Vivo Bioequivalence Studies

Handbook of Pharmaceutical Manufacturing Formulations Semisolid Products 

Topical Dermatological Corticosteroids In Vivo Bioequivalence, June 2, 1995. Van Buskirk, G.A., Shah, V.P., Adair, D., et al., Workshop report scale-up of liquid and semi-solids disperse systems, Pharm. Res., 11, 1216— 1220, 1994. 

Contiguous Campus—Contiguous or unbroken site or a set of buildings in adjacent city blocks Creams/Lotions—Semisolid emulsions that contain fully dissolved or suspended drug substances for external application. Lotions are generally of lower viscosity Diluent—Vehicle in a pharmaceutical formulation commonly used for making up volume or weight (e.g., water, paraffin base) 

Drug Product—Finished dosage form (e.g., cream, gel, or ointment) in its marketed package. It also can be a finished dosage form (e.g., tablet, capsule, or solution) that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)) 

Drug Release—Disassociation of a drug from its formulation, thereby allowing the drug to be distributed into the skin or be absorbed into the body, where it may exert its pharmacological effect 

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III) whether in vitro or in vivo bioequivalence studies, or both such smdies, are... 

Waiver of in vivo bioequivalence studies for major post approval manufacturing changes for the BCS Class I (Biopharmaceutics Classification System highly soluble, highly permeable and rapidly dissolving) solid oral products is NOT recommended for narrow therapeutic index drugs (17). 

In vivo bioequivalence documentation—An in vivo bioequivalence study should be performed. This may be waived if a suitable in vivo/in vitro correlation has been verified. 

To further explore some complexities associated with decisions on the value of dissolution tests, it is postulated that for the selected formulation, in vitro dissolution is likely to be a more sensitive tool for studying formulation differences than in vivo bioequivalence studies. The following arguments can be made to support this postulate. 

A high degree of sensitivity of in vitro dissolution tests to formulation differences raises questions about the appropriate acceptance criteria—how similar should two in vitro dissolution profiles be to be considered similar The SUPAC-IR introduced to the regulatory decision-making process a metric referred to as f2 [43] for profile comparison. Application of this criterion to the examples cited in this report (e.g., piroxicam formulations) would have resulted in a recommendation for the in vivo bioequivalence study. 

Below is a general outline of an in vivo bioequivalence study. It is intended as a guide and the design of the actual study may vary depending on the drug and dosage form. 

The design of in vivo bioequivalence studies for semisolid dosage forms varies depending on the pharmacological activity of the drug and dosage form. A brief general discussion of such tests follows. 

Assessment of the effect of a change on bioequivalence when required under 21 CFR part 320 could include, for example, multipoint and/or multimedia dissolution profiling and/or an in vivo bioequivalence study. 

Information that shows that the product is bioequivalent to the reference listed drug Results of any bioavailability or bioequivalence testing performed in support of a petition Methods and GLP statement for any in vivo bioequivalence studies... 

In vivo bioequivalence studies may be necessary for each additional source of new drug substance if the drug product is known to produce bioequivalency problems resulting from the new drug substance. 

Waiver of in vivo bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system, available http //www.fda.gov/cder/ guidance/index.html. 

In Vivo Bioequivalence Studies In vivo studies are conducted to establish the biological availability or activity of the drug from a topically applied semisolid formulation. Dermatopharmacokinetic studies, pharmacodynamic studies, or comparative clinical trials are generally conducted to assess the bioequivalence of topical products [16,17]. 

Level C IVIVC presents anyway some interest as defined in the FDA note for guidance A single point Level C correlation allows a dissolution specification to be set at the specified time point. While the information may be useful in formulation development, waiver of an in vivo bioequivalence study (biowaiver)... 

Guidelines for organizations performing in vivo bioequivalence studies (Annex 9). 

Have you conducted in vivo bioequivalence studies for some of your products Yes No... 

To ensure interchangeability, the multisource product must be therapeutically equivalent to the comparator product. Types of in vivo bioequivalence studies include pharmacokinetic studies, pharmacodynamic studies and comparative clinical trials. 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 often unnecessary and may be unethical. For these reasons the science of bioequivalence testing has been developed over the last 40 years. According to the tenets of this science, therapeutic equivalence can be assured when the multisource product is both pharmaceutically equivalent/alternative and bioequivalent. 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 comparison of dissolution profile of the multisource product with that of the comparator product, or dissolution studies, may be sufficient to provide indication of equivalence. 

Pharmacokinetic, pharmacodynamic and clinical studies are all clinical trials and should therefore be carried out in accordance with the provisions and prerequisites for a clinical trial, as outlined in the WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products (4). Additional guidance for organizations performing in vivo bioequivalence studies is available from WHO (5). 

Guidelines for organizations performing in vivo bioequivalence studies. In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization (WHO Technical Report Series, No. 937), 2006, Annex 9. 

The objective of this document is to provide guidance to organizations involved in the conduct and analysis of in vivo bioequivalence studies. 

Note the acronym CRO is used throughout this document to refer not only to a contract research organization (CRO), but also to any organization involved in the conduct or analysis of in vivo bioequivalence studies. As defined in the International Conference on Harmonisation (ICH) Tripartite Harmonised Guidelines, Guidelines for Good Clinical Practice (5), a CRO is a person or an organization (commercial, academic or other) contracted by the sponsor to perform one or more of a sponsor s trial-related duties and functions. 

Class 1 drugs must have wide therapeutic index, and their dissolution must be rapid for an in vivo bioequivalence study to be waived. An immediate release product is considered rapidly dissolving when not less than 85% of the labeled amount of the drug substance is dissolved within 30 minutes of using USP Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 mL or less in each of the following media 0. IN HCl or simulated gastric fluid USP without enzymes, in a pH 4.5 buffer, and in a pH 6.8 buffer or simulated intestinal fluid USP without enzymes (29). 

The analytical group produces all of the CMC documents that support the above messages. The support is derived mostly from bridging analytical data that demonstrate technical equivalence between the proposed market formulation and the clinical formulation(s). Technical data from analytical comparability studies or in vivo bioequivalence studies can be used to demonstrate equivalence after synthesis, formulation, packaging, site, and/or process changes. 

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