united states pharmacopeia: inclusion of risk-based … · 2016. 9. 5. · united states...

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


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


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


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



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



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


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


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


Process change• cleaning,

• sterilization

• surface treatment

• fabrication

• assembly/handling

Material change• vendor

• production facility

• formulation

Storage conditions Intended use

Triggers for Reevaluation


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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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


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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

united states pharmacopeia: inclusion of risk-based … · 2016. 9. 5. · united states...

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