RDD Europe 2011 Workshop 4 May 2011

Transcription

1 RDD Europe 2011 Workshop 4 May 2011 This file represents the slides presented on May 4, 2011 by 3M Drug Delivery Systems at the RDD Europe 2011 Conference in Berlin, Germany. Slides have been modified to support electronic distribution in pdf form after the Conference. RDD Europe M DPI Workshop rev 3 FINAL PRESENTED SLIDES modified for post Workshop distribution.pptx

2 DPI Products: Design for Manufacturability and Scale-up (DFMSU) This Workshop will discuss considerations to ensure success during the various phases of development of dry powder inhaler (DPI) products. Topics will include: device design and development, the importance of a disciplined design control process, process design and development, unit cost estimating and the importance of an overall development map. Participants will leave with a deepened appreciation of the role that DFMSU plays in the development of DPI products. 2

3 Workshop Presenters Rich Sitz Stephen Stein 3

4 Workshop Outline Who is 3M Drug Delivery Systems? Why DFMSU? Design Controls DFMSU in Early & Late Stage Development Unit Cost Estimating Wrap Up/Discussion 4

5 Who is 3M Drug Delivery Systems? A Global Leader in Inhalation Drug Delivery 3M Drug Delivery Systems Division Leverages 3M Technologies and Manufacturing Expertise Partner API Over 50 years experience developing and manufacturing inhalation products 5

6 3M Dry Powder Inhaler Platforms 3M Taper Can contain up to 120 premetered doses. Uses active dispersion of drug to increase delivery efficiency. Delivers neat drug (no carrier powder required). When compared to in-vitro results from Advair Diskus, would deliver 50 to 70 percent less drug to a patient while delivering the same therapeutic dose to the lung (as defined by fine particle dose). 3M Conix Is available in single-dose disposable, single-dose reloadable, and multi-dose configurations. Efficiently leverages a patient's inspiratory flow to deagglomerate the drug powder. Has been used in a recently concluded Phase I clinical study, with excellent results. 6

7 Workshop Outline Who is 3M Drug Delivery Systems? Why DFMSU? Design Controls DFMSU in Early & Late Stage Development Unit Cost Estimating Wrap Up/Discussion 7

8 Why DFMSU? What could possibly go wrong during product development? Quality: poor performance. Cost: too expensive (development cost, capital equipment cost, product cost) Time: takes longer than planned. DFM is part of a disciplined process to help you meet your quality, cost and time goals. 8

9 Why DFMSU? high DFM is part of a robust development process to insure you can live long-term with today s decisions. low Development timeline 9

10 Workshop Outline Who is 3M Drug Delivery Systems? Why DFMSU? Design Controls DFMSU in Early & Late Stage Development Unit Cost Estimating Wrap Up 10

11 What are Design Controls? A formal methodology for management and documentation of product development projects Required for development of medical devices and combination products (drug + device) 21 CFR 820, ISO 9001/ISO 13485, ICH Q8 Key components: Design and Development Plan Design History File Design Requirements Specifications Device Specification (Design Input) Design Reviews Design Verification Design Validation Risk Management Process 11

12 Workshop Outline Who is 3M Drug Delivery Systems? Why DFMSU? Design Controls DFMSU in Early & Late Stage Development Unit Cost Estimating Wrap Up 12

13 Background Information Diskus/Accuhaler DPI Design Diskus/Accuhaler DPI developed by GSK Used in multiple drug products (including Advair) 60 dose blister strip ~12 mg of formulation (ordered blend using lactose monohydrate) Blister peeled prior to dosing to expose formulation Serevent, Diskus and Advair are registered to GlaxoSmithKline 13

14 Background Information - Taper DPI Design Microstructured carrier tape (MCT): MCT contains microstructure cavities filled with API Lactose carrier not required, can use neat drug Dose range of to 2 mg API per dose (fine particle doses between and 0.78 mg) Upon inhalation, spring impactor strikes tape and aerosolizes drug Multi-dose device: Up to 120 pre-metered doses with integrated moisture protection Patient-friendly features: Dose counter and dose ready-indicator Visual and audible feedback of dose delivery Simple, 3-step, breath-actuated delivery (open-inhaleclose) with a compact pocket-sized device 14 14

15 Applying DFMSU During Early Stages of Technology Development 15

16 Early Device Design Prototype Development Types of Prototypes: Industrial design prototypes (aka form study prototypes ) Subassembly breadboards Functional Prototypes ( Looks Like/Works Like models) Prototype Fabrication Techniques: Hand fabricating CNC machining Stereolithography (SLA) Rapid injection mold tooling Computer simulations (e.g. CFD, FEA, etc.) Many other techniques available 16

17 Process Development During Early Development Don t forget the processes! Many processes become locked in based on early device design decisions! Map out 20,000 foot view of manufacturing process: Sub-assembly strategy Facilities requirements Failure mode analysis of processes: Identify high priority processes Evaluate feasibility of high priority processes Focus early (limited) resources on these processes Preliminary assessment of process scaleability 17

18 20,000 Foot View of Taper Sub-Assembly Strategy MCT Moisture Control Chamber Subassembly Lower Housing Subassembly Final Assembly Labeling and Packaging MCT Moisture Control Chamber Subassembly Highest value subassembly Keep at 3M site to protect IP Lower Housing Subassembly Standard molded parts and routine pick-&-place assembly Provides manufacturing location flexibility 18

19 Taper DPI Process Development MCT Extrusion Dose determined by number and volume of dimples Control of dimple dimensions in MCT is crucial to controlling dose delivery MCT formed using extrusion embossing process 3M leverages this type of microreplication for many applications Nominally 230 mcg/dose MCT Nominally 1000 mcg/dose MCT Outcome: Demonstration of commercial capability. 19

20 Taper DPI Process Development MCT Coating Proprietary asynchronous roller coating method used to coat MCT High through-put process 1000 doses per minute Outcome: Demonstration of commercial capability. 20

21 Applying DFMSU During Later Stages of Technology Development 21

22 Taper DPI Process Development Threading of MCT through Small Opening Supply of MCT is stored on a spool in a moisture control chamber Chamber maintains RH at desired level Two concepts: (1) Window ; (2) 'Slot' 'Window' preferred for moisture protection; needed to demonstrate ability to thread MCT through window Worked with expert automation vendor to demonstrate PoC Ensure design provides acceptable performance & manufacturability Window Design Slot Design Outcome: Demonstration of high speed process. 22

23 Taper DPI Process Development Foil Sealing of Moisture Chamber Early development used conductive sealing Induction sealing highly desired for automation Unusual seal shape Constraints on foil selection PoC work initiated Utilized external experts Demonstrated acceptable seal performance and cycle times Reduced capital expenditure Outcome: Demonstration of high speed mfg process. 23

24 Design for Injection Molding 24

25 Design for Injection Molding Objectives Minimize cost of molded parts and mold tools Maximize molding reliability (complete shots, no flash, etc.) Utilize industry experts Critically review of every part for moldability Determine Type of Tooling Needed Capacity requirements Regulatory strategy 25

26 Design for Injection Molding No draft Part Attributes that Simplify Molding: Avoid undercuts & secondary tool actions Avoid parting lines on critical feature Place injection gates and ejection pins where they don t disrupt function or aesthetics Ejection pins location selected to ensure good ejection Sufficient draft angle to allow easy ejection Gate location and molding flow analyzed to ensure complete filling (particularly of narrow protrusions) These are guidelines 26

27 Design for Automated Assembly 27

28 Design for Automated Assembly Objectives: Minimize capital costs Maximize capacity of assembly equipment Maximize reliability / minimize down time ( Overall Equipment Efficiency ) Maximize flexibility Low and high volume assembly Location that sub-systems are assembled Keys to Success: Utilize industry experts 3-way interaction (design group, molding vendor, automation vendor) Critical review of every part 28

29 Design for Automated Assembly Part Attributes that Simplify Automated Assembly: Enables single axis (vertical) assembly Has good lead-ins Contain alignment features Design out misalignment/misplacement/tangling Avoid slower secondary process steps Make parts symmetrical when possible These are guidelines 29

30 Lead-In Features Diskus Mouthpiece Cover Mouthpiece cover pivots on small posts on the top and bottom housing. Mouthpiece cover has small receptacle for pivot posts. Tight fit required in order to prevent mouthpiece cover from falling off. 30

31 Lead-In Features Diskus Mouthpiece Cover Mouthpiece cover pivots on small posts on the top and bottom housing. Mouthpiece cover has small receptacle for pivot posts. Tight fit required in order to prevent mouthpiece cover from falling off. Simple lead in feature on posts allows for simple slide assembly. 31

32 Alignment Features Taper Dose Counter Correct orientation of parts is critical to function Can assemble with dose counter at 121, 61, or 31 Small hole in housing and dose counter wheels added Including simple pin hole feature improve assembly reliability 32

33 Alignment Features Taper Dose Counter Correct orientation of parts is critical to function Can assemble with dose counter at 121, 61, or 31 Small hole in housing and dose counter wheels added Including simple pin hole feature improved assembly reliability Including small flat features allows for self-alignment of parts in bowl feeder reduced capital costs Surface to enable alignment in bowl feeder 33

34 Single Axis Pick and Place Assembly - Diskus Blister Strip Assembly Lower Housing Assembly Final Assembly Labeling and Packaging 34

35 Single Axis Pick and Place Assembly - Diskus Molded parts simple to mold Simple single axis pick & place assembly Snap-fits hold parts in place Subassembly could be readily shipped to another location 35

36 Workshop Outline Who is 3M Drug Delivery Systems? Why DFMSU? Design Controls DFMSU in Early/Late Stage Development Unit Cost Estimating Wrap Up/Discussion 36

37 Unit Cost Estimating: Why? A unit cost estimate: 1. Is a critical input to many business processes: Required for Business Opportunity Assessments and Net Present Value calculations do we have a viable business? 2. Is a valuable tool in device and process design, development and scale-up: Gives clear visibility to cost contributors Allows identification and prioritization of future work 37

38 Unit Cost Estimating: Example 1. Create the unit cost calculation. 2. Interrogate the results. 38

39 Unit Cost Estimating: Create The following unit cost estimate is for illustration purposes only and is not intended to be representative of any commercial product or product in development. 1. Mix drug and lactose E-4 E-6 2. Fill into foil foil strip 3. Assemble into device 39

40 Unit Cost Estimating: Create 1. Mix drug and lactose E-4 E-6 2. Fill into foil foil strip 3. Assemble into device 40

41 Unit Cost Estimating: Create E-4 E-6 41

42 Unit Cost Estimating: Create E-4 E-6 42

43 Unit Cost Estimating: Interrogate Don t ignore the impact of Indirect Cost on the total factory cost of the product. Direct Costs: Can be allocated specifically to a product or batch. Indirect Costs: Are shared by multiple products. 43

44 Unit Cost Estimating: Interrogate Interrogate the variables that affect Mix Material cost. 44

45 Unit Cost Estimating: Interrogate What effect would increasing Mix Yield from 90% to 95% have on Unit Cost? 45

46 Unit Cost Estimating: Interrogate What effect would increasing ALL Yields from 90% to 95% have on Unit Cost? 46

47 Unit Cost Estimating: Interrogate Interrogate the variables that affect Fill Labor cost. 47

48 Unit Cost Estimating: Interrogate What effect would decreasing Fill Cycle Time from 10 sec/cycle to 5 sec/cycle have on Unit Cost? 48

49 Unit Cost Estimating: Benefit Provides direction and prioritization to your device and process development activities. 49

50 Unit Cost Estimating: Quantifying Uncertainty of Inputs Some inputs I understand very clearly: Example: 12 mg of lactose per dose. Some inputs have much more uncertainty: Example: Overall Equipment Efficiency: 75%? 50%? 90%? What do I do? Use Sensitivity Analysis to quantify the impact that the potential range of each input could have on Unit Cost. 50

51 Unit Cost Estimating: Sensitivity Analysis 51

52 Unit Cost Estimating: Sensitivity Analysis Sensitivity Analysis: Provides a Unit Cost estimate in the form of distribution, not just a single value. Gives visibility to those factors that have the largest contribution to that variability. 52

53 Unit Cost Estimating: Conclusion Provides development direction to shift the mean and reduce variability (risk). Is a valuable tool in DFMSU. 53

54 Workshop Outline Who is 3M Drug Delivery Systems? Why DFMSU? Design Controls DFMSU in Early/Late Stage Development Unit Cost Estimating Wrap Up/Discussion 54

55 DPI Products: Design for Manufacturability and Scale-up (DFMSU) Key Takeaways: Take advantage of Design Control disciplines starting with a detailed specification documents Prove critical processes early in development Leverage industry experts early Know your unit cost and let it support development planning. 55

56 DPI Products: Design for Manufacturability and Scale-up (DFMSU) This Workshop will discuss considerations to ensure success during the various phases of development of dry powder inhaler (DPI) products. Topics will include: device design and development, the importance of a disciplined design control process, process design and development, unit cost estimating and the importance of an overall development map. Participants will leave with a deepened appreciation of the role that DFMSU plays in the development of DPI products. 56