V. A. Gray Consulting, Inc., Hockessin, DE
email for correspondence email@example.com
The workshop on Drug Substance and Drug
Product Specifications was held on March 18-20, 2002 in Arlington,
VA. The meeting consisted of one day of talks emphasizing areas
of concern between the Agency and industry when setting specifications.
The second day consisted of breakout sessions on several topics
that are of particular interest in specification setting. Dissolution
was one of those topics. There were five breakout sessions during
the day, each discussing the same list of topics. Both an industry
and FDA representative moderated each breakout session. For the
dissolution break-out sessions, industry representatives were
Mrs. Vivian Gray, of V. A. Gray Consulting, Inc. and Mr. Jeff
Hofer of Eli Lilly and Company. The FDA representatives were
Dr. Ravi Harapanhalli, Dr. Mehul Mehta, Dr. Kasturi Srinivasachar,
and Dr. David Lin. This article will present a summary of the
discussions in the dissolution breakout sessions.
Timing and Choice
of Method Test Conditions
At the end of Phase 2, a discussion on dissolution methodology between industry and FDA was recommended. A FDA Biopharmaceutics staff member should participate in the discussions. Industry was encouraged to provide all the relevant data to ensure a productive discussion. For example, data and rationale on the following dissolution topics might be presented and discussed at the end of phase 2 meeting:
· Dissolution Method: Media (justification for surfactants, if applicable), Apparatus, Speed
· Time points for data collection
· Drug product classification according to the Biopharmaceutics Classification System (BCS)
· Drug substance pH solubility profile
· Drug product dissolution profiles in three dissolution media
· Discussion of plan for In Vitro/In Vivo correlation (IVIVC), if relevant
· Need for 2-point specification (BCS Class 2 and 4)
· Method discrimination information including critical manufacturing variables (if available)
· Strategies for Scale-up
· Biowaiver discussion for BCS Class 1
· Specific Acceptance Criteria would not to be finalized at this meeting
Rate Limited Drug Products and IVIVC
For immediate release drug products where dissolution is the rate-limiting factor for absorption, an IVIVC is not required by FDA but might be useful in approval of SUPAC changes.
It was proposed that an In Vivo In Vitro relationship may be a more achievable goal (e. g., rank order) than IVIVC. "Side batches" might be used to justify in-vitro dissolution acceptance criteria.
Dissolution versus Disintegration
The use of disintegration testing
instead of dissolution testing is only applicable to BCS Class
1 compounds. This concept is discussed in the ICH guideline on
drug product specifications (see ICH Decision Tree 7). FDA expects
industry to demonstrate a relationship between disintegration
and dissolution. FDA also expects the disintegration test to be
as discriminating as the dissolution test. Discussions with FDA
regarding the application of this concept should be initiated
early in the drug development process. The meeting participants
expressed concerns that ICH implementation may not be consistent
among regions. The participants also expressed concern over the
difficulties in demonstrating discrimination for a disintegration
test relative to demonstrating discrimination for a dissolution
Establishment for Immediate Release Dosage Forms:
For immediate release dosage forms, the dissolution acceptance criteria should be established based on data from pivotal bioavailability and / or bioequivalence batches, successful clinical trial batches and primary stability studies in the final container closure systems. Data from "supportive" batches (similar formulation/process, etc.) obtained during the drug development process may also be used. The data should cover all strengths. For some immediate release drug products, establishing an IVIVC might be possible but it is not typically pursued.
The discussion on selection of Q values and time points proved to be a very controversial and lively session.
The following is a brief summary
of some of the topics that were discussed during this session.
· Ideally, FDA desires acceptance criteria to allow for discrimination between bioequivalent and non-bioequivalent batches.
· Surveys of participants indicated low probability of first-pass agreement between initial sponsor proposal and initial FDA assessment.
· FDA has a perception that industry proposes acceptance criteria that are too loose given the data.
· Industry has a perception that FDA is overly conservative with respect to acceptance criteria.
· Q-values other than 5-unit increments were not of interest to the participants.
· There was a limited discussion on the impact of stability data on the establishment of acceptance criteria.
· Some participants suggested that FDA publish more definitive guidelines on how the agency evaluates the data for the determination of acceptance criteria.
for Modified Release Dosage Forms
Dissolution data for modified release dosage forms can be reported as the cumulative amount released. The average release rate maybe also be reported for zero-order release. A final time point criteria is required such as not less than 80% released or an alternate value when an asymptote is reached. According to the FDA guidance on dissolution testing for modified release dosage forms, ranges broader than the ± 10% default range need to be justified with IVIVC or bioequivalence data. Development batches are useful for IVIVC establishment and validation. Overlapping ranges for acceptance criteria are generally acceptable.
The workshop provided a balanced and lively exchange of ideas and opinions. The need for improved communication between industry and the Agency was highlighted. The workshop proceedings will be available on the AAPS website (www.aaps.org). A dialogue with FDA will continue via a workshop paper that will be published in the future.
Note: This article is a compilation of comments and suggestions expressed by the participants and moderators of the workshop's dissolution break-out sessions. It does not necessarily reflect the official viewpoints of the FDA.