Presentation on theme: "The ACPS’s Process Analytical Technology Subcommittee"— Presentation transcript:
1The ACPS’s Process Analytical Technology Subcommittee Ajaz S. Hussain, Ph.D.Deputy DirectorOffice of Pharmaceutical ScienceCDER, FDAACPS Meeting November 28, 2001
2Objectives of PAT Discussion To delineate the goals and objectives of the ACPS’s Subcommittee on PATEnumerate expectations of the ACPSreporting and timeline
3Outline Overview (Ajaz Hussain) ACPS discussion and recommendations Background InformationJuly 19, 2001 ACPS DiscussionNovember 16, 2001 FDA Science Board DiscussionA Vision for PAT in Pharmaceutical ManufacturingProposed responsibilities and timelinesOctober 25, 2001 FR Notice on PAT SubcommitteeACPS discussion and recommendations
4July 19, 2001 ACPS Discussion on Optimal Applications of PAT Initiate public discussion on application of process analytical chemistry tools in pharmaceutical manufacturingStrong ACPS support to move forwardRecommendation to form a PAT SubcommitteeRelated discussion on “Rapid Microbial Testing”No further development to report at this time
5FDA Science Board Discussion Nov. 16, 2001 SpeakersJanet WoodcockCDER, FDADoug Dean and Frances BruttinPricewaterhouseCoopersG. K. RajuMITNorman Winskills and Steve HammondPfizerAjaz HussainOPS, CDER, FDA
6Science Board’s Response Strong unanimous endorsement of the proposalWould like to support this initiativetalks, seminars,…Would like to receive updates on progressQuestions from ACPS?
7Current Status US Drug products are of high quality, BUT Dr. Woodcock’s presentation summaryCurrent StatusUS Drug products are of high quality, BUTIncreasing trend toward manufacturing-related problemsLow manufacturing and QA process efficiency--cost implicationsInnovation, modernization and adoption of new technologies slowedIntroduction of new technologies in facilities not for US marketHigh burden on FDA resources
8Dr. Woodcock’s presentation summary How Did We Get Here?System evolved beginning years ago--when sectors of industry lacked rigorous SOPsScience/technology base did not evolve as quickly as in other sectorsEmpirical GMP standards necessitates stringent scrutinyInternational conference on Harmonization--consensus based standards (1990’s)Industry--regulatory risk averse
9Dr. Woodcock’s presentation summary Challenges for FDAHow to encourage innovation while ensuring high qualitySuccessful adoption of new technologies will IMPROVE overall qualityHow to successfully shift from empirical to science based standards for manufacturing process qualityHow to decrease reliance on pre-approval review and physical evaluationHow to recruit and train a scientific workforce proficient in application of new technologies
10Questions for the Science Board Dr. Woodcock’s presentation summaryQuestions for the Science BoardAre you able to support the approach?What resources do you suggest FDA draw on?Are there additional aspects to regulation of pharmaceutic quality that we should focus on?
11Measurement Shows Potential for Improvement 100%Cost reductionTime Compression0%35 days3daysBest Practice: VA Ratio 50%
12Benefits - Increased Effectiveness of Compliance Infrastructure 0%100%Level of ComplianceCost52Compliance GainDirect Cost Recovery
13PROCESS D WITH QC TESTS: Cycle Times including BULK ACTIVE 20 DAYS15 DAYSBLEND 2:PRE-BLENDFILMCOATINGBOTTLEPACKAGINGGRANULATIONSTEPCHEMICALWEIGHINGBLEND 1:FINALBLENDCOMPRESSPROCESSING10 DAYS15 DAYSQC1QC3QC221-90 DAYS60 DAYSMIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
14ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES On-line LIF, NIR, Data Analysis, etc.MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
15LOOKING BEYOND THE “AVERAGE” Lots with ExceptionsLots without ExceptionsOVERALL CYCLE TIMES100200300400500600700800LOT NUMBERNEED FOR FUNDAMENTAL TECHNOLOGYMIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
16Impact of Exceptions PERFORMANCE MEASURE VALUE (Detailed Analysis of 2 Products)PERFORMANCE MEASUREVALUEAverage Cycle time daysStd dev(Cycle time) > 100 daysExceptions increase cycle time by > 50 %Exceptions increase variability by > 100%Capacity Utilization of “System” LOWNEED FOR FUNDAMENTAL TECHNOLOGYMIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
17PAT Applications at DP Sites RM Testing (warehouse based)Packaging ComponentsBlending (at-line or on-line)DryingTableting (potency and CU)Encapsulation (potency and CU)Tablet Coating (coating thickness)Packaged productEquipment cleaning (on line monitoring of CIP)Equipment cleaning (surface monitoring)Note - Less than 15% of applications at US sites
18The “Don’t Use” Scenario What:Modern PAT methods not used/developed during product development so not used for routine process controlWhy:Fear of regulatory delaysWasteful of resources to duplicate method development -“current methods work OK”Concern of “raising the bar” unnecessarily: information generated for one process may be expected from allIssues:Loss of benefit of PAT - improved process information and control
19The “Don’t Tell” Scenario What:PAT methods not registered but used in parallel with registered (conventional) methods to gain greater process insight and controlWhy:Concern over delays in regulatory approvalConcern that data may be interpreted inappropriately by regulators. More data will lead to more deviations from “norms” - need to be able to determine which are relevant and which are notIssues:Duplication, inefficiency, environment of “mistrust”
20The “Win - Win” Scenario What:Modern PAT methods used to gain greater understanding of processes during development, are registered and used as in-process control (and release?) methodsPAT methods accepted as alternatives to traditional lab based methods - but not requiredWhy:Methodology understood and accepted by regulators and industry alikeIssues:This is where we should all want to get to. Making progress, but we are not there yet……….
21How can we create a “Win-Win” Environment? Dealing with the real or perceived regulatory hurdles:Sponsor joint forums to promote discussion and enhance understanding of the issues and opportunities offered by PATDevelop an effective process for the evaluation of new PATsDevelop appropriate guidelines for the development, validation and implementation of new PATslab based extraction/chromatography rules don’t applyparticipate in “dummy run” submissionsEnsure consistent approach to PAT by Review and Inspection
23Issue: Need for FDA to Facilitate Introduction of PAT Ajaz Hussain’s presentation summaryIssue: Need for FDA to Facilitate Introduction of PATIndustry is hesitant to introduce PAT in USRegulatory uncertainty/risk leads to “Don’t Tell” or “Don’t Use” practiceNew Technology = New QuestionsMethod suitability, chemometrics and validationOld products + New technology = New Regulatory ConcernsProblems not visible under the current systemMindset: Why change?PAT application will add to current regulatory requirements
24“Win-Win” Opportunities Ajaz Hussain’s presentation summary“Win-Win” OpportunitiesOptimal application of modern process analytical technologies canImprove quality and manufacturing efficiencyReduce the likelihood of scrap/recallsImprove the scientific and engineering basis of many current FDA-Industry debates
25What Should FDA Do to Facilitate Introduction of PAT? Ajaz Hussain’s presentation summaryWhat Should FDA Do to Facilitate Introduction of PAT?Eliminate regulatory uncertaintyOfficial position - FDA will accept new technology that is based on “good” scienceDevelop standards for PATMethod suitability and validationMultivariate statistical/computer pattern recognitionCritical process control points and specificationsChangesOOS….
26What Should FDA do to Facilitate Introduction of PAT? Ajaz Hussain’s presentation summaryWhat Should FDA do to Facilitate Introduction of PAT?Define a clear science based regulatory processCurrent system “adequate for intended use”Introduction of PAT not a requirementDefine conditions under which PAT may replace current “regulatory release testing”Process for addressing existing “invisible” problems in marketed productsReview and inspection practicesInternational harmonization
27How Should FDA Facilitate PAT? Ajaz Hussain’s presentation summaryHow Should FDA Facilitate PAT?Limited institutional knowledge and experience at FDASeek input and collaborationAdvisory Committee for Pharmaceutical Science - Subcommittee on PATIndustry (individual companies?)Academic Pharmaceutical Engineering and Process Analytical Chemistry programsPQRI
28A Perspective on PAT: One piece of the puzzle “Vision I can see clearly now”Quality & performance by design + Continuous “real time” monitoring of qualitySpecifications based on mechanistic understanding of how formulation and process factors impact product performanceHigh efficiency and capacity utilization“Real time” review and inspection from Rockville, White Oak, NJDO,...
29Key Elements of the Emerging Program on PAT (Draft) A “general principles” guidance on PATArticulate an FDA position on PATDefinitions and terminologyOutline a regulatory process for introducing PATPre- and post approval phasesAddressing existing but invisible problems“Team” approach for review and inspectionTypes of experimental evidence and justification“Alternate” and “Primary” control/test“Direct” and “Correlation-based” control/testAppropriate level of redundancy or backup systemsOn/In/At-line release testing (parametric release)
30Types of Tests/Controls “Alternate” control/testA PAT tool validated by comparison to a traditional in-process test using development data and/or data from routine production for a period of time. Traditional in-process test discontinued after sufficient data collected to support validation.On-line blend uniformity using NIR validated by comparison to data obtained on blend samples collected using a “thief”“Primary” control/testA PAT tool is developed and validated on its own meritsAccuracy, precision, specificity,…….
31Types of Tests/Controls (Contd.) Correlation-based controls/testsUse of chemometrics or pattern recognition methods to identify and develop a correlation between a measurement and product attributeE.g., Prediction of tablet hardness, dissolution rate from NIR spectral fingerprintsValidation based on predictive performance onlyValidation based on predictive performance plus mechanistic justification (causal links)
33Parametric Release & Release Tests What is “parametric release”When "data derived from the manufacturing process sterility assurance validation studies and from in-process controls are judged to provide greater assurance that the lot meets the required low probability of containing a contaminated unit (compared to sterility testing results from finished units drawn from the lot), any sterility test procedure adopted may be minimal, or dispensed with on a routine basis.” (USP)Need to redefine this term
34EMEA's Note for Guidance on Parametric Release (effective since 9/01) Defines Parametric Release as:" a system of release that gives assurance that the product is of the intended quality based on the information collected during the manufacturing process and on the compliance with specific GMP requirements related to parametric release."In addition, this note extends the Parametric Release concept to other dosage forms.
35Parametric Release: Dissolution? Provide a greater assurance (compared to the current dissolution test method)Lot will meet established specificationLot will meet established BA/BEData derived fromProcess that utilizes in-process controls that can measure and control all critical variables that effect dissolutionAppropriately designed manufacturing process validation studiesValidation based on predictive performance plus mechanistic justification (causal links)
36Non-homogeneous distribution of magnesium stearate
37ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR]YESdissolution significantly affect BA?Develop test conditions and acceptancedistinguish batches with unacceptable BANODo changes in formulation or manufacturing variables affect dissolution?YESAre these changes controlled by another procedureand acceptance criterion?YESNONOAdopt appropriate test conditions and acceptance criteria withoutregard to discriminating power, topass clinically acceptable batches.Adopt test conditions and acceptancecriteria which can distinguishthese changes. Generally, single pointacceptance criteria are acceptable.aaps Annual Meeting
38PAT FR Notice Oct. 25, 2001 Request names of qualified individuals Process analytical chemistry, pharmaceutics, industrial pharmacy, chemical engineering, pharmaceutical analysis, chemometrics, pattern recognition, expert systems, IT, and statisticsReport on scientific issues related to application and validation of on-line process technologies (e.g., NIR).Both drug substance and drug product manufactureFeasibility of “parametric” release conceptPotential benefits and risksApplications should be received by 11/30/01
39Subcommittee should report on (?) Current status and future trends: PAT in pharmaceutical development and manufacturingAvailable technologies, capabilities,...Application in US Vs. Non-US plantsPerceived and/or real regulatory hurdlesGeneral principles for regulatory applicationPrinciples of method validation, specifications, OOSAppropriate use and validation of chemometric toolsFeasibility of “parametric release” concept (also, redefine)Case study: vibrational spectroscopy (NIR)?Research and training needs (FDA and industry)