Biowaivers

Thus, some proponents of the clinical mirror school of thought of bioequivalency testing are likely to object on principle to any biowaiver. However, it seems likely that this viewpoint is unlikely to be universally accepted for all drugs. The following are some criteria that might be considered when contemplating a biowaiver ... 

The degradation and formation of nonabsorbable drug complexes in the intestinal lumen is the third factor, in addition to dissolution and permeability, which could affect fraction absorption. Limitations of bioavailability due to these factors seem to be less frequent compared with the two other main factors. Regulatory guidelines for BCS-based biowaivers still ask for in vitro studies of luminal degradation in relevant test media, whereas specific binding studies are not required [17]. 

The FDA currently allows biowaivers (27) (drug product approval without having to show bioequivalence in vivo) for formulations that contain Class I drugs and can demonstrate appropriate in vitro dissolution (rapidly dissolving). 

Over the last quarter century the dissolution test has emerged as a most powerful and valuable tool to guide formulation development, monitor the manufacturing process, assess product quality, and in some cases to predict in vivo performance of solid oral dosage forms. Under certain conditions, the dissolution test can be used as a surrogate measure for bioequivalence (BE) and to provide biowaivers, assuring BE of the product. Dissolution test has turned out to be a... 

The BCS also predicts the possibility of obtaining an in vitro/in vivo correlation. Justification of a biowaiver is based on a combination of the BCS classification of the drug substance and a drug product dissolution profile comparison. In all these instances, an anchor with a bioavailable product is established. Specifically, to obtain a biowaiver for an IR generic product ... 

Dissolution-based biowaivers for generic IR and MR drug products are discussed in the General BA and BE Guidance (4). 

A biowaiver is applicable for beaded capsules when the lower strength differs only in number of beads of active drug and the dissolution profile is similar in the recommended dissolution test media and conditions. 

A biowaiver is applicable for extended-release tablet formulations, where the lower strength(s) are compo-sitionally similar to the highest strength and uses the same release mechanism and the dissolution profile is similar in pH 1.2, 4.5, and 6.8. 

The biowaiver criteria described in BCS guidance (3) are regarded as very conservative. Discussions are underway to consider relaxing some of the requirements for biowaiver of the drug product. These dissolution-based biowaivers exemplify the role of dissolution in regulating pharmaceutical drug products. 

Going beyond the application of the in vitro-release test as a QC tool for special dosage forms to biowaivers and in vitro-in vivo correlations will require more research. 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

Typically, BA and BE are assessed by cumbersome and expensive studies in human volunteers. But, under certain circumstances, regulatory agencies may waive the requirement for the submission of evidence measuring the in vivo BA or establishing BE. This is referred to as a biowaiver . The application of a biowaiver requires that supportive in vitro dissolution data are meaningful in terms of in vivo performance of the drug product. 

It should be noted that in both guidances BCS-based biowaivers do not apply to food effect BA studies or pharmacokinetic studies other than those designed to test for BE. 

The initial step in the evaluation of possible BCS-based biowaivers is the classification of the drug intended for orally administration as follows (17) ... 

Figure 1 Prerequisites for BCS-based biowaivers according to CDER and CPMP guidelines.

Additional criteria for waiver of evidence of in vivo BA/BE are given in 21 CFR 320.22 (d)(3). For certain solid oral dosage forms (other than a delayed or extended-release dosage forms), a waiver for the submission of in vivo evidence of BA/BE is possible if the drug product has been shown to meet the requirements of an in vitro dissolution test, which in turn has been shown to correlate with in vivo data. A biowaiver may also be addressed to a reformulated solid oral dosage form identical to another drug product except for color, flavor, or preservatives for which the same manufacturer has obtained approval, if BA data are available for the approved... 

In summary, the role of dissolution testing as a surrogate for BE studies in humans has assumed increasing importance in the regulation of drug products. It is more than likely that in the coming years, the application of biowaivers based... 

Therefore, the development and validation of a scientifically sound dissolution method requires the selection of key method parameters that provide accurate, reproducible data that are appropriate for the intended application of the methodology. It is important to note that while more extensive dissolution methodologies may be required for bioequivalency evaluations or biowaivers (i.e., multiple media, more complex dissolution media additives, and multiple sampling time points), it is also essential for the simplified, routine quality control dissolution method to discriminate batch-to-batch differences that might affect the product s in vivo performance. 

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