The Use of Pharmaceutical Stability Tools in Medical Device Stability Programs

Transcription

1 Global SYNTHES Institute of Validation Technology Forum on Stability Programs The Use of Pharmaceutical Stability Tools in Medical Device Stability Programs Laure L. Larkin MSc. CPP. Synthes USA 1

2 The Theory of Plate Tectonics (or our stability world is changing) One of the constants in life is change! What does that mean for our stability programs? Changing Regulatory Environment! Changing Technology Changing Understanding 2

3 What is Shelf Life? The length of time a material may be stored without becoming unsuitable for use. What is the Expiration Date? It is the date before which the quality of a device remains acceptable for its intended use. It is predicted from stability tests under general / normal storage conditions or by accelerated stability testing under extreme conditions. Every package of a shelf limited device bears an expiry date. 3

4 What is the Changing Stability Environment? The World is Flat - John II, King of Portugal to C. Columbus Who are the stability stakeholders? - North America - Health Canada, FDA - ROW - EU, Individual Countries - Each group publishes regulations and guidance for the Medical Devices distributed in their jurisdictions 4

5 Why should we require a Stability Program in the US? FDA - QSR 21 CFR Subpart K--Labeling and Packaging Control Sec Device labeling. Each manufacturer shall establish and maintain procedures to control labeling activities. (a) Label integrity. Labels shall be printed and applied so as to remain legible and affixed during the customary conditions of processing, storage, handling, distribution, and where appropriate use. Sec Device packaging. Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution. 5

6 What does ISO say about Medical Device Stability Programs? ISO 13485:2003(E) Preservation of product The organization shall establish documented procedures or documented work instructions for preserving the conformity of product during internal processing and delivery to the intended destination. This preservation shall include identification, handling, packaging, storage and protection. Preservation shall also apply to the constituent parts of a product. The organization shall establish documented procedures or documented work instructions for the control of product with a limited shelf-life or requiring special storage conditions. Such special storage conditions shall be controlled and recorded (see 4.2.4). 6

7 What else does ISO say about Medical Device Stability Programs? ISO :2006(E) 6.4 Stability testing Stability testing shall demonstrate that the sterile barrier system maintains integrity over time Stability testing shall be performed using real-time aging Stability testing, using accelerated aging protocols, shall be regarded as sufficient evidence for claimed expiry dates until data from real-time aging studies are available Real-time and accelerated aging tests should begin simultaneously. NOTE: Stability testing and performance testing are separate entities. Performance testing evaluates the interaction between the packaging system and the products in response to the stresses imposed by the manufacturing and sterilization processes and the handling, storage and shipping environment. 7

8 ISO says even more about Medical Device Stability Programs! ISO :2006(E) 6.4 Stability testing continued When expiry dates are based upon product performance, stability testing for expiry dating should be conducted along with package stability testing If accelerated aging tests are performed, a documented rationale for the accelerated aging conditions and test duration chosen shall be established When it is demonstrated that the product does not interact with the specified sterile barrier system over time, previously documented data for stability testing shall be sufficient to be in accordance with

9 Can Someone Else Do My Medical Device Stability Testing? Sure! But remember, your company is the expert on your product! You don t want the regulating agency in the country to become more of an expert than your company. Getting outside experts to help in areas where your company lacks expertise or equipment capabilities maybe a good strategy. Ignoring knowledge gaps is a bad strategy! - Ignorance Bliss 9

10 When do we do shelf life testing? Must be addressed for all sterile parts. Must be addressed for any non-sterile product that may degrade over time (ex. batteries, oils). Testing strategies should be identified while the project is still in the concept stage. Waiting can be catastrophic to timelines. 10

11 FOR NON-IVD DEVICES SHELF LIFE (STABILITY) HAS BEEN THE DOMAIN OF PACKAGING - (Not so much anymore!) This is still TRUE for metallic Devices. This is FALSE for non-metals or combined metal/non-metals and combination Drug/Devices. 11

12 We know FDA is looking harder! 510K Delays PMA Delays Complete Response Letters 483 s Warning Letters 12

13 Help is Available! 13

14 Helpful FDA Documents and Links for Medical Device Stability (Free) Shelf Life of Medical Devices Guidance for Industry - Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products Guideline for the Manufacture of In Vitro Diagnostic Products International Conference on Harmonization (ICH) - Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products

15 Helpful ISO Documents and Links for Stability (Not Free) ISO 13485:2003 Medical devices -- Quality management systems -- Requirements for regulatory purposes ISO :2006 Packaging for terminally sterilized medical devices -- Part 1: Requirements for materials, sterile barrier systems and packaging systems 15

16 Helpful Standards for Stability (Not Free) AAMI TIR22:2007 Guidance for ANSI/AAMI/ISO 11607, Packaging for terminally sterilized medical devices- Part 1 and Part 2: a2007&source=google&adgroup=aami&keyword=aami%20tir%20 22&gclid=CKaY7pj666QCFeFN5Qod2Uu92A UL 746A & B, the Standard for Safety of Polymeric Materials -- Sort & Long Term Property Evaluations. s/plastics/standards/ ASTM F Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices 16

17 Pharma Has Some Tools That May Help! 17

18 FDA Quality by Design (QbD) Tool Integration of Prior Knowledge and Pharmaceutical Development into CMC Submission and Review. Ajaz S. Hussain, Ph.D. OPS/CDER/FDA Creating regulatory flexibility via design space. Product & process characteristics important to desired performance must be derived from a combination of prior knowledge and experimental assessment during product development. 18

19 QbD for Medical Device Stability Testing Constructing a design space? Design space Multi-dimensional space that encompasses combinations of stability influences; product design manufacturing process design manufacturing process parameters raw materials A Process is well understood when? All critical sources of variability are identified and explained Variability is managed by the process Product quality attributes can be accurately and reliably predicted over the design space 19

20 Using QbD to Create the Device Stability Family Prior knowledge guides product development Pre-characterization of materials Product development Well characterized Materials Process development Intrinsically Stable (Metals) Polymers Manufacturing/Fabrication Package Sterilization Method/Dose or Concentration Know your risks! 20

21 Understanding Risk Which activity has a higher risk? Conducting full scale stability testing. Costly Time consuming Space consuming Possible late stage failures Missed launch dates Approving a Stability Adoption. Cheap Fast Failure is not an option Launch date is a slam dunk 21

22 Stress Testing / Forced Degradation Tool 22

23 ICH Q1A (2 nd revision, Feb., 2003) Stability Testing of New Drug Substances and Products Don t get hung up on the D -word. The concept of Stress Testing is being applied to our new Large Molecule Products. Three Lot concept has not yet been applied to Stand Alone Devices. The 3 lot concept is being actively enforced for Combination Device/Drugs and has resulted in FDA Warning Letters issued by CDRH. 23

24 Degradation Products Wherever significant qualitative or quantitative changes indicative of degradation product formation are detected during long-term, accelerated, and/or stress stability studies, consideration should be given to potential hazards and to the need for characterization and quantification of degradation products within the long-term stability program. Real Time Testing 1998 FDA Stability Guide 24

25 Stress Testing: What, Why and How? Forced degradation studies not conducted to identify/quantify potential degradants. excerpt from FDA

26 What is Stress Testing? Forced decomposition using extreme conditions: Temperature heat freeze/thaw Humidity Chemical ph high oxygen tension hydrogen peroxide oxidation ozone oxidation Sterilization Methods Gamma EtO 26

27 Purposes of Forced Degradation (Stress Testing) Gain experimental evidence of possible degradation pathways. Gain experience with degradation products. Gain information to guide analytical development. Prepare special reference materials for method validation. Assess likely effects of excursions outside of label conditions during distribution. 27

28 Important Points to Consider 28

29 Intrinsic Stability Stephen Yablo provides perhaps the most succinct version: You know what an intrinsic property is: it's a property that a thing has (or lacks) regardless of what may be going on outside of itself. (1999, Intrinsicness, Philosophical Topics 26: 479) Stress Testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. (ICH Q1A(R2)-2.1.2) 29

30 What are Intrinsically Stable Materials? Metals. Many polymers in the pre-sterile state. Create the family and add to it as results from stress testing are obtained. The family should include only materials that are well characterized. Must be supported by objective evidence. 30

31 Don t Forget the Package Stability! Intrinsically stable materials become shelf limited by the package when offered in as sterile. Many common package materials like Tyvek, PETg, Polyamides have excellent stability information available from the vendors that is applicable to intrinsically stable materials. Generally the package will not age at a different rate regardless of the contents. 31

32 Excursion Simulation before Aging? What - Samples are exposed to extremes of cold, heat and humidity for a brief period of time to simulate conditions that would be reasonable to encounter during distribution before they are aged. Why to allow realistic simulation of aging conditions for our provisional shelf life. X LSL No Excursion idealized condition Excursion T0 is impacted but slope is identical Excursion T0 is not impacted but slope is impacted T0 D46 D91 D137 32

33 Can stability specs be different from release specs? YES!!! The shelf-life specifications could allow acceptable and justifiable deviations from the release specifications based on the stability evaluation and the changes observed on storage. The use of different specifications for release and expiration should be supported by sufficient data to demonstrate that the clinical performance is not affected FDA Stability Guide 33

34 Stability Requirements Device Companies Omit When They Enter the Combination Device/Drug Arena 34

35 Additional Requirements Beyond the QSR If the Operating Manufacturing Control System is Part 820 (QS Regulation) If the Operating Manufacturing Control System is Part 210/211 (CGMP Regulation) Carefully Consider These Specific CGMP Requirements Title Testing and approval or rejection of components, drug product containers, and closures Carefully Consider These Specific QS Requirements Title Design controls Calculation of yield Purchasing controls Expiration dating Corrective and preventative actions Testing and release for distribution Stability testing Special testing requirements Reserve samples * Including all subsections, as appropriate. 35

36 What is Missing? Current Good Manufacturing Practice for Combination Products (Draft Guidance)Guidance for Industry and FDA - Current Good Manufacturing Practice for Combination Products (Draft Guidance). Nothing about the International Conference on Harmonization - Standards on Safety, Efficacy and Quality which are required compliance standards. 36

37 But Device Companies do Stability Testing! Not always on three lots/batches. The accelerated aging is commonly pushed above 45ºC, humidity may be omitted as a concern. Studies frequently use a bracketing design or just one worst case size. Companies don t ask FDA to preapprove the bracketing design when they decide not to test all package sizes. 37

38 What s special about biotech stability? Because most finished biotechnological/biological products need precisely defined storage temperatures, the storage conditions for the real time/real temperature stability studies may be confined to the proposed storage temperature FDA Stability Guide Result you may not be allowed to do Accelerated Aging The burden of proof is on industry to prove the new products age in a 1 st order chemical reaction and therefore the Arrhenius Theory applies. 38

39 Stability Testing of Biotech Products: Special Considerations Complex test articles and methods. Many degradation pathways/products. Activity may depends upon 3- dimensional conformation. Liquid and lyophilized dosage forms. Involve biological assays. Non-covalent as well as covalent forces involved in maintaining structure. 39

40 How Do We Decide What To Do For Stability Testing? Stability Determination Process. Intrinsic Stability Stability Families New Product Stability Checklist. Strategic Testing Early Risk Assessments Forced Degradation Studies. Understand The Product Understand The Risks 40

41 Quantify The Risks And Gains 1 = Excellent, 3 = Adequate, 5 = Marginal Product: Comprehensive understanding of material? Package: Comprehensive understanding? Sterilization Method: Comprehensive understanding? Special Regulations / Guidance: Comprehensive understanding? Any score above 16 is high risk and should consider a re-assessment of risk versus gain If the potential gain is low - mitigate! 41

42 How Do We Start Understanding Stability Risk? 42

43 Stability Checklist Complete it early in the design process. I don t know (Unknown) is OK! Forced Degradation (Stress Testing) helps change Unknown to Yes or No. Revise it until everything is a Yes or a No. 43

44 MORE COMPREHENSIVE CHANGES ARE ON THE HORIZON If you have a project that includes an innovative, non-metal potentially shelf limited product, smile, your company is getting it s money s worth from this Stability Seminar! Time for our case studies! 44

45 This is the END of our Training!!! Any Questions???? Thanks for Coming! 45