Manufacturing, and Seeking Order in Complexity

Manufacturing, Measurements & Quality Systems: Seeking Order in ComplexityRichard L. FriedmanDirector,Division of Manufacturing & Product QualityCenter for Drug Evaluation & Research

SLIDE 29 Revised to remove redundancy12ICH Q9Risk ControlRisk ReviewRisk AssessmentRisk EvaluationunacceptableRisk ControlRisk AnalysisRisk ReductionRisk IdentificationReview EventsRisk AcceptanceInitiateQuality Risk Management ProcessOutput / Result of theQuality Risk Management Process Risk Management ToolsRisk CommunicationPharmaceutical ManufacturingConventional pharmaceutical manufacturing is generally accomplished using batch processing with laboratory testing conducted on collected samples to evaluate quality.significant opportunities exist for improving development, manufacturing, and quality assurancethrough innovation in product and process development, process analysis, and process control.Guidance for Industry: PAT A Framework for Innovative Pharamceutical Development, Manufacturing, and Quality Assurance (2004)3The Quality System: Foundation for Assuring an Ongoing State of ControlIncludes:Materials SystemEquipment & FacilitiesProductionLaboratoryPackaging & LabelingQuality System

Adaptation: Process Control and ImprovementFEEDBACK SYSTEMS: Control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (211.110a)

IMPROVEMENT: Firm must review, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. (211.180)

5Goal of a Manufacturing OrganizationProvide a consistent, defect-free product to the marketplace via consistent manufacturing operationsAssure safety & efficacyBut not every company has established adequate quality practices, or achieved predictable output. Some companies, products, or processes make more mistakes /defective units than others. Why?

6Putting out fires is not improvement of the process

- W. Edward DemingEach production day, each dose, each patientIf you are operating at 3.8 Sigma, you are getting it right 99 percent of the time... It turns out that even a 1 percent error can add up to a lot of mistakes pretty fast. Getting it right 99 percent of the time is the equivalent of 20,000 lost articles of mail every hour. Its 5,000 botched surgical procedures every week. Its four accidents per day at major airports...

If you can answer when, where and how often the defects occur you have what you need... But dont just focus on the symptoms of the problem. Find the root causes.Chowdury, 2001Operations in Pharmaceuticals Compare Poorly to Other Industries

The pharmaceutical industry lags similar industries in key measures of operations performanceMany of the shortcomings reflect poor quality practices and represent cost savings opportunities... Estimates are from McKinsey Operations Practice. MeasurePharmaAutomotiveAerospaceComputerConsumer Packaged GoodsOverall equipment effectiveness 10% to 60%70% to 85%50% to 70%80% to 90%70% to 90%Annual productivity improvement 1% to 3%5% to 15%5% to 10%1% to 3%5% to 15%First-pass yield - zero defects 60%90% to 99%70% to 90%90% to 99%90% to 99%Production lead times in days 120 to 1801 to 77 to 1205 to 103 to 7Finished goods inventory in days 60 to 903 to 303 to 305 to 5010 to 40Labor value-add time 20%60% to 70%60% to 70%60% to 70%60% to 90%Direct/indirect labor ratio 1:110:110:110:110:1 The Gold Sheet, January 2009 Current state of Pharmaceutical Manufacturing9Why Measure?10The basis of all scientific work is the conviction that the world is an ordered and comprehensible entity

Einstein

11For a Measurement to provide meaningful evaluation of quality, it should:

Provide a direct measure of the critical in vitro attribute that is the surrogate for the in vivo clinical attribute (ideally with IVIVC)Provide very high assurance that process reproducibly meets its limits & specifications for each batchHave a purpose (why measure?)to detect and prevent non-conforming in-process and finished product output i.e., assure effective control of the processand thus greatly reduce risk of any defective product reaching the consumerBe sufficient and timely (how, where, when & how often?)Be reliable. Measurement capability (good analysis provides the truth; allows for correct decisions)12How, where, when and how often to measure?TestsQualitative vs. quantitative Instrument and operator interfacesto processto sampleTimeliness and frequencyMethod of sampling destructive or non-destructiveat-line (sample removed), offline (sample temporarily diverted off-stream) or in-line (on-stream from a distance)invasion of process stream can affect measurementrepresentative of the batch or providing worst case assessmentperiodic, continuous, stratified to risk

13Sources of VariabilityWhen developing or evaluating a process, essential questions include:

What variables in the process are influential, and require careful control and intensified monitoring?

Why and how can a particular variable affect final product quality?

How should cGMP procedures be designed to control that variable? Each significant variable can be measured in one or more ways. As variables are measured, a reliable picture of batch quality will emerge.

14How Good Are Our Measurements?15Quality System Detection of Variation & Defects before DistributionTest of a firms Quality System is if it will promptly catch a problem in a batch vs. discovering only after it is marketed.Mistakes are, in many cases, not caught by the individual making the error, but instead through final inspection or QC test!QC testing is of limited sample size intended to assess a chemical, microbiological, or physical attribute. To avoid detecting mistakes or defects only after a drug product has been distributed:Use Redundancy of Controls, or PAT16

Product Quality: How good is batch-to-batch QC testing?

Specifications alone can not assure product quality.Quality must be built in (21 CFR 211.100, 211.110)QC testing regimens may be found during lifecycle to be insufficient. Enhanced process control or new/modified QC tests might be needed.Passing result for finished product potency, dissolution or content uniformity, on its own, does not provide high assurance that it will pass again.Sample sizes are not always sufficient, and processes are not always stable.1718Potential for Dissolution VariabilityIf a given lot just barely passes the USP or approved criteria once, what is the probability of passing 2 to 8 more times?Depending on the overall inherent lot variability, it can range from 0.3% to 100%

1819Case Study #1 Dissolution Failure (multivariate cause?)It was concluded that the cause of the dissolution failure was a combination of factors, including a formulation change, specifically a 1% increase in lubricant, a subtle change in the effective density of the tablets, the bulk density of microcrystalline cellulose and the process which changed mixing principle (v-blender vs. shaker mixer).

Dissolution testing on stability ultimately detected the problem.3 batches failed (but only 1 batch/year typically placed on stability by firms)

1920Case Study #2 Subpotency (multivariate cause?)Tablet productAssay failure on Stability (9 months)Firms investigation concludes that product stability needs to be improved by:changing to a different API sourcemodification of formulaimproved container/closure system20Microbiological Measurements: Complexity of Measuring Risk to the Patient Type of organismOpportunistic not primary pathogens cause most infectionInfective dose Very elusive based on next factorHost resistance/susceptibility to infectionRoute of Administration In general, the risk of infection will be much reduced for a drug given orally or applied to intact skin compared with a formulation used for treatment of abraded skin or mucous membrane, or damaged eye.[Bloomfield, Microbial Contamination: Spoilage and Hazard. Chapter 2 in Guide to Microbiological Control in Pharmaceuticals, 1990.]21Interpreting Atypical Measurements: OOS Guidance

5/11/201022OOS GuidanceFDAs 2006 Guidance addresses:

1. Conducting/concluding the investigation2. Interpretation of results3. Handling of inconclusive results4. Retesting5. Appropriate use of averaging6. Appropriate use of outlier tests

5/11/201023

OOS Guidance: GeneralRecommended procedures for OOS investigations are divided into two phases to reflect that the OOS result can be caused by either:An aberration of the measurement process (i.e. laboratory error)An aberration of the production process (i.e. the product is OOS)

5/11/201024OOS Guidance: GeneralToo often root cause is unknown, or arbitrarily attributed to an analyst. Two possibilities:Product related variability: Formulation components, manufacturing process, operator, etc.Measurement system (method) related variability: Sampling bias, apparatus setup, analytical, operator, reference standard, etc.

5/11/201025

Warning Letter Data IntegrityCan You Trust the Reported Measurements? Failure to establish appropriate controls over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel (21 CFR 211.68 (b)). The UV/Visible spectrophotometer data acquisition systems allow analysts to modify, overwrite, and delete original raw data files. This equipment is used for dissolution testing of finished product, stability samples, and process and method validation studies. All laboratory personnel were given roles as Managers, which allowed them to modify, delete, and overwrite results files. This system also does not include an audit trail or any history of revisions that would record any modification or deletion of raw data or files. Your laboratory computer system lacks necessary controls to ensure that data is protected from tampering, and it also lacks audit trail capabilities to detect data that could be potentially compromised. [Paraphrased]26OOS Guidance - InvestigationsOOS results may indicate a flaw in product or process design. For example, a lack of robustness in product formulation, inadequate raw material characterization or control, substantial variation introduced by one or more unit operations of the manufacturing process, or a combination of these factors can be the cause of inconsistent product quality. In such cases, it is essential that redesign of the product or process be undertaken to ensure reproducible product quality. Building knowledgeOpportunities for Variability Reduction and InnovationImplement appropriate product quality improvements, process improvements, variability reduction, innovations and pharmaceutical quality system enhancements. [ICH Q10 ]NIR in PATProvides NIR spectral signature (reflectance from solid or transmission through liquid) with adequate signal/noise ratiospectra contain information on chemical composition as well as physical attributes of particulatesProcess Endpoints: information can be used to monitor progress of a chemical or physical change, and determine unit process endpoints API synthesis, drier moisture endpoint, blending, solvent evaporation, online content uniformity and tablet weights, etc.Increasingly used for real time release

29Development Predictions30Steps in Pharmaceutical Process Development & Scale-upValidation ofPredictions

Predictions using modelsExperimentation and Data AnalysisLearning Building knowledgeDevelopmentMonitoring during scale-up activities can provide a preliminary indication of process performance and the successful integration into manufacturing. Knowledge obtained during transfer and scale-up activities can be useful in further developing the control strategy. [ICH Q10 Technology Transfer]

Monitoring during

scale-up activities

can provide a

preliminary

indication of process

performance and the

successful integration

into manufacturing.

Knowledge obtained

during transfer and

scale up activities

can be useful in

further developing

the control strategyMonitoring during

scale-up activities

can provide a

preliminary

indication of process

performance and the

successful integration

into manufacturing.

Knowledge obtained

during transfer and

scale up activities

can be useful in

further developing

the control strategy33From Development to Commercial ScaleProcess Development predictions can be affected by:Lack of fundamental knowledge and understanding of scale dependent factorsLack of correspondence between equipment used in lab and in factoryLack of full understanding of critical attributes of raw materials, and how they affect physics and mechanics of processingFinite time lines and pressures to market curtail some process development and scale-up activities

Predictions - DOE Weaknesses Based on modelPredictions are extrapolations inside as well as outside explored spaceExperiments done at lab scaleMissed factorsMissed interactions at screeningEach factor alone has little impacte.g., cycle # and regeneration buffer saltGreater weakness for complex products and processesDr. S. Kozlowski, 200834

Pilot Scale and Lot DataMultivariate SPAAdapted from T. KourtiStatistical Process AnalysisGap between process experience and DOE3536

[Jean-Marie Geoffroy, May, 2007]37Building KnowledgeMonitoring and Adaptation

Process performance and product quality monitoring systems for each product should include:Management review of process performance and product qualityCorrective action & preventive action (CAPA) and Change ManagementContinuous Process Verification (CPV ) provides strong scientific basis for maintaining state of control throughout commercial lifecycle.

Pre-approvalPost-approvalProduct Lifecycle37

Constantly and forever improve the system of production and service

- W. Edward DemingCGMP: Every batch, Every dayWe rely upon the manufacturing controls and standards to ensure that time and time again, lot after lot, year after year the same clinical profile will be delivered because the product will be the same in its quality We have to think of the primary customers as people consuming that medicine and we have to think of the statute and what we are guaranteeing in there, that the drug will continue to be safe and effective and perform as described in the label. - Janet Woodcock, M.D.39Summary: Paradigm ShiftQuality Should Be: Proactive, rather than reactiveBuilt on knowledge and understanding of product, process and materialsBuilt in through design of facilities, equipment and processes (CGMP)Based on use of state of the art tools of measurement science to control processesUtility of Better Measurements in Quality AssuranceImproved process controlContinuous quality monitoring in real timeAutomated, objective decision algorithmsData can be analyzed retrospectively (performance monitoring) to trigger improvements in process capability

40Acknowledgments:Tara Gooen Vibhakar ShahLynn TorbeckSteve Wolfgang

For More Information:www.fda.gov/aboutfda/centersoffices/cder/ucm096102.ht41Chart1973

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