Role of Dissolution Testing: Regulatory Perspectives

In the August 2004 Tenth Anniversary Issue of your publication Dissolution Technologies an article entitled “Role of Dissolution Testing: Regulatory Perspectives” by Dr. Vinod P. Shah was published citing his FDA affiliation.

While the article is essentially a commentary on the current regulatory practice with respect to the role of dissolution, Dr. Shah makes a statement that requires clarification and certainly is misleading. I am also sure that this is not the first time he has made this statement.

The statement reads as follows: “The utility of the dissolution test may be greatest in developing countries, where it can be used as an in vitro bioequivalence test”.

Several questions arise from this statement and apparent inferences require specific clarification.

1. 1. How does one conduct an in vitro bioequivalence test? It would be helpful if Dr. Shah would provide specific examples of studies conducted as in vitro tests of bioequivalence. It is well known and accepted that the dissolution test is a quality control tool and Dr. Shah alludes to this point in the article. However, it is not a surrogate test for bioequivalence unless a specific in vitro �in vivo correlation has been established. As these studies require testing in vivo it would be more appropriate to conduct an in vivo bioequivalence study instead.
2. By publishing this article from the Office of Pharmaceutical Science at the FDA, there is an inference that a two-tier system of we (first world) and they (developing countries) is appropriate for healthcare in these different environments, respectively. The question to be asked is whether the FDA would accept in vitro bioequivalence testing, whatever that is, as proof of efficacy? In many developing countries, there has been a drive to ensure that any products and in particular generic drug products that reach the market are likely to be substitutable and prescribed so as to prevent ineffective products reaching the market.
3. Despite the concept of the Biopharmaceutics Classification System in which the basis of high solubility and subsequent rapid dissolution of a highly permeable drug and thus an opportunity for a waiver of in vivo studies, it is still not apparent if any products in this category have reached the market in the first world, based solely on in vitro testing.

I do not feel it is appropriate that developing countries are singled out for what appears to be the use of inferior and/or ineffective drug products on the basis of the opinion of an individual who writes out of an office at the FDA.

Response to the Letter of Prof. R. B. Walker, Ph. D.

The commentary “Role of Dissolution Testing: Regulatory Perspectives” in 10th Anniversary Issue of Dissolution Technologies reflects scientific knowledge gained in dissolution testing over last three decades and a look into the future.

To answer specific points raised by Dr. Walker:

1. (i) First definitions:

   Bioequivalence test: Bioequivalence test is a test that determines the equivalence between a multisource (generic) product and the comparator (reference, innovator) product using either in vivo or in vitro approach. (Ref: WHO Document QAS/04. 093)

   In Vitro Bioequivalence Test: In vitro dissolution test for similarity of dissolution profiles between the multisource product and the comparator product in 3 media, 1. 2 N HCl, pH 4. 5 and pH 6. 8. (Ref: WHO Document QAS/04. 093)

   (ii) A clear distinction between the two types of dissolution tests–the dissolution test as a quality control (QC) test and the dissolution test as a bioequivalence (BE) test should be recognized. When dissolution is used as a QC test, it is generally a single point test under one condition� for immediate release (IR) products. On the other hand, when dissolution is used as a BE test, it requires dissolution profile comparison (f2 > 50) of the test (generic) product with the reference (innovator, comparator) product in three pH media representing the entire GI tract. The reference product is approved based on safety and efficacy data. Dissolution profile comparison (f2 > 50) in all three pH media establishes a link between the test product with the reference product whose safety and efficacy has already been established.

   (iii) The biowaiver described in FDA's guidance for industry�

   1. Bioavailability and bioequivalence studies for orally administered drug products - General considerations (March 2003) and
   2. Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid dosage forms based on a biopharmaceutics classification system (BCS) (August 2000) document the application of dissolution as a surrogate marker for bioequivalence.

   Dr. Walker's statement “it (dissolution) is not a surrogate test for bioequivalence test unless a specific in vitro-in vivo correlation (IVIVC) has been established”is only partially true. However, very few IR products exist for which IVIVC has been established. Dissolution is used as a surrogate test for BE every time a biowaiver is provided based on dissolution profile comparison.

2. What standard exists today for the pharmaceutical products made in developing countries? Can they afford to do and have capabilities to perform bioequivalence testing as done in developed countries? It is not a question of two tier systems, but it is a question of practicality under the circumstances: what is affordable and how the QUALITY of the product can be improved in the developing country. Taking this point into consideration, WHO is working on a 'Proposal to waive in vivo bioequivalence requirements for WHO model list of essential medicines - immediate release solid oral dosage forms', based on in vitro dissolution studies.

   FDA has accepted submissions based on in vitro BE testing.

3. The Agency has seen the data and product has been approved based on BCS.

I trust that this addresses points raised by Dr. Walker and it reaffirms the value and importance of dissolution test in assuring product Quality.

Vinod P. Shah, Ph. D.

 

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