Regulatory officials at the International Conferences of Drug Regulatory Authorities held in Ottawa, Canada, in 1991 and again in The Hague, Netherlands, in 1994, encouraged WHO to develop global standards and requirements for regulatory assessment, marketing authorization and quality control of interchangeable multisource pharmaceutical products. To achieve this objective, WHO held three consultations during 1993 and 1994 which resulted in the publication of Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.

The WHO multisource guideline covers the following seven major topics: regulatory assessment of interchangeable multisource pharmaceutical products, equivalence studies needed for marketing authorization, tests for equivalence, in vitro dissolution tests in product development and quality control, clinically-important variations in bioavailability leading to non-approval of the product, studies needed to support new postmarketing manufacturing conditions, and choice of reference product.

Each section of the guideline provides important information for regulatory authorities wishing to develop a marketing authorization system that establishes the comparator drug product with which all pharmaceutically-equivalent multisource products should be interchangeable. The elements of a regulatory system to achieve this general objective are complex and challenging. They include market control, (including control of imports); marketing authorization of a comparator drug product with established efficacy, safety and quality characteristics that are maintained throughout this period of marketing; marketing authorization of one or more multisource drug products that have been shown, via submission and assessment of an application for marketing authorization to be comparable in all important safety, quality and efficacy attributes to the comparator drug product; and control of both the comparator drug product and the multisource equivalent products following marketing authorization to assure that significant deviations in quality do not occur.

The WHO multisource guideline focuses on many elements which are useful to regulatory authorities wishing to create and maintain a reliable, coherent system of available comparator drug products and interchangeable multisource equivalents. Such a system promotes confidence on the part of health professionals and consumers in the efficacy, safety and quality of pharmaceutical products. The WHO multi-source guideline focuses on equivalence measures for test procedures to determine relative bioavailability or bioequivalence. By definition, pharmaceutically-equivalent drug products contain the same amount of the same active substances in the same dosage form, possess comparable quality attributes, are administered by the same route of administration and are intended for the same general purpose. If two pharmaceutically-equivalent drug products are also shown to have comparable performance, that is, to have the same relative bioavailability as specified by equivalence studies carried out according to the WHO multisource guideline, therapeutic equivalence may be concluded, and the two products may be considered interchangeable.

After completion of the WHO multisource guideline, WHO convened two additional consultations to further consider the question of reference standards - subsequently termed comparator drug products - for multisource Pharmaceuticals, and a model application form for marketing authorization of multi-source pharmaceutical products. WHO subsequently produced a Report of informal discussions on reference standards for multisource pharmaceutical products. This report notes that selection of a comparator drug may be difficult in view of the following possible reasons: the innovator safety and efficacy data in relation to a specific pharmaceutical product is unknown; the relationship between an innovator product and a corresponding product that is the market leader within a sphere of authority may not be clear; the innovator might market the same product in different countries but under different conditions of safety, efficacy and quality due to differing regulatory requirements or other factors; a clear understanding of comparability between an innovator product from different manufacturing sites may not be available; an older product may be available on the market without the required efficacy, safety and quality studies having been conducted.

As discussed in the WHO report, various approaches may be developed to resolve some of the difficulties in selecting and maintaining a comparator drug product. In the United states of America, a system based on comparator drug products and interchangeable multisource products was formally established in 1984 under the Drug Price Competition and Patent Term Restoration Amendments to the Food, Drug and Cosmetic Act. This legislation created an abbreviated mechanism for approval of multisource drug products first approved for safety and efficacy after 1962. A mechanism to allow multisource products for pre-1962 products was already in place. The 1984 legislation thus provided a clear regulatory mandate to allow generic substitution of all innovator drugs so that duplicative, costly, and ethically-questionable preclinical and clinical tests did not have to be repeated by an applicant wishing to market a multisource product. None the less, an applicant wishing to market a multisource product in the United States must demonstrate to the Food and Drug Administration that its product is the same as that of the corresponding innovator product - the comparator drug is termed the "listed" drug in the US sys- tern - in terms of active ingredient(s), strength, dosage form, and route of administration. In addition, the applicant must demonstrate that the labelling of its proposed generic, multisource, version is comparable to that of the innovator product and that it is bioequivalent to the reference 'listed" drug.

The challenge of creating and maintaining a system of comparator drug products and interchangeable multisource products is substantial. It requires identification of a list of comparator drug products for which safety and efficacy are established relative to the performance of an identified drug product. This identified drug product is the clinical trial material on which pivotal studies of safety and efficacy were based. The specifications of this drug product must be established and maintained over the multiple decades that a drug might be available on the market. Responsible regulatory oversight must assure that the comparator drug product and its multisource equivalents are manufactured in such a way that their quality and performance continue to be comparable to the clinical trial material on which safety and efficacy were assessed. Rigid control of the availability of drug products within a market must be maintained to exclude drug products that do not meet these criteria. The tasks associated with this achievement are difficult for any country and they would be much simpler if a single comparator drug product with established efficacy, safety and quality were available globally. Whether this can be achieved depends more on political will than scientific or technical factors, but the value to health professionals and consumers would be considerable. If achieved, a single product with identifiable labelling could be made available worldwide and an applicant wishing to market a multisource product would be required to conduct only a single set of studies to be submitted to any regulatory authority in support of a marketing authorization.

Equivalence: in vitro dissolution as a surrogate for in vivo performance

Part two of the WHO multisource guideline focuses on mechanisms to establish equivalence between a multisource product and its comparator drug product. The section focuses on tests to document equivalence and assess comparability between the performance of a multisource and comparator product. A minor distinction in terminology arises. In the United States, the corresponding term to equivalence is "bioequivalence" which can be assessed as defined in the USA Code of Federal Regulations (21 CFR 320.24). The WHO multisource guideline expresses bioequivalence as one of several approaches to assess equivalence and is based on measurement of the drug/metabolite(s) in an accessible biological fluid. Other approaches, as defined both in the WHO multisource guideline and also in the US 21 CFR 320.24 include comparative pharmacodynamic studies, comparative clinical trials and in vitro dissolution tests. A key component of the discussion in Section 9 of the WHO guideline pertains to when in vivo studies are necessary to document equivalence. The criteria delineated in this section define criteria where in vivo equivalence should be performed. Generally, these criteria are so comprehensive that in vivo studies would be required for most drug substances and drug products when the need to document equivalence arises.

In vitro dissolution serves many purposes in relation to the documentation of bioavailability and bioequivalence. During the investigational phase of drug development, bioavailability may be established to document, for regulatory and other purposes, the rate and extent of absorption of a drug substance from the product. Control of the performance of the product thereafter may be achieved via a dissolution specification that works to assure batch to batch quality. The dissolution specification may be developed during the investigational phase of drug development or shortly after approval. In the USA, the dissolution specification subsequently becomes established as a public standard via processes of the United States Pharmacopeia Inc. (USP). Use of a dissolution specification to assure batch-to-batch quality may not be sufficient to assure unchanged performance (equivalence) in the presence of change. Change frequently occurs in the manufacture of a drug substance and product around the time of and following approval and can involve the synthesis of the drug substance and manufacture of the product. In either case, questions of sameness (equivalence) in the performance of the drug product may arise. Depending on the type of change and its magnitude, these questions may be addressed by the relatively simple dissolution specification used to assure batch-to-batch quality control or may require more extensive testing up to, and including, performance of an in vivo bioequivalence study.

Two new guidances will soon be available from the FDA entitled Dissolution testing of immediate-release solid oral dosage forms and Extended-release oral dosage forms: development, evaluation and application of in vitro/in vivo correlations. These provide recommendations to applicants regarding the development of dissolution specifications and how to develop, where applicable, in vitro/in vivo correlations so that in vitro dissolution may be used as a surrogate for in vivo bioavailability/bioequivalence studies. Recent FDA guidance to industry regarding procedures to assure unchanged quality attributes in the presence of change, entitled Immediate-release solid oral dosage forms/scale up and post-approval changes: chemistry, manufacturing, and controls, in vitro dissolution testing, and in vivo bioequivalence documentation (SUPAC-IR), also acknowledges that dissolution profiles in suitable media may be used for immediate release products to assure "sameness" in the presence of certain changes, even when an in vitro/in vivo correlation has not been established.

The FDA is also considering a more expansive application of in vitro dissolution to document bioavailability and bioequivalence. This application relies on an approach termed the Biopharmaceutical Classification System (BCS). According to Fick's first law, the rate of drug absorption per unit area across a membrane, such as the gastro-intestinal mucosa, is determined by the drug's permeability through the membrane, and the concentration of the drug at the surface of the membrane. Thus, permeability and solubility of a drug substance become key factors in controlling rate and extent of absorption. A drug may be considered to be highly soluble in the gastro-intestinal tract when the largest dose intended for administration is soluble in a volume of 250 ml, or less, over a pH range of 1-8. A drug may be considered highly permeable when the extent of absorption is greater than 90%. The BCS approach allows the following four classes of drug substances to be defined: high solubility/high permeability; low solubility/ high permeability; high solubility/low permeability; low solubility/low permeability. Application of the approach in the documentation of equivalence rests on the assumption that for highly soluble/highly permeable drug substances, an assessment of the release of the drug substance may be adequate to assure optimal availability. A drug product dissolving with sufficient rapidity may be presumed to be optimally-available, as are solutions, even though this optimal availability may preclude the development of in vitro/in vivo correlation. In this setting, requirements for documentation of bioavailability and/or bioequivalence in vivo may be reduced or eliminated. If generally accepted, the approach could provide an additional or alternative way to determine when in vivo studies are and are not necessary, which could provide amplification of the approaches discussed in Part Two, Section 9 of the WHO multi-source guideline.

Quality

To establish and maintain product quality, specifications (tests, procedures, limits of acceptance) are developed for an innovator drug product based on knowledge gained from experimental formulations and other material studied during the investigational phase of drug development. Guidelines now under development within the International Conference on Harmonization (ICH) will provide, when completed, recommendations on how to develop specifications for products containing chemical substances (ICH Q6A) and biotechnological substances (ICH Q6B). Specifications can be legally-binding quality standards that are agreed to by the responsible regulatory authority and the applicant. In the USA, these non-public specifications may subsequently become established as public standards in USP drug substances and drug product monographs. Other components of the overall processes that lead to control of the attributes by which the quality of a pharmaceutical product is established and maintained include validation of the manufacturing process, in-process testing, raw material testing, and stability testing. As noted in the WHO multisource guideline, WHO guidelines are available which provide information on approaches to establish and maintain the quality of pharmaceutical products. The ICH and WHO documents, as well as documents created by individual authorities, may be helpful to regulatory authorities wishing to promote a system of market control based on the availability of comparator drug products with interchangeable multisource equivalents. A goal which merits further consideration is the merging of the WHO, ICH and selected national guidelines that focus on quality aspects of pharmaceutical products. The specific objective to be achieved would be a global set of documents defining harmonized approaches to the quality control of pharmaceutical products. These documents would be relevant for innovator drugs as well as multisource products.

Post-approval change

Section 6 of the WHO multisource guideline provides important comments on studies that are needed to support new postmarketing manufacturing conditions. Because all innovator and multisource manufacturers may change the manufacturing process of a drug product after approval, a system of comparator drug products and interchangeable multisource products can be undermined if regulatory systems are not in place to assure that quality attributes remain the same in the presence of change. In the USA, 21 CFR 314.70 defines certain requirements that must be met when change occurs after approval, whether in the manufacture of a drug substance, a drug product or its packaging. To further clarify the type of information and filing requirements that might be important in the presence of change, the FDA is working on a series of guidance documents that elaborate the type of information that should be submitted in the presence of change. For drug products, these documents are referred to as the SUPACs, one of which - SUPAC-IR - has already been mentioned. Additional SUPACs covering modified-release dosage forms, controlled and enteric-coated products, transdermal dosage forms, non-sterile semisolid dosage forms (topical products), and others are planned. For drug substances, a comparable initiative is under way that will lead to one or more guidances on the type of information that should be submitted when change occurs in the manufacture of a drug substance. This initiative has been termed BACPAC (bulk active compound post-approval change). Finally, a packaging guidance is in the final stages of preparation that will also consider the type of information and filing requirements that are needed when change occurs in the packaging of a drug substance and drug product.

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