fda process validation guideline: stage 3
TRANSCRIPT
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Edward TrapplerPresident.
SP ScientificLyoLearn Web SeminarJuly 23, 2013
FDA Process Validation Guideline: Stage 3
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Current GMP RequirementsOverview of New FDA GuidelineFocus of Stage 3: Continuous MonitoringTechniques in Trending: Control ChartsControl Charts for Product DataComprehensive Trending ProgramGoing Forward
FDA Validation GuidelineContinuous Process Verification: Stage 3
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211.192: Production record review as part of batch release.
Lyophilization Critical Process Parameters (CPP)Product Critical Quality Attributes (CQA)
CFR RequirementsBatch Release
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Routine Manufacturing: Annual ReportAn ongoing program to collect and analyze product and process data that relate to product quality must be established. (§ 211.180(e))
CFR RequirementsContinuous Monitoring
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211.180: Annual review of “representative” number of batches
Evaluate need for changes in manufacturing and control procedures.Assess need for changes in product specifications.
CFR RequirementsContinuous Monitoring
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1987 - 2011: “…documented evidence…”(Run 3 X’s in Manufacturing)
2011 - current: “…collection and evaluation…”(Development - Scale-up – Routine Manufacturing)
FDA Validation GuidelineLife Cycle Approach
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Collection and evaluation of data, from the process design through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.
FDA Validation GuidelineLife Cycle Approach
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Stage 1: Commercial manufacturing process is defined.
Stage 2: Capability to manufacture is evaluated.
Stage 3: Assurance that process is in control.
FDA Validation GuidelineObjectives
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Stage 1: Development and Scale-upProduct and ProcessKnowledge and Understanding
Stage 2: Integrate in ManufacturingEquipment QualificationProcess Qualification
Stage 3: Continuous MonitoringEvaluate ProcessAssess Product
FDA Validation Guideline“Life Cycle “ Validation
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Stage 1: Development to Scale-upThe commercial manufacturing process is defined based on knowledge gained through development and scale-up activities.
FDA Validation GuidelineDevelopment
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Process capabilityProcess knowledge, understandingprocess parameter relationships to quality attributes
Causes of variabilitySourcesImpact
FDA Validation GuidelineDevelopment
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Critical Process Parameters (CPP)◦ Shelf (inlet) temperature◦ Chamber pressure◦ Time
Established Process ParametersCPP and PAR
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Chamber Pressure
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Critical Process Parameters (CPP)◦ Shelf (inlet) temperature◦ Chamber pressure◦ Time
Proven Acceptable Range (PAR)◦ Acceptable parameters above and below
ideal target conditions.◦ Acceptable CQA and stability
Established Process ParametersCPP and PAR
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Shelf Temperature
Chamber Pressure
TEMPERATURE
(oC)
MI
CRONS
TIME (Minutes)
Lyophilization Parameters PAR
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Stage 2: QualificationEvaluate manufacturing operations and process design to establish capability for routine manufacturing.
FDA Validation GuidelineScale-up
(Technology Transfer)
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Equipment QualificationInstallation Qualification Operational QualificationPerformance Qualification (PQ)
Process Performance QualificationProcess VerificationIncreased monitoring / sampling
FDA Validation GuidelineTechnology Transfer
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Stage 3: Routine ManufacturingOperate within established PAR (boundaries)Collect and analyze product and process dataConcurrent review and evaluationState of control for process (reproducibility)Consistent critical quality attributes
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process VerificationOngoing assurance is gained during routine production that the process remains in a state of control.
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process VerificationTrending of process (CPP) and finished product quality (CQA) to monitor process variability and product consistency to verify commercial manufacturing is within a state of control.
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“…measuring and evaluating process stability and process capability...” .
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“…guard against overreaction to individual events as well as against failure to detect unintended process variability.”
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“Homogeneity within a batch and consistency between batches are goals of process validation activities.”
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health.”
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes.”
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3.”
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Continued Process Verification“Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process.”
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Routine ManufacturingAdherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability.
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Routine Manufacturing“…detecting unplanned departures from
the process as designed is essential to accomplish this goal”.
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Routine ManufacturingThe data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products.
FDA Validation GuidelineContinuous Process Verification
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Stage 3: Routine ManufacturingThe data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.
FDA Validation GuidelineContinuous Process Verification
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“…Quality, Safety, and Efficacy are designed or built into the product”.◦ Quantifiable results◦ Mean of multiple samples◦ Individual OOS results are a special case
Data as reported results◦ Quantifiable results◦ Mean has no meaning
Process Validation and Drug QualityFit for the Intended Use
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Measure◦ Identify what is important (CQA).◦ Develop methods of measurements.
Assess◦ Establish suitability for intended use.◦ Compare product to expectations.
Adjust◦ Know what impacts product quality.◦ Modify inputs or process for desired outcome.
Quality ConceptsQuality Control Principles
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Shewart◦ Defined assignable-cause and chance-cause.◦ Developed control charts for assessing process
output (product) and manufacturing success. Juran◦ Popularized Pareto Principle (80/20 rule).◦ Formalized Quality Management.
Deming◦ Refined quality management principles.◦ Developed “Plan-do-check-act”.
Quality ConceptsQuality Control Principles
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Materials Process ProcessOutput(Product)
AssessOutput
Compareto Trend
EvaluateControl
Control ChartsProcess Behavior Charts
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Assessing Process Output◦ Encompasses material input, process
control and product analysis◦ Influenced by number of test samples◦ Indiscriminate of multi-variant factors
Evaluating results in trend◦ Verifies relative level of control◦ Compares average result◦ Discerns single event vs shift in mean
Control ChartsProcess Behavior Charts
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Reflects process variation◦ Variation from common process sources◦ Highlights process events out of control
Provides assessment of control ◦ Shows state of statistical control◦ Identifies parameter beyond normal control◦ Reveals drift in trend
Control ChartsProcess Behavior Charts
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Classical: Process output (product) data◦ Testing a sufficient number of samples◦ Samples representative of batch
Progressive: Process parameters◦ Evaluation of process data (CPP)◦ Significant: Variations that impact CQA
Control ChartsData input for analysis
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Shewhart◦ Trends data and sets limits based on 3 Standard
Deviations.◦ Comparison of single data point relative to trend.◦ Further refinements to data point and trend assessment
(Less than 3 Standard Deviations).
COSUM◦ Cumulative sum of data points.◦ More complicated assessment of data trend.
EWMA◦ Exponentially weighted moving average of data points.◦ Most complicated assessment of data trend.
Control ChartsTypes of Control Charts
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Creating a Control Chart ◦ Collection of at least 9 sets of data.◦ For multiple tests, calculate average of
each set of results.◦ Calculate the mean of all the test results.
Setting Alert and Action Levels◦ Calculate the standard deviation of all
the data.◦ Calculate 2 and 3 standard deviations.
Control ChartsData Analysis
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Plot y-axis scale◦ Based on specifications.◦ Scale so that the centerline is near
the center of the y axis.
Alert Level◦ Two Standard Deviations from the mean.
Action Level◦ Three Standard Deviations from the
mean.
Shewhart Control ChartsTrend Analysis
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Shift Rules◦ Focuses on individual data points near or
exceeding the control limit (Action Level).
Trend Rules◦ Evaluates the group of multiple data points
relative to the centerline of the trended data.
Control ChartsShewhart Trend Rules
Recognizing Special Cause Variation
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Shift Rules◦ A data point above or below a control limit
(Action Level).◦ A series of data points near upper or lower
control limit (Action Level).
Control ChartsShewhart Trend Rules
Recognizing Special Cause Variation
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Trend Rules◦ Multiple data points that are close to the
centerline and are not as large of a difference from the centerline as the majority of the trended data.
◦ Data that exhibits a consistent trend in a direction towards or away from the Centerline.
Control ChartsShewhart Trend Rules
Recognizing Special Cause Variation
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Rule 1: Single point above Action Level (control limits).
Rule 2: Shift of 8 or more consecutive points above or below Centerline.
Rule 3: At least 6 consecutive points with a continually increasing or decreasing trend.
Control ChartsShewhart Trend Rules
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Rule 4: A series of 2 or 3 consecutive points near an Action Level (control limits).
Rule 5: At least 15 consecutive points trending near the Centerline.
Control ChartsShewhart Trend Rules
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Assess Critical Quality Attributes (CQA)AssayPurityResidual MoistureReconstitutionAppearance
Process Output DataProduct Quality Attributes
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Batch MeanAction Level (0.744)
Center Line Mean of All (0.397)
STD DEV = 0.116
Alarm Level: Mean + 2 STD DEV (0.232)
Action Level: Mean + 3 STD DEV (0.347)
Alarm Level (0.629)
Specification
Action Level (0.05)Alarm Level (0.165)
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Batch MeanCenter LineMean of All (0.397)
Action Level (0.744)
Alarm Level (0.629)
Action Level (0.744)
Alarm Level (0.629)
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Reconstitution Time (Seconds)
Batch Mean
Specification
Center LineMean of All (5.2)
STD DEV = 0.67
2 STD DEV = 1.34
3 STD DEV = 2
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Reconstitution Time (Seconds)
Batch MeanAction Level (7.2)
Center LineMean of All (5.2)
STD DEV = 0.67
3 STD DEV = 2
2 STD DEV = 1.34
Alert Level (6.54)
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Physical Appearance Rejects (%)
% Rejects
Common Action Level
Center LineMean of All (0.00025)
STD DEV = 0.000622
3 STD DEV = 0.0019
2 STD DEV = 0.0012
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% Re
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Batch #
Physical Appearance Rejects (%)
% Rejects
STD DEV = 0.000622
Mean of All (0.00025)
Action Level (0.00211)
Alert Level (0.00149)
3 STD DEV = 0.00186
2 STD DEV = 0.00124
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Stage 3: Routine ManufacturingThe data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products.
FDA Validation GuidelineContinuous Process Verification
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CPP variation
Product/Process input materials
Control ChartsFactors that influence CQA
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CPP variation◦ Shelf Temperature◦ Chamber Pressure◦ Time
Control ChartsFactors that influence CQA
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Parameter variation(Engineering Units)
Deviation from target (Engineering Units)
Greatest variation throughout process (Statistical Value)
Control ChartsCPP Variation
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Parameter variation (Engineering Units)◦ Each step◦ Expressed as temperature and pressure◦ Complicated charting: each step◦ Difficult for analysis◦ Overly sensitive to variation
Control ChartsCPP Variation
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Deviation from target (Engineering Units)◦ Each step◦ Expressed as deviation from target◦ Complicated charting: each step◦ Difficult for analysis◦ Extremely sensitive to variation
Control ChartsCPP Variation
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Greatest variation throughout process◦ Conversion to statistical value: z-score
or standard deviation◦ Expressed as deviation from target◦ Greatest variation throughout process◦ Easier to trend◦ Less sensitive to variation in each
parameter
Control ChartsCPP Variation
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Product / Process input materials◦ Formulation components◦ Packaging components
Control ChartsProcess input for analysis
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Formulation Components◦ Related substances◦ Upstream substance carry-over◦ Residual solvents
Control ChartsProcess input for analysis
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Packaging Components◦ “Finished” (tooled) opening◦ Bottom concavity (push-up)◦ Bottom corner radius◦ Stippling
Control ChartsProcess input for analysis
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Continuous Process VerificationOperate within CPP PAR (process boundaries)Collect and analyze product and process dataConcurrent review and evaluationConsistent critical quality attributes (CQA)State of control for process
Summary
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Stage 3: Routine MonitoringTrending should include the process and quality of incoming materials, components, in-process material, and finished product attributes.
SummaryFuture Considerations
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CPP variation◦ Shelf Temperature◦ Chamber Pressure◦ Time
Product / Process input materials◦ Formulation components◦ Packaging components
SummaryFactors that influence CQA
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Assure trended variables are able to discern level of control.
Include inputs to process as well as CPP.
Utilize appropriate approach in trending.
Summary
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Devise a plan for action when exceeding Action Levels.
Avoid overreacting to individual results or shifts in a trend.
Exceeding an Action Level does not mean failing to meet specifications.
Summary
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Materials ProcessProcessOutput(Product)
AssessOutput
Compareto Trend
EvaluateControl
Control (Shewart) ChartsProcess Behavior Charts
Refine materials or adjust process
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Process Validation: Stage 3
Happy to answer questions!
Further contact:Edward [email protected](215) 396-8373
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