FDA, Industry Thinking Outside of the “PAT Box”; Forum on Dissolution Addressed Key Issues

Report on Dissolution Testing for the 21st Century Workshop In the August issue of Dissolution Technologies, Dr. Vivian Gray and Jan Parker recently reported on an interesting AAPS May workshop, "Dissolution Testing for the 21st Century,Linking Critical Quality Attributes and Critical Process Parameters to Clinically Relevant Dissolution Method/Specification." The program illustrates the fact that FDA, and some pharma companies, are thinking more broadly about PAT, as it relates to Quality by Design, and they are tackling the limitations of both compendial tests and PAT methods as they apply to stability testing. Generic companies such as TEVA appear to be making great strides in assessing requirements; generics would like to establish standards for their own products, rather than relying on patented product manufacturer data.  Moheb Nasr,Ph.D.,FDA,the authors wrote, set the tone for the conference with his talk, Quality by design and its relevance to dissolution, to guide drug development in selecting formulations,bridging clinical studies, surving as a surrogate for in vivo bioequivalence, and providing quality control for batch-to-batch consistency, stability,and support biowaivers for the Biopharmaceutics Classification System (BCS) Class I. Dr. Nasr, they wrote, examined the current system for setting specifications where (1) there is an empirical approach used to fit the available data, (2) specifications are set through negotiation, (3) specifications are established late in the approval process,and (4) the linkage to safety and efficacy is not always assured. Apparently, Dr. Nasr then went on to explain that specifications may not be reflective of trueproduct quality; out-of-specification results may lead to production delays, inefficiency, and drug shortages,and setting specifications is a regulatory hurdle that needs improvement. The limitations of the current system were highlighted with an emphasis on lack of adequate product and process understanding. The dissolution test may not be a sensitive indicator of product performance for dosage forms such as highly soluble and highly permeable drugs or potent or narrow therapeutic index drugs with low solubility. He posed the question,Could disintegration or some other quality attributes substitute for dissolution?The desired state is to have a knowledge-rich submission,one that understands and controls variation with specifications based on product performance requirements. In summary,the authors wrote, his message was that dissolution may play a more important role in QbD with drug development by providing accurate clinical linkage and less as a quality control test. He expressed the FDAs willingness to work with scientific organizations such as the AAPS focus group,PQRI,universities,and the USP. The Future of Drug Development at Novartis To give the industry perspective on the future of dissolution,Yatindra Joshi,Ph.D,Novartis Pharmaceuticals, reportedly looked at the future of technical development where development time lines will become even more aggressive with more frequent use of modeling, in vitro methods for prediction of in vivo behavior,PAT, robotics and automation,and elimination of scale-up risk. He pointed out some dissolution issues that need further exploration such as hydrodynamic effects, low volume dissolution testing,increased speed as an in-process test,and overencapsulation. Merck examines use of Particle Size Analysis and NIR in place of Dissolution Testing A case study using PAT and dissolution was presented by Kimberly Gallagher and Robert Green,Merck Research Laboratories,Process analytical techniques and dissolution:a Merck case study using surrogates for particle-size mediated dissolution mechanisms. The case study presented used a BCS Class IV compound where the feasibility of using particle size analysis and NIR as a surrogate for dissolution testing was evaluated, the authors wrote. "The use of the entire particle size distribution (PSD) of the overencapsulated formulation contents using laser diffraction of the sieved contents proved to have observations consistent with the dissolution data.The NIR studies were quite useful,satisfying all release requirements,composite assay,dosage form uniformity, identity,and dissolution. In addition,the technique gaveinformation on lubricant level and moisture content.The conclusion was that for the BCS Class IV,both PSD and NIR were suitable surrogates for dissolution analysis with NI, providing an attractive real-time release option." NIR Predicts Dissolution Behavior at Pfizer The authors also singled out a lecture by Fiona Clarke, Ph.D.,Pfizer. Her talk,Building understanding of dissolution behavior using near-infrared chemical images:A prediction of performance, illustrated how chemical images can be used to provide a mechanistic understanding of how formulation and process factors influence product performance. The visualization offered by NIR is a good means of problem detection, Dr. Clarke said. In the search for a root cause,the dissolution test can tell you there is a change but not what has changed, the authors summarized. However, images can provide information on component distribution,size,or matrix change.The NIR chemical images have been used to troubleshoot,build understanding of the dissolution performance,understand processing effects on formulation changes,provide a design space for dissolution based on process DoE,and show a direct correlation to dissolution performance. Some case studies were presented. In the future, this technology has the potential to be used to predict dissolution performance, and at the blend stage,the analyst can understand if the same matrix has been produced. A scientific understanding of dissolution properties can be obtained from NIR chemical images. Another highlight must have been FDA's presentation by Lawrence Yu, on Challenges in Dissolution Testing, in which Dr. Yu addressed some of the issues with the current dissolution test and bioequivalence. The test can sometimes be nondiscriminating, he said, by failing to detect a difference in products that are not bioequivalent and sometimes over-discriminating by failing products that are in fact bioequivalent, the authors reported. An excerpt from the article " One issue is that single-point dissolution tests often do not adequately reflect in vivo behavior. Another is that IVIVR cannot always be demonstrated,and when it is,the correlation is only for the sponsors product. These issues are related to the way the drug is absorbed by the body, depending on whether absorption is dissolution-limited, solubilty-limited,or permeability-limited. Part of the problem may be expecting the dissolution test to detect batch-to-batch inconsistencies in a QC setting and yet not be so sensitive that it fails bioequivalent batches for biowavers. Dr.Yu proposed designing a single biorelevant medium that would be used for all products,at least for purposes of bioequivalence. This would permit direct comparison among similar products from different manufacturers and streamline dissolution testing in the analytical laboratory. Further study is needed to determine whether the biorelevant medium would be acceptable for QC testing. The purpose of the release dissolution test is to detect inconsistencies in the product,some of which might not be biorelevant but might still be unacceptable in the finished product. Representing the generic industrys views on the same topic was John Kovaleski,Ph.D.,Teva Pharmaceuticals USA. Since generic products are bioequivalent to the brand-name drug by definition,the authors wrote, the generic drug must meet the same dissolution requirements as the brandname product. This means that the generic competitor is not free to develop a dissolution method based on its own generic formulation. If the product is USP,the generic company is effectively locked into the USP requirements; if it is not USP,the generic company must turn to the method supplied by the Office of Generic Drugs (OGD.) Many times the Qvalue is not supplied,and there is uncertainty on setting the specifications. Since the goal of the QbD is to build quality into the product beginning with the product development stage,the generic industry would like to design dissolution tests around its own products rather than have the tests be handed down from another manufacturer. The critical attributes for each manufacturer may be different due to excipients or manufacturing processes, and each manufacturer should be able to design dissolution tests that are the best measure of these critical attributes. OGD has recently implemented a Question Based Review (QBR) system that will allow generic companies to justify the tests and acceptance criteria that they develop specifically for their products. This approach may allow the generic industry to develop more meaningful dissolution methods. Comparators present some unique dissolution challenges for method development and validation. This topic was addressed by Diane Worrell,Bristol-Myers Squibb with input from Jamie Bell,Aptuit and Ruben Lozano. The FDA Guidance for Industry,Dissolution Testing of Immediate Release Solid Dosage Forms,can be used as a guideline in developing a method..." The article in its entirety is not yet posted on the publication's web site, but the peer-reviewed Dissolutions Technologies appears to be an extremely useful resource for anyone interested in this topic. -AMS
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