BIOANALYTICX

It is important to note that the emphasis is on the “practice” and not the drug dissolution testing itself. A drug dissolution test is an important and extremely useful test and is required for the development and evaluation of pharmaceutical products, in particular tablets and capsules. However, how the test is conducted, referred here as the “practice,” is very different from dissolution testing itself. One should keep this difference in mind. 

There are numerous issues with the practice (or conducting a test). For example:

The test is to be done to determine drug dissolution characteristics of the product, but in practice it is done to establish experimental conditions to obtain pre-set (or preconceived) dissolution characteristics of the product. The analyst would never know the true drug dissolution characteristics of the product, thus its quality.

The most commonly used apparatuses, particularly paddle and basket, have never been validated to establish their suitability for drug release (or product) evaluation. These apparatuses usually do not even differentiate a slow-release product from a fast release product and vice versa. Thus, separate methods for these types of products are required. However, their use within the same product type is required to differentiate drug release based on manufacturing/formulation attributes.

Commonly, the practice is rationalized to monitor batch-to-batch consistency in product manufacturing. However, the consistency of the test (repeatability and reproducibility of the test itself) has never been established.

Often, tests are expected to be conducted using irrelevant experiment conditions, de-aeration in particular with a non-verifiable parameter or end point.

A product is expected to have more than one value (result) of the parameter (dissolution). Even USP performance verification tablets (USP) have two sets of dissolution results based on apparatuses used. The question is, what are the correct (true) dissolution characteristics of USP performance verification tablets?

The reason for these problems appears to be that for the past number of years, the focus has been to rationalize the use of paddle and basket apparatuses, which have been known to be flawed.

For appropriate testing, the focus must be on obtaining relevant and reproducible dissolution results of a product. The practice of adjusting experimental conditions to obtain certain desired or pre-conceived dissolution results should be discouraged.

Hello Vivian:

As suggested, I am posting your response to the post mentioned above, along with an Editorial note from myself. Regards. Saeed

Editorial Note:

To address this response, I would like to clarify that I was referring to a potentially diminished role in the future in my post. Also, I assume that your comments reflect your personal views and not those of the USP or the new Expert Advisory Committee.

Response:

Dear Saeed, I feel I have to respond your recent posting on your website about Changes at USP. Please be sure you have seen the article in the August issue of Dissolution Technologies that gives the make up of the new USP committee. This information in is the USP update with Tom Foster achieving the Beal award. In that article the new members of the new committee are listed. There are five members of the BPC committee that are now on this new committee. They are Mario Gonzalez, Johannes Kramer, Tom Foster, Alan Parr and I. These people were very much involved with the PVT and I can assure you that the work will continue in the new committee and at the USP labs. The USP has published many articles in Pharmacopeial Forum (PF) about the PVT and evaluations of variables using the Prednisone Standard Tablets. Also if you look in Dissolution Technologies (DT), www.dissolutiontech.com back issue there are a plethora of articles on the dissolution variables and the USP Prednisone Tablets. Also in DT we have reprinted many of the PF articles about the PVT and the new criteria. So the “absence of clear information” is not accurate. If you go to the USP website there are many places for information on the subject including the USP Tool Kit on mechanical calibration. As a point of interest, the PF will be available on line for free in 2011.

I was hoping that I could respond on your website but the comments are closed. Please consider posting my reply to you in this public forum.

Best regards, Vivian

9 Yorkridge Trail
Hockessin, DE 19707 USA
Tel. 302-235-0621
Fax 443-946-1264

vagray@rcn.com
www.vagrayconsulting.net
www.dissolutiontech.com (now searchable, check it out)

Current practices of drug dissolution testing require that the experimental conditions, such as medium and its volume and apparatus and its associated stirrer rotation speed, be established for each test product to achieve certain ‘expected’ dissolution characteristics or results. In reality, however, the purpose of dissolution testing should be to determine potentially unknown dissolution results reflective of a test product based on its formulation and/or manufacturing attributes. For appropriate testing, particularly for comparative purposes, the experimental conditions must be the same or consistent from product to product, i.e., product independent. This article describes a newly developed spindle, known as crescent-shaped, which can easily be installed in the vessel-based dissolution apparatuses (basket and paddle) to provide a product-independent dissolution testing approach for improved drug dissolution assessments. The new spindle provides an improved stirring and mixing environment, leading to better characterization of pharmaceutical products. The use of the crescent-shaped spindles offers additional significant advantages over the current practices, such as (1) allows analyses using a single method, compared to hundreds as currently required, for both immediate and extended-released products having the same or different active ingredients; (2) provides improved dissolution characteristics of products by avoiding false slow-release properties for fast release type products; (3) simplifies testing by avoiding the necessity of developing separate QC and bio-relevant dissolution methods; (4) provides a rugged testing environment free from common sensitivities, in particular to de-aeration and vibration effects. (Link to the article).

It may be said that analysts performing drug dissolution tests are in a pretty difficult situation. They are expected to conduct appropriate dissolution tests to determine the quality of a product based on its in vitro drug release characteristics. However, procedures described in the literature (e.g., USP <1092>) or commonly taught in courses provide suggestions for choosing/selecting experimental conditions to achieve (match) a desired or pre-set dissolution outcome. These desired dissolution characteristics are commonly obtained by selecting apparatuses (mostly between basket and paddle) and/or adjusting rpm, pH, or molarity of medium/buffer and/or solubilizer (nature or amount). Therefore, it is important to note that the analyst, following the currently suggested procedures, will never know the true or actual nature of drug dissolution characteristics of the product, thus its quality.

A similar confusing situation exists when one is expected to establish bio-relevant characteristics of a product. Here, the analyst also does not determine the potential in vivo dissolution characteristics of a product but requires that in vitro dissolution results match those obtained from a bio-study by adjusting the experimental conditions. An even more confusing aspect of this practice is that the analyst is expected to describe this matching exercise as developing a bio predictable dissolution method. Sometimes such confusion and misunderstanding are quite obvious, for example, as described in a recent publication.

“Adjusting dissolution testing conditions to match the behavior of the formulations in vitro with that in vivo by taking into account the properties of the drug and the formulation is a straightforward and useful approach in identifying a predictive method in the development of the IVIVC. These investigations will definitely help by derisking of new formulations as well as by rating changes in existing formulations with regard to their impact on bioavailability before entry into human”.

Such described methods are neither bio-relevant nor predicable, instead, it is simply obtaining expected results by adjusted experimental conditions. A simple analogy to such an approach would be that one could start dissolution testing with a high-speed stirrer (blender) and keep adjusting the stirring speed lower and lower until desired dissolution results are obtained. Obviously, this will not be considered a predictable of the bio-relevant test. The analysts must work with a standard and common procedure independent of the test product for appropriate testing. If a product does not provide relevant or expected dissolution characteristics, then the product attributes (formulation/manufacturing) are to be changed, not the dissolution method to achieve or match certain desired results. This is not a requirement for just dissolution testing but a standard scientific principle and procedure of analytical chemistry. This is where current practices of dissolution testing have deviated from standard scientific principles.

The reason for this deviation is because of the recommended dissolution apparatuses, in particular paddle and basket, which are flawed. There are numerous examples/studies provided in the literature describing their flaws. These apparatuses are not capable of providing relevant and reproducible dissolution results. However, the analysts and manufacturers are required to use these flawed apparatuses and experimental procedures to meet regulatory requirements. Thus, the dissolution results reported are often fulfilled the regulatory requirements. These results often do not reflect the characteristics or quality of the products.

As it stands now, therefore, analysts face a tough situation where, in principle, s/he is expected to establish the quality of drug products, but with the use of apparatuses that are known to be flawed. A more detailed discussion on this topic is provided in the literature and in various posts on this blog (please see under sub-menu “useful lists“).

 A  modified spindle has been proposed to address the flaws of the basket and paddle apparatuses. The use of the crescent-shaped spindle with a single set of product-independent experimental conditions simplifies the dissolution practice significantly. In addition, it provides more appropriate and relevant dissolution characteristics of the products. The details about crescent-shaped based approach may be found in the literature (e.g. Link), on this website/blog and the upcoming course.

The USP, in general, and its Biopharmaceutics Expert Advisory Committee (EAC) in particular, has been at the center of developing standards and procedures for drug dissolution testing for the past three decades. However, this EAC has been dissolved for the coming cycle (2010-2015) of the USP expert committees. The activities/responsibilities of the now-dissolved EAC have been transferred to a committee for General Chapter on Dosage Forms, with very few members from the earlier EAC. There has been a lack of clear information from the USP on this particular change, especially when the dissolution community is seeking answers for the difficult and frustrating problems related to drug dissolution testing. Often, these relate to the use of drug dissolution testing for product evaluations and the use and relevance of PVT.

 In the absence of clear information and an apparent significantly diminished role in the future, one can only speculate on the possible scenarios. One of those could be that the USP may be reducing its laboratory-based activities (research?) in the dissolution area as there has been limited or no success, but rather frustrations, during the past number of years. The USP may be reversing to a more traditional role for setting objective standards based on the contributions from external sources. If this assumption is correct, then the change at the USP may be considered good. This will allow the industry and others to make needed contributions and for the USP to critically evaluate the problems and accept the solutions.

Like any other analytical test, a dissolution test must also be repeatable and reproducible, with a reasonable/acceptable variability as reflected by RSD (or CV) values, say within 5 to 10%. This acceptable variability should be based on a reference product (e.g., PVT) obtained from a multi-lab evaluation.

It has been shown from experimental studies and computer simulation models that such a desired variability is not possible to obtain using the current apparatuses, in particular paddle/basket. In addition, recent discussions of the unexplained high failure rate of PVT are also a reflection of high variability in testing. Therefore, in general, it is not possible to rely on such a highly variable method to establish consistency of the product quality.

As a common practice, analysts prefer to use compendial methods, if available to evaluate pharmaceutical products. There are clear advantages of using such methods, as the results obtained are easier to be accepted by third parties, including regulatory agencies.

On the other hand, in some cases, where compendial methods lack desired characteristics or have flaws, such a practice seriously hampers the appropriate testing and thus proper evaluations of the products. This leads to significant frustrations on analysts’ part and demands for a large resource (human and financial) burden on the pharmaceutical industry.

The drug dissolution testing appears to fall in this category where the literature clearly shows that the currently used compendial apparatuses (paddle/basket) do not provide reproducible and relevant results. Although these flaws have generally been recognized, addressing the issue would take time.

During this transitional period of addressing the issue, analysts may use alternate methods to obtain reproducible and relevant results and then adjust the experimental conditions using paddle/basket apparatuses to obtain the “expected” results. Such an approach would be perfectly acceptable under current compendial practices as using the paddle and basket apparatuses, one never determines the relevant and reproducible dissolution results. Analysts usually adjust the experimental conditions (apparatuses, rpm, media, etc.) to obtain the “expected” dissolution results. The question is how to obtain the “expected” dissolution results.

New approaches have been described in the literature to obtain such “expected” results. One such approach is the use of a crescent-shaped spindle which has been shown to provide product independent dissolution results using common and pre-defined experimental conditions. One may use vessel-based apparatuses with the crescent-shaped spindle to obtain the “expected” dissolution results.

Taking this approach, one would have the expected (or “true”) dissolution characteristics of the product and then develop experimental conditions using paddle/basket apparatuses to obtain the “expected” results using compendial approaches.  Using such an approach would help meet the compendial requirements and provide the data using the alternate approach for modifying/improving current compendial methods—a win-win situation.

Provided are links to two recent articles, written by Dr. L.T. Grady who was Vice President and Director of USP Division of Standard Developments (1980-2000), from the website of Dr. T. Layloff, who later himself was Vice President and Director of USP Division of Standard Development. 

The titles of the articles are “Letter on the Adequacy of Dissolution Testing” and “Perspective on the History of Dissolution Testing”.

The contents of the articles are quite revealing, indicating that the high variability in dissolution results and their poor link to the product quality were well known within USP.

The objective of drug dissolution testing is to determine drug release characteristics of a product i.e. how fast or slow a drug would be released from the product reflecting its formulation and/or manufacturing attributes (properties).

In reality, however, current practices of dissolution testing seek product-dependent experimental conditions based on choices of apparatus, rpm/flow rate, and medium (its pH and strength) to attain a desired or expected dissolution rate. “True” dissolution characteristics of a product can never be known. Using the current dissolution practice or approach, multiple dissolution methods are often described for the same product under different names such as bio-relevant method, discriminating method, QC method, USP method, FDA method, etc. differing in experimental conditions, each providing different dissolution results.

That is why it is commonly referred that one should consult the authorities to establish the method and to determine if the results would be acceptable to the authorities.

For establishing “true” dissolution characteristics, like any other analytical method, a dissolution method must be product-independent. Developing a product independent test leading to determining “true” dissolution characteristics of a product is relatively simple, saving significant financial and human resources compared to the current practices. For further discussion on this aspect, please see the article and details of the upcoming course.

Summary:

Using a recently suggested approach, based on IVIVC principles, C-t profiles (or blood levels) are determined for different strengths and release types (IR and ER) of carbamazepine products from in vitro drug dissolution results. Drug dissolution tests were conducted using the crescent-shaped spindle (25 rpm) with 900 mL of water containing 0.5% of SLS as the dissolution medium. Predicted blood levels along with the derived pharmacokinetic parameters (Tmax, Cmax, and AUC) compare remarkably well with the corresponding human in vivo values reported in the literature. It appears that the approach described previously, and further detailed here, provides a powerful analytical technique for predicting blood levels and then evaluating product quality by establishing their equivalencies. (Link to complete article)