How to Prepare MedDevice Packaging for Regulatory Success A Chemical Characterization (E&L) Perspective

Transcription

1 How to Prepare MedDevice Packaging for Regulatory Success A Chemical Characterization (E&L) Perspective Frank Bieganousky, AMRI Wei Zhang, Ph.D., AMRI

2 Purpose» Demonstrate a proactive approach for integration of IS into IS in terms of Chemical Characterization/Biocompatibility» Provide awareness of the importance of Chemical Characterization in the process of Biological & Toxicological Risk Assessment» Appreciate the role of analytical chemistry within the overall qualification process to identify probable Leachables in a systematic manner to control for safe use.

3 utline» verview of IS & IS for Medical Device & Packaging» The upcoming IS revision for the 1 st time, highlights testing requirements for medical device packaging» IS lays out requirements for all biocompatibility assessments Starts with chemical characterization & risk evaluation» Importance of Chemical Characterization for Packaging Selection & Medical Device Regulatory Success» When & How to conduct an E&L study

4 verview of IS Packaging for Terminally Sterilized Medical Devices Part 1: Requirements for materials, sterile barrier systems and packaging systems. Package materials should be qualified. Packages should be tested and validated. Part 2: Validation requirements for forming, sealing and assembly processes. Processes should be validated. The objective is to ensure that the product is protected, the system is sterilized, and the sterility is maintained throughout distribution and shelf life of the device.

5 IS verview 5 Materials and preformed sterile barrier systems 5.1 General requirements 5.2 Microbial barrier properties 5.3 Compatibility with the sterilization process 5.4 Compatibility with the labelling system 5.5 Storage and transport 6 Design and development requirements for packaging systems 6.1 General 6.2 Design 6.3 Packaging-system performance testing 6.4 Stability testing Annex A (informative): Guidance on medical packaging Annex B (informative): Standardized test methods and procedures that may be used to demonstrate compliance with the requirements of this part of IS Annex C (normative): Test method for resistance of impermeable materials to the passage of air

6 Key Requirements per IS : General Requirements: The following properties should be evaluated: a) microbial barrier, b) biocompatibility and toxicological attributes, c) physical and chemical properties; d) compatibility with respect to forming and sealing processes; e) compatibility with respect to the intended sterilization process >> suitability for the intended use <<

7 Key Requirements per IS Continued : General Requirements Materials shall meet the following general performance requirements. a) Materials shall be non-leaching and odourless under specified conditions of use, to such an extent that neither performance nor safety is impaired and the medical devices with which they are in contact are not adversely affected. f) Materials shall comply with established specific chemical characteristics (such as ph value, chloride, and sulfate content) to meet the requirements of the medical device, packaging system or sterilization process. g) Materials shall not contain or release material known to be toxic in sufficient quantity to cause a health hazard either before, during or after sterilization under the conditions of use.

8 Key Requirements per IS Continued 5.1.9: General Requirements sterile barrier systems shall meet the requirements listed below. a) materials and components, e.g. coatings, ink or chemical indicators, shall not adversely affect the medical device by reaction, contamination and/or transfer before, during or after the defined sterilization process. 5.4: Compatibility with the labelling system: the labeling system shall b) be compatible with the materials, sterile barrier system and medical device during and after the specified sterilization process(es) and cycle parameters and shall not adversely affect the sterilization process, and c) not be printed or written in ink of a type which can be transferred to the medical device nor react with the packaging material and/or system to impair the utility of the packaging material and/or system

9 Key Requirements per IS Continued 6 Design and development requirements for packaging systems 6.1.1: General Requirements The packaging system shall be designed to minimize the safety hazard to the user and patient under the intended specified conditions of use.

10 Product Package Interaction

11 Product Package Interaction Packaging may impart leachates that may affect safety of the device. Device may react with the packaging materials and compromise package integrity.

12 verview of Regulatory Guidelines for Medical Device Evaluation Strategy IS :2009 Biological Evaluation of Medical Devices: Part 1: Evaluation & testing within a risk management process. Test Methods Part 5: Part 10: Part 11: Part 3: Part 6: Part 4: Part 16: Part 20: Cytotoxicity Irritation & hypersensitivity Systemic toxicity Genotoxicity, carcinogenicity and reproductive toxicity Implantation and local effects Blood compatibility Toxicokinetic study design for leachables and degradation products Principles and methods for immunotoxicology testing Animal Welfare Part 2: Animal welfare requirements Sterilization Residuals Part 7: Ethylene oxide sterilization residuals Degradation Products Part 9: Framework for Identification and quantification of degradation products Part 13: Part 14: Part 15: Identification and quantification of polymeric degradation products Identification and quantification of ceramic degradation products Identification and quantification of metallic degradation products Risk Assessment Part 17: Establishment of allowable limits for leachables Reference Materials Part 8: Selection of reference materials Part 12: Sample preparation and reference materials Materials Characterization Part 18: Chemical characterization of materials Part 19: Physico-chemical, morphological and topographical characterization

13 Considering Chemical Characterization per IS » Chemical characterization in lieu of, or as a substitute for, biological testing (traditional biocompatibility) shall be fully justified when (adequate & appropriate).» A Framework to ensure appropriate & sufficiently comprehensive Chemical Characterization is performed to examine the device relative to patient safety Understanding what was introduced during manufacturing of the material (Device/Packaging) Determining what may leach or extract from the material (Device/Packaging) Utilizing appropriate analytical methodologies to ensure detection & quantitation of chemicals of concern Ensure data will adequately address Toxicological Impact (Tox Risk Assessment)

14 Chemical Constituents and Consideration of Chemical Characterization per IS » Packaging materials that contact the device can transfer chemicals to the device and then indirectly to the patient or user.» The biological risk assessment of materials shall be re-evaluated if any change in the formulation, processing, primary packaging or sterilization of the products.» Risk analysis begins with identification and characterization of the direct and indirect patient contacting materials and components of the device The potential for interactions with or introduction of contaminants from packaging materials should also be considered.

15 Understand Biocompatibility The way a material/product is made Catalysts, additives, manufacturing residues Storage conditions and/or Sterilization Use Conditions Temperature, duration, etc. Contact Environment Source: USP Workshop on <87>, <88>, & <661>

16 Extractables & Leachables: Basics» Extractables: Extractables are compounds that migrate from the contact surface under more aggressive conditions such as elevated temperature, extended contact time, or aggressive solvent system. Any component that is added to or pulled from the device or the materials used to make the device, including degradants and residuals. What CAN come out.» Leachables: Leachables are compounds that migrate from the contact surface under normal conditions of exposure. Leachables are usually subset of extractables. What DES come out.

17 Extractables and Leachables Sources» Polymer oligomers» Polymer degradation products» Polymer/Rubber Additives Antioxidants Photostabilizers Plasticizers Lubricants Acid Scavangers Pigments/Colorants Carifying/Nucleating Agents Cross Linking Agents (Rubbers) Initiators (Rubbers) Accelerators (Rubbers) Colorants» Polymer additive degradation products» Impurities in polymer additives» Catalysts» Polymer residues (e.g. monomers)» Adhesives» Manufacturing impurities/residuals H H H H H Irganox 1010 H H C 2 H Degradant Derivatives degradant H BHT Br Br-C 13 -Rubber ligomer H H erucamide BPA Si Si Si NH 2 DEHP D3 benzophenone 17

18 Analytical Test for Chemical Characterization» Protocol Based Study customized for the device application (IS and )» Comprehensive analytical techniques HSGC-MS target VC (Volatile rganic Compounds) GC-MS target SVC (Semi-Volatile rganic Compounds) LC-UV-MS target NVC (Non-Volatile rganic Compounds) ICP-ES target trace metals (Inorganic Compounds) ther non-specific tests: TC, NVR, ph, etc. Potential Inorganic Compounds of concerns

19 Considerations of Execution of Chemical Characterization Extraction Ratios» Sensitive enough to evaluate relevant exposure IS Lifetime exposure Analytical Evaluation Threshold (AET) Extraction Solutions» Consider the environment of concern Biocompatibility Assay: IS : polar & nonpolar Body Contact: tissue, blood, etc. Drug formulation Reprocessing (re-usable medical devices) Identification and quantitative estimation Extraction Temperature & Duration» Consider body contact, storage, & any reprocessing conditions Leachables: Simulated Extractables: Exhaustive, Aggressive, or Exaggerated Adequate & Sufficiently Comprehensive

20 Systematic Study Design from Material to Use Consideration» Risk Assessment and DS (Design of Study)» Controlled Extraction study using forcing extraction conditions to bracket real-time use conditions.» Leachable Studies is to monitor leachates with validated quantitative methods.» Simulation Study to bridge the gap between Extractables and Leachables studies. Simulate minimum 6 month equivalent real-time storage conditions. Program Designed Controlled Extraction Study Simulation Study Leachable Study Leachable Extractable Simulation

21 Case Study: E&L Study of V-Ring and Packaging Materials Item Ring pouch material Liquid Silicone Rubber, light mineral oil (lubricant) Composite: Polyester (PET) and LDPE Controlled Extraction Study Extraction Conditions: IPA and acidified water (ph 3.5) 50 C for 72 hrs, diluted acid extraction at RT for 24 hrs for ICP-ES, extraction ration 2.5 ml/ring/pouch Comprehensive analytical methods applied: HSGC-MS, GC-MS, LC-UV-MS and ICP-ES AET calculated based on SCT consideration and extraction ratio is 1.0 ppm. ~50 extractable detected above AET for pouch, and >100 silicon compounds for the ring Examples of extractables of the pouch (partial): Dimethyl Sulfone 1.1 µg/pouch VC, manufacture residue (/P)-Toluenesulfonamide 5.3 µg/pouch SVC, plasticizer, adhesive, fungicide, etc. Tinuvin µg/pouch NVC, light stabilizer

22 Case Study: E&L Study of V-Ring and Packaging Materials» Tox Assessment Based on the Controlled Extraction Profile» Method Suitability Study (MST) Target Proposed from both the pouch (packaging) and the Ring (device)» Simulation Study Extraction Conditions: Extraction Medium: Simulated Vaginal Fluid (SVF)* Extraction Conditions: 37 C for 24 h, 3 Days and 7 Days bjective: Leachable release kinetic studies per request» Leachable Studies Based on simulation results and thorough toxicological consideration *Margareth R. C. Marques, Raimar Loebenberg, and May Almukainzi, Simulated Biological Fluids with Possible Application in Dissolution Testing. Dissolution Technologies AUGUST

23 Summary» Expansion of the existing expectations in IS regarding chemical characterization & suitability» Chemical Characterization needs consideration for medical device packaging material Driven by not only IS 11607, but also by IS Guided largely by IS & IS » Extractable & Leachable studies serve as a critical component of material qualification, including suitability for use and safety assessments Chemical Characterization provides the insight needed in appropriate biocompatibility evaluations

24 Acknowledgement John Iannone, Albany Molecular Research, Inc. Thank You!