In a recent addition to USP 37 GENERAL NOTICES AND REQUIREMENTS (link), USP describe that:

“Compliance with any of the [dissolution] tests does not assure bioequivalence or bioavailability”.

The above mentioned statement clearly indicates, or establishes, the fact that compendial (USP) tests and, by extension hundreds and hundreds of similar tests reported in literature, cannot provide in vivo or bio-relevant results.

It is also important and/or critical to note that in most cases there are no differences between methods suggested in compendia and what the manufacturers use during product development stages. In fact, it is commonly suggested and recommended that one should preferably follow the compendial suggested methods as a first choice. Point being, in reality, there are no differences between methods/testers whether they are used for compendial or bio-assessment purposes. Therefore, if compendial methods cannot assure BE/BA then the same methods/testers cannot assure BE/BA in other situations as well, such as for the purpose of product development, bio-waiver, IVIVC etc.

It appears that people are not realizing a potentially profound implication of this statement or view. Some even believe, and are promoting, that it is simply a clarification or “stating the obvious or of already known”. However, in my view, such an interpretation is incorrect. By stating and establishing that compendial dissolution tests do not assure BE/BA, it has clearly challenged all the regulatory guidances and requirements where dissolution tests are recommended for assessing BE/BA. In fact, in my view again, the statement and view has practically made related guidances useless.

Therefore, it is not a simple “stating the obvious or of already known” scenario. It is a profound development which people have not yet realized. However, I believe, it is good and positive news concerning dissolution testing, i.e. by acknowledging the flaws of current practices, USP has opened the door for discussions in seeking modifications and improvements for dissolution testing.

In a recent addition to USP 37 General Notices and Requirements (link), USP clearly describes that:

“Compliance with any of the [dissolution] tests does not assure bioequivalence or bioavailability”.

The reality is that dissolution testing has been introduced as an alternative to bioequivalence (BE) or bioavailability (BA) evaluations based on the principle that the dissolution is one of the most critical parameters for the assessment of BE/BA. Drug dissolution tests are, therefore, required to be conducted using physiologically relevant experimental conditions such as 37 ºC temperature, aqueous buffers within physiological pH range, moderate stirring etc.

There has been tremendous effort made in predicting BE and BA (e.g. predicting plasma drug concentration) using testers and methods commonly suggested in the compendia. Dissolution tests have been recommended for bio-waivers i.e. using them in lieu of BE/BA. In addition, it is a common practice and requirement that prior to a test becoming a compendial method the product development step must use, or at least be tried, testers and methods to establish their relevance to BE/BA data. Eventually, the selected dissolution method would become the pharmacopeial test commonly known as QC-test or tool.

The underlying assumption for conducting the test remains that the test monitors potential in vivo dissolution, hence BE/BA. USP Chapter <1092> highlights and stresses that method development exercises should be relevant to in vivo performance describing “The procedure should be appropriately discriminating, capable of distinguishing significant changes in a composition or manufacturing process that might be expected to affect in vivo performance.” Numerous guidance documents, including those from the FDA, stress the dissolution and BE/BA link. Some of the examples to this effect from the FDA guidance’s are reported at the bottom of this post as an appendix.

Therefore, the recent addition to the USP, as noted above,  does not make sense. Continue reading →

In a recent posting on the USP site, under the heading of (USP–NF General Notices; Updated: 08–Aug–2013) it is stated that the following text will be added to the USP 37 GENERAL NOTICES AND REQUIREMENTS (http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/2013-07-09_general_notices_usp37-nf32_final.pdf (link not working) [try this one]

“4.10.11. Dissolution, Disintegration, and Drug Release Tests

Multiple Dissolution, Disintegration, or Drug Release tests may be present in the monograph. The order in which the tests are listed in the monograph is based on the order in which they are approved by the relevant Expert Committee for inclusion in the monograph. Test 1 is not necessarily the test for the innovator or for the reference product. Compliance with any of the tests does not assure bioequivalence or bioavailability” [emphasis is mine].

So what good are these testers/methods then? Furthermore, if their use is to be continued as usual then one requires knowing which characteristic/parameter of the product these compendial dissolution tests are measuring and how. In addition, some supporting evidence should also be provided showing how the current dissolution testers/methods have been qualified and validated for the suggested characteristic/parameter. Continue reading →

A similarity factor (F2) is commonly described in drug dissolution testing area to reflect the similarity of two dissolution profiles by a number i.e. if the number is between 50 and 100 then the two profiles are considered similar.  The question arises is in what respect are they similar; do numerically similar profiles show similar dissolution characteristics in the human GI tract- a commonly understood implication. No they do not, making this implication faulty. This is because the numbers are usually based on results obtained using apparatuses, and experimental conditions, which have never been qualified and validated for dissolution testing purposes. Therefore, similarity or dissimilarity of in vitro-in vivo profiles based on an F2 value has no meaning or relevance. Hence, presenting it as a useful parameter for bio-relevance is certainly a faulty fact.

It is often suggested, and in fact strongly promoted, that drug dissolution testing is a quality control tool, or an aid during the development of a product. This in itself is also a faulty fact. Drug dissolution testing by itself, without its in vivo link, has no meaning because both applications (QC and aid in product development) are derived from in vivo relevance, such as mandatory use of bio-relevant experimental conditions (e.g. 37 ºC, aqueous buffers etc.).

The similarity factor (F2) does not have any added value because a number between 50 and 100 reflects an average difference of dissolution 10% or less. Therefore, by definition, a quick way to establish similarity of the profiles is to calculate the average differences at different dissolution sampling times. If the value is less than 10% then, the curves meet the similarity (or F2) criteria. Derivation of the F2 value can often add biases and/or errors, e.g. one is restricted to use only one data point beyond 85% drug release. One is required to have two or more dissolution points to be able to calculate F2, however, a 10% difference would be easier to use and applicable irrespective to product type (fast release vs slow release) or the number of points/results available.

The range of 50 to 100 is not in line with current pharmacopeial requirements, even for QC purposes where a Q-based tolerance of 80% certainly allows a difference of 15 to 20% for products to have similar dissolution characteristics. However, F2 approach allows only differences of less than 10%.

Mathematically, the formula or calculations for the F2 does not appear to be more than a fancy skill testing question, such as “(2 × 4) + (10 × 3)” (Answer: 38) (link) or (8 x 6 – 5 + 9=52, link). The point being, it is a sort of arbitrary arithmetic exercise without any scientific relevance or value, however, it certainly adds burden on to the resources and interpretation.

In short, a similarity factor (F2) may be considered as not a very useful parameter which can lead to erroneous interpretation. The  approach based on difference criteria (e.g. 10%) offers perhaps a simpler, logical and more robust approach for assessing the similarity or dissimilarity of the dissolution curves or results.