Food and Drug Administration Perspective on Regulation of Pharmaceutical Excipients

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Harold Davis

Division of Drug Information (HFD-240), Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration, Rockville, Maryland, U.S.A.

The Food and Drug Administration (FDA) is generally recognized as one of the, if not the, premier therapeutic agent gatekeepers among nations. Consequently, the pharmaceutical and medical library stacks are laden with journals and manuals devoted to drug development and instructions on how to run the FDA gauntlet to reach the jackpot of drug approval. However, little attention is paid to the regulation of excipients. A number of standard texts on the subject are exhaustive in their reviews, although they offer little on how this agency regulates excipients, an integral and essential part of drug development in the review process for drugs. We trust the following provides a window on our actions and thinking in this area.

The regulation of drug inactive ingredients was an outgrowth of the regulation of food colors (1). That began with the Pure Food and Drugs Act of 1906. The adulteration of foods and drugs was prohibited. Seven synthetic organic colors, chosen to give the required range of color, and because no mention of their causing unfavorable effects on humans and animals could be found in the scientific literature, were permitted for food use. A procedure was set up for voluntary certification of the identity and purity of these seven colors, and the use of artificial coloring other than these colors could be grounds for prosecution. This list was revised in subsequent years.

The Elixir of Sulfanilamide disaster, in which 107 people died as a result of the use of a toxic inactive ingredient, dramatized the need to establish drug safety before marketing and provided the impetus to pass the pending Federal Food, Drug, and Cosmetic Act of 1938. Certification of colors became mandatory, with all coal-tar colors used in foods, drugs, and cosmetics required to be from a certified batch. The law also created, out of less than 20 colors, three categories of certified colors: food, drugs, and cosmetic (FD&C) colors acceptable for food, drug, and cosmetic use, drugs and cosmetics (D&C) colors allowed in drugs and cosmetics only, and external D&C colors intended for external use only (2). The 1938 Act required that the presence of an uncertified coal tar be shown to prove that a food, drug, or cosmetic was adulterated, whereas under the 1906 Act, a color was considered to be in compliance until it was shown that its addition to a food rendered that food "injurious to health'' (3). Most importantly from our standpoint, the 1938 Act required the submission of a New Drug Application (NDA) for drugs wherein the drug product was considered in its entirety, active and inactive ingredients together. This remains in effect for all drugs subject to an NDA or an abbreviated NDA (ANDA). Inactive ingredients in nonprescription drugs subject to a monograph as described in Title 21 Code of Federal Regulations Part 330.1 and 330.10 (21CFR 330.1 and 330.10) are considered separately from active ingredients and need to be suitable and "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'' (4).

Chronic toxicity studies showed that most color additives were toxic when fed at high levels. The position of the FDA was that it lacked authority under the 1938 Act to permit the certification of a coal-tar color that was not harmless when fed to animals in any amount or to impose tolerances or limitations on the use of such colors; this position was confirmed by the U.S. Supreme Court. It appeared that in the future, few, if any, coal-tar colors would be permitted to be certified. The passage of the Color Additive Amendments of 1960 solved the problem of permitting the safe use of colors in foods, drugs, and cosmetics. All color additives had to be listed, regardless of their nature, by regulation (only after a complete showing of safety was made) and also required defining in the regulation the necessary conditions of safe use of the color additive. These amendments placed the burden of proof upon the party interested in obtaining the listing of the color additive (5). Colors derived primarily from plant, animal, and mineral (other than coal and petroleum) sources are exempt from FDA certification.

An inactive ingredient is defined by the FDA as "any component of a drug product other than an active ingredient" [Title 21 Code of Federal Regulations [21CFR Part 218.3C(b)(8)]. While the agency regulations are consistent in using this perhaps obsolescent term, an FDA guidance document (6) defines "new excipients'' as "any ingredients that are intentionally added to therapeutic and diagnostic products, but which, we believe, (i) are not intended to exert any therapeutic effects at the intended dosage (although they may act to improve product delivery, e.g., enhancing absorption or controlling release of the drug substance) and (ii) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration. Examples of current ingredients include fillers, extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, flavoring agents, absorption enhancers, sustained-release matrices, and coloring agents.'' This definition is very much in line with those offered by numerous researchers in the field.

Compendia that describe excipients used for various formulations such as parent-erals, vaginal formulations, and antibiotics are offered in a number of publications (7-9). The FDA publishes on its internet site, www.fda.gov, the downloadable "Inactive Ingredient Database.'' The components of proprietary inactive ingredients are not always included. All inactive ingredients that are present in currently approved final dosage form in drug products are listed. Whenever included, one may need to search for such data under individual component entries.

Synonyms of many ingredients do not appear in the database. Inactive ingredients are listed as specifically intended by the manufacturer. Some of these ingredients could also be considered as active ingredients under different circumstances.

Radiopharmaceutical kit reactants, and inactive ingredients, which chemically or physically combine with active ingredients to facilitate drug transport, are considered as inactive ingredients for the purposes of the database.

The inactive ingredients are updated quarterly, by the fifth working day of April, July, October, and January. To search for the excipient, one can enter any portion of the name of an excipient, of at least three characters. Search results are displayed alphabetically, sorted first by ingredient, then by the route of administration and dosage form. Routes of administration and dosage forms are derived from current approved labeling. Refer to the IIG query search results' column headers for data field definitions.

Industry can use this information to assist in developing drug products. Once an inactive ingredient has appeared in an approved drug product for a particular route of administration, the inactive ingredient is no longer considered new and may require a less extensive review the next time it is included in a new drug product. If, for example, a particular inactive ingredient has been approved in a certain dosage form at a given potency, a sponsor could consider it safe for use in a similar manner for a similar type of product.

Another source of very useful excipient data is the United States Pharmacopeia-National Formulary (USP-NF). Despite certain limitations, it appears that this compendium may become more useful in the years to come.

There are over 400 excipient monographs listed in the current USP 28-NF23. It is of interest to note that 32 new monographs were admitted this year (2005), 10 new monographs approved to USP 28-NF23 (Supplement 1 to USP 28), and four new monographs proposed to USP 28-NF23 (Supplement 2). These contrast sharply with, in chronological descending order, the 12, 4, and 3 new monographs admitted in earlier years.

Informational guidelines, Chapter 1024 in the USP, provides a scientifically based protocol for the safety assessment of new excipients intended for use in any dosage form. The USP has moved beyond addressing identity and purity concerns (9). The issues of physical characteristics are being examined by excipient committees. Methods have been and are being developed to incorporate (quality standards) basic physical characteristics such as particle size, density, and surface area into monographs. Such characterization can aid in identifying differences in materials manufactured in different locations by different suppliers. The point is that by focusing on physical characterization, further assurance is given that functionality will be maintained for a specific intended application. For example, this label claim approach now assures that different physical properties deliver different functionalities, such as liquid retention or ease of compressibility, which may be because of a change in particle shape. These could be appropriately defined. Methodology can be standardized so that the manufacturer and supplier are following the same rules. However, Moreton (10) cautions that variability is an inherent part of any production process. One concern is the extent to which improvement of an excipient's quality can be made without pricing it out of the market. Pharmacopeial monographs should include tests that establish excipient safety. Tests that are needed to differentiate between available pharmaceutical grades should be included, and placed in a labeling section allowing the flexibility to include all the various grades in the monograph.

''... Requests for Revision of the USP-NF, Chapter 3'' at the USP Web site www.usp.org offers guidance on various tests useful for new monograph excipients. Details as to what should be included in the submission package are given. Assuming all the required data are present, the package is sent to the expert committees on excipients for review. If, after a thorough evaluation, the submission package is accepted, it will be incorporated in the Pharmacopeial Forum (PF), published every two months. This allows for public review and comment.

After the comments are received and considered, the complete package is sent back to the committee. If no comments are received, the committee may allow the monograph proposal to become an official monograph 60 to 90 days after its PF publication. If comments are made, the committee may reject them or revise the monograph. A revised monograph must be published in the PF. It then can be voted upon to become official 60 days after publication. If a monograph requires only one publication in the PF, it can become official in about six to eight months. The process can take 15 months or longer, should a second publication cycle be needed.

Excipient manufacturers have a number of reasons for wanting their novel excipients to be included in the USP/NF. The NF publishes the highest quality standard publicly available for the product. Drug manufacturers then have confidence in product quality, with corresponding higher excipient sales. The USP has a document disclosure policy, subject to negotiation, which serves to protect confidential, proprietary information and intellectual property rights. The company that submits a new monograph has a dominant role in developing the various tests, procedures, and acceptance criteria that should be performed when evaluating substance quality. Drug manufacturers who purchase compendial grade materials for inclusion in their products are assured that the appropriate tests and procedures have been used with appropriate quality standards.

Compendial grade materials also give FDA inspectors a high degree of confidence, and they do not generally question the tests and acceptance criteria used. Indeed, FDA chemistry reviewers ordinarily do not review the manufacturing of compendial excipients. A new or inadequately qualified inactive ingredient proposed for use in any product pursuant to an NDA, Biological License Application, or ANDA should be supported by adequate data, which may be placed in the application directly or in a Drug Master File (DMF) (11). For compendial excipients that have an unusual use (e.g., lactose for inhalation products), FDA expects to see complete Chemistry, Manufacturing, and Controls (CMC) information (12), which is usually submitted in a DMF.

There are a few concerns about inclusion of an excipient monograph, however. The excipient can only be considered if it has been used in at least one FDA-approved product, or is on the generally recognized as safe (GRAS) list. Under 21CFR211, excipients, as with active drug substances, are required to be manufactured under current good manufacturing practices. Often, the excipient may be used primarily in other applications such as food or non-FDA-regulated products not requiring the same level of manufacturing standards. Significant additional costs may be incurred to meet Good Manufacturing Practice (GMP) requirements. The FDA does not review excipients separately from formulations. They are only approved as part of an NDA or Investigational New Drug Applications (IND). For novel excipients, the manufacturer must essentially develop the same amount of safety data required for a new active ingredient. A strong need for a certain characteristic may make such an investment worthwhile.

FDA guidancesa serve as a flexible approach to assist compliance with FDA's requirements. Safety testing of novel and potential excipients is addressed in the aThe Center for Drug Evaluation and Research List of Guidnces, which includes ICH Guidances for Industry, can be accessed at http://www.fda.gov/cder/guidance/index.htm. All the documents can be downloaded.

FDA's 2002 draft Guidance for Industry "Nonclinical Studies for Development of Pharmaceutical Excipients.'' This guidance lists safety-related issues that should be addressed under an IND or NDA in support of proposals to use excipients in new drug products. The safety-related topics that must be considered under different exposure conditions are given. All pivotal toxicological studies should be performed in accordance with state-of-the-art protocols and good laboratory practice regulations. These excipients should be appropriately evaluated for pharmacological activity using a battery of standard tests. Osterberg and See (13) have reviewed this guidance and discussed in some detail specific development strategies to support marketing of new excipients in drug products.

Some safety issues for excipients with a history of use may be addressed by citations of the clinical and nonclinical database, marketing history, or regulatory status of the compound, e.g., "GRAS" status as a direct food additive may support oral administration of that product up to the levels allowed in foods.

For antibacterial liquid dosage forms, preservative stability and effectiveness require thought. The sterilization method and its effects on the active pharmaceutical ingredient (API) and excipients of ophthalmic liquid dosage forms take on significance. Assurance of sterility for parenterals is paramount, and the effect of the method of sterilization on excipients, API, and preservative (when applicable) stability need investigation. Antimicrobial properties of the preservative require investigation to assure preservative effectiveness. Compendial tests (antimicrobial preservative effectiveness test, microbial limits test, and sterility test, and biological assay tests for antibiotics) appropriate to a specific dosage form should be tested to evaluate the microbiological component during preformulation studies (14). Control of composition and impurities in excipients are briefly discussed (15).

Genotoxicity or carcinogenicity potential may need to be addressed. The FDA's Center for Drug Evaluation and Research (CDER) uses a "cause for concern'' approach when determining the scope of the database needed to support a given use of an excipient. The International Conference on Harmonisation (ICH-S1A) (1996) document should be consulted for an analogous approach.

Mitigating circumstances may affect the decision. Duration of exposure, levels of local and systemic exposure, patient population (pediatric, geriatric, debilitated, and healthy), route of administration, knowledge of excipient congeners, and earlier studies that point to areas needing further study are examples. All are part of the risk-benefit assessment. If one can show that an excipient provides benefits to the product, such as promoting absorption of the active ingredient or affecting its release rate, or if it can be shown that the excipient provides some unique and critical property, that therapeutic enhancement (benefit) will be weighed against any risk to the patient. Each proposed use of an excipient must be considered on a case-by-case basis consistent with a positive risk-benefit ratio. Similar to new drug substances, the potential pharmacological activity of the new excipient must be delineated. The ICH guidance S-7A (2001) should be followed with the focus on testing for effects on the central nervous, cardiovascular, and respiratory systems. The ICH M-3 (1997) document identifies these as vital functions. Any activity found could involve performance of detailed investigations to more precisely determine excipient effects on the affected system(s) and the no-observed-effect levels and to calculate acceptable daily intakes.

Silverberg and See also point out that often proper planning will allow assessment of an excipient's toxicity in a relatively efficient manner. A less expensive "study within a study'' can be conducted by developing new excipients concurrently with the development of new drugs. Satellite groups of animals receiving an excipient may be added to studies that would have been conducted anyway to develop a drug substance.

Other examples are given. Suitable safety data may be present in DMFs and NDAs. It may be necessary, however, to document a right to reference such data by submitting written permission, from the owners of the data, to the agency, thereby allowing the agency to review the information.

The September 2000 draft guidance considers excipient databases associated with drug products with three different therapeutic durations. For a drug product intended for a 14-day therapy or less, and for infrequent use, the excipient should be tested in acute toxicity studies and in one-month, repeat-dose toxicity studies in two mammalian species (one being a nonrodent), using the intended route of therapeutic administration.

Pharmacokinetic profiling (ICH-S3B 1995) may prove useful. Review of the battery of genetic toxicity tests ICH-S2B (1997) and the ICH reproduction toxicity guidances (S5A) (1994) and S5B (1996, 2000) are valuable.

All of the above studies should be performed if the intended therapeutic duration is less than or equal to 90 days. In addition, two 90-day, repeat-dose studies, with the procedure as previously mentioned, need to be conducted. An intended use of more than 90 days requires all of the above studies plus chronic toxicological studies in both a rodent species (usually six-month duration) and an appropriate nonrodent species (usually nine-month duration). The agency will request, under certain circumstances, chronic toxicology studies of different duration [ICH S4A (1999)]. Excipients intended for use in chronically administered drug products should have a carcinogenicity evaluation. The sponsor has the option of conducting a two-year bioassay in rats and an alternative assay as per the ICH documents S1A (1996) and S1B (1997) or two 2-year bioassays in rodents. The need for such data can be waived (see ICH-S1A), if the sponsor can adequately document that carcinogenicity data are unnecessary. As usual, these decisions will be reviewed on a case-by-case basis. The appropriate division-level staff will make the evaluation together with the center's Pharmacology and Toxicology Coordinating Committee's (PTCC) Executive Carcino-genicity Assessment Committee. The sponsor's decisions will be reviewed from the following aspects:

• Any previous demonstration of carcinogenic potential in the relevant excipient class

• Structure-activity relationships suggesting a carcinogenic risk

• Evidence of preneoplastic lesions in repeated-dose toxicity studies

• Long-term tissue retention of the excipient or a metabolite of the excipient, resulting in local tissue reaction or other pathophysiological responses that are suggestive

• Genetic toxicity data

Sponsors may need data generated from all of the above tests for excipients used in drugs administered by topical or inhalation routes. Data on sensitization potential by either route would be needed. Data obtained from a parenteral or oral (if supported by toxicokinetic data) study may be needed to evaluate the excipient's potential for producing systemic toxicity if systemic exposure is identified in the pharmacokinetic studies. Safety evaluation of the excipient should also include its ability to absorb ultraviolet and visible light. If such a capacity is obtained, the phototoxicity potential could be evaluated using the FDA Guidance for Photosafety Testing (16). Other guidelines provide information on, for example, Liposome Drug

Products, as do Kumi and Booth (17). De George et al. offer guidance on excipients used in inhalation drug products (18).

Toxicological test results may cause the agency to request further studies to examine the toxicity in question to understand the level of risk that the compound may pose. Thus, special studies may be requested to clarify some adverse effect or finding. On the other hand, during the course of product development, some studies could conceivably be eliminated. A decision from the appropriate FDA division can be rendered upon consultation. The division responsible for a given drug product can answer information requests regarding use in the product. Questions are typically posed in pre-IND meetings or in an IND or NDA submission, depending on the product's regulatory status. Guidance on general excipient issues that do not pertain to a specific drug product or questions that pertain to potential excipients not yet associated with a drug product should be directed to the Inactive Ingredient Subcommittee of the PTCC of CDER.

To sum up, the issues and recommendations discussed in the guidance for industry relating to the nonclinical development of excipients, as with other agency guidances, are flexible and open to discussion and modification, as long as any change can be validated. The issues and recommendations should be viewed as a series of topics that should be addressed in an acceptable manner. Again, information or guidance specific to a particular excipient or drug product concerning the development of a safety database is usually available from CDER.

Pharmaceutical manufacturers may wish to change an excipient in a marketed drug. The reasons are several. For example, there may be a change in compendial standards. The USP does revise excipient monographs. Those changes can force a firm to reevaluate and change the excipient used in a formulation to meet the com-pendial requirements, especially when it comes to grades of excipients. An excipient on occasion may become unavailable due to a loss of source—for example, natural disasters (fire, war, etc.). Some excipients are available only in limited geographic areas, much like many other natural resources. Firms may make formulation modifications tailored to a specific patient population—pediatrics for example. Some changes are driven by the specialty excipient manufacturer—often excipients are also foodstuffs and food additives. Certainly, economics plays a role. Specialized excipients tailored to pharmaceutical market are a small portion of the total excipient market. The demand for excipients in vitamins and food supplements can cause pharmaceutical manufacturers to reduce or reevaluate their use of those excipients (19).

It is requested, but not required, that drugs listed according to 21CFR207.20 qualitatively list the inactive ingredients in the format given in Form 2656 (Drug Product Listing). An external color change of a drug product requires the submission of a new National Drug Code [21CFR35 (4)(i)]. Neither the Act nor the regulations mention that the wholesaler or retailer be notified if an excipient change is made. This is often done in practice, however.

If the product is the subject of an NDA or an ANDA, a supplemental NDA must be filed [21CFR314.70(b)(2)]. It must be shown that the change does not affect the bioavailability of the active ingredient(s). CMC information for drug substances used in over-the-counter (OTC) products covered by an OTC monograph (e.g., calcium carbonate) are not reviewed. Therefore, a DMF need not be filed. The fact that there are existing DMFs for calcium carbonate does not mean that they are reviewed. CMC information for OTC products not covered by an OTC monograph (e.g., famotidine) does need to be reviewed. A DMF is an appropriate mechanism to submit such information.

Section 502(e) of the Act requires that the drug label bear the ''established name of each inactive ingredient (and also be) listed on the outside container of the retail package.'' This includes any quantity of alcohol. Based on this section, 21CFR201.10(c)(4) does not allow ''the featuring ... of ... inactive ingredients in a manner that creates an impression of value greater than their true functional role in the formulation." If for other than oral use, the names of all inactive ingredients must be listed [21CFR201.100 (a) (5)]. The members of the Pharmaceutical Manufacturers Association (now the Pharmaceutical Research and Manufacturers of America) voluntarily agreed to list inactive ingredients in Rx drugs for oral use (20). Generic manufacturers followed suit. As a result, a regulation to this effect was never issued.

Whenever data demonstrating a relationship between inactive ingredients in drugs and possible adverse reactions come to the FDA's attention, appropriate steps are taken by the agency. These changes include requiring labeling to contain information about the relationship or prohibiting the use of the ingredient. Thus, the labeling for Rx drugs containing aspartame and sulfites, except epinephrine, for injection, when intended for use in allergic or other emergency situations, requires specific warning statements (21CFR201.21 and 22, respectively).

Section 706(b) (3) of the Act provides that regulations for the listing of a color additive shall ''prescribe the conditions under which such additive may be safely employed for such use or uses (including but not limited to... and directions or other labeling or packaging requirements for such additive).'' The FDA's position then is that the name of a color additive will not routinely be required on the labels of all foods and drugs unless its declaration is necessary for safety reasons. The presence of FD&C Yellow #5 and/or FD&C Yellow #6, potential sensitizing agents for many individuals, must be declared on the label of foods and certain drugs (21CFR201.20).

In 1984, the FDA welcomed a voluntary program, adopted by the Proprietary Association, now the Consumer Health Products Association, to identify on the product label the inactive ingredients used in OTC drug products (21). The listing of these ingredients was on an alphabetical basis instead of in the descending order of predominance.

The voluntary program was mooted by the 1997 FDA Modernization Act [see FDC Act Section 502(e) (1) (A) (iii)].

Nonprescription drug labels are required by law to identify all active ingredients and to identify and list quantities of certain ingredients, such as alcohol, whether active or not. Sodium content per dosage unit of oral OTCs is required (21CFR201.64). Terms that may be used, such as low sodium, very low sodium, and sodium-free, are defined. Inactive ingredient-labeling requirements are discussed in 21CFR201.66, both for drugs and for drugs that may also be considered as cosmetics. A number of Guidances for Industry that describe OTC labeling are available (22-24).

Interest in facets of excipient development is growing and in some cases is forced upon us. The agency has published an Interim Final Rule and proposals regarding the use of materials derived from cattle in human food and cosmetics (25). This addresses the potential risk of bovine spongiform encephalopathy in human food, including dietary supplements and cosmetics. Registration of all manufacturing sites and prior notification of all food ingredient imports will be required. It is a certainty that comparable systems for drug excipients will follow. Of course, many pharmaceutical excipients are used in food products. Thus, excipients may be required to be registered if used in food products. The excipient supplier then is under the gun and may face charges. Such a regulation would affect animal-derived excipients, including tallow, gelatin, stearyl alcohol, lactose, and glycerin. It appears then that the status of the generally cheaper offshore sourcing of pharmaceutical excipients may change or they may adapt themselves to the regulations (26).

There are a number of review refinements in the works that should streamline the review of some excipients. These were discussed at the October 2004 Generic Pharmaceutical Association meeting. Among these is a "fast-track" system for handling changes-being-effected (CBE) supplements. If either a CBE-0 or a CBE-30 supplement arrives at the office and is reviewed, and a determination is made that the proposed change is acceptable and no additional review is needed, the project manager will draft and send a letter notifying the company immediately. This action obviates the need for the supplement to be placed in a queue for review by the chemists, as had been the case earlier. The agency will undoubtedly seek other methods to speed review time. New DMFs are almost always found deficient on review. More information contained in the file can mean a quicker acceptance, but it can also mean more fodder for questions from the FDA.

Dr. John Kogan (27), speaking at a January 2005 International Pharmaceutical Excipients Council (IPEC) conference, said he believed that, because of downward price pressure, a lack of innovation, and rising costs of new product development, the excipient industry will diversify into two groups: one, focusing on high-tech excipients with greater functionality and high prices—developed in partnership with drug companies and in a manner akin to an API—and the other, a commodity sector. Helping in driving this split is the development of pharmaceuticals without the need for excipients, with the exception of diluents to provide bulk. Work on identifying the best physical or crystalline form of an API is already doing away with the need for wet/dry binders and making APIs more compressible. Next in line could be lubricants, dissolution agents, and disintegrants. A second problem facing the industry is that, on the whole, the 1200 plus marketed excipients fulfill the needs of most of the finished drug products, at least for immediate-release dosage forms. The big exception is for modified-release dosage forms.

A different view is taken by Apte and Ugwu (28), who focus on predicting trends and classifying delivery systems for parenterals, especially biotechnology products. The need to deliver drugs to specified therapeutic targets is a major driver for investigating the use of new excipients. They contend that in the near future, kilogram quantities of fusion proteins, polylysine, fibronectin, or alpha hemolysin could become available as "off-the-shelf" excipients or as designer excipient kits.

Apte and Katdare (29) aver that new mechanisms in the form of guidelines and procedures are needed to regulate the functionality of new and emerging excipients. In the examples below, the pharmacological effectiveness of a drug can be influenced by the excipient. These new excipients may be antigens, viral vectors, microbial products, or other complex proteins. Their pharmacological activities are not completely independent of their excipient functionality and straddle the line between excipients and APIs. For example, paclitaxel bound to albumin (30) (Abraxane) improves breast cancer therapy.

Solvents are no longer needed and the albumin passes into the body. More pertinent examples include the pegylated interferons (31). Polyethylene glycol (PEG) is attached in a random fashion and at variable numbers of sites on each molecule. A single dose of the combination in each cycle of chemotherapy is as effective as the original version, which required daily injections for up to two weeks. The PEG

moiety is essential for the increased effectiveness, yet at the same time is inactive by itself. The U.K. company Biocompatibles reports (32) that it has developed a system of bioinert etched microspheres that not only block blood vessels supplying tumors, but also deliver a payload of chemotherapeutic drugs. A device then serves as an active weapon against a disease at the same time that it serves as a drug.

Apte and Katdare question whether a molecule classified as both an excipient and an API can be regulated as both. Excipients are only reviewed as part of an NDA. Including a new excipient is a gamble on a new drug approval that includes a heavy financial investment. Vital issues that must be addressed include expanding the definition of excipients—but they must still wend their way as part of an NDA. Perhaps there should be an independent excipient review—possibly by outside experts. How can excipient innovation and creativity be promoted by government policies? Of course, one problem is that regulatory guidance always trails innovation.

Osterberg (33) comments that our draft excipient guideline be consulted together with the procedures outlined by Steinberg and Silverstein (34). The FDA stands ready to consult with innovators. He also suggests that an expert panel could be developed to pass on the safety of excipients.

As discussed in Chapter 20 by Apte and Ugwu, the future for new, unusual excipients that have exotic properties is hot and sunny. A quick scan of pharmaceutical science and pharmacology journals demonstrates very active research that could bear fruit unimaginable at this time.

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Responses

  • Stewart
    How the GRAS guidance is applicable to Pharmaceutical products?
    6 months ago
  • Abdullah
    Does excipient need to be regisetered with fda?
    4 months ago
  • hanna
    How are excipients regulated by FDA?
    4 months ago
  • eemil
    Do excipients need to be tested for pharmaceuticals?
    4 months ago
  • abraham
    Can food grade excipients be used in over the counter drugs?
    2 months ago
  • Arcangelo
    Do manufacturers of excipients need to drug list?
    1 month ago

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