Recently a question was asked as to whether my suggested approach of IVIVP for predicting plasma drug levels, based on convolution technique, is applicable for evaluating the stability samples as well. The answer is yes, an explanation follows:

It appears that this question originates from the current thinking and belief that dissolution methods depend on the nature and source of a product. For example: it is quite common that different products such as IR and ER are often analyzed using different dissolution methods. Similarly, often dissolution methods for QC purposes and for product development are different. Unfortunately, this current thinking i.e. product dependent dissolution testing, is not correct.

Appropriate prediction of plasma drug levels requires that dissolution results should be obtained using physiologically relevant experimental conditions. As the physiological (GI tract) condition or environment is independent of the nature or source of the product one, therefore, requires the use of product independent dissolution testing as well.

The artefact of the poor stirring and mixing within dissolution vessels dictates that the tests using paddle and basket apparatuses should be conducted using product dependent experiment conditions. Therefore, results obtained using these apparatuses cannot be considered as physiologically relevant. The predicting of plasma drug levels to evaluate products using these apparatuses obviously becomes a futile exercise. Continue reading →

As a part of ongoing discussion on the LinkedIn Network group (Quality-by-Design), I posted the following response. For the interest of people who do not participate in the LinkedIn Network or the particular group, I am posting the response on the blog as well. I hope that you will find the post useful.

Bill:

With all due respect and with all my humbleness, I say that your post in response to my question about a fairy tale, itself is a fairy tale. Do this or do that and fire some people, who file papers/data which were created by others, you know who, but keeping the lobbyists should hardly be considered as defining and describing the problem and let alone solving it.

Let me go one step further, in my view, a bigger and juicier fairy tale is QbD itself. It is an adult version of children fairy tales, only it cost a lot more than children versions. Let me explain:

In our area (related to drug product quality), the quality of products, in particular oral products such as tablets and capsules, is determined by plasma levels of the drug. However, in most cases, the quality after initial stages of product development is established based on in vitro methods. The leading test in this regard is a drug dissolution test. People, who are not familiar with this area/subject, can take my words for it (considering my 25+ years of experience in all aspect of such testing) that it is the most simple test one can have in the entire science area perhaps after the procedure for taking body temperature. The idea behind this test is that if the drug dissolves (which we measure by this test) the drug will be absorbed in the body and will provide its intended efficacious effect. It is part of all GMP requirements and all national and international guidances and standards. Continue reading →

There is no doubt that drug dissolution evaluation is a very important and critical step for the development and assessment of products and will remain so in the future. However, dissolution testing itself will change significantly and dramatically.

The simplification will be reflected by the availability of a very small number of methods, if not only one or two, even for QC purposes. It is important to note that the currently described methods, which are in the hundreds, if not in thousands, will be discontinued as they will not be considered as dissolution methods. These will, in fact, be considered as sets of experimental conditions to show presumed or pre-set dissolution results which will be of limited use. For an appropriate dissolution characterisation of a product the test must be product independent, which is currently not the case.

The test procedures and the apparatuses mostly used, in particular, paddle and basket, are not validated and qualified for their intended use. It is surprising that these apparatuses have been in use for such a long time, however, this practice cannot continue further in a modern and highly regulated and standardized industry such as pharmaceutical, in particular for QC purposes.

It is to be noted that these apparatuses (paddle/basket) cannot be qualified and validated: (1) these apparatuses are inherently flawed because of the poor hydrodynamics within the dissolution vessels hence cannot provide the required repeatability and reproducibility for testing; (2) the stirring/mixing environment within the vessels is such that they cannot simulate the required GI tract physiology appropriately, thus they will never provide physiologically relevant results. Therefore, the use of these apparatuses will be discontinued.

In addition, it should be noted that as the results and conclusions drawn from many years of work are based on the use of these flawed apparatuses, all the observations and claims will require reconsideration.

Considering the above described facts, it should be prudent that one should start preparing for this eventuality of discontinuation of paddle/basket apparatuses.

The good news, however, is that the dissolution characteristics, including the prediction of the plasma drug levels, can easily be determined using a modified approach of Assay and CU determination. For further discussion in this regard, please see the selected links below:

http://www.drug-dissolution-testing.com/?p=1349
http://www.drug-dissolution-testing.com/?p=1328
http://www.drug-dissolution-testing.com/?p=1214
http://www.drug-dissolution-testing.com/?p=1183

The present day confusion regarding IVIVC comes from a poor understanding of the concept and its presentation in the literature. The commonly presented description of the IVIVC concept in literature is the development of the relationships, or lines, between in vitro (dissolution profiles) and in vivo (dissolution or plasma profiles) results, as described earlier (see link).  The confusion comes from both aspects i.e. theoretical, along with its associated mathematical procedures, and the experimental.  Please click here for complete article

The development of IVIVC is often described as follows: In vitro in vivo correlation (IVIVC) is an important concept and a tool in the development and evaluation of pharmaceutical dosage forms, especially modified release dosage forms. The objective of developing an IVIVC is to establish a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. Please click here for complete article