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I have had the opportunity to read the (review) article titled

“In vitro models for the prediction of in vivo performance of oral dosage forms (2013), link”

and certainly, it is quite a (very) long article, but is it useful? In one way, it might be, since it implies that the practices of dissolution testing have not been successful, at least from the in vivo perspective. It is claimed that for QC purposes, the practices may be successful (however, without going into details, I would argue against this view, see below).

My biggest surprise, a pleasant one, is that there is no or limited emphasis on the IVIVC aspect. I am assuming that the lack of use or relevance of IVIVC for the predictability of plasma drug levels has been recognised. This is great!

On the other hand, there is an emphasis on PBPK (physiologically based pharmacokinetics) modelling (perhaps starting of a new “fad”), with an underlying assumption that one requires complex instrumentation and mathematical modelling to predict plasma drug levels. In my view, such an approach may not be necessary as a simple convolution approach can predict plasma drug levels very well and easily.

Surprisingly (or perhaps not surprisingly), there is no mention of crescent shape spindle, convolution technique or the name Qureshi in the publication. This may reflect the lack of credibility of the publication for the literature assessment/review.

In addition, in my view, the publication does not provide any suggestion as to how one should determine dissolution characteristics of a, or any, product (IR or ER). So, the question remains, if one cannot determine dissolution characteristics of a product (e.g., see link), one cannot move further, may it be for QC, PBPK modeling or prediction of plasma drug levels, etc.

However, answers to such questions can easily be found as described in the following articles:

(1) Determining blood concentration-time (C-t) profiles from in vitro dissolution results and product evaluation – carbamazepine (link).

(2) A Simple and Unique Approach for Developing and Evaluating Products (link).

In a recent addition to USP 37 GENERAL NOTICES AND REQUIREMENTS (link), USP describes 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 the 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. The 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, such as product development, bio-waiver, IVIVC etc.

It appears that people do not realize 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 guidelines and requirements for recommending dissolution tests for assessing BE/BA. In fact, in my view again, the statement and view have practically made related guidances useless.

Therefore, it is not a simple “stating the obvious or of already known” scenario. It is a profound development that 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.

A similarity factor (F2) is commonly described in the 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 that 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, the 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 the 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 a 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 different 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.

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”.

In reality, 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. Therefore, drug dissolution tests must be conducted using physiologically relevant experimental conditions such as 37 ºC temperature, aqueous buffers within physiological pH range, moderate stirring, etc.

There has been a 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. Read the rest of this entry �

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 the relevant Expert Committee approves them 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 must know which characteristic/parameter of the product these compendial dissolution tests measure 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. Read the rest of this entry �

[As part of a discussion on the LinkedIn Network group (Pharmacokinetics), I posted the following response. For the interest of those who do not participate in the LinkedIn Network or the particular group, I am posting the response on this blog as well. I hope that you will find the post useful.]

Thanks again, Simon: [Simon’s post is attached at the end of my response]

I do not think we are going in circles, but in my opinion, you are either not following my point or avoiding it. Let me explain it another time.

“IVIVC aims to Predict in vivo behavior from in vitro data.” This is incorrect. As the name (or “C”) implies, it is not a prediction exercise but an exercise in developing a correlation. For IVIVC, one has to have in vitro (i.e. dissolution) data and in vivo (plasma drug levels) data to relate them. No prediction whatsoever.

Please click here for the complete article

Before using any tester, it is commonly understood and often in fact is a requirement to establish that the tester is capable of measuring the expected parameter or characteristics. For our purpose, prior to its use, the apparatus or tester must be shown that it is capable of providing appropriate dissolution characteristics (i.e., percent drug dissolution at times) of a pharmaceutical product. There are different ways of saying the same thing, for example:

The tester is capable of measuring the dissolution characteristics with the required precision; the tester is fit for its intended purpose, or the tester is qualified and validated for its intended purpose.

The usual practice for establishing the “fit-for-purpose” or performance of a tester would be to determine dissolution characteristics of a reference product with its associated precision. If the tester provides the dissolution value with required precision, the tester will be considered qualified and validated. Read the rest of this entry »

July 14th, 2013 | Author: Saeed Qureshi

The above title is self-explanatory, clear, and says it all.

When offered help in developing and/or validating dissolution methods based on non-validated apparatuses (e.g. paddle/basket) and/or experimental conditions, people have to be careful. The results obtained would not be of any use, even for QC purposes, no matter how they are presented.

The following links may be of further help in this regard

(1)    If one cannot determine the dissolution characteristics of a product, then how would one be able to establish its quality or bio-relevance? A serious flaw of current practices! (link).

(2)    De-aeration of a medium and vibration-free environment – perfect attention deflectors (link).

(3)    Note that no one can determine, or has determined, dissolution characteristics of any product using the currently suggested apparatuses and/or methods. It has all been an illusion! (link).

(4)    Assessing drug dissolution characteristics using product-dependent methods is simply unscientific and invalid practice. (link).

(5)    Dissolution method development: Perhaps the most wasteful of all the current practices! (link).

(6)    Current practices of drug dissolution testing using paddle/basket apparatuses – A complete waste of time! (link).

(7)    Promotion of simplicity of paddle/basket apparatuses – A marketing gimmick for scientifically useless and non-validated apparatuses (link).

(8)    Drug Dissolution Testing – A serious concern! (link).

(9)    Drug dissolution testing: Limitations of current practices and requirements (link).

(10)Dissolution Apparatuses: Compliant vs Qualified and Validated (link).

(11)Costly mistake formulators/analysts often make, i.e., developing a product-dependent dissolution test (link).

(12)Apparatus Calibration or Performance Verification: Misleading Conclusions and False Comfort (link).

For further details, please see the following links:

1. A Simple and Unique Approach for Developing and Evaluating Products (link)
2. Assay and Content Uniformity (CU) based on dissolution testing (Poster Presentation). (link)

Some more relevant links:

• The science of drug dissolution testing: Testers or apparatuses, experimental conditions, and interpretation of results – A systematic approach for learning. (link)
• Selecting a Dissolution Apparatus – Some Practical Considerations. (link)
• Drug Dissolution Testing Using Simple and Common Experimental Conditions (link)
• One Step (Product Evaluation) Approach (link)
• Can a dissolution test be used for assay and content uniformity testing? Of course! (link)

An In-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response.” For pharmaceutical products (tablets and capsules in particular) development purposes, in-vitro property and in vivo response mean in vitro drug dissolution/release characteristics and the plasma drug concentration profiles, respectively.

It is important to note that this relationship, or model, always exists between the two variables (dissolution vs plasma profile) for a given drug, which forms the basis for in vitro dissolution testing and its use to assess the quality of pharmaceutical products. Therefore, developing this relationship or modeling should have never been part of the practice of drug dissolution testing or its applications for products development or evaluation. However, this is precisely what has happened during the past two decades, i.e., repeated recommendations were made for correlating dissolution results with plasma drug levels. In fact, such developments have been suggested as regulatory requirements.

A quick review of the literature will clearly show that the exercises of developing IVIVC have never been successful. Obviously, the first question would then be why has the development of IVIVC not been successful when it always exists, as stated above? One of the main reasons for such a lack of success is the choice of experimental conditions, particularly dissolution testers. The recommended dissolution testers, particularly paddle and basket, have never been shown to provide in vivo (or bio-) relevant results. That is, these apparatuses have never been qualified and validated for their intended purpose. There are reports describing that these testers cannot provide bio-relevant dissolution results. Therefore, these recommended apparatuses should have never been suggested and used for IVIVC developments. On the other hand, sporadic claims of successes of IVIVC are usually based on adjusting dissolution experimental conditions to reflect in vivo results, which by definition are not IVIVC but matching of in vitro-in vivo results, with no predictability potential. Therefore, it is often difficult to accept, but the fact remains that the current practice of IVIVC development has been a futile exercise.

The second issue with the current practice of IVIVC is that it does not predict plasma drug concentrations/profiles, which has been the promoted objective of IVIVC. As noted above, it is an approach for describing a relationship between dissolution and plasma drug profiles, but not for predicting plasma drug profiles from dissolution results. However, the latter has been assumed, unfortunately incorrectly.

It is important to note that the only objective of conducting a dissolution test is to estimate/predict plasma drug levels/profiles from dissolution results. In particular, at the product development stage, a formulator would like to estimate in vivo behavior of a test product/formulation based on drug dissolution results. This can only be achieved by combining the dissolution results of the product with the pharmacokinetic characteristics of the drug (usually available from literature). The process of combining dissolution results and pharmacokinetic parameters is known as the convolution method/technique. Thus, there is no need for developing IVIVC if the objective is to estimate/predict plasma drug levels, which indeed it is.

In short, to predict/estimate plasma drugs levels from dissolution results, one does not require IVIVC or deconvolution approach, but the convolution. Therefore, the requirement or current practice may be considered as a futile exercise, which can easily be discontinued. In addition, even for the success of the convolution approach, one would require properly qualified dissolution apparatuses, certainly, paddle and basket apparatuses in this regard are to be avoided.

To address the above-described issues, the following two suggestions have been made:

• A modified apparatus; based on currently used vessel-based apparatuses, but with a modified stirrer, known as crescent shape spindle.
• A simple convolution-based approach using Excel spreadsheet software to determine plasma drug levels from drug dissolution results.

For further details in this regard, the following links would be helpful:

1. In Vitro-In Vivo Correlation (IVIVC) and Determining Drug Concentrations in Blood from Dissolution Testing – A Simple and Practical Approach. (link)
2. Determining blood concentration-time (C-t) profiles from in vitro dissolution results and product evaluation – carbamazepine. (link)
3. A New Crescent-shaped Spindle for Drug Dissolution Testing—But Why a New Spindle? (link)

Presently, only the use of the crescent shape spindle provides true dissolution characteristics of a product (link)