Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol.
1) 2011 ISSN: 2231-2560
Review Article 1 Asian Journal of Biochemical and Pharmaceutical Research
Dissolution Testing of Formulations: A Regulatory, Industry and Academic Perspective *1, 2 Sachin Kumar Singh, 1 Dev Prakash and K.K. Srinivasan 3 1 Faculty of pharmacy, Karpagam University, Coimbatore 641021, Tamilnadu, India. * 2 Department of Pharmaceutical Analysis, Bharathi College of Pharmacy, Bharathinagara, Mandya Dist., Karnataka- 571422, India 3 Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Dist.- Udupi, Karnataka, India. Received: 28 February 2011; Revised: 5 March 2011; Accepted: 8 March 2011 Abstract: Drug dissolution testing plays an important role as a routine quality control test, for characterizing the quality of the product, for accepting product sameness under SUPAC (Scale-Up and Post-Approval Changes) related changes, in waiving bioequivalence requirements for lower strengths of a dosage form, and in supporting waivers for other bioequivalence requirements. The guidance of dissolution developed by the regulating agencies provides recommendations on the development of dissolution test methodology, on how to set the specifications for dissolution testing. As the time is passing away, the in vitro dissolution testing is relied on to assure product performance, therefore one must design an appropriate dissolution test procedure which should be simple and economical method that can be utilized effectively in developing countries to assure acceptable drug product quality. The dissolution testing is enjoying a resurgence of interest on an academic as well as on industrial and regulatory levels. Provided the groundwork continues to be focused on the development of dissolution tests and testers that are both bio relevant and can be adapted to routine quality control, it is likely that dissolution testing will become an even more powerful tool for the assurance of product quality, in its broadest sense in the years to come. Keywords: Drug dissolution, SUPAC, bioequivalence, regulating agencies, bio relevant INTRODUCTION: Dissolution testing over the last quarter century has emerged as a highly valuable in vitro test to characterize drug product performance. For a useful dissolution test: it must be simple, reliable and reproducible and must be able to discriminate among different degrees of product performance. Dissolution test value is significantly enhanced when product performance is evaluated as a function of time (drug release profile with respect to time), which means that, when the dissolution profile is determined rather than a single point determination, which is a standard compendia for batch release. Drug dissolution testing plays an important role as a routine quality control test, for characterizing the quality of the product, for accepting product sameness under SUPAC (Scale-Up and Post-Approval Changes) related changes, in waiving bioequivalence requirements for lower strengths Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 2 of a dosage form, and in supporting waivers for other bioequivalence requirements [1].Dissolution from the dosage form involves mainly two steps: liberation of the drug from the formulation matrix(disintegration) followed by the dissolution of the drug(solubilisation of the drug particles) in the liquid medium. The overall rate of dissolution depends on the slower of these two steps. In the first step of dissolution, the cohesive properties of the formulated drug play a key role. For solid dosage forms, these properties include disintegration and erosion. If the first step of dissolution is rate- limiting, then the rate of dissolution is considered disintegration controlled. In the second step of dissolution (i.e., solubilisation of drug particles), the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical form (e.g., amorphous or polymorph and primary particle size) play an important role. If this latter step is rate-limiting, then the rate of dissolution is dissolution controlled [2]. This is the case for most poorly soluble compounds in immediate-release (IR) formulations whose solubility is less than 12 mg/L in the pH range of 28. Recent advanced technologies like combinatorial chemistry and high-through put screening are effective in the discovery of new drugs with good pharmacological activities [3]. About 3540 % of the drugs discovered with these technologies have poor aqueous solubility [4]. Dissolution testing of poorly soluble compounds in immediate-release (IR) solid dosage forms poses many challenges. These challenges include developing and validating the test method, ensuring that the method is appropriately discriminatory, and addressing the potential for an in vivoin vitro relationship (IVIVR) or correlation (IVIVC). Satisfying all of these challenges and developing a meaningful dissolution method is a large task, because the extent of release is too low (i.e., one cannot get 100% of the dosage form dissolved) and secondly, the rate of release is too slow (i.e., one cannot get dissolution fast enough for a convenient test) [5]. ROLE OF DISSOLUTION TESTING IN REGULATING PHARMACEUTICALS: Dissolution tests are meant for assessing batch to batch quality, where the approach makes the basis for specification (test, methodology and acceptance criteria) to allow batch release. It is also used to provide process control and quality assurance and assess the need for further bioequivalence studies relative to minor post approval changes, where it can function as a signal of bioinequivalence. If an in vivo absorption characteristic has to be defined for the different product formulations, then the in vitro dissolution studies for all product formulations are investigated (including proto type formulations). These effects may allow an in vitro / in vivo correlation. The in vitro test can serve not only as a quality control specification for the manufacturing process, but also as an indicator of how the product will perform in vivo. The guidance of dissolution developed by the regulating agencies provide recommendations on the development of dissolution test methodology, on how to set the specifications for dissolution testing [6, 7]. A recent FDA guidance draft on bio waiver based on the Bio pharmaceutics classification system suggests that documentation of bioequivalence for highly soluble, highly permeable and rapidly dissolving orally administered immediate release drug products via dissolution studies may be an appropriate approach [8]. At least a two point determination should be used to characterize the in vivo performance of an orally administered immediate release drug products. The only reason behind this is that, a modified Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 3 release dosage form is a more complex formulation and not less than four dissolution time points are needed to characterize the drug product. In the presence of Scale Up and Post Approval Changes (SUPAC), the dissolution profile comparison has been extensively used in assessing product sameness. In order to avoid subjective evaluation of dissolution profile comparison, FDA has adopted a simple method to compare dissolution profiles, which is termed as similarity factor, f 2 [9]. The art and science of dissolution testing have come on long way since its inception about 25 years ago. This procedure is well established, reliable and reproducible. As the time is passing away, the in vitro dissolution testing is relied on to assure product performance, therefore one must design an appropriate dissolution test procedure which should be simple and economical method that can be utilized effectively in developing countries to assure acceptable drug product quality. The SUPAC initiatives were started to provide scientific rationale to expedite the processes of post approval changes of drug products so that FDA can assure their safety and effectiveness and at the same time lower the regulatory burden for industry. Problem areas were identified and research was performed at academia, industry and FDA laboratories to support changes in (1) components and composition (2) manufacturing (process and equipment) (3) scale of manufacture; and (4) site of manufacture. The specifications for the drug product include sterility, dissolution rate, containers and closure systems. It was the intent of the research to improve specification requirements and modify testing procedures for the product quality aspects of drug production. The changes may shorten the application process for industry and facilitate the approval process with the FDA. Investigators at University of Maryland/Baltimore, FDA and pharmaceutical industry gathered data on the impact of scale-up, formulation, and other manufacturing changes on product quality, resulting in the release of a number of guidance by FDA, including: (1) Immediate release solid oral dosage forms, scale-up and post-approval changes: chemistry, manufacturing and controls, in vitro dissolution testing, and in vivo bioequivalence documentation (SUPAC-IR). (2) Modified release solid oral dosage forms, scale-up and post-approval changes: chemistry, manufacturing and controls, in vitro dissolution testing, and in vivo bioequivalence documentation (SUPAC-MR). (3) Semi-solid dosage forms scale-up and post approval changes: chemistry, manufacturing and controls, in vitro dissolution testing, and in vivo bioequivalence documentation (SUPAC-SS). (4) Intermediates in drug substances synthesis/bulk actives post approval changes: chemistry, manufacturing, and controls documentation (BACPAC I) and ( 5) SUPAC-IR/MR manufacturing equipment addendum. Several other SUPACs are at various stages of development including one for transdermal delivery systems (SUPAC-TDS) and one for sterile aqueous solutions (PAC-SAS). As can be deduced, the guidances have been developed on the basis of types of dosage forms. The guidance provide specific recommendations on documentation of equivalence in post approval changes of drug products in component-composition, batch size, manufacturing process and site of manufacture. Each category is divided into 2 or 3 levels based on the degree and type of changes in the approved product. Post-change product batch is considered the same as the pre-change Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 4 product batch when there are no discrepancies in their dissolution profiles or the release rates. The similarity in the physicochemical properties of the batches from the release test or dissolution profile can be used to infer that the pre-change products and post-change products are also the same in terms of safety, efficacy or bioequivalence. SUPAC-IR uses in vitro dissolution tests to indicate product sameness. Dissolution profile comparison on post-change batch and pre-change batch is indicated by the similarity factor, f2. log = logarithm to base 10 n = number of sampling time points Rt = dissolution at time point t of the reference (pre-change batch) Tt = dissolution at time point t of the test (post-change batch) In vitro-in vivo correlation is an important measure for SUPAC-MR involving development, validation and application and dissolution profile comparison. In vitro release test is used in SUPAC- SS as a measure of product quality and sameness. The equivalence approach based on a standard confidence interval procedure is utilized to verify that the lots are close enough for product sameness between pre-change and post-change batches. The International Society for Pharmaceutical Engineers (ISPE) collaborated with FDA to provide equipment equivalence lists which clearly define classes and subclasses of equipment by unit operation. The Equipment Addendum Guidance documents provide assistance for changes in equipment. Further updating of the SUPACs is possible based on the approach delineated in FDAMA Section 116 to permit pre-approved supplements, change-being-effected supplements and annual report filings. The concept of SUPAC on drug product is being extended to drug substance (BACPAC I and II). The general approach works to achieve continuing pharmaceutical equivalence and bioequivalence after approval for NDAs and ANDAs, as well as other approved FDA products. There were 1,039 SUPAC supplements submitted for generics and 263 for new drugs from 1995 to 1998. Immediate release and alternate site changes dominated the topics for SUPAC supplements with 582 and 431 submissions, respectively, for generic drugs and 142 and 66, respectively, for new drugs. Semi-solids and modified release dosage forms accounted for less than 30 submissions for both types of drugs during the three year period. Based on qualitative estimates provided by pharmaceutical company representatives, consulting experts, and the number of SUPAC- IR submissions during 1997, the Office of Planning and Evaluation, FDA, estimated savings for 1997 chemistry, manufacturing and control changes to be $70.7 million. The savings generated by SUPAC were realized through shorter waiting times for site transfers, more rapid implementation of process and equipment changes, more rapid implementation of batch size increase, production of fewer Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 5 unmarketable stability test batches, and reduced stability tests and reduced administrative cost. For example, there was documentation that the times taken for one company in submissions and reviews of supplements on packaging and manufacturing were 600 and 111 months, respectively, before and after the adoption of SUPAC guidance [10]. Overall, several industrial representatives at the workshop stated that there were no major issues with SUPAC. The coordination at CDER was excellent. After the initial learning period, pharmaceutical companies and the review divisions and district offices of FDA were comfortable with the processes involved in SUPAC. It was the consensus of the scientists at the SUPAC workshop that there are several issues that need to be addressed for future SUPAC applications. The topics that need to be addressed are dosage form independent issues, SUPAC IR/MR/SS issues, site transfer, and equipment process changes. Dosage form independent issues include multiple changes, packages, and sizes. SUPAC-IR/MR issues include: 1) mechanism to control changes to specification and in-process control; 2) capsules (size, shapes, color); 3) tablet weight; 4) shape, size, scoring, energizing; 5) need to simplify Case C dissolution; 6) product-specific selection of media; and 7) f 2 specification/profile. Site transfer issues include:1) harmonization of IR/MR site transfer requirements for stability; 2) transfer of experiment date to new site, and 3) the need for a bioequivalent test for level 3 SUPAC-MR. Equipment process change issues include 1) the use of biopharmaceutical classification system to justify changes being effected (CBE) and 2) clarification of deposition of other types of level 2 and 3 changes. SUPAC-SS issues include preservatives and in vitro release testing. As stated by Larry Augsburger, President of AAPS, the range of dissolution profiles of products found bioequivalent in the Maryland study may be broad enough to encompass many major changes. Consideration should be given to: 1) reducing the dissolution requirement for Class I drugs. For the examples studied, the requirement of 85% dissolution in 15 minutes was not justified, 2) reducing the filing requirements for a change in technical grade of excipient at least to CBE classification in accordance with 21 CFR 314.70(c). Though limited in the number and classes of excipients tested, the Maryland data do not support Level 2 (PAC), 3) shifting of levels downward by an increment of one for compositional changes, 4) removing reference to 10X in re scale changes, and 5) reducing the media required in Level C dissolution tests to two or three. ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL INDUSTRY: Dissolution testing in pharmaceutical industry is a very important tool in drug development and in quality control. While traditionally developed for solid oral dosage forms, in the last years, the use of dissolution testing has been widened to a variety of dosage forms, such as semi-solid or parenteral (e.g. implant) preparations. Scientifically, a lot of progress has been made through more than three decades. Also, from the perspective of (pharmacopoeia) standardization, international harmonization of regulations, and thus consistent concepts and test methods being applied around the world, we have reached a high level. But, does that mean that we have no more questions, no more issues to be addressed? No, definitely not! The burning questions and issues are not necessarily new but, it is a set of aspects coming up again and again whenever experts meet and discuss in vitro dissolution: Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 6 Is there a value or need for calibrator tablets? Is there a scientific justification for further standardization of dissolution media? Is there a scientific rationale for standardization of dissolution specifications (e.g. 75% in 15 min; 75% in 45 min), or do we need to treat each product on a case-by-case basis? How important is stage 3 testing (especially when being strict in post-marketing stability studies)? Are we really having a good understanding of which criteria would allow us to use in vitro dissolution as a surrogate for bioequivalence studies- Where are we too strict? Where are we not conservative enough? What level of in-vitro-in-vivo-correlation requirement is justified for validation of test method and specifications? For which type of products? Is the basic concept of searching for the most discriminating in vitro method justified, when at the same time we continue to: face difficulties when applying low rotation speeds with apparatus 2 (and 1)? Learn that typically, differences in vitro are more pronounced than those in bioavailability, when comparing similar products? Is their value in dissolution testing, when an in-vivo-in-vitro-comparison has proven a non- correlation (for any test condition considered reasonable)? The use of bio relevant media is how much justifiable as it is very costly [For example, one liter of FeSSIF can cost as muchas US$700, whereas the price of one liter of medium containing synthetic surfactants (mixed micelles) is only around US$1] (11). Whether this problem can be overcome by the use of mixed micelles? Which concepts for comparison of in vitro dissolution profiles are truly scientifically sound and still pragmatic-to-handle in terms of being easily applied and meaningful? This list is not at all meant to be complete. Interesting enough, we are collecting more and more examples, many of them supporting established concepts, many other data sets raising these questions again. Sometimes we tend to question the basic concepts of dissolution testing (completely abstract, conventional method which we still believe to reflect gastro-intestinal processes?). What are we really looking for? Maybe we need further scientific studies and investigations. But definitely, we need pragmatic approaches to make sure that we are staying on scientific ground, have sufficiently (adequately!) standardized tests in place, and still allow for enough flexibility to handle specific products or situations. Industry needs to focus on speed in registration of new products Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 7 and in implementing post approval changes/variations. The objective is the safety and efficacy of our products for the patient. As long as regulatory requirements are illustrated in guidelines rather than bureaucratic directives, we will manage to the benefit of the patient, scientifically sound, and still economically feasible. The SUPAC approaches and the FIP-Guideline are going into the right direction. Not necessarily all other recent proposals are obviously consolidating all available experience. Reoccurring same or similar questions may also be an indicator that, in some areas, we could be turning in circles rather than adding value. FUTURE DIRECTIONS FOR ACADEMIC RESEARCH IN DISSOLUTION TESTING: A quarter of a century ago, it was already recognized that particle size of the active substance could have a great influence on the dissolution rate and also on the bioavailability of the compound. Efforts to establish in vitro/in vivo correlations (IVIVC), for example with digoxin products containing different particle size of the active ingredient, met with success. Subsequently, IVIVC was tried for many other products, but good correlations could mostly only be obtained on an a posteriori basis and dissolution testing for IVIVC purposes became less popular. With the advent of the Bio pharmaceutics Classification System (BCS) it became evident that IVIVC cannot be expected for drugs with certain properties. At the same time, dissolution tests that attempt to be closer model, the physiological conditions were developed, for example the flow-through tester and certain more bio relevant media. As a result, we now have the tools necessary to determine when an IVIVC is reachable, and what in vitro tests we need to do to achieve an IVIVC on an a priori basis. To further improve the predictive capability of dissolution testing, there needs to be further refinement of the media used, use of appropriate volumes, and hydrodynamic designs that can provide better flow patterns in the gut. These points will continue to be a focus of academic research in the coming years, with the greatest challenges being associated with the development of suitable tests for controlled release products and the translation of the dissolution tests used for IVIVC into workable tests for quality control purposes. A further challenge is to establish suitable dissolution tests for non-conventional oral dosage forms, for example chewable tablets, swell able dosage forms and wafers that are designed to dissolve on the tongue. The classical methods do not provide suitable agitation conditions on the one hand, and the volumes used are unrealistic for wafer-type dosage forms on the other hand. Likewise, the suitability of current methods for non-oral dosage forms continues to be an area of controversy and research. The evaluation of results is also an area of continued interest for the academic as well as the regulatory community. The utility of the recently proposed f 2 factor and its benefits and disadvantages compared to other evaluation methods (both model dependent and independent) will need to be carefully scrutinized using a wide variety of data sets, including drug products from each of the BCS categories and data sets for controlled release products. Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol. 1) 2011 8 Finally, the controversy related to calibration of dissolution testers continues. Alternatives to the current USP calibrator tablets need to be developed, with the most desirable approaches being those that avoid the batch to batch reproducibility problems associated with the current tablets, those that are efficient in terms of time and effort required and those that can be applied in a wide variety of laboratory settings. In summary, dissolution testing is enjoying a resurgence of interest on an academic as well as on industrial and regulatory levels. Provided the groundwork continues to be focused on the development of dissolution tests and testers that are both bio relevant and can be adapted to routine quality control, it is likely that dissolution testing will become an even more powerful tool for the assurance of product quality, in its broadest sense in the years to come. REFERENCES: 1. Dissolution Testing of Immediate Release Solid Oral Dosage Forms; Guidance for Industry; U.S. Department of Health and Human Services, Food and Drug Administration, U.S. Government Printing Office: Washington, DC, 1997. 2. C. Brown, H. Chokshi, B. Nickerson, R. Reed, B. Rohrs, P. Shah; Pharm. Technol.; 2004, 28 (12), 56. 3. T. Ohara, S. Kitamura, T. Kitagawa, K. Terada; Int. J. Pharm.; 2005, 302, 95. 4. C. Lipinski; Poor aqueous solubilityan industry wide problem in drug discovery. Am. Pharm. Rev.; 2002, 5, 82. 5. B. Rohrs; Dissolution Technol.; 2001, 8 (3), 1. 6. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Form, August 1997. 7. Guidance for Industry: Extended Release Solid Oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations, September 1997. 8. Draft Guidance for Industry: In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Containing Certain Active Drug Ingredients/Active Moieties Based on a Biopharmaceutics Classification System, January 1999. 9. V. P. Shah, Y. Tsong, P. Sathe and J.P. Liu.; Pharm. Res.;1998, 15, 889. 10. D. C. Pang.;AAPS Workshop on SUPACs: Where are We Going? Have We Reached the Limit? Dissolution Technol.; 1999, 6, 16. 11. T. Zoeller, S. Klein, Dissolution Technol.; 2007, 14, 8. *Corresponding author: Sachin Kumar Singh: Department of Pharmaceutical Analysis, Bharathi College of Pharmacy, Bharathinagara, Mandya, India