BIOANALYTICX

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)

Often analysts face a dilemma as to how to approach the situations mentioned above, which appear to be quite common in the industry. Such situations arise because of the current practices of developing and using product-specific experimental conditions such as apparatuses, rpm, media, etc. The experimental conditions are set by obtaining desired or expected drug release characteristics of the test product, which are only associated with that test product. If the expectation of dissolution results are changed or change is made to the product (formulation/manufacturing), the test would require a different set of experimental conditions, reflecting new expectations. In short, the current practices do not provide true dissolution characteristics of products.

To avoid such a situation or developing a modified method, one should develop a product-independent method based on a physiologically relevant environment that does not change from product to product. The physiologically relevant method provides appropriate and unbiased dissolution characteristics of the products and frees the analyst from a constant struggle of looking into altering and selecting experimental conditions.

There are suggestions in the literature (1, 2, 3) for conducting physiologically relevant tests independent of products, which may answer the above-mentioned situations and significantly simplify dissolution testing in general.

The terminology of “developing IVIVC” is often used in the area of drug dissolution testing, which reflects developing a relationship between in vitro (dissolution) and in vivo (bioavailability) results.  However, the statement appears redundant, as this relationship always exists between in vitro and in vivo results. In fact, the existence of this relationship (IVIVC) forms the basis of dissolution testing practice. 

So, then the question is, why are these IVIVC development studies frequently conducted and described in the literature? The reason may be explained as follows:
 
The apparatuses commonly used for dissolution testing, particularly paddle and basket, do not provide relevant dissolution results as they do not appropriately simulate an in vivo environment. So, instead of using apparatuses that would appropriately simulate an in vivo environment, studies are conducted to find or “develop” experimental conditions to obtain in vitro results that match the in vivo results. Thus this practice of developing product-specific experimental conditions (apparatus, medium, rpm, etc.) has become known as “developing IVIVC”. However, this practice of IVIVC does not serve any useful purpose for predicting in vivo results, relating in vitro results to in vivo outcomes or assessing drug release characteristics of the product. Having said that, the question then becomes, what is the intended purpose of IVIVC development?  The purpose is not to develop IVIVC, as stated above, this relationship always exists, but to determine/predict the drug concentrations in blood utilizing the IVIVC concept. Thus, the practices of IVIVC and dissolution testing are for establishing (calculating/predicting) drug concentration-time (C-t) profiles in humans. For a more detailed discussion on this subject, along with a description of a simple method for determining C-t profiles,  please see the article (The Open Drug Delivery Journal, 2010, 4, 38-47. (Link).

European Medicines Agency (July 14, 2010): A concept paper on the revision of the note for guidance on the quality of modified-release oral dosage forms and transdermal dosage forms: Section I (quality).

… The main topics to be discussed during the revision of the guideline in the context of modified-release oral dosage forms are: … (Link)

USP provides Reference Standards (Abbreviated by RS symbol) for drug substances. In practical terms, their purpose is to provide a goal post or reference against which purity (quality) of drug substances, and then drug products, be established. An RS comes with its purity certificate, established independently by different analytical tests. These RS compounds are used extensively for qualification, development, and validation of analytical methods such as chromatographic or spectrophotometric. In addition, for cost/expense savings, often these standards are used as primary standards for developing in-house secondary standards.

As stated above, these standards are used for various purposes utilizing numerous analytical techniques, such as HPLC, TLC, GC, GC/MS, and other much more involved analytical techniques. However, they are not described as performance evaluation standards or faults/deficiencies detectors of the apparatuses. These standards are to be used to indicate deviation/variations in diameters of the glass capillary or HPLC columns, flow rate of mobile phase (gas or solvent) through columns, temperatures of oven or enclosures of columns, or the training/expertise of the analysts. It is usually understood that if the apparatuses are operating under their expected physical and operational specifications in the hands of experienced and trained analysts, then their output using RS would be exactly as described in the certificate of analyses. If not, then necessary corrective measures are to be taken, which may or may not be relevant to the technique itself. For example, purity or composition of the mobile phase and the instability of electric current may cause out-of-spec results or apparatus performance. This does not mean that the RS will become a performance evaluation procedure for solvent purity or stability of electric current or related circuit boards.

With this background, if one sees the current practices of Performance Verification Test or Tablets (PVT), which are also marketed by the USP as Dissolution RS Tablets, these tablets do not appear to meet the requirement of a reference standard. The reasons are: (1) Dissolution RS Tablets release values are not independently determined. The values are set using the apparatuses, which are then assessed by the use of these tablets. (2) The RS tablets have different values for different apparatus (e.g., Basket and Paddle). PVT must have the same values for all commonly referred apparatuses, Basket, Paddle, Reciprocating, Flow-through, and any other apparatus or technique suggested in the future. This is similar to the current practices for other RS standards, which are expected to provide the same results (purity) whether tested by UV, TLC, HPLC, GC, etc. (3) These PV Tablets do not have desired outcome characteristics. As the dissolution testers are used to establish potential drug release quality/characteristics of products in humans, the RS tablets should have known release characteristics in humans independently determined, e.g. based on pharmacokinetic studies. (4) Similarly, the RS Tablets should also be from an approved product for human use and within its shelf-life duration.

It is hoped that the suggestion will help develop improved RS Tablets and alleviate the difficulties one faces in using current Performance Evaluation Tablets.

In the absence of appropriate RS tablets, one may evaluate and establish operational parameters of the apparatus based on relative dissolution testing. In this case, one may analyze two products of know release characteristics in humans of the same API product, such as IR and ER. Both products should provide differential drug release characteristics within their recommended (prescription) dosage intervals. Based on such testing, the operational parameters of the apparatuses are set (fixed), which would be used for testing the test product. The product(s) used to establish or determine the operating parameters for the apparatuses would become the RS Tablets.