Two-Tier Dissolution Testing*

1 Two-Tier Dissolution Testing* In early t 993, the USP S ubcomrnittce o n Disso-lution and Bioavailabili ty (DBA) decided that the soft gelatin capsules Dissolution test exemp-tion in the USP <711> Dissolutio n General C ha pter sho uld be de leted. It was determined that there s hould be" Dissolution test for all types of capsules. For capsules where a dissolutio n test could not be develo ped, a rupture test was pro-posed in Pharmacopeial Forum (PF), the revision journ a l of th e USP. In July 1993, at a DBA Subcommittee meeting it was decided dlat "aged capsules" that did not pass the Dissolution test would undergo a second disso-lutio n test using m edium containing enzyme. Ilowcvcr, this was only .111owed providing that t he re was no evidence t hnt the bioavailabilty of the capsules had been adversely changed. The ch ange was proposed in the USP <71 I> Dissolu-tion General C hapte r in the Previews section o f the PF in early 1994.

2 This was a fairly stringent standard, in most cases a bioequivalence snldy, and objections were raised by the phann3ceurical industry. At t hi s point, the FDA/Industry Gelatin Caps ules Wo rking Group was formed and USP became a par-ticipant. The USP DBA Subcommit-tee decid e d to defer the "aged capsules" proposal until the Wo rking G roup had completed it, bioequiva-Ic nce studies. The bioequivalence studies s howed that th e stressed hard gelatin capsules were biocquivalent to unstressed C:lpsulcs. In early 1997, a PF proposal, rec-o lllmended by the Working Group and the DBA Subcommittee, 3110wed for a two tier Dissolution tcst, in which a second Dissolution test could be performed using enzyme in th e medium if a hard gelatin capsule failed t h e officia l di ssolution test. T he proposal stated that the second Vivian A. Gray DuPont A'fe,.rk Pbltrl1l11 CfllficlI1s Wi/tJJillgtOIl, DE Dissolution test would be shown in the individual monograph.

3 However, a revised proposal, shown in PI' 23 (5) ( 19971, describes the appro priate second Dissolution test medium in th e Gen eral C hapter <711> D issolutio n e liminat-ing the need to include a second Dissolution test in the inclividuall11ollograph. The proposal reads as follows: "I-lard gelatin capsules t hat do not conform to the Dissolution specification may be tested, except when the medium is water, using the same medium as indicated in the mo nograph fo r the drug product with t he addition of grams o r purified pepsin o r less, with an activity of 800 to 2500 units per mg of protein, or 5 grams of pancrc3tin or less, per 1000 mL of DissoifltiollTecimoiogieslMAY 1998 Dissolution Testing .. continued mediulll, as appropriate. Pepsin should normally be ridded ro ::lcidic media, while p:1I1cre,Hin is appropriate for Illedia at or above p11 6 .8. if the initia l test is water, the second tcst medium could he either 0.)

4 1 N hydrochloric ~lcid with pe psin or pll phosphate buffer with pancre:nin, depending on lhe drug solubility. Conformance to the specification upon testing in o ne of th ese media is acceptable." 'T'herc are certain aspects of the proposal that should be noted. It does not address the lise of SUf-facranLS. The product can fail any time-that is even at release. I [ owever, the analyst s hould be warned that if t h e product fails at the time of rclcasc--on stability the <lddcd enzyme may not be sufficient to overcome the crosslinking problem. This propos:ll W,-lS adoptcd:ls an [ntc rilll Revi-sion Announcement and was o lli cial on Decclll-bel' 1, 1997. It is the leg-II standard put forth by VSP and enforced and followed by the FDA. The rDA has not givcn guidance ~lS to how using the second Dissolution test is to be docu-mented, whether it will be in an annllal report as any USP change, or by some othcr mechanism.]]

5 Dissoilltion Tecbllologiesl MA Y 1998 The two tiered test will be revised again to add the application to soft gelatin capsules . With soft gelatin capsul es the current information suggests that a different activity of pepsin or a different concentration of pancreatin will be needed. The standnrd for products that arc gelatin coated tablets will also be addressed. USP was g lad to be a part of t he efforts of the \ Vorking Group and was pleased with the out-COIllC. It is hoped t hat this kind of inte raction invo lving USP, FDA, and industry will continue. * Excerpts frol11 a talk in the Invitcd Podium Session, Hard and Soft Gelatin Capsules: ]ssucs, Research <lnd Outcomc, AAPS Natioflj]l lv1eeting, November 5,1997, given o n behalf of the usp as part of the FDA/Industry Gelatin Capsule Work-ing G roup