United States Pharmacopeia:Inclusion of Risk-based Approaches in USP Chapters
Cheryl LM Stults, M.M., Ph.D. Packaging and Distribution Expert Committee
September 9, 2016Qingdao, China
Risk-based approaches are expected
There are several guidances and standards
• ICH Q9 Quality Risk Management (2005)
Risk-based approaches are expected
There are several guidances and standards
• ISO 14971:2012 Application of Risk Management to Medical Devices
Risk = Combination of the probability of occurrence of harm and the severity of that harm Harm = Physical injury or damage to the health of people, or damage to property, or the environmentReduce risk as far as possible
Stults et al. 2015DOI 10.1007/s11095-015-1770-7
Probability Severity Negligible Minor Major Critical Catastrophic
Frequent Probable Occasional Remote Improbable
Green = no action, Yellow = investigate mitigation, Red = mitigate
Risk-based approach to Leachables
USP has an updated version of the US FDA packaging guidance risk table
Proposed Revision of USP Biological Reactivity Testing to Biocompatibility Evaluation
(OLD) USP Biocompatibility Decision Tree
Proposed Revision of USP Biological ReactivtyTesting to Biocompatibility Evaluation
(NEW) USP Biocompatibility Evaluation ProcessGather Relevant Available Data
Conduct Risk Analysis
Document Risk Acceptance
Gaps in Aqcuired Data?
(based on intended use)
Risk Evaluation(based on thoroughness and
relevance of test article to Final Product)
YesNo Conduct Testing
Risk Control (implement mitigations to
reduce residual risk)
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Identify the drug and patient contacting materials• Non-drug and non-patient contacting materials do not get evaluated
Materials of construction• Composition, e.g., base polymer, additives, colorants• Compliance statements, e.g., food, TSE/BSE, phthalates• Compendial test results, e.g., USP , , ; Pharm. Euro Chapter 3
Components/Packaging/Delivery system• Chemical additives, e.g., processing aids, coatings, surface treatments• Processing steps, e.g., washing, sterilization• Physicochemical test results, e.g., USP , , Pharm Euro Chapter 3• Biocompatibility test results, e.g., USP /; ISO 10993• Controlled extraction study results, e.g., volatiles, semi-volatiles, non-volatiles, elemental
analysis• Leachable study results (internal use for pharmaceutical manufacturer)• Toxicological evaluation of test and/or study results
Step One: Gather Available Information
Biocompatibility Evaluation: Steps
Utilize cross-functional expertise• Design engineer (packaging, device, process)• Materials specialist• Development scientist• Manufacturing• Toxicology/Clinical• Regulatory• Quality
Organize gathered information• Describe intended product use – dosage form, frequency, route of
administration, duration of use• For each component or system make a list of what is known from the
information gathered in step one
Step Two: Risk Analysis
Biocompatibility Evaluation: Steps
Consider potential hazards – impact to patient safety• If the intended use is unknown, assume all baseline test requirements
must be met (go to Step three)• Known biocompatibility concern with material of construction• Chemicals of safety concern in composition, processing steps or
chemical characterization results, e.g, irritants, sensitizers, mutagens, carcinogens; toxicologically assessed or utilize evaluation threshold of 20 ug/g
• Chemicals in the profile above evaluation threshold whose identity is not feasible
• Potential chemical reaction with formulation
Determine gaps in information based on intended use• What data do we have to indicate each is low probability?• What data do we need to help us decide?
Step Two: Risk Analysis
Biocompatibility Evaluation: Steps
Consider a tiered approach to testing• Is there chemical composition information that can be obtained that will
provide the needed information to fill the gap identified in step two?
• If not, is it possible to do an in vitro test that will provide the needed information to fill the gap identified in step two?
• If not, is it possible to do an in vivo test that will provide the needed information to fill the gap identified in step two?
Step Three: Test and Repeat Risk Analysis
Biocompatibility Evaluation: Steps
Baseline tests represent the minimal requirements expected to be met based on route of administration; others may be added based on product-specific risk
Components/Systems - Biocompatibility testing based on route of administration• Category 1 – Unknown
• Category 2 – Non Oral
• Category 3 – Oral
Components/Systems are expected to meet the criteria for the following tests:• Category 1 – cytotoxicity, irritation, sensitization, mutagenicity (Ames)
• Category 2 – cytotoxicity, irritation, sensitization
• Category 3 – cytotoxicity
Step Three: Test and Repeat Risk Analysis
Biocompatibility Evaluation: Steps
Baseline tests represent the minimal requirements expected to be met based on nature and duration of contact with the patient; others may be added based on product-specific risk
Additional tests for product-specific risk:• Implantation• Hemocompatibility• Genotoxicity• Systemic toxicity (acute, sub-chronic, chronic)• Carcinogenicity• Reproductive/Developmental toxicity
Step Three: Test and Repeat Risk Analysis
Biocompatibility Evaluation: Steps
From risk analysis and test results evaluate any residual risk based on intended use with regard to the following:• If intended use is unknown – go to step six
• Route of administration
• Duration of use
• Availability of toxic chemical entities (proximity of contact, likelihood of leaching)
• Patient population
Document evaluation and any recommended controls such as:• Material monitoring
• Material change
• Process monitoring
• Process change
Step Four: Risk Evaluation
Biocompatibility Evaluation: Steps
Implement risk controls to minimize patient exposure such as:• Composition amounts in materials
• Process steps to eliminate source of exposure
• Others specific to application
Evaluate impact of risk control• Collect additional information or test results after implementation
• Perform risk analysis
• Perform risk evaluation
• Modify risk control as needed
Step Five: Risk Control
Biocompatibility Evaluation: Steps
List components/system
List acceptance criteria
Summarize all information gathered• Information on materials
• Information on components/systems
• Test results
• Toxicological evaluation summary
Provide status against criteria
Step Six: Document Results
Biocompatibility Evaluation: Steps
Process change• cleaning,
• sterilization
• surface treatment
• fabrication
• assembly/handling
Material change• vendor
• production facility
• formulation
Storage conditions Intended use
Triggers for Reevaluation
Biocompatibility Evaluation: Steps
Manufacturing Components and Systems including:– vessels, bags, connectors, tubing, valves, diaphragms, gaskets, O-
rings, filling needles– bioreactors, cassettes, chromatographic columns, filters, sensors
Plastic components and systems assessed to address the possibility that:– any extractables (as potential leachables) released into a process
stream would persist through the manufacturing process – become process related impurities in the process output, and – could potentially adversely affect the safety of the process output.
Match the risk of such an outcome with the required level of characterization by a two stage approach
A risk-based approach to evaluation and testing
Plastic Components and Systems Used in the Manufacturing of Pharmaceutical Drug Products
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Component in Contact with Liquid
StreamNo Actions
Conduct Initial Assessment
Comparator Component/System
Established
Proceed to Risk Assessment
No Actions
No
No
Yes
Yes
Initial Assessment Process
Step One: Initial Assessment
If the component is in contact with the liquid stream and a comparator component does not exist, components must be characterized
The level of characterization of a component is dictated by its risk profiles• The greater the risk, the more characterization
necessary Establish the risk profile for a component or system
by the application of a Risk Evaluation Matrix
Step Two: Risk Assessment
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The Risk Evaluation Matrix establishes the relative risk that:(a) substances will leach from the plastic component,(b) the leachables will persist through the manufacturing process and accumulate in the process output and(c) the leachables in the process output could have an effect on safety.
• The matrix links this risk to a prescribed level of characterization
Step Two: Risk Assessment
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Risk Dimension
Duration Temperaturea Solvent Material Reactivity
Level 1 30°C) Highly organic or extreme pH (9)
Reactive
a The gap in the temperature ranges reflect temperature ranges that are rarely experienced in manufacturing process
Risk Evaluation Matrix – Four Dimensions
Dimensions Relevant to Risk Level
Step A: Establish values for each risk dimension• A component being assessed for risk is “rated”• A level assignment of 1, 2, or 3 in each of the four
dimensions is made– For example, a component or system that is rated as highest risk in all
four dimensions has a generated numerical risk sequence of 3333– For example, a component or system that is rated as lowest risk in all
four dimensions has a generated numerical risk sequence of 1111
Use of the Risk Evaluation Matrix
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Use of the Risk Evaluation Matrix
If And… Characterization Level
Four dimension scores are Level 3 No additional qualifier (3333) Level CThree dimension scores are Level 3 Other dimension score is Level 2 (3332) Level C
Other dimension score is Level 1 (3331) Level CTwo dimension scores are Level 3 Other two dimension scores are both Level 2
(3322)Level C
One dimension score of Level 2 (3321) Level B or C
Other two dimension scores are Level 1 (3311) Level A or BOne dimension score is Level 3 All of the three other dimension scores are Level
2 (3222)Level B
One of the other dimension scores is Level 1 (3221)
Level B
Two of the other dimension scores are Level 1 (3211)
Level A or B
All of the three other dimension scores are Level 1 (3111)
Level A
No dimension scores are Level 3 All of the four dimension scores are Level 2 (2222) Level B
One or more of the dimension scores are Level 1 Level A
Step B: Link the numerical risk sequence with a level of characterization.
Linking risk to characterization methodologies• The various adjusted characterization levels
established previously are linked to the following characterization methodologies:
− Level A = Baseline Assessment
− Level B = Expanded Baseline Assessment
− Level C = Full Testing
Use of the Risk Evaluation Matrix
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Use of the Risk Matrix to Drive Testing
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Table 2. Testing Requirements for Three Risk Levels (Revised)Risk Assessment Testing RequirementsLevel Level Materials of Construction Component or System
A (lower risk)
Baseline All individual materials of construction comply with for identity as follows:•Biocompatibility •Extracts comply with physicochemical characteristics (Solution C1) and extractable metals (Solution C2)•Additives (by proper reference to 21 CFR Indirect Food Additive regulations)
Biocompatibility
B Expanded Baseline
All individual materials of construction comply with for identity as follows:•Biocompatibility and Class VI •Materials of construction comply with for identity (individual polymers only)•Extracts comply with physicochemical characteristics (Solution C1) and extractable metals (Solution C2)•Additives determined by testing
Biocompatibility and USPClass VI
(Extractable Metals)
C (higher risk)
Full All individual materials of construction comply with for identity as follows:•Biocompatibility and Class VI •Materials of construction comply with for identity (individual polymers only)•Extracts comply with physicochemical characteristics (Solution C1) and extractable metals (Solution C2)•Additives determined by testing
Biocompatibility and Class VI
Full Extractables Profiling via Standard Extraction Protocol (Solutions C3, C4 and C5)
Bolded entries represent testing required in addition to the testing required in the lower risk levels.
Systematic approaches are being developed to evaluate risk associated with packaging/delivery system/manufacturing components
Risk mitigation may involve testing or other controls It is important that all stakeholders are involved in
the risk evaluation process Risk evaluation guides experimentation and
implementation of controls Risk evaluation is an ongoing process throughout
the product lifecycle that depends on regular updates to material and process information
Summary
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United States Pharmacopeia:�Inclusion of Risk-based Approaches in USP Chapters�Risk-based approaches are expectedRisk-based approaches are expectedRisk-based approach to LeachablesProposed Revision of USP Biological Reactivity Testing to Biocompatibility EvaluationProposed Revision of USP Biological Reactivty Testing to Biocompatibility EvaluationBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsBiocompatibility Evaluation: StepsPlastic Components and Systems Used in the Manufacturing of Pharmaceutical Drug Products Step One: Initial AssessmentStep Two: Risk Assessment�Step Two: Risk Assessment�Risk Evaluation Matrix – Four DimensionsUse of the Risk Evaluation Matrix Use of the Risk Evaluation Matrix Use of the Risk Evaluation Matrix Use of the Risk Matrix to Drive TestingSummary幻灯片编号 27