Left to Our Own Devices Design Control & Risk Management Strategies for Combination Products

Transcription

1 Left to Our Own Devices Design Control & Risk Management Strategies for Combination Products DR. RICK WEDGE 12 MAR 2018

2 Overview Definitions Current Regulatory Landscape Design Controls Risk Management Conclusions 2

3 Definitions - FDA 3 FDA 21 CFR 3.2 (e)

4 Definitions - FDA 4 FDA 21 CFR 3.2 (e)

5 Definitions - EU Entirely dependent on primary mode of action Drug/Device: Regulated as medicinal product (MAA + MDD Annex I) Device/Drug: Device component CE Marked separately 5

6 Current Regulatory Landscape - US 21 CFR 3.2(e) Combination Product Definition 21 CFR 4 Regulation of Combination Products 21 CFR 210 cgmp in Manufacturing Processing, Packing or Holding of Drugs; General 21 CFR 211 cgmp for Finished Pharmaceuticals 21 CFR 820 Quality System Regulation Combination Product regulations cgmp regulations 6

7 21 CFR 4 - Streamlined Approach 21 CFR DEVICE 21 CFR DRUG Management responsibility Design controls Purchasing controls Corrective and preventive action Installation Servicing 21 CFR 4 Streamlined Approach Combination Product Testing and approval of components, drug product containers and closures Calculation of yield Tamper-evident packaging Expiration dating Testing and release for distribution Stability testing Special testing requirements Reserve samples Company Quality Policies and Standards SOPs, Work Instructions etc. 7

8 Design Controls - Overview 8 FDA Guidance (CDRH): Design Control Guidance for Medical Device Manufacturers

9 Design Controls - Application The user shall be able to successfully operate the device Lab testing performed with production equivalent Prefilled Pens to confirm activation force is < 12 N User testing performed with production equivalent Prefilled Pens to confirm user can successfully operate the device. The force to activate the device shall be less than 12 N Spring added to device powerpack to reduce activation force Specifications for spring are defined Prefilled Pen manufactured according to all specifications 9 FDA Guidance (CDRH): Design Control Guidance for Medical Device Manufacturers

10 Design Controls - Process Risk Management 10

11 Design Controls Translation of Requirements 11

12 Design History File Specifications Planning Documents Risk Management File Design Review Minutes Verification and Validation Documents Labelling / Instructions for Use 12

13 DHF Components Stage 1 Project Initiation Document Project Research Report URS 13

14 DHF Components Stage 2 Design & Development Plan Risk Management Plan Hazard Analysis User Task Analysis / ufmea dfmea Design & HF Validation Plan Product Requirements Specification Technical Analyses / Engineering Reports 14

15 DHF Components Stage 3 CQA Analysis, Tolerance Analyses Drawings, Specifications, Spec Rationales etc. Updates to Risk Management File inc. pfmea Design Verification Plan, Protocols & Reports HF Studies Shelf Life Strategy Control Matrix, Design Transfer Checklist Device Master Record 15

16 DHF Components Stage 4 HF Summative Report, HFER Updates to Risk Management File Risk Management Summary Report (RBAR) Process Validation Clinical Evaluation, Design Validation Reports Traceability Matrix Post Launch Plans 16

17 DHF Components Stage 5 Updates to Risk Management File based on complaints Design Changes Post Market Clinical Data 17

18 Risk Management Devices Perspective Based on ISO 14971/24971 Focusses on patient harms Applies over the life cycle of the device Risk Management File is a living document. 18 ISO Medical Devices Application of Risk Management to Medical Devices

19 Risk Management Devices Perspective 19 ISO Medical Devices Application of Risk Management to Medical Devices

20 Risk Management Standard Narrative 20

21 Risk Management Lifecycle Waterfall 21

22 How Does This Work? Reliability Proper sequence followed; device failure Usability Incorrect sequence followed; device failure HAL Provides reliability specification based on patient risk Harms linked to hazardous situations Severity of harms determined by clinician Targets for occurrence defined, updated over lifecycle ufmea Input to both usability and reliability Proper use vs. foreseeable misuse 22

23 How Does This Work? dfmea / pfmea Defines capability of design, manufacturing and inspection processes to produce reliable product Identified risks addressed in Control Strategy by incoming inspection, IPC, AQL, release testing etc. 23

24 How Does This Work? Link to HAL No Dose / Lack Of Effect Reliability Usability Validation of Risk Control Device Failure Safety Failure Environmental HF Failure Forms part of PMS activities Evaluation of controls linked to patient risk Spontaneous Activation Failure To Activate Glass Breakage Bent Needle Defect List Link multiple failure modes to create cumulative risk profile Interference User Lacks Strength Foreign Material Incorrect Dimension Environment Mfg Resin Moulding Process Tool Wear Failure Modes 24

25 Advantages Of This Approach Defines quantitative acceptance criteria Design Verification (Reliability) Design Validation (Reliability + Usability) Activities/acceptance criteria linked directly to patient risk Justification for incoming inspection / release criteria Feedback to design and manufacturing Incoming inspection data, IPC, release data, PMS Identify risk at any stage of process 25

26 Risk Management Drug Product 26

27 Risk Management Drug Product Quality Target Product Profile Prior Knowledge Product / Process Development Product / Process Design Space Control Strategy Regulatory Flexibility Definition of product, intended use, and predefinition of quality targets (with respect to clinical relevance, efficacy, and safety). Summary of prior scientific knowledge (drug substance, excipients; similar formulations and processes). Initial risk assessment. Overview of Quality By Design, key actions and decisions taken to develop new scientific knowledge, e.g., DoE, risk assessment, and risk control. Summary of scientific understanding of product and process. Justification and description of multidimensional space that assures quality (interrelationships and boundaries of clinical relevance) Definition of control strategy based on design space leading to control of quality and quality risk managment (process robustness). Proposal of regulatory flexibility based on product and process, scientific knowledge, and quality risk management (materials, site, scale, etc.). 27

28 Risk Management Drug Product Impact of Process on Quality Attributes Update process understanding FMEA to de-risk control strategy Impact of Process on Quality Attributes Risk Assessment 1 Experimental Plans Risk Assessment 2 Draft Control Strategy Risk Assessment 3 Commercial Control Strategy Small scale experiments and at scale data Validation and additional batch experience 28

29 Risk Management Alignment of Approaches DRUG PRODUCT Right First Time / Cause & Effect / DoE / PI PUP DEVICE Specifications, AQLs etc. Design Controls / Risk Management CONTROL STRATEGY DHF / RISK MANAGEMENT FILE POST LAUNCH 29

30 Risk Management Alignment of Approaches 30

31 Conclusions Device design control and risk management requirements apply to combination products Manufacturers required to establish and maintain DHFs Increased scrutiny on risk management of device component of combination products Approaches for drug products and devices can be reconciled and inform one another. 31

32 THANKS! 32