Global Regulatory Affairs

Transcription

1 Global Regulatory Affairs

2 Perspectives on the Development and Commercialization of Combination Products Regulatory Requirements and Functionality Tests for Pre-filled Syringes and Auto-injectors t Presented by: Douglass Mead Director, RA-CMC, Medical Devices & Combination Products Janssen Research & Development, LLC WCBP 2012 January 23, 2012 Disclosures: The following presentation includes the personal views of the presenter and do not necessarily represent the official views of Janssen R&D, LLC. Data presented should not be associated with any specific biological product. Regulatory requirements presented may differ from actual regulatory requirements imposed by Health Authorities for specific combination products. Global Regulatory Affairs

3 Topics A summary of regulatory requirements for functionality of prefilled syringes and autoinjectors The fundamentals of Design Controls under the proposed rule for cgmps for Combination Products The principles of functionality characterization - with examples The use of Design Inputs in justifying release specifications Assessment of usability in human factors studies and in clinical trials Strategies for delivery device post-approval changes when and how Global Regulatory Affairs 2

4 Historical Regulatory Requirements for Drug Delivery Device Functionality FDA Guidance: Container Closure Systems for Packaging Human Drugs and Biologics (May 1999) Suitability for the Intended Use: Every proposed packaging system should be shown to be suitable for its intended use: it should adequately protect the dosage form; it should be compatible with the dosage form; and it should be composed of materials that are considered safe for use with the dosage form and the route of administration. If the packaging system has a performance feature in addition to containing the product, the assembled container closure system should be shown to function properly. p p y (emphasis added) ICH M4Q Common Technical Document for the Registration of Pharmaceuticals for Human Use Quality (2003/2001) The suitability of the container closure system discussion should consider, for example reproducibility of the dose delivery from the device when presented as part of the drug product. Global Regulatory Affairs 3

5 Historical Regulatory Requirements for Drug Delivery Device Functionality ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (1999) parenteral formulations packaged in pre-filled syringes, autoinjector cartridges, or the equivalent should have test procedures and acceptance criteria related to the functionality of the delivery system. ICH Q1A (R2) Stability Testing of New Drug Substances (2003) Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system). For a PFS, Health Authorities have expected information on: Syringe piston (stopper) break loose and travel forces from multiple lots Confirmation of expelled volume Silicone content (associated with glide) Elastomer and tungsten interactions with protein formulations DMF for additional design, manufacturing, and quality information Container closure integrity Global Regulatory Affairs 4

6 Historical Regulatory Requirements for Drug Delivery Device Functionality Autoinjectors and Pre-filled Pens ISO 11608:2000 Pen-injectors for medical use; Part 1: Peninjectors, Part 2: Needles, Part 3: Finished cartridges, Part 4 (2006): [Electronic functions] -Requirements and test methods Intended primarily for insulin pens but portions relevant to autoinjectors were assessed. FDA Draft Guidance: Technical Considerations for Pen, Jet, and Related Injectors Intended d for Use with Drugs and Biological i l Products (2009) Drug/device compatibility if in direct product contact Suggested tests: dose accuracy, flow rate, injection time, functional reliability, depth of injection, functionality of the safety mechanism, verification for absence of leakage, chemical resistance, structural testing, actuation force, force to defeat needle safety feature, needle penetration force, cap/shield removal force, functional stability, human factors/usability, etc. EU: MDD 93/42/EEC as amended and MEDDEV 2.1/3 rev 5.1 Typically addressed with a CE Mark or by demonstrating conformance to Annex 1 Essential Requirements - of the Medical Device Directive Global Regulatory Affairs 5

7 The New Paradigm in Regulatory Requirements FDA Combination Products Regulations 21 CFR Part 3 (1991) Product Jurisdiction Rules - Definitions Integral (single-entity) delivery devices (pre-filled) [21CFR 3(e)(1)] Kitted (co-packaged) products [21CFR 3(e)(2)] Cross-labeled l products [21CFR 3(e)(3)] [plus investigational 21CFR 3(e)(4)] Proposed21 CFR Part 4 Regulation of Combination Products (2009) Subpart A ( ) Current Good Manufacturing Practice Requirements for Combination Products Applies to integral and kitted combination products Product development impact is: Design Controls (21 CFR ) Not yet a final rule. New ISO Standards - ISO/FDIS Needle-based injection systems for medical use - Requirements and test methods (near final) Part 1: Needle-based injection systems Part 2: Needles Part 3: Finished containers Part 5: Automated functions And ISO 23908: Sharps injury protection ti -- Requirements and test t methods Global Regulatory Affairs 6

8 Key Elements of 21CFR Design controls Design and Development Planning (Device/Combination Product Development Plan) Design Inputs (What does the user require of the device? What technical and suitability characteristics a are required of the device? How is a biological drug a design input?) Design Outputs (design phase - performance acceptance criteria, specifications, drawings) May be used to specify off-the-shelf products. Biological drug specification Design Output Design Verification [bench performance tests to confirm specifications (Outputs) are met] Confirmation that the specific device(s) are suitable with a specific biological i l drug. Design Validation [Establishing by objective evidence that the device(s) meets user needs and intended uses (Design Inputs); user/clinical studies and testing of the IFU, process validation, functional stability] Tested with the target population (and biological drug, where necessary). Global Regulatory Affairs 7

9 Examples of Functionality Characterization - PFS Plot of Viscosity and Average Piston Travel Force vs Glycerin/WFI concentration (N=24) Measured Piston Travel Force Piston Travel Fo orce (N) X = Literature t values Viscosity (cs) % Glycerin in WFI Viscosity of mab formulation of interest Measured Kine ematic Viscosity (c cs) 27 Gauge, ½ inch needle Plot of kinematic viscosity (cs) vs piston travel force was linear Global Regulatory Affairs 8

10 Examples of Functionality Characterization Autoinjector Delivery Time vs Viscosity administration time [N] administration time vs glycerin conc Mean 4 Specification Expon. (Mean) glycerin conc [%] Autoinjector Delivery Time specification = 15 seconds glycerin% N Mean StDev Median Gauge, ½ inch needle, 1.0 ml volume PFS Conclusion: Main spring drive force should be sufficient for most mab formulations up to about 9 + cs. Global Regulatory Affairs 9

11 Autoinjector spring force characterization F o r c e Needle insertion & syringe plunger force as a function of spring extension Spring force (F) available for complete PFS delivery Autoinjector design principles suggested that PFS Glide Velocity was an important parameter of interest for characterization In addition to glide forces measured at an arbitrary fixed plunger drive velocity, plunger Glide Velocity at a fixed force (F) will be assessed Plunger travel distance (for 1.0 ml fill) max specified Delivery Time determined Glide Velocity acceptance criteria Global Regulatory Affairs 10

12 Glide Force and Glide Velocity Characterization Fixed piston speeds to measure glide forces are not standardized, and forces are highly dependent on test velocity Influence of test velocity on piston travelforce Force [N] Representative mab with viscosity ~ 1.2 cp Average Piston Travel Force Trendline: y = x R 2 = Average Piston Release Force Trendline: y = -4E-05x R 2 = Velocity [mm / min] Typical mab glide velocity curve Force (N) Breeakloose force Typical mab glide force curve mm/sec Effect of PFS bubble Piston travel distance Piston travel distance Global Regulatory Affairs 11

13 The Device Design Controls Paradigm for a PFS Health Authorities have treated piston break loose and travel forces like biochemical release specifications. Registered force specifications for commercial release may be restricted to test results on clinical trial lots Should a device Design Controls approach be considered in setting specifications? Users can accommodate a wide range of forces by varying injection speed. PFS plunger thumb rest diameter and finger flange design are as important to usability as PFS injection forces Separate human factors studies* can establish user requirements and justify force specifications Dermal/tissue fillers approved by FDA (CDRH) have much higher injection forces than typical mab solutions. (e.g., Artecoll, Coaptite, Radiesse ) * Example: Cilurzo F et al. Injectability Evaluation: An Open Issue, AAPS PharmSciTech, Vol. 12, No. 2, June 2011 Global Regulatory Affairs 12

14 mab characterization study - two formulations (PFS) - Glide Velocity assessment - Needle gauges g - 26 vs 27 - Two temperatures 10 C vs 30 C Target minimum glide velocities Red (30 C) and Blue (10 C) results suggested a benefit to the nominal formulation and 26 ga needle mab Formulation Description 20 C Viscosity (cp) 10 C Viscosity (cp) Nominal 104 mg/ml optimized i excipients i 5 to 6 7 to 9 Maximized (Worst case) 113 mg/ml enhanced excipients 8 to to 19 Global Regulatory Affairs 13

15 mab characterization study two formulations (AI) - Autoinjector Delivery Time assessment - Needle gauges - 26 vs 27 - Two temperatures 10 C vs 30 C Red (30 C) and Blue (10 C) results suggested a slight benefit to the nominal mab formulation and 26 ga needle mab Formulation Description 20 C Viscosity (cp) 10 C Viscosity (cp) Nominal 104 mg/ml optimized excipients 5 to 6 7 to 9 Maximized (Worst case) 113 mg/ml enhanced excipients 8 to to 19 Global Regulatory Affairs 14

16 Autoinjector functional stability challenges specific to protein (mab) solutions PFS glide forces can increase as product ages affecting autoinjector delivery time and other performance attributes. Potential root causes include: Protein aggregation on PFS barrel walls causes increased friction. Potential for aggregation on surfaces may be linked to potential for particle formation.* Velocity (mm/s) PFS glide velocity (mab aged 25 C) (worst case) Nominal Force (N) PFS glide force (mab aged 25 C) (worst case) *Bee JS, Randolph TW, Carpenter JF, Effects of Surfaces and Leachables on the Stability of Biopharmaceuticals. J Pharm Sci. Vol. 100 No. 10 (2011) Global Regulatory Affairs 15

17 Autoinjector functional stability challenges specific to protein (mab) solutions PFS glide forces can increase as product ages affecting autoinjector delivery time and other performance attributes. Potential root causes include: Silicone lubrication quantity and distribution on syringe barrel and the potential for silicone migration* PFS Silicone layer thickness (e.g., RapID) Marginal silicone distribution *Cairns, A_ PDA 2008 poster: The Impact of Therapeutic Protein Adsorption on the Mechanical Performance of Pre-Filled Syringes and Auto-Injectors Global Regulatory Affairs 16

18 Parameters that may affect autoinjector functionality and stability with an mab Design of Experiments Studies Assessed parameters (32 parameter combinations, 160 samples, 320 datapoints; T=0 and 3 mos.): Polysorbate concentration - minimal vs 2.5 X concentration Particle content (pooled with product of known protein particle content) Silicone content (solvent wash to various levels vs nominal specification) Silicone distribution (silicone wash/spiked into empty barrel vs nominal characteristics) Initial stopper position ±2 mm Spring forces (lower vs nominal) Autoinjector component s age (youngest vs oldest) Storage orientation horizontal storage vertical storage Time at room temperature before testing Results: Polysorbate concentration High concentration reduced particles but increased friction in 3 samples (vertical storage) uncertain root cause (potential washing effect). Silicone content and distribution - affected stopper friction. (solvent wash to various levels vs nominal specification) Initial stopper position ±2 mm marginal effect? Spring forces - no impact Autoinjector component s age (youngest vs oldest) - no impact Storage orientation - horizontal storage preferred Time at room temperature before testing no effect Global Regulatory Affairs 17

19 Parameters that may affect autoinjector functionality and stability Design of Experiments Studies Implications: Selection of type and quantity of surfactant Improved glide & Delivery time stability Compensated for by adequate ate silicone quantity or distribution? Silicone quantity or distribution may be critical Surfactant quantity Increasing surfactant may reduce protein aggregation on PFS barrel walls Surfactant quantity Increasing surfactant may wash silicone from barrel walls Surfactant quantity Suggests an ideal surfactant quantity that may be assessed by PFS glide studies Unresolved question: We don t know if protein is binding to bare glass in PFS barrel areas without sufficient silicone or if there are protein-silicone complexes on glass that reduce silicone s lubricity or increase piston/stopper stiction. Global Regulatory Affairs 18

20 Functionality assessed in human factors studies CDER may now require formal, summative human factors studies* for delivery devices and request that protocols be submitted for FDA (CDRH) review prior to initiating them. Protocols should include a final draft IFUs and a User Risk Analysis including critical tasks. This activity is an essential element of Design Validation that FDA is implementing right now. Prepare a Task Analysis based on the IFU identify critical tasks Conduct formative studies (intervention) and a summative study (no intervention) Population (groups) categories should be justified; subjects per group Actual field experience will magnify results; expect that use complaints may be higher than rates for product defects; IFU and design changes can help; Human behavior (e.g., startle reactions) isn t always predictable. Autoinjector trainer devices can help. CDER is moving to requiring final to-be-marketed presentations to be used in Phase 3 trials. Usability should be assessed. Comparability of drug delivery with different delivery devices may be a question. (Potential for bioequivalence or PK studies) *FDA Draft Guidance - Applying Human Factors and Usability Engineering to Optimize Medical Device Design (June 22, 2011) Global Regulatory Affairs 19

21 Functionality specifications for combination products Functional device specifications can be derived from Design Inputs (user requirements and technical design requirements) which are then verified and validated. This is in contrast to biological drug product specifications that are determined by the production process, studied in clinical trials, and then registered. Autoinjector examples: Delivery time: 15 seconds based on market research; a 510(k) cleared predicate autoinjector has a 20 second maximum delivery time Injection depth: determined by user requirements and dermal thickness data Actuation forces: determined by human factors studies in intended population. The ectd Justification of Specifications module (32P56) should include a discussion of user requirements in the context establishing specifications. Global Regulatory Affairs 20

22 Post-approval delivery device changes Motivations Design improvements to enhance usability New technology available over the biologic product life-cycle. FDA s Office of Combination Products is finalizing a guidance on submission requirements for post-approval changes. There is currently no clear guidance other than to follow the respective center (drug) requirements. FDA/OCP is recommending (March 2011) premarket discussions of potential changes, post-market comparability assessment strategies (e.g., bench tests, HFS, clinical studies), and inventory planning sufficient to allow for FDA approval of changes prior to implementation. CDRH guidances may be a useful metric* *Guidance for Industry and FDA Staff - 510(k) Device Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device (July 27, 2011) Draft Guidance for Industry and Food and Drug Administration Staff - The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (December 27, 2011) Global Regulatory Affairs 21

23 Conclusions Patients are prescribed a biologic drug but they see and use a medical device; Usable delivery devices are a key component of personalized medicine and are a significant benefit to patients (e.g., hand-impaired patients) Formulations can be optimized for drug delivery; devices can be optimized for the formulations (Design Inputs). Combination product regulations and Health Authority expectations are evolving and vary in different markets; frequent interactions, adequate justifications, and flexibility in development programs are necessary Design Controls do not necessarily increase the tests required and can be an effective tool for development and justification of specifications. Combination products require the application of both drug and device regulations and principles. Device and combination product competencies and experience are essential for success. Global Regulatory Affairs 22

24 Acknowledgements Tom Hogan Tony Lubiniecki Nishant Bhasin Rene Spycher Jasminka Kovac Christian Braun Global Regulatory Affairs 23