United States Pharmacopeia: Revision Process for USP Biocompatibility General Chapters <87>, <88> and <1031>

Daniel L. Norwood, M.S.P.H, Ph.D.USP Packaging and Distribution Expert Committee

Executive PartnerSCĪO Analytical Consulting, LLC

Why are we concerned?

Food, Drug and Cosmetic Act (1938)- Section 501(a)(3)

• “a drug is deemed to be adulterated if its container is composed, in whole or part, of any poisonous or deleterious substance which may render the contents injurious to health…”

21 CFR Part 211.94 (a)

• “Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality or purity beyond the official or established requirements.”

What are our considerations?

Protection – light, moisture, leakage Compatibility – interaction of drug product with the

package Safety – constructed of materials that will not leach

harmful or undesirable amounts of substances to which a patient will be exposed when being treated with the drug product

Performance – ability to function in the manner for which it was designed

“Quality Attributes of a Packaging System”, USFDA “Packaging Guidance” (1999)

“High-Risk” Patients: Chronic

Renal Failure

• EPREX used to treat anemia• Increased incidence of “Pure Red Cell Aplasia”

Not an “Academic” Issue

Not an “Academic” Issue

Public Perception of Plastics

USP & Extractables/Leachables

<1031> The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants (informational guidance)

<87> Biological Reactivity Tests, In Vitro (standard) <88> Biological Reactivity Tests, in Vivo (standard) <381> Elastomeric Closures for Injection (standard) <661>, <661.1>, <661.2> Plastics (standard) <1661> Plastics (informational guidance) <1663> Extractables (informational guidance) <1664> Leachables (informational guidance) <1664.1> Leachables OINDP (informational guidance)

New Chapters and Chapter Revision (2016)• Revision

− <87> and <88> Biological Reactivity, In Vitro and In Vivo• Expert Panel Formed (June USP Workshop)

− <381> Elastomeric Closures for Injections• Expert Panel Formed

• New− <661.3> Plastic Systems Used for Manufacturing Pharmaceutical

Products• Chapter drafted (June USP Workshop)

− <661.4> Plastic Medical Devices used to Deliver or Administer Pharmaceutical Products

− <1664.2> Parenteral and Ophthalmic Drug Products− <1665> Toxicological Assessment of Drug Product Leachables− <662> Metal Packaging System and their Materials of

Construction

Efforts on the Horizon

IUPAC DefinitionBiocompatibility: Ability to be in contact with a living system without producing an adverse effect.

Biocompatibility (biomedical): Ability of a material to perform with an appropriate host response in a specific application.

Generally...Biocompatibility is: Interaction of a living system or tissue with a finished medical device or component materials. A biocompatible material or device does not cause harm to the patient; it is not toxic and does not cause injury or immunological rejection.

Biocompatibility Testing is: A suite of in vitro and in vivo tests which are performed to determine the potential toxicity resulting from bodily contact with a material or medical device. Local and systemic effects are evaluated with biocompatibility testing.

What is Biocompatibility?

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Biocompatibility

Even if a material that makes up the container/closure delivery system or medical device has been tested for biocompatibility, processes such as manufacturing, shipping, packaging, and sterilization may have adverse affects on the material's composition and how it reacts in different environments. Because of these potential changes, biocompatibility evaluation must be completed for every container/closure delivery system and medical device end product prior to receiving global regulatory approvals.

What Does Regulatory Guidance Say?

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Code of Federal Regulations (21 CFR 814)

§ 814.20 Premarket Approval of Medical DevicesA section containing results of the nonclinical laboratory studies with the device including microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests as appropriate. Information on nonclinical laboratory studies shall include a statement that each such study was conducted in compliance with part 58*, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

*21 CFR 58 Good Laboratory Practice for Nonclinical Laboratory Studies

Question?

Is biocompatibility testing alone sufficient to ensure safety and suitability for intended use for a container/closure delivery system, medical device, or the corresponding components and materials of construction thereof?

Examples of Packaging Concerns for Common Classes of Drug ProductsDegree of Concern Associated with the Route of Administration

Likelihood of Packaging Component-Dosage Form InteractionHigh Medium Low

Highest Inhalation Aerosols and Sprays

Injections and Injectable Suspensions; Inhalation Solutions

Sterile Powders and Powders forInjection; Inhalation Powders

High Transdermal Ointments and Patches

Ophthalmic Solutions and Suspensions; Nasal Aerosols and Sprays

—

Low Topical Solutions and Suspensions; Topical and Lingual Aerosols; Oral Solutions and Suspensions

—

Oral Tablets and Oral (Hard and Soft Gelatin) Capsules; Topical Powders; Oral Powders

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Table 1. Modified FDA/CDER/CBER Risk-Based Approach to Consideration of Leachablesa

Dosage Form “Risk”: USP <1664>

<1031> The Biocompatibility of materials used in Drug Containers, Medical Devices...

Gives guidance on procedure for evaluation of biocompatibility;

Tests procedures designed to detect non-specific, biologically reactive, physical or chemical characteristics of packaging systems, medical devices, components, or their materials;

In combination with chemical assays, these biological procedures can be used to detect and identify the inherent or acquired toxicity of medical products prior to or during their manufacturing and processing.

Biocompatibility Evaluation

The procedures used to evaluate the biocompatibility of a medical product or its construction materials have been categorized as a panel of biological effects (toxicity procedures)

USP Chapters and Standards for Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants

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<87>

Agar diffusion

Direct contact

Elution

In vitro

<88>Systemic Injection

(acute systemic toxicity)

Intracutaneous(Irritation)

Implantation

<1184>

Magnusson/ Kligman Guinea

Pig Maximization Test (GPMT)

Local Lymph Node Assay

(LLNA)

Standard Buehler

(patch) test

Alternate tests:• Open Epicutaneous• Freund’s Complete

Adjuvant• Optimization• Split Adjuvant• Mouse Ear Swelling• Vitamin A

Enhancement

In vivoIn vivosensitization

<1031>

Biocompatibility Evaluation

TOXICITY PANEL: Cytotoxicity ( <87>), sensitization ( <1184>), Irritation or Intracuteneous reactivity (<88>), Systemic (acute) Toxicity (<88>), subchronic toxicity, genotoxicity, implantation (<88>), hemocompatibility, chronic toxicity, carcinogenicity, reproductive or developmental toxicity, and biodegradation.

Others are found elsewhere ( e.g., ISO 10993 series or OECD guidelines)

In vitro testing for Biocompatibility <87>

Agar Diffusion Test: Leachables from material diffuse from elastomer and contact the cell monolayer. Extracts can also be placed on filter paper.

Direct Contact Test: For materials that will not damage the cells

Elution Test: Evaluates extracts of polymeric materials

Test Articles

Evaluation of the biocompatibility of a whole medical product is often not realistic; thus, the use of representative portions or extracts of selected materials may be the only practical alternative for performing the assays.

When representative portions of the materials or extracts of the materials under test are used, it is important to consider that raw materials may undergo chemical changes during the manufacturing, processing, and sterilization of a medical product.

Although in vitro testing of raw materials can serve as an important screening procedure, a final evaluation of the biocompatibility of a medical product is performed with portions of the finished and sterilized product.

Test Articles

When choosing extraction conditions, select the temperature, solvent, and time variables that best mimic the “in use” conditions of the product.

The performance of multiple tests at various conditions can be used to simulate variations in the “in use” conditions.

Although careful selection of extraction conditions allows the simulation of manufacturing and processing conditions in the testing of raw materials, an evaluation of the biocompatibility of the product is performed with the finished and sterilized product.

Classification of Plastics/ Polymers(<88>)

Six classes are defined Based on responses to a series of in vivo

tests for which extracts/ materials/ and route of administration are specified

Classification does not apply to plastics intended for use as containers for oral or topical drug

Classification of Plastics (<88>)

Classification of Plastics Table• Table defines 6 classes (I-VI), with

increasing number of tests required for higher class numbers

Tests include:• Multiple extracts• Implantation

USP <1031> Plastic Classification

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Surface Devices

Limited Limited LimitedProlonged Prolonged ProlongedPermanent Permanent Permanent

USP Class I

USP Class I

USP Class I

USP Class I

USP Class III

USP Class V

USP Class III

USP Class V

USP Class VI

Skin Mucosal Surfaces

Breached or Compromised

Surfaces

Externally Communicating

Devices

USP Class VI

USP Class VI

USP Class VI

USP Class VI

USP Class VI

USP Class V

USP Class IV

USP Class IV

USP Class IV

Blood Path Indirect

Tissue/Bone/Dentin Communicating

Circulating Blood

Limited Limited LimitedProlonged Prolonged ProlongedPermanent Permanent Permanent

Question?

Is the USP plastic classification system still relevant (in other words, should it be modified, replaced or eliminated altogether)?

Good Question Dr. Dan!!!!!

Chapters transferred to Packaging, Storage and Distribution Expert Committee in 2014

Expert Panel formed late in 2014 Initial face to face meeting of panel in 2014 Expert Panel continued into a new Expert

Committee cycle (2015) Various Working Groups formed (Chemical

Characterization; Biological Testing) USP Workshop held in June 2016

Revision Process for <1031>, <87> and <88>

Biocompatibility Expert Panel

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• Daniel Norwood (Co-Chair), SCIO Analytical Consulting• Cheryl Stults (Co-Chair), C&M Technical Consulting• Anita Sawyer, Becton Dickinson• John Iannone, Albany Molecular Research, Inc.• Denise Bohrer, Federal University of Santa Maria• Doug Ball, Pfizer• Jill Glosson, Baxter• Renaud Janssen, Datwyler• Stephen Barat, Allergan• Tage Carlson, Baxter• Wendy Mach, Nelson Laboratories• William Beierschmitt, Pfizer• Michael Eakins, Eakins and Associates • Desmond Hunt, USP

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Questions?

Should a “Risk-based” approach be incorporated into the design and application of USP biocompatibility testing?

Is there a role for chemical characterization within USP biocompatibility testing?

Do the biocompatibility tests and testing procedures need to be modernized?

Are the USP biocompatibility tests and standards properly aligned with other standards (i.e., ISO 10993)?

What should <1031> look like? Overall safety assessment guidance chapter?

Science and best practice based testing Incorporation of Risk Assessment and Risk

Management Principles Biological and chemical assessments complement

and inform each other Alignment with other international standards and

best practices Consideration regarding use of laboratory animals

Guiding Principles

Revision of USP Biocompatibility Standards and General Chapters

Incorporation of Risk Assessment Principles

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Revision of USP Biological Reactivty Testing to Biocompatibility Evaluation

(NEW) USP<1031> 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 <87>, <88>, <661.1>; 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 <661.2>, <381>, Pharm Euro Chapter 3• Biocompatibility test results, e.g., USP <87>/<88>; 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

In cases where the route of administration is not determined biocompatibility evaluation may utilize composition information and testing

Materials of Construction - Biocompatibility evaluated based on known chemical composition with consultation given to the respective SDS; if not available perform tests for components/systems

Components/Systems perform the following tests:• cytotoxicity,

• irritation,

• sensitization,

• mutagenicity (Ames)

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

Revision of USP Biocompatibility Standards and General Chapters

Incorporation of Chemical Characterization

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ISO 10993-18 definition Chemical Characterization: Identification of a material and the

identification and quantification of the chemicals present in materials or finished medical devices.

USP <1663> definition Characterization (chemical): The discovery, identification, and

quantitation of each individual organic and inorganic chemical entity present in an extract above a specified level or threshold. Such thresholds can be based on patient safety considerations, materials considerations, the capabilities of analytical technology, etc.

What is Chemical Characterization?

43

What is the Role of Chemical Characterizationin the Context of Biocompatibility Testing?

44

Chemical characterization can provide understanding of materials, components, or a system as part of risk assessment and management

Chemical characterization is important in performing failure analysis to provide a clear and scientifically sound rationale for a failed biocompatibility test

Chemical characterization is important in upholding the “3 Rs” initiative to reduce unnecessary use of live animals and in vivo testing

Prior to biocompatibility testing, chemical characterization may provide information permitting the toxicological evaluation of chemical entities that may predictably elicit irritation, sensitization or acute toxicity responses and potentially negating need for subsequent biocompatibility testing.

Chemical characterization may not necessarily be sole means to unequivocally declare absence of irritants, sensitizers, or acute toxicants. Comprehensive evaluation of all available data should be performed to permit a risk-based testing approach.

What is the Role of Chemical Characterizationin the Context of Biocompatibility Testing?

45

Challenges Biocompatibility testing solvents and media are not necessarily compatible

with appropriate analytical techniques to permit comprehensive chemical characterization

Analytically expedient solvents are necessary to permit detection and characterization of diverse classes and structures of chemical entities

Ideally, sample preparation and solvent selection can be chosen to represent as closely as possible, or more conservatively, extraction characteristics of solvents used in biocompatibility testing (particularly for failure mode analysis)

Important to correlate chemical characterization with biocompatibility results

When appropriate and available, extractables study results may suffice if appropriately conservative and permit a meaningful correlation

Performing Chemical Characterization

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Generate the extract- Chemical nature of extraction medium (pH, polarity, formulation

excipients, surfactants) using analytically expedient alternate as appropriate- Extraction time and temperature- Extraction should be performed on representative final molded, sterilized

component rather than raw resin if possible

Characterize the extract - Employ multiple analytical techniques- Discovery- Identification: “Known unknowns” vs “unknown unknowns”- Quantification

Chemical characterization:•Can Provide understanding of materials, components, or a system and assist with risk assessment•Enables failure analysis to support a scientifically sound rationale for a failed biocompatibility test•Advances the “3 Rs” initiative to reduce unnecessary in vivo testing•Prior to biocompatibility testing, judicious application may provide information permitting the pre-emptive toxicological evaluation of chemical entities that may be irritants, sensitizers or elicit acute toxicity response•May not unequivocally declare absence of irritants, sensitizers, or acute toxicants, and does not preclude a comprehensive evaluation of all available data to permit a risk-based testing approach

Conclusions

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USP <1031> will become an overall extractables/leachables safety evaluation informational chapter, including biocompatibility evaluation.

Risk analysis principles will be incorporated into the USP biocompatibility evaluation process.

Chemical characterization (extractables assessment) will be integrated into the USP biocompatibility risk analysis process.

Biocompatibility Evaluation: Present Situation

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Acknowledgements

USP Biocompatibility Expert Panel (Drs. Daniel L. Norwood and Cheryl L. M. Stults; Chairs)

USP Packaging and Distribution Expert Committee (Dr. Mary Foster; Chair)

Dr. Desmond Hunt; USP Expert Committee Liaison

Dr. Radhakrishna S. Tirumalai; USP Expert Committee Liaison