Workshop Summary: AAPS Workshop on Special Dosage …

1 Workshop summary : AAPS Workshop on Special Dosage Forms what 's New with In Vitro Drug Release? e-mail: Vivian Gray Dissolution Technologies, Hockessin, DE 19707. T. he AAPS Workshop on Special Dosage Forms Novel/ Special Dosage Forms during the 2010. what 's New with In Vitro Drug Release? took place at calendar year. the AAPS Annual Meeting in Los Angeles, CA on November 7 8, 2009. This is my personal summary of each Speaker: Henk de Jong, presentation and discussion, written from the perspective of a Workshop attendee on a press pass from AAPS. International Perspectives on the Drug Release of Special Dosage Forms-The European Pharmacopoeia Day 1 The EDQM and European Pharmacopoeia were defined. Speaker: Vinod P. Shah, The EDQM is committed to applying ICH guidances. Thirty-seven countries are members of the European International Perspectives on the Drug Release of Union, and each is required to follow the European Special Dosage Forms Pharmacopoeia. Any exemption from a Ph.

2 Eur. This Workshop was co-sponsored by FDA and FIP. requirement must be justified and approved. One key This kick-off presentation introduced the Workshop by difference between the Ph. Eur. and the USP is that there providing background and objectives. The Workshop are not specific monographs for Dosage forms. Each focused on modified-release drug forms and included Dosage form is required to meet approved specifications regulatory perspectives and specific by following general Dosage form monographs. The Ph. presentations for orally disintegrating tablets, chewable Eur. dissolution general chapter ( ) is harmonized with oral drug products, ophthalmic products, aerosol drug the USP and JP on the majority of points for oral solid products, drug-eluting stents, and parenteral products Dosage forms. Apparatus 1 4 are defined in the Ph. Eur. The including nanoparticles, microspheres, and liposomes. nonharmonized issues between compendia are as follows: Each product is classified (sections in each of Tiers 1 3), Apparatus 3 is not accepted by JP, sequential testing is not and tests including product quality tests (identity, accepted by JP, pooled samples are not accepted by Ph.)

3 Strength, potency, and quality) and product performance Eur., and calibrator tablets are not accepted by Ph. Eur. Ph. tests (in vitro release) are carried out. Examples were given Eur. has an informational chapter regarding guidance on for product quality tests and product performance tests dissolution testing and list of media lacking. Ph. Eur. has a for each Tier 1 classification. The most complex test for dissolution test for transdermal patches ( ). A noted each Tier 1 classification tends to be product performance difference for this chapter is the defined skin (model). in determining an in vitro release method that is temperature that is lower than that in chapter Ph. Eur. predictive of in vivo performance is complex. Other also has a chapter in progress for medicated chewing complex initiatives exist for transdermal products such as gums ( ) that defines the mechanical kneading leak testing, which is critical to ensure understanding of principle (not yet completely defined).

4 There is one potential toxicology issues. USP Apparatus 5, 6, and 7 are apparatus (mastication instrument) in the monograph and generally sufficient for evaluation of the release of patches. a second is under discussion. Ph. Eur. also has a chapter The discussion of aerosol drug products highlighted the available for lipophilic solid Dosage forms ( ). importance of particle size testing, and particles <5 m are Proficiency testing was summarized. This effort was carried ideal for effective performance for this Tier 1 classification. out by the EDQM to look at consistency of dissolution Mucosal products have multiple applications, and much testing versus pre-established criteria for six different work has been performed around in vitro release testing studies. All have been completed over the past nine years, for this Tier 1 classification. To date, none have been but none has been published externally. The study standardized and various apparatus have been utilized for concluded that high percentages (77 96) of satisfactory analyses of this class of products (mini-paddles have been results were obtained in the study.)

5 With the exception of employed but are not standardized). There are many USP the mesh-size issue for baskets (being evaluated for chapters readily available to provide insight to the testing impact now), conventional Dosage forms are well-defined of oral, aerosol, injectable, mucosal, and skin drug with respect to dissolution testing. Proficiency testing products. Some are finalized and many are in further supports sufficiency of mechanical calibration. The development phases. main outstanding chapter for Ph. Eur. at this time is FIP has committed to revise the publication FIP/AAPS An additional point that was discussed in the questions Guidelines for Dissolution/In Vitro Release Testing of segment was a request to define how the Ph. Eur. will react Dissolution Technologies | NOVEMBER 2010. 47. 47 11/26/2010 9:26:03 AM. to new chapters published by the USP. The goal is to disintegrated tablets and nasal Dosage forms, lozenges, maintain as much harmonization as possible and not to patches, and chewable gums were presented.

6 Stents and head back into the current harmonization project that is microspheres were summarized based on the London on-going for so many chapters. conference. Recommendations from the conference were presented for modified scaling, modified temperature, and summary of Questions modified apparatus. Apparatus 4 and its application with The use of organics or enzymes is not defined or microspheres were identified. It is necessary to optimize harmonized. Will this be identified as a condition when the in vitro method to reflect in vivo activity appropriately dissolution methods are harmonized? There will be a and discriminate between manufacturing changes. symposium as part of AAPS on the performance of alcohol Recommendations for inhalation products and studies with dissolution. suppositories were presented and include impactor Additional explanation on failures for the proficiency testing and modified dialysis tubing method, respectively. test was requested.

7 The explanation provided was Dissolution is necessary to assess batch-to-batch quality, that failures were investigated (equipment, protocol and methodologies need to be simple, reliable, and interpretation, etc.) and concluded before retesting. reproducible. A question of how stents and implants would be covered in the Ph. Eur. was posed. It was indicated that Speaker: Lucinda Buhse, these will fall under devices, but would also be considered combination products. It will be useful to have Orally Disintegrating Tablets or Orodispersible Tablets standardization for these device requirements. Definitions from both the FDA and Ph. Eur. for orally dispersible tablets were presented, and identification of Speaker: J. Michael Morris Dosage forms not within the classification was provided. There are advantages to orally disintegrating tablets, International Regulatory Views on Special Dose Forms but many issues are observed due to the specialized The necessity for sound science in Dosage form design, formulation.

8 These tablets should be assessed similarly to in the manufacturing process, and in the simulation of in other tablets, but disintegration testing may have greater vivo performance by in vitro testing was emphasized. The value. Disintegration and dissolution testing should be state of harmonization between regulatory agencies and used to guide development and to understand potential their requirements to follow ICH were summarized. ICH impact of manufacturing changes and IVIVR/IVIVC. guideline topics as well as learning points from their Acceptance criteria should be based on scientific merit development were provided. The list of priority and statistical evaluation. In later stages, these tests should harmonization chapters was included and their status was be used as a quality control tool. Development of a presented. The focus was then shifted to in vitro release dissolution method may be complex due to and Q6A, where items not covered were identified.

9 The formulation-driven limitations such as rapid disintegration importance of thorough development of methods with or necessity for sinker use. In vivo versus in vitro respect to Q8 (QBD) was emphasized. Submissions should comparisons for disintegration are complicated because include all relevant data for IVIVC or IVIVR. Determination the in vivo characteristics can only be measured with of relationships/correlations is more complex with respect to patient input. Standards for in vitro testing were modified-release products. Different routes of not intended for ODT and will likely not perform administration and nanotechnology and liposomes were appropriately without modification. Examples of issues presented. The importance of determining the right with measurement of disintegration (both in vivo and in method with appropriate specifications, no matter what vitro) were presented, and the potential importance of formulation, was reiterated. texture was identified.

10 Modified Apparatus 2 and CCD. cameras were presented as options for measurement of Speaker: Cynthia Brown disintegration. Both dissolution and disintegration are important for ODTs, and additional development will be In Vitro Release Testing of Special Dosage Forms necessary to ensure proper comparisons for summary of 2008 London Workshop disintegration. This presentation provided high-level information for each modified-release formulation as presented in London Speaker: Gordon McKay, in 2008. The FIP SIG was introduced, and a commitment was made to revise the 2003 publication of FIP/AAPS In Vitro Evaluation of Chewable Oral Drug Products guidelines for in vitro release. Much progress has been This presentation summarized in vitro testing for made since the original publication in the area of gum-based and chewable tablets. The introduction modified-release Dosage forms, and recommendations/ summarized various in vitro techniques utilized to analyze standardization would be beneficial.