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Working document QAS/04.093/Rev.4
WORLD HEALTH ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE
MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS:
GUIDELINES ON REGISTRATION REQUIREMENTS TO
DRAFT REVISIONThis document is a revision of a text drafted by Dr Rein Pähkla, Estonia. The first draft was extensively discussed among the members of the FIP/WHO BCS Task Force by mail, as well as during an informal meeting held in Geneva on 16-18 August 2004. Thereafter further modifications were discussed in a second informal consultation held in New Orleans. Dr Vinod Shah and Dr K. Midha served as rapporteurs of these meetings. The draft was then presented to the 39th WHO Expert Committee on Specifications for Pharmaceutical Preparations. All comments received were collated and categorized by Professor Dressman, Germany, and subsequently discussed during a consultation held on 18-22 July 2005 in Geneva.
Please send any comments on this revised text to Dr S. Kopp, Quality Assurance and Safety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or e-mail: email@example.com (with a copy to firstname.lastname@example.org) by 30 November 2005.
The World Health Organization acknowledges with the thanks the input of the following FIP/WHO BCS Task Force members: Kamal K. Midha, Vinod P. Shah, Gordon Amidon, Dirk Barends, Jennifer Dressman, John Hubbard, Hans Junginger, Rabi Patnaik, James Polli, Salomon Stavchansky.
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Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland.
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Working document QAS/04.093/Rev.4 page 2
TIMETABLE FOR MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS:
GUIDELINES ON REGISTRATION REQUIREMENTS TO ESTABLISH
INTERCHANGEABILITY. DRAFT FOR REVISION
First draft document (QAS/04.093) prepared by June 2004 Dr Rein Pähkla, Estonia and mailed for comments Collation of comments and revision 1 drafted by 16-18 August 2004 Dr K.K. Midha and Dr V.P. Shah and other FIP/WHO BCS Task Force members for discussion during consultation at WHO headquarters, Geneva Revision 2 drafted during consultation in 4-6 September 2004 New Orleans, USA Revision 3 drafted and mailed for comments 27 September 2004 Presentation to Thirty-ninth WHO Expert Committee 25-29 October 2004 on Specifications for Pharmaceutical Preparations
1. INTRODUCTION This general guidance is intended to provide recommendations to sponsors for the requirements of a multisource (generic) pharmaceutical product approval in their respective countries. The guidance is prepared to provide appropriate in vivo and in vitro requirements to assure interchangeability of the multisource product without compromising safety, efficacy and pharmaceutical product quality.
The national health and drug regulatory authorities should ensure that all pharmaceutical products subject to their control are in conformity with acceptable standards of safety, efficacy and quality, and that all premises and practices employed in the manufacture, storage and distribution of these products comply with Good Manufacturing Practice (GMP) standards so as to ensure the continued conformity of the products with these requirements until such time as they are delivered to the end user.
All pharmaceutical products, including multisource products, should be used in a country only after approval by the local authority. Regulatory authorities should require the documentation of a multisource pharmaceutical product to meet (i) GMP, (ii) quality control specifications, and (iii) pharmaceutical product interchangeability. Multisource pharmaceutical products need to conform to the same appropriate standards of quality, efficacy and safety required of the originator's (comparator) product. In addition, reasonable assurance must be provided that the multisource product is therapeutically equivalent and interchangeable with the comparator product. With some Working document QAS/04.093/Rev.4 page 5 classes of product, including - most evidently - parenteral formulations of highly water soluble compounds, interchangeability is adequately assured by implementation of GMP and evidence of conformity with relevant pharmacopoeial specifications. For other classes of product, including many biologicals such as vaccines, animal sera, products derived from human blood and plasma, and products manufactured by biotechnology, the concept of interchangeability raises complex considerations that are not addressed in this document, and these products are consequently excluded from consideration.
In order to ensure interchangeability, the multisource product must be therapeutically equivalent to the comparator product. Direct practical demonstration of therapeutic equivalence in a clinical study usually requires large numbers of patients. Such studies in humans can be financially daunting, are many times unnecessary and in certain cases may be unethical. For these reasons the science of bioequivalence testing has been developed over the last forty years. According to the tenets of this science, therapeutic equivalence can be assured when the multisource product is both pharmaceutically equivalent /alternative and bioequivalent.
Types of in vivo bioequivalence studies include pharmacokinetic studies, pharmacodynamic studies and comparative clinical trials. To exert an optimal therapeutic action, an active pharmaceutical ingredient should be delivered to its site(s) of action in an effective concentration for the desired period. To allow reliable prediction of the therapeutic effect, the performance of the pharmaceutical preparation should be well characterized by in vivo and/or in vitro studies. Direct or indirect comparison of therapeutic performances of two pharmaceutical products containing the same active pharmaceutical ingredient is a prerequisite for interchangeablility between comparator and multisource products. Assuming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations at the site(s) of action and thus an essentially similar therapeutic outcome, pharmacokinetic data may be used instead of therapeutic results. In selected cases, in vitro dissolution profile comparison of the multisource product with the comparator product or dissolution studies may be sufficient to provide indication of equivalence.
This guideline refers to the marketing of pharmaceutical products that are equivalent and hence intended to be therapeutically equivalent and thus interchangeable but produced by different manufacturers. It should be noted that the concept of interchangeability includes the equivalence of the dosage form as well as the indications and instructions for use. This guidance is generally applicable to orally administered multisource pharmaceutical products, as well as to non-orally administered pharmaceutical products where reliance on systemic exposure measures is suitable to document bioequivalence (e.g. transdermal delivery systems and certain parenteral, rectal and nasal pharmaceutical products). Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. The WHO guideline should be interpreted and applied without prejudice to obligations incurred through existing international agreement on trade-related aspects of intellectual property rights (1).
2. DEFINITIONS Some important terms used in this guideline are defined below. They may have different meanings in other contexts.
Bioavailability The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and becomes available at the site(s) of action. In the majority of cases reliable measurements of drug Working document QAS/04.093/Rev.4 page 6 concentrations at the site(s) of action are not possible. The substance in general circulation, however, is considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can be therefore defined as the rate and extent to which the active pharmaceutical ingredient or active moiety is absorbed from a pharmaceutical dosage form and becomes available in the general circulation. It is assumed by PK-PD theory that in the same subject an essentially similar plasma concentration time course will result in an essentially similar concentration time course at the site(s) of action.
Bioequivalence Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavialbility in terms of peak (Cmax and Tmax) and total exposure (AUC) after administration of the same molar dose under the same conditions are similar to such a degree that their effects can be expected to be essentially the same. Bioequivalence focuses on the equivalence of release of the active pharmaceutical ingredient from the pharmaceutical product and its subsequent absorption into the systemic circulation.
Biopharmaceutics Classification System (BCS) BCS is a scientific framework for classifying active pharmaceutical ingredients based upon their aqueous solubility and intestinal permeability. When combined with the dissolution of the pharmaceutical product, the BCS takes into account three major factors that govern the rate and extent of drug absorption (exposure) from immediate release oral solid dosage forms: dissolution, solubility, and intestinal permeability.
Biowaiver The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is approved based on evidence of equivalence other than in vivo bioequivalence test.
Comparator product Comparator product is a pharmaceutical product with which the new multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality has been established. The selection of the comparator product is usually made at the national level by the drug regulatory authority. A national drug regulatory authority has in principle options which are described in section 6.5.2.
Dosage form The finished formulation of a pharmaceutical product, e.g. tablet, capsule, suspension, solution for injection, suppository.
Equivalence requirements In vivo and/or in vitro testing requirements for multisource pharmaceutical product approval and marketing authorization.