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

Transcription

1 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 Partner SCĪO Analytical Consulting, LLC

2 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 (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.

3 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)

4 Not an Academic Issue High-Risk Patients: Chronic Renal Failure EPREX used to treat anemia Increased incidence of Pure Red Cell Aplasia

5 Not an Academic Issue

6 Public Perception of Plastics

7 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)

8 Efforts on the Horizon 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

9 What is Biocompatibility? IUPAC Definition Biocompatibility: 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. 9

10 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.

11 What Does Regulatory Guidance Say? Code of Federal Regulations (21 CFR 814) Premarket Approval of Medical Devices A 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 11

12 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?

13 Dosage Form Risk : USP <1664> Table 1. Modified FDA/CDER/CBER Risk-Based Approach to Consideration of Leachables a Examples of Packaging Concerns for Common Classes of Drug Products Degree of Concern Associated with the Route of Administration Highest High Low Likelihood of Packaging Component-Dosage Form Interaction High Medium Low Inhalation Aerosols and Sprays Transdermal Ointments and Patches Topical Solutions and Suspensions; Topical and Lingual Aerosols; Oral Solutions and Suspensions Injections and Injectable Suspensions; Inhalation Solutions Ophthalmic Solutions and Suspensions; Nasal Aerosols and Sprays Sterile Powders and Powders for Injection; Inhalation Powders Oral Tablets and Oral (Hard and Soft Gelatin) Capsules; Topical Powders; Oral Powders 13

14 <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.

15 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)

16 USP Chapters and Standards for Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants <87> In vitro <1031> In vivo <88> In vivo sensitization <1184> Agar diffusion Direct contact Systemic Injection (acute systemic toxicity) Intracutaneous (Irritation) Magnusson/ Kligman Guinea Pig Maximization Test (GPMT) Local Lymph Node Assay (LLNA) Alternate tests: Open Epicutaneous Freund s Complete Adjuvant Optimization Split Adjuvant Elution Implantation Standard Buehler (patch) test Mouse Ear Swelling Vitamin A Enhancement 16

17 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 series or OECD guidelines)

18 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

19 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.

20 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.

21 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

22 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

23 USP <1031> Plastic Classification Surface Devices Skin Mucosal Surfaces Breached or Compromised Surfaces Limited Prolonged Permanent Limited Prolonged Permanent Limited Prolonged 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 Externally Communicating Devices Blood Path Indirect Tissue/Bone/Dentin Communicating Circulating Blood Limited Prolonged Permanent Limited Prolonged Permanent Limited Prolonged Permanent USP Class IV USP Class V USP Class VI USP Class IV USP Class VI USP Class VI USP Class IV USP Class VI USP Class VI 23

24 Question? Is the USP plastic classification system still relevant (in other words, should it be modified, replaced or eliminated altogether)? Good Question Dr. Dan!!!!!

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

26 Biocompatibility Expert Panel 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 26

27 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? 27

28 Guiding Principles 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

29 Revision of USP Biocompatibility Standards and General Chapters Incorporation of Risk Assessment Principles 29

30 Revision of USP Biological Reactivty Testing to Biocompatibility Evaluation (NEW) USP<1031> Biocompatibility Evaluation Process Gather Relevant Available Data Conduct Risk Analysis Periodic monitoring/change control Monitor/feedback effectiveness No Risk Evaluation (based on thoroughness and relevance of test article to Final Product) Risk Control (implement mitigations to Gaps in Aqcuired Data? (based on intended use) Yes Conduct Testing reduce residual risk) Document Risk Acceptance

31 Biocompatibility Evaluation: Steps Step One: Gather Available Information 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 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

32 Biocompatibility Evaluation: Steps Step Two: Risk Analysis 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

33 Biocompatibility Evaluation: Steps 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?

34 Biocompatibility Evaluation: Steps Step Three: Test and Repeat 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?

35 Biocompatibility Evaluation: Steps 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

36 Biocompatibility Evaluation: Steps Step Three: Test and Repeat Risk Analysis 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

37 Biocompatibility Evaluation: Steps Step Three: Test and Repeat Risk Analysis 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)

38 Biocompatibility Evaluation: Steps Step Four: Risk Evaluation 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

39 Biocompatibility Evaluation: Steps Step Five: Risk Control 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

40 Biocompatibility Evaluation: Steps Step Six: Document Results 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

41 Biocompatibility Evaluation: Steps Triggers for Reevaluation Process change cleaning, sterilization surface treatment fabrication assembly/handling Material change vendor production facility formulation Storage conditions Intended use

42 Revision of USP Biocompatibility Standards and General Chapters Incorporation of Chemical Characterization 42

43 What is Chemical Characterization? ISO 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. 43

44 What is the Role of Chemical Characterization in the Context of Biocompatibility Testing? 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. 44

45 Challenges What is the Role of Chemical Characterization in the Context of Biocompatibility Testing? 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 45

46 Performing Chemical Characterization 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 46

47 Conclusions 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 47

48 Biocompatibility Evaluation: Present Situation 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. 48

49 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

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