Multisource products

In an effort to codify bioequivalence information, the FDA publishes Approved Drug Products With Therapeutic Equivalence Evaluations, with monthly supplements, commonly called "the Orange Book." The book contains listings of multisource products in one of two categories Products coded "A" are considered bioequivalent to all other versions of that product with a similar "A" coding. Products not considered bioequivalent are coded "B." Of the approximately 8000 products listed, 90% are coded "A."... 

Seek bioequivalency information. Only A-rated multisource products should be prescribed. 

These guidelines are intended to provide recommendations to sponsors on the requirements for approval of multisource (generic) pharmaceutical products in their respective countries. The guidance provides appropriate in vivo and in vitro requirements to assure interchangeability of the multisource product without compromising the safety, quality and efficacy of the pharmaceutical product. 

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 the following ... 

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. 

The comparator product is a pharmaceutical product with which the 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 have been established. The selection of the comparator product is usually made at the national level by the drug regulatory authority (see section 6.5.2). 

A test that determines the equivalence between the multisource product and the comparator product using in vivo and/or in vitro approaches. fixed-dose combination (FDC)... 

An in vitro equivalence test is a dissolution test that includes comparison of the dissolution profile between the multisource product and the comparator product in three media pH 1.2, pH 4.5 and pH 6.8. 

A signed and dated study protocol together with the study report should be presented to the authorities in order to obtain the marketing authorization for the multisource product. 

Bioequivalence studies are designed to compare the in vivo performance of a multisource product with that of a comparator product. Pharmacokinetic bioequivalence studies on products designed to deliver the API for systemic exposure serve two purposes ... 

The multisource pharmaceutical product used in the bioequivalence studies for registration purposes should be identical to the projected commercial pharmaceutical product. Therefore, not only the composition and quality characteristics (including stability), but also the manufacturing methods (including equipment and procedures) should be the same as those to be used in the future routine production runs. Test products must be manufactured under GMP regulations. Batch-control results of the multisource product, and the lot numbers and expiry dates of both multisource and comparator products should be stated. 

For some pharmaceutical products however, an innovator product cannot be identified and in some cases no innovator product is available on the market. A generic pharmaceutical product should not be used as a comparator as long as an innovator pharmaceutical product is available, because this could lead to progressively less reliable similarity of future multisource products and potentially to a lack of interchangeability with the innovator. 

The primary concern in bioequivalence assessment is to limit the risk of a false declaration of equivalence. Statistical analysis of the bioequivalence trial should demonstrate that a clinically significant difference in bioavailability between the multisource product and the comparator product is unlikely. The statistical procedures should be specified in the protocol before the data collection starts. 

It should be noted, that although the dissolution tests recommended in The International Pharmacopoeia (26) for quality control have been designed to be compatible with the biowaiver dissolution tests, they may not fulfil all the requirements for evaluating equivalence of multisource products with comparator products. Dissolution tests for quality control purposes in other pharmacopoeia do not generally correspond to the test conditions required for evaluating bioequivalence of multisource products and should not be applied for this purpose. 

Determination of dissolution characteristics of multisource products in consideration of a biowaiver based on the Biopharmaceutics Classification System... 

For exemption from an in vivo pharmacokinetic bioequivaience study, an immediate-release multisource product should exhibit very rapid or rapid... 

A multisource product is considered to be very rapidly dissolving when no less than 85% of the labelled amount of the drug substance dissolves in 15 minutes using a paddle apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 ml or less in each of the following media ... 

The risk of reaching an inadequate decision that the multisource product is equivalent to the comparator product can be reduced by correct classification of the API and by following the recommendations for dissolution... 

Evidence that each excipient present in the multisource product is well established and does not affect gastrointestinal motility or other processes affecting absorption, can be documented using the following information ... 

As a general rule, the closer the composition of the multisource product to that of the comparator product with regard to excipients, the lower the risk of an inappropriate decision on equivalence using a biowaiver based on the BCS. Sub- and suprabioavailable products... 

The first arises when the multisource product is sub-bioavailable. In this case substitution of the comparator with the multisource product could lead to reduced therapeutic efficacy. APIs which must reach a certain concentration to be effective (e.g. antibiotics) are most susceptible to problems of sub-bioavailability. 

If the comparator and multisource products are very rapidly dissolving, i.e. at least 85% dissolution in 15 minutes or less, in all three media, using the recommended test method, a profile comparison is not necessary. 

BCS Class 2 weak acids if the API has a dose solubi I ity ratio of250 ml or less at pH 6.8 and the multisource product is rapidly dissolving (no less than 85% in pH 6.8 in 30 minutes) and its dissolution profile is similar to that of the comparator product at pH 1.2, 4.5 and 6.8 under the dissolution test conditions described in section 9.2. 

If it is deemed that the risk of reaching an inappropriate biowaiver decision and its associated risks to public health and for individual patients is acceptable, the multisource product is eligible for a biowaiver based on BCS when both the comparator and the multisource dosage forms are very rapidly dissolving (85% dissolution in 15 minutes as described in section 9.1.2.1). 

Dosage forms of APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (by definition, some but not all BCS Class 2 compounds with weak acidic properties) are eligible for a biowaiver based on BCS provided that criteria (b), (c) and (d) described in section 9.2. are met, that the API has high permeability (i.e. the fraction absorbed is 85% or greater) and a dose solubility ratio of 250 ml or less at pH 6.8, and that the multisource product ... 

For delayed-release tablets, when the multisource product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients and has the same delayed-release mechanism, a lower strength can be granted a biowaiver if it exhibits similar dissolution profile, f, > 50, in the recommended test condition for delayed-release product, i.e. dissolution test in acid medium (pH 1.2) for 2 hours followed by dissolution in pH 6.8. 

The national authority should be aware that some excipients can influence motility and/or permeability in the gastrointestinal tract. Therefore, the excipients used in the multisource product formulation should be scrutinized. 

If the multisource product under consideration contains excipients that have been used before in similar amounts in other formulations of the same API, it can be reasonably concluded that these excipients will have no unexpected consequences for the bioavailability of the product. If, however, the formulation contains different excipients, or amounts of the same excipients that are very different from usual, the national authority may choose to declare the biowaiver procedure inapplicable. 

The decision of a national authority to allow a biowaiver based on the BCS should take into consideration the solubility and permeability characteristics as well as the therapeutic use and therapeutic index of the API, its pharmacokinetic properties, the similarity of the dissolution profiles of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37 °C. Data related to the excipients composition in the multisource product are also required. A systematic approach to the biowaiver decision has been established by the International Pharmaceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences (http //www3.interscience.wiley.com/cgi-bin/jhome/68503813). The relevant documents can also be downloaded from the FIP web site at http //www.fip.org/. These monographs provide detailed information which should be taken into account whenever available in the biowaiver consideration. 

For rapidly dissolving (as defined above) pharmaceutical products containing BCS Class I APIs, more than 85% dissolution of the labelled amount is required within 30 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm. The dissolution profiles of the comparator and the multisource products should be compared by an f > 50 or an equivalent statistical criterion. 

These are eligible for a biowaiver provided that the multisource product ... 

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