Author: Dr. Saeed Qureshi, Ph.D.

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)

It is often suggested that it must first be validated to use an apparatus (or method) for dissolution testing. There is nothing wrong with this statement or requirement. One should follow this requirement.

The question, however, is how one should validate a dissolution apparatus? This is where the problem is! In principle, validation means establishing that an apparatus is capable of measuring required characteristics. Here capability means the ability to measure relevant dissolution characteristics or results.

In the case of current practices of dissolution testing, however, there is an interesting twist in the validation requirement. Here, promoted validation means obtaining dissolution results similar to those obtained using one of the compendial apparatuses, particularly paddle or basket apparatus. It is important to note that the requirement is not that of relevant and/or reproducible results, but the similarity of results obtained using compendial apparatuses (read similar practices with vibration and de-aerations aspects). This would have been acceptable if compendial apparatuses were validated themselves against some relevant reference product or value. Unfortunately, the compendial apparatuses have never been validated. In fact, these apparatuses have been shown repeatedly to provide irrelevant and irreproducible results. As per current practices or requirements, any new or different apparatus also become non-validated, by default, if it provides similar results as those of the compendial apparatuses. Therefore, current recommendations require developing and using non-validated apparatuses and methods.

Not only are the current requirements and practices scientifically invalid, they also create serious hindrances in developing new and improved apparatuses and methods. For example:

(1) Current recommendations will allow using only those apparatuses that will be as bad as the current ones known to be flawed (particularly paddle and basket).

(2) In reality, the requirement/practice will not allow using any comparable method as it will be argued that if one obtains similar results using current apparatuses, then why introduce new variations. In fact, it is a clever way of maintaining the status quo or the use of flawed apparatuses and methods.

(3) It is very important to note that any new or improved apparatuses will have to provide different results, which will be the only reason for their development or use. However, considering the current mindset, these improved variations will be considered non-validated as the results obtained will be different than the ones obtained using currently recommended approaches. Therefore, improved apparatuses (or methods) would be rejected against current practices.

The implication of the above-mentioned practices may be explained as follows: Suppose someone would like to develop a physiologically or bio-relevant apparatus. Such an apparatus would be based on simulating the physiological environment. As the physiological environment is product independent and consistent across products (e.g. IR and ER), the new and improved method will be based on a single set of product independent experimental conditions. However, current requirements promote and stress product-dependent experimental conditions. Therefore, if one will compare results based on current requirements with those obtained with an improved method, those will not be equivalent or comparable. Therefore, the results obtained will be considered non-validated and will be rejected (even those obtained using an improved method simulating the physiological environment). Therefore, if current promoted validation practices continue, there is a limited chance of developing an improved and physiologically relevant dissolution method, apparatuses or obtaining dissolution results.

The only option available to develop physiologically or bio-relevant and reproducible apparatuses and/or methods is to validate these against their intended purpose and not against results obtained using arbitrarily selected apparatuses, methods and experimental conditions.

In conclusion, one should be watchful of current validation recommendations and requirements. These requirements are logically and scientifically invalid. The validation should be performed against the intended objective and not by comparing results obtained from non-validated or irrelevant apparatuses and/or using arbitrary experimental conditions.

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 example, before its use, the apparatus or tester must be shown to provide 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 can measure 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.

A usual practice for establishing a tester’s “fit-for-purpose” or performance would be determining a reference product’s dissolution characteristics with its associated precision. If the tester provides the dissolution value with the required precision, then the tester will be considered qualified and validated.

One of the critical requirements for the reference product would be that it must be directly linked to the products the tester will be used for. This reference product must be a drug product (tablet/capsule) for human use with a known dissolution value because this is what the tester will be used for, i.e., evaluating products for human use. If one does not have such a (reference) product, one cannot establish the tester’s performance. Thus, it cannot be used to determine a product’s dissolution characteristics, hence its quality.

As no reference product is available with known dissolution characteristics, one cannot check/establish the performance of any of the dissolution testers. Therefore, the testers should not be considered as qualified and validated dissolution testers. Hence, results obtained using these testers/apparatuses should not be considered valid for the assessment of any product, new or old.

The USP promotes its prednisone tablets as performance verification tablets (PVT) for two apparatuses, paddle/basket. As described above, in the true sense of the requirements, these tablets cannot be considered PVT because they neither represent a product for human use nor have known dissolution characteristics. The dissolution values reported for the USP PVT are arbitrary because the same product cannot have two or more sets of values for the same parameter. It is like saying one can have multiple solubility values of a compound depending on how it is measured (e.g., using a beaker with a laboratory stirrer, an Erlenmeyer flask with a magnetic stirrer, or using a top-loading shaker, etc.). Obviously, it will not be accurate because the solubility of a compound is the property of the compound and should be independent of the method used to measure it.

On the other hand, there are no PVT/tablets available for other commonly suggested apparatuses (USP 3 and USP 4). Therefore, no mechanism is available to establish the validity of claims for these to be considered as (qualified and validated) dissolution testers.

With an apparent twist in defining and practice of PVT, USP promotes the use of these tablets for monitoring the appropriateness of de-aeration of dissolution media, establishing a vibration-free environment of a dissolution tester and its surroundings and/or overall establishing “fitness” of the testers/analysts. Unfortunately, these are not legitimate claims and may be considered as scientifically invalid or useless, as explained below with an analogy.

In seeking the source of the lack of stability of results from a laboratory balance, one might consider that the instability issue may be due to instability of the laboratory environment, such as room temperature and/or airflow within a laboratory. To monitor the stability (or lack) of laboratory environment, the laboratory balance itself be used as a monitor by weighing a Styrofoam-based piece (say a tablet). Note, by its very nature, Styrofoam material, due to its lightness, will add to the variability.  The question would be; why is the performance of a balance to be monitored using a Styrofoam tablet and not using the reference weight itself? What is the link between the Styrofoam tablet, room temperature and airflow? If the issue is the instability of room temperature and/or airflow, then these should be measured using their own respective meters or instruments; how does the balance become the monitor of these variables?

This is precisely the situation with PVT for paddle and basket, in that they are being suggested for monitoring stability or “fitness” of the dissolution media and/or vibration-free laboratory environment. This is simply not a logical or scientific practice. The reality is that, at present, these are made-up reasons for calibration or performance verifications that have no relation to assessing or validating a dissolution apparatus/tester. The fact is that these testers are neither stable nor relevant for drug dissolution testing, and unfortunately, attention has been diverted to promoting useless practices rather than fixing the problem.

In short, as of now, used dissolution testers are not qualified and validated dissolution testers. Their qualification and validation can only be performed using a reference product with known dissolution characteristics, which is not currently available.

In the interim, one may qualify and validate the testers using a relative dissolution testing approach. Relative dissolution testing refers to evaluating two products (approved for human use), one IR and the other ER, having the same drug using the same experimental conditions. Using the tester and experimental conditions to provide the dissolution characteristics reflective of the drug’s bio behavior (bioavailability/bioequivalence) in humans. Such a tester would be considered an appropriate tester. They should be used to evaluate the test products using the same experimental conditions.  For further detail and explanation, the following links may be of help:

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

(2)    MQ (Mechanical Qualification) vs PVT (Performance Verification Testing) which one to choose and why? (link)

(3)    Two-Tier System for Setting Tolerances – (PVT vs Products) (link)

(4)    PVT (Performance Verification Test) – Difficulties and a suggestion to address those (link)

(5)    The issue of validation/qualification of dissolution apparatuses (link)