There appears to be serious and unfortunate confusion among the dissolution scientists/analysts, which implies that the compliance and qualification/validation of apparatuses are one and the same or at least interchangeable. This is incorrect. The data obtained using apparatuses such as pharmacopeial paddle/basket, which usually are in compliance but NOT qualified/validated. They have limited scientific validity and lack relevance to products’ attributes or qualities, as explained below:

A compliant apparatus means that it meets the required specifications commonly set by standard-setting organizations (such as pharmacopeias, e.g., USP 1 & 2) for the manufacturing and operating of the apparatuses. On the other hand, a qualified and validated apparatus can be used for its intended purpose to evaluate or assess, reproducibly, the product’s characteristics, which in this case is drug dissolution testing. The qualification/validation step usually requires a reference (product) with known characteristics, established independently of the apparatus. It is generally assumed that if an apparatus complies with the required specifications, it is qualified and validated as well. This is often the case, but not with dissolution apparatuses. No reference product is available with known dissolution characteristics established independently, so one cannot qualify and validate these apparatuses. If one cannot qualify and/or validate a dissolution apparatus, one cannot determine the test product’s dissolution characteristics either.

Interpretation of dissolution results obtained from such apparatuses will be misleading at best and incorrect in general. A quick and simple method to assess the qualification and validation of a dissolution apparatus without a reference product is to conduct a comparative dissolution test using IR and ER products of the same drug. The IR and ER products have known dissolution characteristics independently established using human bioavailability studies.

A qualified and validated apparatus will be the one that will differentiate the drug dissolution characteristics of these products using a common set of experimental conditions simulating the GI tract environment. A qualified and validated dissolution apparatus can be compliant by including its specifications in a pharmacopeia. However, current compliant apparatuses cannot be made qualified and validated, in particular paddle/basket, as they lack the capability of providing relevant and reproducible dissolution results.

The use of a qualified and validated dissolution apparatus, which may not have compliance specifications, will be more appropriate at present for the development or evaluation of products than the one which has compliance specifications but has not been qualified and validated. The crescent-shaped spindle has been developed to address the deficiencies of the currently used apparatuses and practices to provide a more appropriate choice for conducting dissolution testing and, thus product development and evaluation.

This article presents a practical view of the QbD (Quality by Design) approach and its implementation. It is argued that the critical component of the approach, the defined “quality” attribute to be achieved, is lacking. To address this issue, from the consumer/patient perspective, the quality of a tablet/capsule product may be defined as the availability/release of the drug in an expected amount and manner. However, the technique most often used (known as drug dissolution testing) to evaluate such quality has been recognized to be flawed. Therefore, it is highly unlikely that the QbD approach as presented will be successful in providing improved quality of the products. Suggestions are made for addressing the issues for a potentially successful implementation of the QbD practice. Please click here for the complete article

A set of slide presentations from FDA Scientists at the “Advisory Committee for Pharmaceutical Science and Clinical Pharmacology” was held on August 8, 2012. (link)

Impressive and highly complicated and complex material. Unfortunately, the crescent-shaped spindle (link) and simple convolution approach (link) did not make it up to there. Perhaps it was too simple and straightforward in concept, which may actually solve the issues highlighted in the presentations.

Well, maybe the next time!

As a fundamental scientific principle, it should be obvious that one should NOT develop or use product-dependent methods or parameters to characterize the product itself. However, this is precisely the practice in the pharmaceutical area for product development and/or its evaluation, i.e., everyone seeks/develops and uses a product-dependent dissolution method.

This is clearly an example of a mindset that is incorrect and scientifically invalid. It appears that the practice of pharmacopeial testing has created this mindset. Most pharmacopeial tests (e.g., USP) are drug and/or product-dependent. However, these should be considered scientifically invalid or useless. If a dissolution test is product-dependent, then it will not be possible to establish whether observed dissolution characteristics are because of the product or due to the experimental conditions used. Therefore, it should be noted that one cannot rely on product-dependent (e.g., pharmacopeial) methods to establish dissolution characteristics of a product, thus its quality.

To evaluate the quality of a drug product, the dissolution method must be product-independent. Therefore, developing product-dependent dissolution methods for any purpose, i.e., QC, discriminatory, bio-relevant, IVIVC, bio-waiver, QbD etc should be considered a mistake and complete waste of time and resources.

At present, a vessel-based dissolution tester with crescent shape spindles (link) has been suggested for product independent dissolution testing. Thus, it provides unbiased and scientifically valid dissolution testing but also helps in saving large resources.

Commonly described dissolution methods are product-dependent. Therefore, it is not possible to know whether the observed dissolution characteristics are a reflection of the product (formulation and/or manufacturing) attributes or because of the experimental conditions (apparatus, rpm, medium, etc.) employed.

For an appropriate and accurate assessment of dissolution characteristics of a product, the dissolution method must be product-independent. The use of crescent shape spindle has been suggested based on this principle, thus providing true product dissolution characteristics. Please see the following links for further discussion:https://bioanalyticx.com/simpler-and-more-appropriate-dissolution-testing/
(2) http://www.drug-dissolution-testing.com/blog/files/Flyer.pdf
(3) https://bioanalyticx.com/product-dependent-dissolution-testing-a-scientifically-invalid-practice/
(4)

The Crescent-Shaped Spindle

A drug dissolution test is an analytical test of such significance that it is hard to imagine that any oral drug product such as tablet and capsule would be developed and manufactured without its use. The majority of the tests are conducted using testers, commonly known as paddle and basket apparatuses. It is a well-accepted and implied understanding that not using one of these apparatuses will require a long and unkind explanation for deviating from the “norms,” resulting in potentially extensive and costly delays in bringing the products to the market. Therefore, Please click here for the complete article

A suggested definition of “quality” for QbD purposes is described. It is hoped that the article will help highlight the underlying scientific issues and deficiencies that will prevent achieving the intended objectives of the suggested “QbD-based ANDA example documents.” It is argued that the documents are based on invalid analytical (dissolution) methodologies, which also makes the suggestions/recommendations invalid. Suggestions for improvement are provided. Please click here for the complete article

A method based on the convolution technique has been described earlier to predict plasma drug concentration-time (C-t) profiles. This article describes further refinement of the method for a more realistic representation of a human bioavailability study outcome by including variabilities in stomach emptying time and bioavailability factor (F). The advantages of such refinement are discussed, including setting physiologically relevant specifications for dissolution testing. Please click here for the complete article

PS: Please note that an error in the text was detected on page 2, column 2, and paragraph 2, which has been corrected. The revision reads as follows: “For this particular example, it is assumed that the filter will release (not adsorb) on average 44%±10(±SD) of the drug, representing average F (bioavailability) and variation in the F for diltiazem.”  My apologies for the oversight and any inconvenience it may have caused. Saeed (July 27, 2012).

This article summarizes the principles of drug dissolution testing, emphasizing the underlying scientific assumptions that are often not clearly described or understood. It should be noted that the dissolution technique itself is extremely simple to use. However, current practices of selecting experimental conditions and the interpretation of dissolution results are seriously misunderstood and require attention. To address these deficiencies, analysts should seek essential training in the areas of relevant physiology and pharmacokinetics. In the absence of such required training and knowledge of the subjects, it is highly unlikely that an analytical laboratory can generate relevant and accurate dissolution data, thus failing to meet the products development and evaluation objectives. Links to some articles on the subjects are provided, which may help the analysts in improving their overall skills in these areas. Please click here for the complete article