Bioequivalence bioequivalency testing

FDA, in its continuing attempts to promote the rational evolution of bioequivalency testing, sometimes appears to be caught between a rock and a hard place. Pharmaceutical scientists who have served on or testified before FDA Expert Advisory Committees, that have considered generic bioequivalency problems... 

When a generic manufacturer completes an Abbreviated New Drug Application (ANDA), the bioequivalency test data are highly likely to be the section... 

The topic of bioequivalency tests for controlled-release products has attracted comment from a number of groups. For example, Bialer and co-workers [4] have proposed four new parameters ... 

Another circumstance in which there may be generally compelling reasons to require quantification of active metabolites is when a controlled-release drug-delivery system is used for a drug that has an active metabolite. Some of the papers that consider the topics of bioequivalency testing for drugs with long half-lives or active metabolites are listed in the references section of this chapter [12-17]. 

A topic in bioequivalency testing that has in recent years attracted spirited discussion is whether there is any need for standards controlling intrasubject variabilities. 

Obviously, if the clinical mirror approach to bioequivalency testing gains momentum, we may expect to see more quantification of clinical response in bioequivalency studies. In some instances pharmacodynamic parameters that are amenable to precise quantification are easily identified. Thus, if we are working with an antihypertensive drug, measurement of blood pressure using an electronic sphygnomanometer is an obvious option. However, for many drugs there is no simple way to quantify pharmacodynamic response. In some cases we may have to rely, to some extent at least, on patient diaries [41]. Such techniques are open to criticism of subjectivity and imprecision. 

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 ... 

C. T. Rhodes, Some observations on current and possible future developments in bioequivalency testing, Drug. Dev. Ind. Pharm., 25, 555 (1999). 

Christians U, First MR, Benet LZ (2000) Recommendations for bioequivalence testing of cyclosporine generics revisited. Ther Drug Monit 22 330-335 CPMP (2000) European Medicines Agency. Committee for Proprietary Medicinal Products. Note for guidance on the investigation on bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98.http //www.emea.europa.eu/pdfs/human/qwp/140198en.pdf. Cited 30 Dec 2008... 

Shah VP. Dissolution a quality control test vs. a bioequivalence test. Dissol Technol 2001 ll(4) l-2. 

Shah VP. Dissolution quality control test vs. bioequivalence test. Dissolut Technol 2001 8(4) 6—7. 

The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

Westlake WJ (1981) Bioequivalence testing - a need to rethink (Reader Reartion Response) Biometrics, 37, 589-594... 

Chemistry—Identify location of new site and updated batch records. No other documentation is required beyond application/compendial release requirements, although one batch produced at the new site should be placed on long-term stability and the data should be reported in the annual report. Dissolution data other than normal release requirements are not required nor is in vivo bioequivalence testing required. 

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