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On September 16-18, 2002, an AAPS Workshop co-sponsored with FDA was held on Dissolution/ In Vitro Release Testing and Specifications for Special Dosage Forms. This workshop was a continuation of the exploration of methods for novel dosage forms started in Europe by the FIP (International Pharmaceutical Federation). There were two workshops, one in London in Sept. of 1999, followed by another in Frankfurt in March 2001. The proceedings of these two workshops were reported in Dissolution Technologies (1,2). The FIP Dissolution Working Group has undertaken the task, based on information obtained in this recent workshop and the other previous two workshops, to develop a harmonized report on special dosage forms that can be used as a reference for future guidelines and/or compendial activities.
The objectives of the workshop, including the aforementioned
FIP report, were to discuss methodologies for dissolution/in vitro
release testing of special dosage forms, review and discuss the
process of setting release specifications for dosage forms, and
discuss the roles and interactions with FDA and USP. Since the
technical aspects of the dissolution/in vitro release testing
will be covered in the FIP white paper that will be published
shortly, this report will mention the topics of the technical
presentations and highlight the content of the other presentations
that dealt with specifications, regulatory issues, and FDA/USP
The meeting began with Vinod Shah of the FDA discussing whether the principles of dissolution/ drug release tests could be extended to the non-oral special dosage forms such as topicals, creams, ointments and gels, transdermal patches, suspensions, suppositories, implants, microparticles, liposomes, etc. The answer was yes; he went on to say that at a minimum, the in vitro test could be a quality control test to assure batch to batch reproducibility. These tests could reflect the combined effect of several physical and chemical parameters, including solubility and particle size of the active ingredient and rheological properties of the dosage form. He continued to say that especially in the case of semi-solids the release test could assess product sameness between pre-change and post-change. He went on to discuss setting specifications. The specifications should be based primarily on manufacturing experience, including pivotal clinical trial batches and biobatches. There is the case where the specifications are suggested from the company on a limited data set. In this instance, the FDA determines an interim spec, when the in vitro results of the first three production batches are obtained, then a final specification in put in place.
Ngozi Okafo of the Alza Corporation continued the discussion on specifications, mainly in the area of extended release products. He gave an overview of the OROS delivery platform and associated release rate testing methods using USP Apparatus 7. For the IND stage, specifications were not necessary unless there was some safety concern. He pointed the discussion to ICH guidelines and FDA guidances. For extended release products it is critical to identify the midpoint with a test including at least 3 time points. The specifications should be based on average data. He went on the say the company should stay away from having both a release rate and a cumulative rate specification because it is difficult to align both and still give a consistent view on product performance.
Ajaz Hussain of the FDA reiterated the proceedings of the March AAPS/FDA workshop on specifications (3), commenting that the FDA strives to set specifications that will distinguish between bioequivalent and non-bioequivalent batches and products. He discussed opportunities for improving the current thinking for manufacturing using a systems based approach that utilizes process analytical technology. In the summary for Dennis Bashaw's talk, there is also a discussion of specifications from a regulatory point of view.
Vivian Gray gave a presentation that emphasized the
importance of using properly calibrated and qualified equipment
for in vitro release tests. She described how the analyst would
qualify and calibrate non-compendial equipment or compendial equipment
that did not have USP calibrator tablets available. Vivian went
on to elaborate on sources of error in dissolution testing.
Cynthia Brown of Eli Lilly and Company provided a comprehensive overview of method validation for the dissolution test. In the case of special dosage forms that may possess different physical properties than the traditional solid oral dosage forms, it is still imperative that the dissolution method provides accurate and precise data. She discussed the steps in validation by first defining the intended applications of the method, developing a protocol with defined acceptance criteria, executing the validation experiments, and documenting the results. The ultimate result is a method that guarantees accurate, precise and reproducible results, assures acceptable drug product quality, and allows for some interpretation of the product's in vivo performance. Special considerations were mentioned when validating automated equipment.
Martin Siewert of Aventis Pharmaceuticals presented a summary of the FIP Special Dosage Forms Workshops preceding this workshop. He stated that the methodology was well evolved and specific recommendations can be made for suspensions, suppositories, chewable tablets, transdermal patches, and for semisolid topical dosage forms, such as creams, ointments, and gels. More method development and refinement is needed for chewing gums, soft gel capsules, granules, powders, and parenterals. Formulation characterization, experimental test conditions, applications were presented and these slides were used later as a springboard for discussion in the breakout sessions.
The meeting continued with technical discussion of methodologies and apparatus used for special dosage forms. Industry representatives provided data and methodologies for liquid filled gelatin capsules (John Crison, Pfizer), orally disintegrating (fast dissolving) tablets (James Klancke, CIMA), topical dosage forms (Shravan Parsi, DPT), controlled release parenteral products (Thomas Ingallinera, AAI International). The academic community presented cutting edge information on orally administered dosage forms for targeted drug delivery in the GI tract (Jennifer Dressman, Johann Wolfgang Goethe-University), accelerated release methodology for microspheres (Patrick DeLuca, University of Kentucky), insoluble systems, including suspensions, implants, and microspheres (Diane Burgess, University of Kentucky), and suppositories (Jean-Marc Aiache, University of Auvergne of Clermont).
Patrick Marroum of the FDA spoke on the value of the In Vitro/In Vivo correlation (IVIVC) for special dosage forms. When dissolution is the rate-limiting step, which is the case for many non-oral specialized dosage forms, an IVIVC is possible. He gave examples for transdermal patches, vaginal rings, implants, and drug eluting cardiac stents as possibilities. The special challenge is in designing the appropriate in vitro release test. The FDA will work with a sponsor to encourage developing IVIVC's for special dosage forms, as a correlation will be useful in alleviating the regulatory burden. It is also useful to correlate release with safety and efficacy outcome. His last point, in response to a question, was that in all cases validated in vitro tests were expected for approval of special dosage forms.
Dennis Bashaw of the FDA discussed transdermal patches and the apparatus used most commonly for the in vitro testing. He discussed the critical aspects of setting specifications including type of system controls (skin or membrane), number of sampling times, sampling times, and rate of release. He also reiterated the utility of an IVIVC in setting specifications. He illustrated a statistical approach to setting release rate limits and commented that the main reason initial rate specifications are not accepted by the agency is that the proposed acceptance limits do not reflect in vitro or in vivo experience. He went on to say that the "ideal" specification should reflect in vivo release, provide quality assurance, be simple to perform and have a low failure rate. For a test specification to be valid, there must be the possibility of failure. Without the possibility of failure, a test ceases to have any quality assurance value. However, the specification should not embody the probability of failure of properly manufactured lots.
Kofi Kumi of the FDA gave the regulatory perspective on liposomes. Kofi emphasized the utility of an in vitro test that has relevance to in vivo performance toward ensuring safety and efficacy. She also discussed the cell culture and animal data usage in the development of the in vitro test. She stated that the FDA draft guideline on liposome products was now posted on the FDA website.
The role of USP and USP and FDA interaction was the topic of three talks given by Thomas Foster (University of Kentucky), Larry Ouderkirk (FDA), and Roger Williams (USP).
Thomas Foster described the revision process of the USP and how the process encourages input from a broad constituency of pharmaceutical scientist, the pharmaceutical industry, healthcare providers, FDA and international regulatory bodies. He talked about the activities of the USP and the Biopharmaceutics expert committee, and mentioned the new general chapter on dissolution test selection, method development and validation.
Larry Ouderkirk talked in detail about the FDA and USP interactions. He described the Compendial Operations Staff that interacts with the USP expert committee and the committee's liaisons. Larry gave examples of successes that the USP and FDA have had over the years, such as, the placing of multiple drug release tests in USP monographs, the USP two-tiered dissolution test, and the CDER /OPS field dissolution research program. He encouraged the generic industry to meet the innovator dissolution requirement. He recommended that all the pharmaceutical companies heed all Pharmacopeial Forum monograph proposals affecting marketed products and those under development. He discouraged industry from submitting to USP: tests for unapproved products, tests never submitted in their application and tests submitted in applications but rejected by the CDER reviewers.
Roger Williams described the efforts on the Pharmaceutical Dosage Forms Expert Committee on a taxonomy that will assist manufacturers in naming and classifying currently available and novel dosage forms. He discussed the performance test as related to the classification system. He explained how the USP is giving extensive study to understanding how to evaluate the data and better ways to determine acceptance criteria.
The workshop breakout sessions dealt with an analysis of the slides Martin Siewert had given on the technical aspects of dissolution/ in vitro release methodology for special dosage forms. The summaries can be found on the AAPS website (www. aaps.org) under meetings past meeting and summaries. Some of the presentations of this workshop can also be found at this site. This information will be available for only three-months, so do not delay checking it out. There is also another way to view the proceeding of the workshop at the AAPS website. Go to Education, then Distance learning and under this workshop title the presentations with overlay of the speakers voices are available for all the talks of the workshop. An excellent way to get the full information of the meeting. You must be an AAPS member to get to this information.
1. H. Moeller, V. Shah, C. Brown "Meeting Report: Dissolution
Testing of Special Dosage Forms Workshop", Dissolution Technologies,
2. V. Shah, M. Siewert, J. Dressman, H. Moeller, C. Brown, "Dissolution/In Vitro Release Testing of Special Dosage Forms", Dissolution Technologies, 2002:9 (1):6-11.
3. V. Gray, "Meeting Report:AAPS/FDA Workshop on Drug Product and Drug Substance Specifications-Dissolution Summary", Dissolution Technologies, 2002:9 (2):11-12.