

Committees of the U.S. Pharmacopeial Convention Inc., an independent body that publishes and maintains the United States Pharmacopeia, National Formulary (NF), and USP Reference Standards. [Top]

6. What information is contained in these compendia and what status do they have?

Since 1980 the United States Pharmacopeia and the National Formulary have been published under the same cover. Today, USP-NF contains legally recognized and scientifically valid standards of identity, strength, quality, purity, packaging and labeling for more than 3,500 drugs. NF also includes similar standards for more than 250 excipients, vitamins, minerals, and botanicals. Standards (monographs) for substances which have an FDA-approved use as a drug are published in USP. Monographs for substances which are considered to be primarily excipients, a vitamin, mineral, botanical, or herbal are published in NF, provided they have been established as safe. "USP Reference Standards" is not a separate document per se but instead are substances used with official test methods in analytical testing to demonstrate a drug or excipient's identity, strength, quality and purity. Once final standards are published in USP-NF they are recognized as official and U.S. and state government agencies are authorized to enforce them to assure that pharmaceutical products marketed in the U.S. are in total compliance.

Source: U.S. Pharmacopeial Convention, Inc. [Top]

7. How are excipients "approved" for use in pharmaceutical products?

Under U.S. law, an excipient, unlike an active drug substance, has no regulatory status and may not be sold for use in food or approved drugs unless it can be qualified through one or more of the three U.S. Food and Drug Administration (FDA) approval mechanisms that are available for components used in food and/or finished new drug dosage forms.

These mechanisms are:

1. determination by FDA that the substance is "generally recognized as safe" (GRAS) pursuant to Title 21, U.S. Code of Federal Regulations, Parts 182, 184 or 186 (21 CFR 182, 184 & 186);

2. approval of a food additive petition as set forth in 21 CFR 171; or

3. the excipient is referenced in, and part of, an approved new drug application (NDA) for a particular function in that specific drug product.

Excipients contained in over-the-counter (OTC) drug products subject to FDA monographs referenced in 21 CFR Parts 331-358 must comply with the requirements in 21 CFR 330.1(e) which reads as follows:

"The product contains only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity. Color additives may be used only in accordance with section 721 of the Act and subchapter A of this chapter."

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8. How are new excipients permitted for use in U.S. drug products? Would the procedure be similar in the case of a previously allowed (GRAS) excipient for a new pharmaceutical use?

As noted in the answer to the previous question, data supporting the safety and functionality of an excipient in a drug product is included in data and clinical reports submitted to support a new drug application (NDA). In the case of a new pharmaceutical use for an excipient, it is likely that some necessary data may exist in a confidential drug master file at FDA. However, in all instances involving pharmaceutical use, FDA will require an applicant to provide data demonstrating that 1) the excipient is safe in the amount it will be used or consumed in the finished drug throughout the product's recommended or prescribed duration of use by those who will take the product. In addition, the applicant must 2) demonstrate that the substance meets applicable compendial standards where they apply; 3) that it performs its intended function in the product; that it 4) does not adversely affect the bioavailability and performance of the active drug; and 5) is manufactured in accordance with appropriate standards of good manufacturing practice suitable to that kind of excipient. Still, as noted earlier, there is no FDA regulatory approval system that is exclusively applicable to pharmaceutical excipients. Thus, the scope and amount of necessary data to support a substance or its use always must be negotiated with FDA and will be determined on a case by case basis. [Top]

9. What is a Type IV Drug Master File (DMF) and what information is contained in this type of DMF?

A Type IV DMF is a file within the FDA which can be used by excipient manufacturers to submit confidential formulation, safety and manufacturing information about the excipient that may be needed by the agency in reviewing a new drug application (NDA) for a drug product containing that excipient. These files are only referenced by FDA as part of a specific NDA review and are not authorized or approved by FDA.

Users of the excipient are required to submit a DMF reference letter from the excipient manufacturer to the FDA as part of their NDA to allow FDA authority to access the DMF for their application. An FDA guidance document exists which describes what types of information are required in a Type IV DMF and the format which should be used. Not a lot of detailed information is required. Mostly, it is up to the excipient manufacturer to determine what types of information they want to include in the DMF. Further, there is no requirement that an excipient have a DMF. This determination is entirely up to the manufacturer of the excipient, depending on the nature of any confidential information which may exist. [Top]

10. How can one assure that excipients used in the formulation of a new drug undergoing clinical trials will continue to be available for purchase when the product reaches the market ­ three to five years later?

There is no absolute answer. However, if established, previously used excipients made in conformance with good manufacturing practice are used to formulate a new drug, the risk would seem to be minimized. If new excipients are to be used, availability from the supplier should be assured. A finished drug manufacturer, therefore, probably would be wise to purchase excipients made by firms with a good business history who are able to guarantee future deliveries. [Top]

11. Can USP/NF grade excipients be used in drug applications in other countries?

This depends on the countries in question and whether the excipient has had a previous precedent of use in a drug application in that country. The USP/NF is a recognized compendia in many countries around the world; however, in various regions local or regional pharmacopeias take precedent over USP/NF requirements. For example, in the European Union, an excipient must meet the criteria of the European Pharmacopeia (PhEur) if a monograph for that excipient exists in PhEur. However, if no monograph exists in PhEur, the use of USP/NF grade excipients may be acceptable.

A similar situation exists in Japan. If a monograph exists in the Japanese Pharmacopeia (JP) or the Japanese Pharmaceutical Excipients (JPE), the excipient must meet the requirements of the respective monograph. However, if the excipient has previously been used in an approved Japanese drug application and no standard exists in JP or JPE, then USP/NF grade material may be acceptable until such time as a monograph is developed in JP or JPE. [Top]

12. If it is so difficult to qualify a new excipient for pharmaceutical use, doesn't that have a chilling effect on the ability of finished drug manufacturers to develop better delivery systems for new, improved drug therapy for heart disease, cancer, and other serious conditions?

Yes. This is why far-sighted makers and users of excipients used in finished drug dosage forms joined together in 1991 to form the International Pharmaceutical Excipients Council (IPEC). We have made progress, as you will see on other pages of our website, but there still is a long way to go. Will you join us?