Global Regulatory Perspective of Bulk Pharmaceutical Excipients

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Abstract:

Regulations for pharmaceutical bulk excipients are stringent as same as pharmaceutical medicines. In case of new excipient, applicant has to submit safety & quality data. In case of approved or existed excipient applicant has to submit literature reference data i. e. FDA inactive ingredients guide, the national formulary, U.K. ABPI data sheets as part of the drug submissions. In U.S, FDA assesses & permits use of excipients as part of a new drug application (NDA). In E.U, it is assumed that novel excipients need to be evaluated as new chemical entities. In Japan, separate evaluation process is there for novel excipients. The main drawback of development of excipients is lack of specific regulatory (national & international) guidelines. The lack of international regulatory guidelines lead to the formation of the international pharmaceutical excipients council (IPEC) in 1991.It has championed the international standardization of excipients, the introduction of useful new excipients, and the development of safety evaluation guidelines. These guidelines, addressing all the primary routes of drug administration, have been published. Due to the harmonization of standards of the excipients among the member states, rapid development occurred in pharmaceutical excipient industry.

Key-words:Pharmaceutical industry, Excipients, New Drug Application, Toxicology studies, Quality, Safety.

Introduction:

Pharmaceutical excipients are additives used in the formulation of pharmacologically active drugs and can be viewed as any ingredient of a medicinal product other than the active ingredient. Excipients include diluents, fillers and bulking agents, binders and adhesives, propellants, disintegrants, lubricants and glidants, colors, flavors, coating agents, polishing agents, fragrances, sweetening agents, polymers, and waxes. The term comes from the Latin word excipients, present participle of the verb excipere which means to receive, to gather, and to take out. This refers to one of the properties of an excipient, which is to ensure that a medicinal product has the weight, consistency and volume necessary for the correct administration of the active principle to the patient

Source of Excipients:

1. Animal origin: e.g. lactose, gelatin, and stearic acid.

2. Plant origin: e.g. starches, sugars, cellulose, and arginates

3. Mineral origin: e.g. calcium phosphate, silica

4. Synthesis: e.g. PEGs, polysorbates, povidone, etc

Regulation of Excipients:

Excipients are categorized as compendial or non-compendial materials. Compendial excipients have composition consistent with monographs published in compendia such as USP-NF. Generally speaking, compendial excipients are the better characterized excipients and most likely to possess the desirable qualities previously stated. These materials are recognized as preferred excipients for pharmaceutical formulations. Non-compendial excipients might also be applied in pharmaceutical formulations. The use of these noncompendial materials is supported by Type IV drug master files (DMFs) in regulatory dossiers (i.e., new drug applications, abbreviated new drug applications, and investigational new drug applications). These files are maintained by excipient manufacturers with the agency and support the safety of the excipient as well as the quality and consistency of excipient manufacturing.

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.

In recent years, an awareness and understanding of excipients has increased based upon several important factors.

1. As pharmaceutically active ingredients continue to become more ''potent,'' the effective doses have become smaller. As a result, excipients now often constitute the major portion of many pharmaceutical dosage forms and as such can have profound impact on the reproducibility of manufacture and overall quality of the dosage forms

2. Regulatory authorities, especially the U.S. Food and Drug Administration, have clearly set an expectation that quality should be built in drug products from the beginning of development and manufacture rather than simply testing quality of the finished product. This stance has forced the industry and academia to develop a thorough understanding of the functionalities and modalities of excipients, as well as to develop and adopt testing methodologies from other industries to refine the characterization of excipients.

3. The technical complexities associated with drug development have increased due to challenges such as poor drug solubility, complex drug actives, and, in cases of biotech products, stabilization of the active ingredient. Often times, the current array of excipients in approved products are not sufficient to formulate challenging molecules, forcing pharmaceutical scientists to explore new excipients. The development and testing of new excipients require a multidisciplinary understanding of technical, safety, quality, and regulatory aspects.

4. The drawback of excipient development is lack of specific regulatory (national & international) guidelines.

5. Lack of international regulatory guidelines lead to the formation of the international pharmaceutical excipients council (IPEC) in 1991, which publishes the Quality standards and Toxicology tests (Safety)

U.S-FDA Perspective:-

An inactive ingredient is defined by the FDA as ''any component of a drug product other than an active ingredient''. In the United States, the Food and Drug Administration (FDA) assesses and permits use of excipients as part of a new drug application (NDA). Interestingly, in the U.S. guideline relating to preclinical data for NDA submission, excipients are not mentioned. Under U.S. law, a new pharmaceutical excipient, unlike an active drug, has no regulatory status unless it can be qualified through one or more of the approval mechanisms available for components used in finished drug dosage forms.

Approval Mechanisms:

*Generally Recognized as Safe (GRAS) determination pursuant to 21 Code of Federal Regulations (CFR) 182, 184, and 186.

*Approval of a food additive petition under 21 CFR 171

*As contained in a New Drug Application (NDA) approval for a specific drug product and for a particular function or use in that dosage form.

Regulation Of Excipients:

Later discussions from industries, FDA has released a guidance document entitled ''Nonclinical Studies for Development of Pharmaceutical Excipients,'' which was finalized in May 2005 (a draft version of this document first appeared in September 2002). Guidance is intended to foster and expedite the development of new excipients and to communicate agency expectations to industry.

This document provides guidance concerning development of safety profiles to support use of new excipients as components of drug or biological products. This guidance describes the types of toxicity data that the Agency uses in determining whether a potential new excipient is safe for use in human pharmaceuticals. It discusses recommended safety evaluations for excipients proposed for use in OTC and generic drug products, and describes testing strategies for pharmaceuticals proposed for short-term, intermediate, and long-term use. It also describes recommended excipient toxicity testing for pulmonary, injectable, and topical pharmaceuticals.

Safety data:

1.OTC Products: For products marketed under OTC drug monographs, 21 CFR 330.1(e) requires: "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." The provisions of 21 CFR 330.1(e) does not apply to OTC products marketed under NDAs or abbreviated new drug applications (ANDAs). Some excipients used in NDA-approved drug products may not be safe for use in OTC products (e.g., some toxic excipients used in cancer chemotherapeutics).

2. Generic Products: Drug products intended for parenteral, ophthalmic, or otic use should contain the same excipients in the same concentrations as the reference listed drug product, with the exception of buffers, antioxidants, and preservatives, provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety of the proposed drug product. For other routes of administration (e.g., topical dermal, oral), there is no requirement that the excipients in the final formulations be the same as those in the reference listed drug product, although the applicant must demonstrate that the inactive ingredients do not affect the safety or efficacy of the proposed drug product.

3. New Drug or Biological Product Application: For new products, the required supporting data can be placed in application directly or in a drug master file (DMF). In Certain Circumstances, FDA may request additional safety data if FDA determines that the Proposed conditions of use are not fully supported by the available data. For example excipients that are extensively absorbed or biotransformed, FDA may request a pharmacokinetic profile of excipient. When applicable, drug-excipient interaction studies may also be requested.

Recommended strategies to support marketing of new excipients in drug products:

1. Safety Pharmacology:

All potential new excipients are appropriately evaluated for pharmacological activity using a battery of standard tests according to ICH guidance for industry S7A Safety Pharmacology Studies for Human Pharmaceuticals. These evaluations can be performed during the course of toxicology studies or as independent safety pharmacology studies. It is useful for these data to be obtained at an early point during the safety evaluation of an excipient, since, if the excipient is found to be pharmacologically active, this information can influence subsequent development.

2. Potential Excipients Intended for Short-Term Use:

New excipients that are intended for use in products that are limited by labeling to clinical use of 14 or fewer consecutive days per treatment episode and are infrequently used include at least the following:

*Acute toxicology studies

*Toxicokinetics & Pharmacokinetics of an excipient

*Standard battery of genetic toxicology

*1-month repeat-dose toxicology studies are performed in both a rodent species and a mammalian nonrodent species by the route of administration intended for clinical use. It includes complete clinical pathology, histopathology, and toxicokinetic analysis.

*Reproductive toxicology

3. Potential Excipients Intended for Intermediate Use:

New excipients that are intended for use in drug products that are labeled for clinical use of more than 2 weeks but less than or equal to 3 months per treatment episode include at least the following:

*All tests of safety pharmacology & intermediate use except of 1-month repeat-dose toxicity studies.

*3-month repeat-dose toxicology studies are performed in both a rodent species and a mammalian non-rodent species by the appropriate route of administration. It is important that the studies include complete clinical pathology, histopathology, and toxicokinetic analysis

*Additional studies (e.g., studies involving Parenteral administration)

4 Potential Excipients Intended for Long-Term Use:

New excipients that are intended for use in drug products labeled for clinical use of more than 3 months in a given patient (either as a single treatment episode or as a result of multiple courses of therapy to treat a chronic or recurrent condition) include at least the following:

*All tests of safety pharmacology, short term and intermediate use. 1-month and 3-month toxicology studies are not essential, but may provide useful dosage selection data.

*6-month repeat-dose toxicology study is performed in a rodent species by the appropriate route. It includes complete clinical pathology, histopathology, and toxicokinetic analysis. FDA recommend that studies that involve excipients of low toxicity in general use the limit dose as the highest dose for testing.

*If toxicity and pharmacologic effect were absent in state-of-the-art sub chronic studies, a 6-month study may be sufficient. When toxicity is detected in shorter duration studies, or in rodents, a chronic study in nonrodent of 9 to12 months may be appropriate

*Carcinogenicity studies according to ICH. (ICH guideline for industry S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals)

5. Potential Excipients for Use in Pulmonary, Injectable, or Topical Products:

*All studies from Safety Pharmacology, Short term use, Intermediate use, and Long term use as appropriate, using the appropriate route of administration. Studies that include the to-be-marketed formulation of the drug product are preferred, if this information is available at the time of excipient evaluation.

*Sensitization study (e.g., guinea pig maximization study or murine local lymph node assay) according to CDER guidance for industry Immunotoxicology Evaluation of Investigational New Drugs for more information

*For excipients intended for injectable use, the following considerations may be appropriate:

a.An in vitro hemolysis study could be performed at the intended concentration for I.V. administration (bolus and/or infusion) to determine the hemolytic potential.

b.The plasma concentrations of creatinine kinase determined at the intended excipient concentration for I.M. or S.C. administration can provide information on potential muscle damage.

c.An evaluation of protein binding in relation to local site tolerability could be done.

*Excipients intended for topical use may need support from toxicology studies by both the intended clinical route and the oral or Parenteral route if clinical pharmacokinetic studies conducted under conditions of maximum exposure show patients would experience systemic exposure to the excipient or its metabolite, particularly if limited systemic exposure were observed in nonclinical studies conducted by the clinical route of administration.

*For topical dermal products and ophthalmic products, it may be appropriate to conduct an ocular irritation study

6. Photo stability Testing :

FDA recommend that excipients be evaluated regarding the need for photo safety testing as described in the CDER guidance for industry Photo safety Testing. Either the excipient or the complete drug product could be tested.

Source of information about the excipients

*The FDA publishes on its internet site, www.fda.gov, the downloadable ''Inactive Ingredient Database.'' All inactive ingredients that are present in currently approved final dosage form in drug products are listed. Industry can use this information to assist in developing drug products.

*Another source of very useful excipient data is the United States Pharmacopeia National Formulary (USP- NF). An informational guideline, Chapter 1024 in the USP, provides a scientifically based protocol for the safety assessment of new excipients intended for use in any dosage form.

*Chapter 3 - Requests for Revision of the USP-NF, at the USP Web site www .usp.org offers guidance on various tests useful for new monograph excipients

E.U -EMEA Perspective:

Within the EU there is a directive that makes it clear that new excipients will be treated in the same way as new actives. In Europe, the need for companies to fully consider the types of excipients in new drug formulations has been the focus of a guideline released recently by the European commission on drug label and package leaflet excipient information for all MAAs. This guideline indicates that all excipients must be listed on the drug label for parenteral, topical, inhalation, and ophthalmic products. For other medicinal products, only those excipients with a defined and recognized action of effect need to be declared on the label. In drug package leaflets, all excipients must be included. European regulations and guidelines also require that a full statement of the excipients used be given in the Summary of Product Characteristics (SPC) document for new drug formulations.

Regulation of excipients

1. If the excipient is described in European pharmacopeia applicant has to submit to the current edition of the pharmacopoeia should be included in the dossier for marketing authorization. If tests other than those mentioned in the pharmacopoeia are used, proof should be supplied that the test methods are at least equivalent to those described in the pharmacopoeia (see European Pharmacopoeia, 1.1. General Statements). It may be necessary to add tests and acceptance criteria to the pharmacopoeial specification, depending on the intended use of the excipient (functionality-related characteristics).

2. Where an excipient is neither described in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia (e.g. United States Pharmacopoeia/National Formulary and Japanese Pharmacopoeia) can be accepted. The applicant should justify the reference to such pharmacopoeia and submit justified specifications in accordance with the general monograph of the European Pharmacopoeia: Substances for Pharmaceutical use.

3. Excipients not described in any pharmacopoeia the applicant has to submit the following types of tests:

*Physical characteristics

*Identification tests

*Purity tests, including limits for total and individual impurities, which should be named, e.g. by reference to a chromatographic relative retention time. Purity tests may be physical, chemical, biological and, if appropriate, immunological.

*Assay or limit tests if necessary and corresponding validation parameters.

*Other relevant tests e.g. tests on parameters (quantitative), which have been determined to influence the performance of the dosage form.

4. Novel Excipients: Full details of manufacture, characterization and controls with cross references to supporting safety data should be provided for novel excipients, according to the drug substance format.

a)A detailed description of the excipient, its function and its conditions of use should be provided. If the excipient is complex or consists of a mixture of compounds, the composition should be specified in qualitative and quantitative terms.

b)Documentation on chemistry of excipients is required for all novel excipients, should include:

*The origin of the excipient, including the name and address of manufacturer.

*A general outline of the manufacturing and purification procedures.

*Structure.

*Physical, chemical properties, identification and purity tests.

*Validated methods of analysis with a presentation of batch results.

*Miscellaneous information (microbiological tests, etc).

*Contamination,presence of foreign substances, residual solvents, etc.

*In the case of an excipient obtained from a mixture of several components, the quality of each component and the physico-chemical tests for the mixture should be described.

*Stability data should be provided as required for the active substances

Source of information about the excipients:

*European Pharmacopeia

*Guideline on Excipients in dossier for application for marketing authorization of a medicinal product

*ABPI Compendium of Data Sheets and Summaries of Product Characteristics 1998-1999.

Japan - MHW Persepctive:

The formal structure for regulating pharmaceutical excipient is quite complex. Responsibilities are divided among several divisions in the MHW & National institutes for hygienic sciences (NHS) & central pharmaceutical affairs council (CPAC) play key roles in the regulation of excipients.

Source of information about the excipients

There are two compendia containing monographs that describe Japanese standards for pharmaceutical excipients.

*Pharmacopeia of Japan (JP)

*Japanese standards of pharmaceutical ingredients (JSPI)

Regulation of excipients:

1. If the excipient is new, manufacturer has to submit an informal draft monograph to the committee on new pharmaceutical excipients i.e. one of the 15 committees of the (CPAC) for approval in Japan. The committee provides guidance to the applicant that the monograph is complete & in the proper form. When the committee is satisfied, the excipient manufacturer is used in drug dosage form application. The full drug dosage form application is then formally reviewed by the CPAC committee on new drugs. The results of this review are made known to the drug dosage form applicant by the new drugs division.

2. If the excipient is already existed in pharmacopeia, the manufacturer has to submit an informal draft of a revised monograph either to JP or JPSI committee. Once again, the relevant committee provides guidance to the manufacturer to ensure that the monograph is complete before accepting it for formal review & recommendation. The final step is publication in either J.P & JSPI.

3. In Japan, Uchiyama has recently published requirements for the safety evaluation of new excipients. These requirements include studies on acute, sub acute, and chronic toxicity, mutagenicity, effects on reproduction, dependency, antigenicity, carcinogenicity, and local irritation (human patch test). The first five of these tests are mandatory. With the exception of the local irritation test, for which a domestic trial is required, non-Japanese data are acceptable for these studies. Even if a material has been used in a pharmaceutical product outside Japan, the material is treated as a new excipient if there has been no prior use in Japan, although relevant overseas data for the material are acceptable for regulatory submission. A material is treated as a new excipient when the route of administration differs or the dose level exceeds that of prior use even after approval for the Japanese market.

IPEC:-

The lack of international regulatory guidelines led to the formation of the International Pharmaceutical Excipients Council (IPEC) in 1991. This industry association, with European, U.S. and Japanese membership, has championed the international standardization of excipients, the introduction of useful new excipients, and the development of safety evaluation guidelines. These guidelines, addressing all the primary routes of drug administration (toxicology) & quality, have been published. The intention of IPEC is to ensure that these guidelines reflect the concerns and intentions of responsible parties in the United States, the European Union (EU), and Japan. In other words, the guidelines are harmonized so that excipients that meet the requirements of a harmonized monograph can be sold and used in these three areas of the world.

Safety guidelines (toxicology):

The required safety tests are depends upon the type of excipient.

1. New (Novel) Excipients:

A new excipient is a compound that has not been used previously or permitted for use in a pharmaceutical preparation. The need to develop an excipient as a new chemical entity, leading to expense and potential time delay (the excipient would be of low regulatory priority compared with active new drug formulations), has resulted in a reluctance in the pharmaceutical industry to introduce new excipients. Thus IPEC has developed a safety guidelines, it would be expedite the review of a proposed new excipient by regulatory agencies. This organization has defined a testing strategy for human exposure to single or limited dosing (less than 2 weeks), limited and repeated dosing (2-6 weeks), and long-term dosing (longer than 6 weeks).

Different tests for oral, mucosal, transdermal, topical, parenteral, inhalation/intranasal and ocular routes in humans are described. Common recommended toxicity studies for longer term use in humans include acute oral and dermal toxicity studies, eye and skin irritation studies, a skin sensitization study, genotoxicity and ADME studies, sub acute and chronic studies, and reproduction studies. These guidelines are useful as a basis for the development of a new excipient, although they raise some questions.

Finally, and most important, if a drug company was developing a drug with a completely new excipient in the formulation, it is possible to include the excipient alone as an extra dose group in the preclinical studies. These studies would presumably use the clinical formulation (containing the excipient).

It is vital that kinetics studies identify any drug-excipient interaction. As for active drug, a sensitive analytical method is needed to measure levels of excipient (if possible) in plasma samples from toxicology studies. If the impurity profile of the new excipient causes concern, addition toxicological evaluation of each impurity has to be carried out as well. It is crucial to clarify the excipient impurity profile because even established pharmacopoeia-listed materials such as magnesium stearate can raise questions as to the safety and toxicity of its impurities.

2. Essentially New Excipients:

Essentially new excipients can be thought of as substances resulting from a structural modification of an ''approved'' excipient, a recognized food additive, a structurally modified food additive, or a constituent of an over-the-counter (OTC) medicine. However, some form of preclinical testing will probably be required

An Ames study determines that the new excipient has no genotoxicity potential, and a single-dose toxicity study shows that there are no adverse effects after administration of the material at the limit (high) dose generally used in the pharmaceutical industry. An investigative mass, balance, whole-body autoradiography study provides information on absorption, distribution, metabolism, and excretion. This study also involves an investigation of suitable labeling of the material. An in vitro metabolism study (e.g., in rat vs. human hepatocytes) may also be useful for modified food additives and excipients to compare the break-down process and to show possible differences between rat and human in these processes. A 1-month toxicity study will establish whether the limit dose is causing any form of high-dose toxicity or metabolic overload. It may be useful to include toxicokinetic satellite animals in this study to demonstrate what level of exposure to the excipient occurs in the blood. Favorable findings from these studies can be presented to the regulatory bodies and advice sought as to whether additional testing is recommended. As with other preclinical studies in drug development, all these investigations should be performed according to good laboratory practice (GLP). The cyclodextrins (CDs) fall into the categories of new and essentially new excipients

3. Established (''Approved'') Excipients:

The presence of well known established excipients in a new drug formulation does not necessarily mean that regulatory authorities question wills not their inclusion. However, issues can be avoided if the excipient is clearly characterized in the quality section of the documentation and addressed sufficiently in the preclinical section. Similarly, the establishment of global standardized monographs in major pharmacopoeias is helpful. Problems can arise when the currently available published data suggest that there may be potential toxicity concerns, especially when an excipient approved for one dose route is applied to another route with a different systemic exposure and target site. A less important but interesting point is that many of the established and pharmacopoeia-listed excipients are not accompanied by strict standardized assay methods. In this situation, a ''new' ' assay needs to be established by the company with the new drug formulation for characterization and/or plasma measurement of the excipient.

Quality guidelines:

The aforementioned IPEC guidelines that address quality include:

*Good Manufacturing Guide for Bulk Pharmaceutical Excipients.

*Good Manufacturing Practices (GMP) Audit Guideline for Distributors of Bulk Pharmaceutical Excipients.

*IPEC-Americas Significant Change Guide for Bulk Pharmaceutical Excipients.

*GMP Audit Guideline for Suppliers of Bulk Pharmaceutical Excipients.

*New Excipient Safety Evaluation Guidance.

*IPEC-Americas Guide for the Development of an Impurity Profile.

*Format and Required Content of Certificates of Analyses.

Conclusions:

Pharmaceutical excipients have no official regulatory status independent of the finished dosage form in which they are used. As a result, the mechanism for regulation of these ingredients is uncertain and variable. For excipients found in OTC drug products regulated under the FDA's OTC monograph system, the agency operates under a set of proposed rules (still pending) that provide the general considerations for acceptable excipients and their functions. For prescription drugs, excipients are reviewed as a part of the drug application, and not given any independent review. The FDA looks to several sources to identify these previously reviewed excipients, including food additive or food GRAS status, inclusion in the USP/NF, or prior review in other new drug applications. These previously used/acceptable excipients are identified in the FDA's Inactive Ingredient Guide. Inclusion of an ingredient in this guide provides the FDA a reasonable assurance that an ingredient, used within the scope of the usage provided in the guide, will be acceptable. Therefore, regulation of well-known excipients in both OTC and prescription drugs are subject to a reasonably certain set of procedures. However, the lack of an independent review for excipients creates significant issues for companies that wish to use new or novel excipients in their drug products. Existing regulations and guidelines indicate that new excipients be treated as new chemical entities and therefore, by inference, undergo full toxicological evaluation. Other drug requirements in Europe and Japan require that information on excipients appear in patient literature, although there is no similar legal requirement in the United States

For new (novel) excipients, drug companies need to carefully assess the benefits of using the new substance in consideration of the extra workload, costs, and possible regulatory delays or rejection. However, now that an active role for excipients is recognized in the form of sustained-release or drug-delivery systems, there is more need for companies to use new excipients. The publication of the IPEC recommendations for safety evaluation of new excipients is helpful, to develop the excipients.

References:

1. Ashok K, Mahesh Chabul V. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. New York (USA). Informa Health Care USA.2006. FDA Perspective on Regulation of Pharmaceutical Excipients, P.no 3-14. Regulation of Pharmaceutical Excipients, P.no 37-50.

2. James.S, Encyclopedia of Pharmaceutical Technology. Third Edition. New York (USA) Informa health care. 2007, Vol-3. Excipients: Safety Testing, P.no 1656-1662. Pharmaceutical Excipient Testing: Regulatory & Preclinical Perspective: 2771-2782.

3. Steinberg, M.; Borzelleca, J.F.; Enters, E.K.; Kinoshita, F.K.; Loper, A.; Mitchell, D.B.; Tamulinas, C.B.; Weiner, M.L. A new approach to the safety assessment of pharmaceutical Excipients. Regul.Toxicol. Pharm. 1996, P.no 24, 149-154.

4. Center for Drug Evaluation and Research (CDER). Guidance for Industry: Nonclinical Studies for Development of Pharmaceutical Excipients. Final guidance issued by FDA CDER, May 2005, www.fda.gov/cder/guidance.

5. Inactive Ingredients Guide; U.S. Food and Drug Administration, Division of Drug Information Resources: Rockville, MD, 1996.

6. ICH Guideline S7A: Safety Pharmacology Studies for Human Pharmaceuticals. Add citation for ICH S7 guidance.

7. FDA Inventory of GRAS Notifications. Department of Health and Human Services. Food and Drug Administration, August 2004 (available from: http://www.cfsan.fda. gov/~rdb/opa-gras.html).

8. The IPEC Europe Safety Committee. The proposed guidelines for the safety of new excipients. Eur. Pharm. Rev. 1997, November

9. European Pharmacopoeia, 3rd Ed.; European Pharmacopoeia Commission, Council of Europe: Strasbourg, France, 1997; 1299-1300.

10. United States Pharmacopeia, 23rd Ed.; United States Pharmacopeial Convention, Inc.: Rockville, MD, 1995.

11. Japanese Pharmacopoeia, 13th Ed.; the Society of Japanese Pharmacopoeia, Yakuji Nippo Ltd.: Tokyo, 1996.

12. Uchiyama, M. Regulatory status of excipients in Japan. Drug Inform. J. 1999, 33, 27-32.

Table.1:
A.Exposure Less Than 2 Weeks

Tests

Route of administration

Oral

Mucosal

Transdermal

Topical

Parenteral

Inhalation / Intra nasal

Ocular

Acute oral toxicity

R

R

R

R

R

R

R

Acute dermal toxicity

R

R

R

R

R

R

R

Acute inhalation toxicity

C

C

C

C

C

R

C

Eye irritation

R

R

R

R

R

R

R

Skin irritation

R

R

R

R

R

R

R

Skin sensitization

R

R

R

R

R

R

R

Acute Parenteral toxicity

-

-

-

-

R

-

-

Application site evaluation

-

R

R

R

R

R

-

Pulmonary sensitization

-

-

-

-

-

R

-

Photo toxicity / photo allergy

-

-

R

R

-

-

-

Bacterial gene mutation

R

R

R

R

R

R

R

Chromosomal damage

R

R

R

R

R

R

R

ADME-Intended route

R

R

R

R

R

R

R

28-day toxicity(two species) intended route

R

R

R

R

R

R

R

B. Exposure 2 To 6 Weeks

Tests

Route of administration

Oral

Mucosal

Transdermal

Topical

Parenteral

Inhalation / intranasal

Ocular

90- day toxicity (most appropriate species)

R

R

R

R

R

R

R

Teratology (rat &/ or rabbit)

R

R

R

R

R

R

R

Additional assays

C

C

C

C

C

C

C

Genotoxicity assays

R

R

R

R

R

R

R

C. Exposure Greater Than 6 Weeks

Tests

Route of administration

Oral

Mucosal

Transdermal

Topical

Parenteral

Inhalation /intranasal

Ocular

Chronic toxicity
( rodent, non-rodent)

C

C

C

C

C

C

C

One generation reproduction

R

R

R

R

R

R

R

Photo carcinogenicity

-

-

C

C

-

-

-

Carcinogenicity

C

C

C

C

C

C

-

R- Required,
C- Conditional,
- Not required.
Source: Reference 3

Table 2: Essentially New Excipients

Ames Test
Acute oral toxicity study
Mass/ balance/whole body auto Radio graphy (WBA) study abd/or in-vitro metabolism study
One month repeat dose toxicity study

About Authors:

G.L.Pramod, S.G.Vasantharaju*, K.Sumalatha Reddy, J. Dwaraka Reddy

S.G.Vasantharaju

S.G.Vasantharaju,
Faculty, Dept of Pharamaceutical Quality assurance, Manipal College of Pharmaceutical Sciences, MANIPAL-576 104.

G.L.Pramod

G.L.Pramod

K.Sumalatha Reddy

K.Sumalatha Reddy

J. Dwaraka Reddy

J. Dwaraka Reddy

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