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Generics are drug products that are considered identical in dose, strength, route of administration, safety, efficacy, and intended use as an innovator’s product. However, generics are different from innovators’ products about formulation and manufacturing attributes. Because of these differences in formulation and manufacturing, it is expected from the generics that they demonstrate that the drug release from their product is similar to those of the corresponding innovators’ product.

This similarity or equivalence in drug release between generic and innovator products is established by conducting bioavailability/bio-equivalence studies. Such bioequivalence studies, in fact, establish that drug release (dissolution) in vivo from both products is the same. A critical point in understanding this principle is that generics strive to achieve similarity of drug release from innovators’ products in vivo having vastly different formulation and manufacturing attributes. Otherwise, generics and innovators’ products would have different bio-availabilities and would not be bioequivalent. Therefore, a difference in formulations or manufacturing attributes or finding these differences by in vitro dissolution tests are of no real consequences. Thus, the practice of finding such differences or developing dissolution tests under the terminology of “discriminatory test”, is an erroneous and misguided exercise.

The purpose of any analytical procedure, including dissolution testing, is to determine an unknown property of a test substance/matrix. However, in the case of current practices of drug dissolution testing, this is not the situation. Here, one seeks experimental conditions to obtain desired or expected release characteristics of the products. These are then described incorrectly, as procedures for method development, getting discriminatory tests and/or bio-relevant tests, etc. Furthermore, it is important to note that a test product itself is used as its own reference for all these practices. Therefore, one can never know the actual or real dissolution characteristics of any product.
 
For appropriate dissolution testing, the dissolution method (apparatus with associated experimental conditions) must remain constant, i.e., these should not change from product to product. For example, a method must remain the same if one would like to test or compare characteristics of an IR vs. ER product. For further discussion, the linked article may be useful.

Often it is suggested that one should use a de-gassed or de-aerated dissolution medium. But, unfortunately, conducting a dissolution test using such a condition makes the test and results obtained invalid; why?:

1. Dissolution tests are conducted to evaluate drug dissolution characteristics in vivo, i.e., in the human GI tract. However, the GI tract contents are not de-aerated or de-gassed, therefore, in vitro tests conducted in a de-gassed medium will not be reflective of the in vivo environment and thus the results will be invalid.
2. Commonly suggested procedure for preparing a de-aerated medium is by vacuum filtering of heated (41-45 ºC) dissolution medium. Dissolution tests are conducted at 37 ºC, thus dissolution medium temperature will change from ~45 to 37 ºC during testing. Therefore, de-aeration creates a non-physiological condition and introduces instability in the medium characteristics during testing.

For more appropriate drug dissolution testing, the medium should be equilibrated at 37 ºC, which would provide a more appropriate physiological condition and stability in the testing environment.

It is generally accepted that the pH of the aqueous phase within the GI tract ranges from pH 1 to 7 (or 8). This range may further be divided into two sub-groups; one is of pH 1 (perhaps to 3) and a second of pH 5-7.  The segment having pH 1 represents the stomach and the other, in the range of 5-7, is the (small) intestinal part.

It is commonly accepted that most of the drug (or food) ingested gets absorbed from the intestinal part. As absorption depends on dissolution, most of the drug should be available in the solution form in this segment of the GI tract. Obviously, for dissolution purposes, this environment of pH appears to be relevant and critical. Therefore, dissolution tests are to be conducted in media having pH in the range of 5-7.

Conducting dissolution tests, thus, in acidic (HCl) media (pH ~1), does not appear to be an appropriate choice.

Drug dissolution tests are to be conducted using physiologically relevant experimental conditions. The physiologically relevant conditions do not imply that one needs to duplicate or simulate the anatomy or physiology of the GI tract in vitro, but that the environment or the process which facilitates the product/drug dissolution in vivo.

For example, for dissolution testing, one is required to maintain a temperature of 37 °C. However, it is not necessary or required that this temperature be attained or maintained in vitro by biochemical or enzymatic means as it occurs in vivo. The in vitro temperature can be attained and maintained by any means such as using a water bath, heating coils or plates, etc. The critical aspect is that the temperature has to be 37 °C.

Similarly, for in vitro dissolution purposes, one would require a container or vessel (reflecting intestinal space), water or aqueous buffer (reflecting liquid in the intestine), and a stirrer (reflecting churning within GI tract). These parameters should be chosen in such a way that they may or may not look or feel similar to the physiology/anatomy, but their effects have to be similar to the in vivo effects. The more one deviates from producing the in vivo effects in vitro. The less reliable and useful the drug dissolution test will become and vice versa. It is to be noted that, as described in the literature extensively, the currently used paddle and basket apparatus lacks in providing mixing or stirring (the equivalent of churning in vivo). Therefore, dissolution results obtained using these apparatuses may be of limited use or value.

Furthermore, as the physiological environment or process remains the same or constant from product to product, i.e., product independent, the in vitro experimental conditions should remain product independent. If dissolution testing requires changing of experimental conditions from product to product (e.g. IR vs ER), then that testing procedure needs to be reconsidered, as the in vitro (dissolution) procedure may not be valid.

The only limitation for the volume of dissolution medium is that the expected amount of test drug must be freely soluble in the volume at 37 ºC. It is possible that the drug may not be soluble at room temperature, but at 37 ºC, it may be freely soluble. In such situations, for dissolution testing purposes, the drug will be considered freely soluble.

This freely soluble drug requirement/concept is often referred to as a “sink” condition. The sink condition may be any condition where a drug is freely soluble. Often, in the literature, it is defined as 2, 3, 5 or more times the volume of the dissolution medium required to dissolve the expected amount of the drug. These choices may be personal preferences; however, the drug should be freely soluble in the medium in practice. Therefore, before conducting a dissolution test and choosing a volume, one must determine the solubility of the drug in the medium at 37 ºC. Once this volume is known, one may use 10% extra volume than needed to be on the safe side.

It is to be noted that if the volume required is 250 mL. Then there is no harm in using larger than the required volume, for example, 900 mL. The excess volume should not impact dissolution. However, lower than required should and may make the dissolution test and results invalid. In the event, the excess volume provides differences in dissolution results. Then this would be an indication of a lack proper or efficient stirring in the vessel. In such situations, the use of such an apparatus may not be appropriate. The results would not reflect true dissolution characteristics of the test product but an interaction of the product and the dissolution apparatus.

As 900 mL is the commonly used or suggested volume, there is no harm in following this suggestion or tradition. In fact, one should try to use this standardized approach of using 900 mL. In such cases, the analyst must make sure that the expected amount of drug is freely soluble in 900 mL. If not, then the use of a solubilizing agent such as SLS may be considered to establish that the drug is, indeed, freely soluble in the 900 mL medium.

The PVT (Performance Verification Test) for all practical purposes is a name change of an old test known as dissolution apparatus calibration. This test has been propagated to provide some sort of assurance about the performance of the drug dissolution apparatuses commonly known as Paddle and Basket. However, the test has been faced with criticism about its relevance and usefulness almost from the beginning. In fact, it is generally considered a severe economical burden on pharmaceutical manufacturers. To minimize this burden and a lack of scientific rationale, FDA recently provides an alternate to avoid the PVT.

On the other hand, USP, which propagates the use of PVT, and the provider of the tablets used for PVT, has been making tremendous efforts in convincing that the PVT is indeed a useful practice. However, selling this idea appears to be becoming difficult because, generally, analysts/scientists consider this as “an effort to maintain the status quo”. This status quo impression appears to have merit because there has been no experimental evidence provided to address the users’ concerns or establish the usefulness and relevance of the PVT.

At this stage, the question remains that if PVT fails (which it often does without any apparent reasons), what experimental evidence are available to reflect that the apparatus was not functioning as expected? Otherwise, why propagate the use of PVT?

On the other hand, lack of evidence regarding the usefulness of PVT gives strength to the reported observations that problems with PVT are reflections of problems of Paddle and Basket apparatuses (poor hydrodynamics, variable and unpredictable results) themselves.

Bio-waiver is a term used for establishing and accepting quality of a pharmaceutical product (tablet and capsule) based on in vitro drug dissolution testing without corresponding bioavailability/bioequivalence data.

The scientific rationale behind this practice is that, in general, the bioavailability of a drug product depends on its release and solution formation (dissolution) characteristics. The in vivo (physiological) dissolution is monitored or simulated in vitro by a dissolution test. Therefore, an assumption made here is that the in vitro dissolution test will appropriately and accurately reflect in vivo dissolution in humans and thus the bioavailability/bioequivalence characteristics of the products. This linkage is commonly referred to as an in vitro-in vivo (co)relationship or IVIVC. Therefore, a pre-requisite for bio-waiver practices is a well-established IVIVC.

It is, however, generally well recognized and documented in the literature that current practices of dissolution testing do not relate well to in vivo outcomes or often lack IVIVC. Therefore, presently, a bio-waiver should be considered as a scientifically weak case.

There are, however, guidances available for considering bio-waivers in certain, very specific cases.  For example, bio-waivers are considered for products having drugs with high aqueous solubilities and absorbabilities from the GI tract in humans. In addition, the products should show fast dissolution. The underlying thought is that if drugs are highly soluble and absorbable, and the products show fast and complete in vitro dissolution (usually in less than 30 minutes). The products are not expected to pose any potential problems in vivo, and thus they may be considered for bio-waivers. Therefore, it may be assumed that current practices of bio-waivers are based on faith rather than their scientific merits.

In short, for an appropriate and scientifically valid bio-waiver inference, one has to establish IVIVC, with evidence that the techniques and methodologies (dissolution apparatus, medium, and associated experimental conditions) employed are indeed capable of providing physiologically relevant results.

Often in literature and discussion, terminology of a discriminatory test is used to describe that a dissolution test can differentiate or discriminate between products based on formulation and/or manufacturing differences. However, the implied understanding of this terminology is that these differences may reflect products’ in vivo differences, thus their quality in humans. The underlying implied assumption of in vivo relevance is emphasized by suggestions that dissolution testing is conducted using in vivo relevant experimental conditions, e.g., dissolution medium be aqueous having pH in the range of 1 to 7. Interestingly, the literature also well documented that dissolution results with formulation/manufacturing differences seldom reflect corresponding in vivo behavior.

It is, therefore, safe to consider that the use of the terminology of “discriminatory test” as commonly used does not appear to be correct. To be accurate, the discriminatory test terminology should clearly identify a test as an “in vitro discriminatory test” or “in vivo discriminatory test,” also known as a bio-relevant test.

An in vitro discriminatory test would be the test to reflect differences in physical characteristics of the test products (formulation/manufacturing) with no direct or definite consequences in vivo. Such tests may be conducted using any of the experimental conditions necessary concerning apparatuses (paddle/basket, Erlenmeyer flask with magnetic stir, etc.) and media (organic or aqueous solvents having any pH), etc. In this respect, the disintegration test may be considered a discriminating test if formulation/manufacturing differences are linked to disintegrating time. It may be important to note that although often in vitro discriminatory dissolution tests are developed and used but their usefulness is limited and may be an unnecessary burden on the pharmaceutical industry and the regulatory agencies.

An in vivo discriminatory test or a bio-relevant test, on the other hand, would be a test that would relate differences in formulation/manufacturing of products to corresponding differences in vivo such as bioavailability/bioequivalence characteristics. An essential requirement for an in vivo discriminatory test is that the test be conducted using physiologically relevant experimental conditions. For example, an apparatus must provide a gentle but efficient stirring and mixing environment. The medium must be aqueous with pH in the range of 5-7 and maintained at 37C. The medium must not be de-aerated but equilibrated with dissolved gasses. In addition, as the testing environment is linked to the GI tract physiology, which does not change from product to product (e.g., IR to ER), the experimental conditions should not be changed from product to product.

Therefore, it is prudent to indicate the nature of the test described, whether it is an in vitro or in vivo discriminatory type so that proper evaluation and use of the test be considered.

An f2 parameter is commonly used to establish the similarity of two dissolution profiles. The formula and procedure to obtain f2 value is described in one of the publications.

In short, two profiles are considered identical when f2=100. An average difference of 10% at all measured time points results in a f2 value of 50. A public standard of f2 value between 50-100 to indicate similarity between two dissolution profiles. Another way of saying this is that, on average, if the difference at each sampling time is 10% or less, then f2 value will be between 50 and 100. Therefore, a quick way to establish the similarity of two profiles is to see if differences in dissolution results at each sampling time are less than 10%.

In general, there is not much literature or debate available reflecting its relevance or link to the assessment of the compared products for their qualities or release characteristics in vitro (dissolution) or in vivo (bioequivalence). At best, the parameter (f2) appears to be a rule-of-thumb type gauge, and perhaps appears to add some extra burden for evaluating and reporting dissolution results without real gain in data analysis.

There has been some discussion on the tightness of the standard, which may result in rejection of products of similar drug release characteristics. Suggestions appear to have been made to lower the limit from 50 to say 30.

It also appears that this limit of 50-100 range for f2 (or a difference of less than 10% in dissolution results) may conflict with the commonly accepted pharmacopeial (e.g., USP) standards, where a lot to lot testing (without formulation/manufacturing differences) the acceptable deviation is significantly higher than 10%. However, f2, which is generally suggested for evaluating products with formulation/manufacturing differences (for product developments and/or alterations), the allowance should be greater; thus, a wider range with a lower cut-off value than 50 may be more appropriate.