Meeting Report: AAPS–NIFDC Joint Workshop On Dissolution .
dx.doi.org/10.14227/DT230416P46Meeting Report:AAPS–NIFDC Joint Workshop on Dissolution Testing,Biowaiver, and Bioequivalencee-mail: xujin.lu@bms.comXujin Lu , Vivian A. Gray , Nikoletta Fotaki , Jian-Hwa Han , Johannes Krämer , and Erika Stippler61,*23451Bristol-MyersSquibb Company, New Brunswick, NJ, USAA. Gray Consulting, Hockessin, DE, USA3University of Bath, Bath, UK4Abbvie, Inc., North Chicago, IL, USA5PHAST GmbH, Homburg, Germany6U.S. Pharmacopeia, Rockville, MD, USA2V.Ajoint workshop of the American Associationof Pharmaceutical Scientists (AAPS) and theChinese National Institutes for Food and DrugControl (NIFDC) on dissolution testing, biowaiver, andbioequivalence took place in Tianjin, China, from June 21to 22, 2016.The AAPS and NIFDC cosponsored this event. Theorganizing institutions were the AAPS In Vitro Releaseand Dissolution Testing (IVRDT) Focus Group, ChineseJournal of New Drugs, and Tianjin Institute for DrugControl, supported by the Medical Instrument Branchof China Instrument and Control Society and the ChinaPharmaceutical Enterprise Development PromotionAssociation. The goals and objectives of the workshopwere: (1) enhance the communication among Sino andAmerican industry scientists, regulators, and academics inthe field of in vitro and in vivo drug release and the use ofdissolution as a tool for drug development, biowaiver, andbioequivalence studies; (2) share knowledge in dissolutiontesting, apparatus calibration, bioequivalence application,and drug specification settings; (3) disseminate regulatoryand compendial information to facilitate methoddevelopment, current Good Manufacturing Practicecompliance, and quality control (QC) of generic products;and (4) establish networking and collaboration amongscientists from the drug control and inspection agencies,academia, and the pharmaceutical industry.The workshop was co-chaired by Dr. Xujin Lu (IVRDTFocus Group) and Dr. Baoming Ning (NIFDC). Membersof the Organizing Committee were Ms. Vivian Gray (V. A.Gray Consulting), Ms. Lan Lin (NIFDC), Professor QimingZhang (NIFDC), Professor Jianqiang Shao (Tianjin Institutefor Drug Control), Mr. Dawei Liu (Chinese Journal of NewDrugs), and Mr. Yucheng Gao (China Instrument andControl Society).46*Corresponding author.NOVEMBER 2016DAY 1Session 1In his opening remarks, Dr. Xujin Lu reiterated the goalsof the workshop. Ms. Lan Lin (Director of ChemicalDrugs Division, NIFDC) expressed strong support fromthe Chinese co-sponsor and organizing institutions andintroduced the first session.Professor Nan Nan (NIFDC) delivered the first presentationtitled “Application of Dissolution Testing in BiorelevanceEvaluation of Generic Drugs.” Following recentpublications by China Food and Drug Administration(CFDA) on #106-2016, “Guidance for BioequivalenceEvaluation of Generic Drugs,” and #61-2016, “Guidancefor Measurement and Comparison of Dissolution Profilesfor Solid Oral Dosage Drugs,” Professor Nan elaboratedthe requirements of these guidelines. She addressed thescope of Guidance #61, the objective of the dissolutionprofile studies, the dissolution profile measurement, thedissolution profile comparison and similarity, and a casestudy.Professor Nan indicated that Guideline #61 is to formalizethe current studies and work in China using in vitrodissolution for the bioequivalence evaluations of genericdrugs in solid oral dosage forms, which is an integralpart of executing Guidance #106. An in vitro dissolutionprofile, as opposed to a single point of drug release,demonstrates the entire process of drug release that mayprovide relevant information on drug in vivo performanceand, therefore, could be a simple and direct tool forformulation development, batch-to-batch consistencyevaluation, and QC for formulation and process change.Studies of dissolution profiles will be beneficial to learnthe characteristics of a comparator or branded drug, toapply the learning to evaluating the quality of a generic
drug versus branded drug, to guide a bioequivalencestudy, and to establish a reliable dissolution testingmethod. Professor Nan provided detailed instructionson the measurement of dissolution profiles anddevelopment and validation of dissolution methods. Sherecommended first finding the compendial methods thathave been published in USP, FDA dissolution database,Japanese Orange Book, and the other pharmacopeia.She also indicated it is not realistic to establish IVIVCdissolution methods for every drug product. However, itis possible to develop a dissolution method that can beused for QC and drug inspection through differentiationof the changes in formulation, process, and batch-tobatch consistency. For dissolution profile comparisons,Professor Nan recommended using Similarity Factor f2over other non-model dependent methodologies. Inaddition, she emphasized the conditions that have to bemet when using the f2 method. Professor Nan describeda case study in great detail. Terazosin Hydrochloride (TH)is a highly soluble drug in BCS Class I or III. Compendialmethods for the tablet dissolution can be found in FDAdatabase, Japanese Orange Book, USP 38, as well as CHP2015. A method was determined for the comparisonof a branded TH tablet product made by Abbott with ageneric TH tablet product, which utilized four differentdissolution media: water, 0.1 N hydrochloric acid, pH4.0 and pH 6.0 buffers, and six sampling time points. Acomparison between the average dissolution profilesfrom 12 dosages of the reference TH product and thegeneric TH product passed the f2 test and thereforedemonstrated in vitro similarity.(IR) products, he pointed to 21 CFR 320.22(b)(2) thatstates one of the requirements for biowaiver is “bothdrug products meet an appropriate in vitro test approvedby FDA.” Telmisartan tablets provided an example. FDAcompares the dissolution profile data of the waiverstrengths (typically the lower strengths) with the strengthof the batch used in the pivotal BE study. If dissolutionprofiles are “similar,” dissolution is considered to besupportive of the waiver request. Assessing biowaiver formodified-release (MR) products is not a “waiver.” Rather,as stated in 21 CFR 320-24(b)(6), “Any other approachdeemed adequate by FDA to measure bioavailabilityor establish bioequivalence,” which usually requiresproportional similarity, an understanding of the drugrelease mechanism, and a similar dissolution approachto that used in IR products (with the exception ofmultimedia testing with different pH values). For DrugEfficacy Study Implementation (DESI) products, Dr.Munshi described the biowaiver with the example of theAcetaminophen/Butalbital/Caffeine capsule, which is aDESI-effective drug and exempted from in vivo BE study.For a Biopharmaceutics Classification System (BCS)-basedbiowaiver, he explained why waivers can be based onsolubility, permeability, and dissolution, and clarified thatonly IR solid oral dosage forms with a BCS Class I drugsubstance that exhibit rapid dissolution or a BCS ClassIII drug substance that exhibit very rapid dissolution areeligible for waiver. The others, like MR drug products,narrow therapeutic range drugs, and dosage formsintended for absorption in the oral cavity are exemptfrom waiver.Dr. Utpal Munshi (Division of Bioequivalence I, Office ofGeneric Drugs, CDER, FDA, USA) gave the second talk,entitled “Dissolution: A Critical Tool in the Evaluationof Generic Drug Product.” Dr. Munshi started with aquestion, what do we use dissolution for? From theperspective of drug product evaluation, he said theanswer is for the QC of the finished dosage form, a toolto assess waiver requests of the in vivo bioequivalencestudy requirement, to support post-approval changes, toassess dumping of dose from the product, and as part of aweight-of-evidence approach to assessing bioequivalence(BE). He elaborated each of the applications throughouthis talk.Dissolution can be used to support post-approval changes.Dr. Munshi explained the general concepts of related FDAguidances for Scale-Up and Post Approval Changes of IRand MR. Changes in the formulation and manufacturingare classified into different levels depending on the extentof the change from the originally approved product. Thenature and number of studies needed depend on thelevel of the change. Comparative dissolution is often usedto support a post-approval change. In some cases, an invivo BE study may be recommended to support the postapproval change. In lieu of an in vivo study this case, an invitro–in vivo correlation (IVIVC) may be used to supportthe change.As a method to control the quality of the finisheddosage form, the products where the QC dissolutionmethod is employed include solid oral dosage forms,oral suspensions, transdermal products, and injectablesuspensions. The assessment of biowaiver requests wasaddressed from several aspects. For immediate-releaseTo assess the dumping of dose from the product,dissolution has been playing an important role. Hedescribed the requirement for in vitro alcohol dosedumping testing, and indicated if the test (T) andreference (R) products do not behave in the same wayin the presence of alcohol, the safety/efficacy profileNOVEMBER 201647
may differ between T and R, causing concerns about thetherapeutic equivalence. He also listed four drug productswhere alcohol dose dumping is currently requested.Another application of dissolution is as part of a weightof-evidence approach to assessing BE. He listed someexample cases and presented details for three cases.First, he discussed ergocalciferol capsules that containthe active pharmaceutical ingredient (API) in “ediblevegetable oil.” An in vitro approach may suffice providedcontrol of the formulation similarity between the test andreference products. The in vitro approach is a specializedtype of dissolution test known as Quantitative CapsuleRupture Testing, which can assess BE provided that theT and R products are qualitatively and quantitatively thesame. Secondly, he discussed vancomycin HCl capsules, alocally acting drug product that is poorly absorbed afteroral administration but is solubilized and transportedby gastrointestinal (GI) fluid to the site of action in thelower GI tract. The BE can be assured when the effectof the excipients on transporting the drug and on theeffectiveness of the drug at the site of action are similarbetween the T and R products. Also, the release ofvancomycin from the T and R is equivalent, e.g., similar Tand R dissolution at all physiologically relevant pH ranges.Third, he discussed cyclosporine ophthalmic emulsionto reduce regulatory burden and regulatory risk. Twooptions can be adopted to demonstrate BE for thisproduct. One is an in vivo option using a clinical endpointstudy. The other option is an in vitro option consistingof two parts: (1) a comparative study on globule sizedistribution and other comparative physicochemicalstudies and (2) a comparative in vitro drug release ratetest that can discriminate the effect of process variabilityin the production of the test formulation. In conclusion,Dr. Munshi emphasized the importance of dissolutionto all the applications and provided references to FDAguidances and published documentation.Dr. Erika Stippler (U.S. Pharmacopeia, USA) gave apresentation titled “USP Compendial Dissolution/DrugRelease Testing—Overview and Update.” Dr. Stipplercompiled the USP General Chapters relevant to theperformance testing of various dosage forms andpresented the recent changes and updates on each ofthese chapters.48The USP General Chapters 701 Disintegration, 711 Dissolution, and 724 Drug Release are mandatorychapters and describe test apparatus for the evaluationof the performance of various dosage forms. Whereasdissolution Apparatus 1 and 2 are well-establishedtest apparatus and are widely used in each phase of aNOVEMBER 2016formulation’s life cycle, the other dissolution apparatusstill find limited use. These limitations can be due tothe apparatus design or due to limited experience inapplicability and use of those apparatus.Dr. Stippler presented the most recent changes in GeneralChapter 711 being effective in USP 39–NF 34. This refersto the dissolution tests of hard and soft gelatin capsulesand gelatin-coated tablets, which do not conform to thedissolution specifications in the specific drug productmonograph. In those cases, the dissolution test can benow performed with the addition of different enzymesdepending on the pH value of the dissolution medium.Several information chapters describing the performancetests of various dosage forms other than those for solidoral dosage forms have been developed in recent years.General Chapter 1724 Semisolid Drug Products–Performance Tests became official in USP 37–NF 32(May 01, 2014) and describes three apparatus for drugrelease testing of semisolid dosage forms. The officialrevision of the General Chapter 1094 Capsules–Dissolution Testing and Related Quality Attributes (USP37–NF 31, Supplement 1, Aug. 01, 2014) provides detailedinformation on the specific challenges of crossed-linkedgelatin capsules in the dissolution test, and describesapproaches to resolve them. The revised General Chapter 1092 The Dissolution Procedure: Development andValidation has become effective in USP 38–NF 33Supplement 1 (Aug 01, 2015) contains very useful step-bystep recommendations on how to develop and validatedissolution procedures. The new General Chapter 1771 Ophthalmic Products–Performance Tests becameofficial in USP 39–NF 34. The General Chapter 1090 Assessment of Drug Product Performance–Bioavailability,Bioequivalence, and Dissolution recently underwenta major revision, and the proposed new version of thischapter was published in Pharmacopeial Forum (PF)42(4). Also, a new informational General Chapter 1004 Mucosal Drug Products–Performance Tests has beenpublished in PF 41(5).Dr. Stippler concluded her presentation presentingthe USP’s Dissolution database accessible online. Thisdatabase is a searchable list of all dissolution/drug releasetest procedures described in the USP drug productmonographs.The next speaker was Ms. Vivian Gray, whose talk wastitled “Differences and Harmonization of CMC Area ofDissolution, EU/US Perspectives.” This talk began with adescription of the successful harmonization of the FDABCS Biowaiver guidance with the other global guidances.
The talk focused on the reduction of the 90% permeabilitycriteria to 85%, the allowance for 75-rpm paddle speed;the inclusion of BCS Class III to be eligible for a biowaivergiven very rapid dissolution (85% dissolved in 15 min) inall three prescribed media; the pH range reduced to 1.2 to6.8 pH; and the volume of media was reduced to 500 mL.She highlighted the differences and similarities in the USPand the European Pharmacopeia regarding dissolutiontopics. There was a discussion of the elements that arefound in the USP 711 Dissolution General Chapter thatare not present in the European Pharmacopeia. Theseelements are the Performance Verification Test (PVT),enzyme addition for cross-linking, pooled sampling, and2- to 4-L vessels. Ms. Gray gave an account specificallyregarding f2 criteria and rules that are different or slightlydifferent in difference regions and in the many guidancedocuments.Session 2The second session began in the afternoon with Ms.Vivian Gray giving an overview of the AAPS, the U.S.organization that co-sponsored the event. She highlightedthe availability of e-membership for Chinese scientists.She told the audience about the new eLearning course ondissolution.The next speaker, Dr. Johannes Krämer (PHASTGmbH, Germany), presented a talk titled “PredictiveDissolution Testing for Development of New Drugs.”Dr. Krämer started with a clarification—the results of invitro dissolution testing may be used as a surrogate ofbioequivalence testing to prove a similarity of dosageforms. However, dissolution testing alone does not allowfor the prediction of oral bioavailability of an oral drugproduct. Dissolution testing does not provide an absolutemeasure of bioavailability, rather, it allows for relativeestimates of bioavailability changes and can revealrelative differences in formulation variations.The goal of predictive dissolution testing is to evaluatethe in vitro performance of dosage forms. Dr. Krämerindicated that, in order to assign any results clearly tothe impact of the dosage forms, preliminary testingshould cover the physicochemical properties of the drugsubstance, given that drug substance characteristics maybe leveled out or amplified or masked by technologicalmeans.In the lifecycle of drug products, in vitro dissolutiontesting may have different goals. The general requirementis to predict changes of bioavailability as the surrogateof the therapeutic efficacy. In early development, thediscriminatory power of in vitro methods is required. Atthat stage, different dosage forms may be evaluated. Invitro methods are expected to be sensitive to the dosageform properties. In the subsequent development phase,discriminatory power is, again, required, whereas thefocus of in vitro testing is on the formulation differences(e.g., differences caused by changes in the composition).Also, sensitivity to variations in the manufacturingprocess with critical influence on the dosage form’s invivo performance is demanded. Once the drug productis registered and the market supply has started, thediscriminatory power of dissolution methods is, again,required. At that stage, dissolution testing as a part of QCprovides the proof of similarity of released lots to thoselots included in early bioavailability (BA) studies and forwhich safety and efficacy data are available. Intra-lothomogeneity and lot-to-lot conformity are the qualityparameters. Specifications of dissolution testing maybe based on in vivo bioequivalence findings, providingthat all batches “in spec” are bioequivalent. With that inmind, there is an ongoing scientific debate on whetherpredictive in vitro performance testing should reflect thein vivo dissolution, which takes place in the human GI tract,or whether it should reflect the composite kinetics as itis observed from blood concentration analyses. In bothcases, the likelihood of predicting the in vivo performanceis assigned to in vitro experimental designs that arebased on the most relevant in vivo conditions, such aspH value, surface-active ingredients, and lipids. This isof great importance in the case of evaluating IR dosageforms. For those extended-release (ER) dosage forms,which are designed to release the drug independentlyfrom the physicochemical surroundings of the human GItract, in vitro simulation of in vivo conditions may be lessimportant.According to Dr. Krämer, predictive dissolution may belinked to biorelevant methods. The term biorelevantmay have different meanings, depending on whetherthe API is for local or systemic application. The use ofbiorelevant media, as first described by Dressman et al.,may be beneficial. Besides the composition of dissolutionmedia, which has a great influence on the solubility ofthe drugs substance and, hence, on its dissolution rate,their volume is an important experimental detail. Inthe fasted state, physiologically available volumes aresmaller than the typically used 900 mL of the classicalUSP paddle, Apparatus 2. However, an excessive volumemay create conditions that mimic the in vivo absorption.To complete the dissolution medium list of functions, thetransfer of mechanical energy from the stirring elementto the surface of the specimen, at the given viscosity, isworth noting. Provided that in vivo dissolution is theNOVEMBER 201649
rate-limiting step in the composite pharmacokinetic (PK)process, a relationship between parameters of in vitrodissolution kinetics and the rate and amount by which theactive moiety is absorbed from the dosage form (i.e., itsbioavailability) may be established.The next speaker was Dr. Jian-Hwa Han (AbbVie Inc.)whose presentation was titled “Diss
presentation titled “USP Compendial Dissolution/Drug Release Testing—Overview and Update.” Dr. Stippler compiled the USP General Chapters relevant to the performance testing of various dosage forms and presented the recent changes and updates on each of these chapters. The USP General Chapters 701 Disintegration, 711
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The American Association of Pharmaceutical Scientists (AAPS) is a professional, scientific society of more than 13,000 members employed in academia, industry, government and other research institutes worldwide. Founded in 1986, AAPS provides a dynami
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