1. IPAC-RS GMP Guideline for OINDP Component Suppliers: Development, Application, and Use Barbara Falco (KOS), Chair of IPAC-RS Supplier Quality Control Working Group

2. Outline  Background  Process for Development of the IPAC-RS GMP Guideline  Content, Application, and Use of the Guideline  FAQs  Next Steps and Conclusion

3. Background: Why IPAC-RS?

4. Definitions and Acronyms  IPAC-RS – International Pharmaceutical Aerosol Consortium for Regulation and Science  OINDP – Orally Inhaled and Nasal Drug Products (e.g., MDIs, DPIs, Nasal Sprays, etc)  OINDP manufacturer: Pharmaceutical company that manufactures and sells OINDP  N-1 Supplier (aka OINDP component supplier): Supplier of components or materials directly to the OINDP manufacturer  N-2 Supplier: Supplier of materials to n-1 supplier

5. IPAC-RS 1989: International Pharmaceutical Aerosol Consortium (IPAC) formed to address regulatory consequences for MDIs of Montreal and Kyoto Protocols 1999: IPAC formed a Working Group to prepare comments on the FDA draft CMC Guidances for MDIs and DPIs 2001: International Pharmaceutical Aerosol Consortium for Regulation and Science (IPAC-RS) formed as a separate Consortium –IPAC-RS Mission: To advance consensus-based and scientifically driven standards and regulations for inhaled and nasal drug products (OINDP) –IPAC-RS Overall Goal: Development of scientifically justified regulatory approaches for orally inhaled and nasal drug products

6. IPAC-RS Member Companies Aradigm AstraZeneca Boehringer Ingelheim Eli Lilly GlaxoSmithKline INyX Kos Nektar Therapeutics Novartis Novo Nordisk Pfizer Sanofi-Aventis Schering-Plough

7. Why Supplier QC?

8. OINDP Components Sources of Images: IPAC-RS SQC WG and suppliers’ public catalogues

9. FDA-Required CMC Tests for OINDP 1.Assessment of Packaging Materials 2.Appearance / Description of Product 3.Color 4.Identification (2 specific tests) 5.Chiral Specificity, if applicable 6.Microbial Limits 7.Microbial Challenge 8.Water Content 9.Alcohol Assay if applicable 10.Content Assay 11.Assay for other excipients 12.Net Content Weight 13.Leak Rate 14.Pressure Testing 15.Spray Pattern 16.Plume Geometry 17.Valve Delivery (Shot Weight) 18.Dose Content Uniformity (uniformity of API delivered from mouthpiece) 19.Dose Content Uniformity Through Canister Life (API delivered from mouthpiece at beginning, middle, and end of canister) 20.Particle Size Distribution of API – Mass Balance and Groupings (Cascade Impactor) 21.Effect of Storage on Particle Size Distribution 22.Microscopic Evaluation (particle size, morphology, crystallinity, amorphous forms, agglomerates, etc.) 23.Foreign particles (enumeration, characterization) 24.Leachables 25.Extractables 26.Dissolved metals 27.Impurities and Degradation Products 28.Number of Doses Delivered 29.Effect of Resting Time 30.Priming and Re-priming 31.Drug Deposition on Mouthpiece and/or Other Accessories 32.Profiling of Actuations Near Canister Exhaustion 33.In vitro Dose Proportionality (multi- strength doses) 34.Effect of Flow Rates Component quality plays a critical role in many CMC tests

10. Impetus for Supplier QC Working Group IPAC-RS recognized that: –Quality of OINDP components is critical to quality of drug/device combination and significantly impacts many required CMC tests –Some aspects of quality control are particularly important to OINDP components, e.g., Change Control Control of Extractables –No existing quality guideline provides guidance specific to development and manufacture of OINDP components Quality practices vary widely between component suppliers OINDP manufacturers (IPAC-RS members) each have slightly different expectations for component suppliers, and audit them using different standards.

11. Formation of Supplier QC Working Group IPAC-RS formed the Supplier QC Working Group, made up of representatives from OINDP manufacturers and suppliers –Leachables and Extractables was spun off as a separate topic within the Product Quality Research Institute (PQRI) –PQRI L&E Working Group has issued specific recommendations regarding extractables and leachables control, testing, and thresholds Supplier QC Working Group Mission: –To encourage quality through design rather than through testing and enable the provision of consistently high quality OINDP components by promoting the implementation of robust quality systems at OINDP component manufacturers –To simplify the quality control process by promoting harmonized quality standards for OINDP components

12. Working Group Objectives Survey Component Suppliers and OINDP Manufacturers to determine: –Whether a quality guideline for OINDP suppliers is needed –If so, what topics this guideline should address Develop guideline for OINDP component suppliers Conduct education/training for OINDP manufacturers and their suppliers on use of the GMP Guideline Consider development of an auditing service or certification of suppliers against the GMP Guideline

13. Development of the IPAC-RS GMP Guideline

14. Supplier Survey Survey of OINDP n-1 suppliers completed in 2001/2002 Suppliers surveyed specialize in: –Pumps and valves –Molded rubber components –Printed materials –Specialty chemicals –Plastic components –Etc 14 suppliers responded Also surveyed OINDP manufacturers regarding expectations for OINDP Suppliers

15. Survey Results: Extractables Control 4 of 14 suppliers control for extractables How do you control for extractables? –“Where required we have our adhesive supplier testing and reporting extractables under their control.” –“We have specifications for the materials and specialized, validated pre-extraction processes. Use validated analytical test methods to assure compliance to specifications.” –“Only indirectly by gross methods – not by detailed analytical methods” –“Via outside laboratory” –“On customer request”

16. Survey Results: Cleaning  9 of 14 suppliers have equipment cleaning and use logs  4 of 14 suppliers have validated cleaning procedures  How do your manufacturing systems minimize the potential for cross-contamination? –“We have area clearance procedures that require line clearance prior to product switch-over. In addition we have dedicated lines and pumps where required to prevent contamination of adhesive or silicone systems.” –“Clear product labeling and segregated work cells where applicable” –“Cleaning the mixer between batches” –“At each stage or process, the operators must perform a line clearance and have it verified by a co-worker. Both are documented. In addition, all product is bagged and identified by customer and job number.”

17. Conclusions from Survey Survey results showed differences in quality expectations among OINDP manufacturers and differences in quality practices among OINDP suppliers. Need for quality guidance for OINDP suppliers Review of existing quality guidelines (ISO, PS 9000) showed insufficient guidance on topics important to OINDP Based on survey results and review of quality guidelines, Supplier QC Working Group defined areas where further guidance specific to OINDP components is needed. –These areas became the topics addressed by the IPAC-RS GMP Guideline

18. Topics Addressed by IPAC-RS Guideline  TESTING AND RELEASE –Characterization and functionality testing of OINDP components –Control of ancillary materials and extractables –Components and materials use-by/expiry date and shelf-life determination  QUALITY SYSTEMS –Supply agreements, specifications, quality agreements, and documentation –Design and development planning –Subcontracting, supplier qualification, and supplier data verification –Change control and notification –Quality unit authority and responsibilities –Product recalls and complaints –Drug master files (DMFs)

19. Topics Addressed by IPAC-RS Guideline  ENVIRONMENT/CLEANING –Environment –Equipment use and cleaning; dedicated/non-dedicated equipment; cleaning validation –Component cleaning –Foreign particulates

20. Development of the IPAC-RS Guideline  Working Group drafted text addressing each topic –Reviewed text to ensure harmonization with and no duplication of existing quality guidelines  Based on supplier suggestion, Working Group decided to incorporate IPAC-RS Guideline into PS 9000 Guideline for Pharmaceutical Packaging Materials –PS 9000 already used by many OINDP component suppliers –Includes ISO 9001:2000 and ISO 9004:2000 –Obtained permission from ANSI and PQG/IQA for use of PS 9000 and ISO text

21. Guideline Review Process Consensus Process: –Draft Guideline discussed, reviewed, and approved by Working Group members –Draft Guideline circulated to IPAC-RS Board of Directors for review, comment, and approval (13 OINDP manufacturers) –Draft Guideline circulated to external reviewers for comment External reviewers included most major n-1 OINDP suppliers (3M, Bespak, Honeywell, Kinetics, Pfeiffer, Presspart, Valois, West), and individuals at the PQG Comments received from 8 of 9 external reviewers Overall, comments were very positive and indicated that the Guideline will be useful Comments were reviewed by the Working Group, and revisions were made to the Guideline. Where revisions were not appropriate, IPAC-RS responded to the commenter indicating why the revision was not made

22. Guideline Review Process Regulatory Review: –IPAC-RS also sought feedback on Guideline from FDA Feedback was positive and noted that Guideline is in alignment with FDA’s new Quality by Design Initiative FDA has not provided formal approval/endorsement because the Guideline did not go through an official FDA review process –IPAC-RS welcomes comments from other regulatory authorities –NOTE: OINDP Suppliers are not regulated by FDA or other regulatory authorities. The IPAC-RS Guideline does not change this status

23. Application and Use of the IPAC-RS GMP Guideline

24. Application  Applies to suppliers of components for OINDP not regulated by FDA or other device regulations, e.g., –Canister or reservoir –Actuator –Pump –etc  Does not address devices or device manufacturers  Applies to n-1 suppliers –n-2 and n-3 suppliers who supply to n-1 suppliers are encouraged to read and follow Guideline

25. Layout  Guideline includes requirements from 3 standards: –ISO 9001 (Boxed black text) –PS 9000 (Boxed blue text) –IPAC-RS (Boxed green text)  Guideline also includes ISO 9004 as guidance (non-boxed black text)  Layout follows layout of PS 9000, e.g., –ISO 9004 1 –ISO 9001 1, 1.1, 1.2 –PS 9000 1, 1.1,1.2 –IPAC-RS 1, 1.1, 1.2 –ISO 9004 2 –ISO 9001 2, etc.

26. Use  N-1 suppliers are expected to read and follow the contents of the IPAC-RS, PS 9000, and ISO 9001 sections of the Guideline (boxed text) –ISO 9004 text provides additional guidance but is not required  N-1 suppliers may be audited by their customers against IPAC-RS, PS 9000, and ISO 9001 sections  Guideline allows room for variation based on needs of customer and supplier : –Many requirements are "as defined by the customer," "as agreed between the supplier and the customer," or "where applicable“  Communication between the supplier and customer is emphasized in the Guideline and is a key element of the Guideline

27. Use: Informational Sections  IPAC-RS Sections of the Guideline includes several informational sections –Drug Master Files (DMF) –Process Analytical Technology (PAT)  These sections are included for information only and are not required –For example, DMF section explains what a DMF is, its uses and benefits, and how an interested supplier may obtain more information on DMFs. Suppliers are not required to submit a DMF.

28. IPAC-RS GMP Guideline: FAQs

29. IPAC-RS Guideline FAQs Q: Why did IPAC-RS choose to incorporate its Guideline into the PS 9000? A: Suppliers on the Working Group noted that the PS 9000 standard is already used by many suppliers, and that it includes ISO 9001, providing a useful “all-in-one” standard addressing many areas of GMP. WG members agreed that it would be useful to incorporate the IPAC-RS Guideline into the PS 9000, thus providing suppliers with a comprehensive GMP Guideline.

30. IPAC-RS Guideline FAQs Q: The format of the Guideline is confusing. How do I know which sections to follow and what is required? A: All BOXED text (black, blue, and green) is required, except for the IPAC-RS informational sections on DMFs and PAT. These sections are clearly marked “For information only”. Non-boxed text is NOT required.

31. IPAC-RS Guideline FAQs Q: Who enforces the Guideline’s requirements? A: Initially, your customers (OINDP manufacturers). It is expected that most OINDP manufacturers will begin auditing their suppliers against this Guideline. IPAC-RS is also exploring the possibility of implementing a certification process, whereby suppliers could be certified against this guideline, or an independent auditing service (similar to IPEA) that would audit against the Guideline.

32. IPAC-RS Guideline FAQs Q: I am an n-2 supplier (e.g., a resin manufacturer). Should I still follow the Guideline? A: We encourage you to read the Guideline, familiarize yourself with its requirements, and implement its requirements to the extent possible. However, n-2/n-3 suppliers are not required to follow the Guideline.

33. IPAC-RS Guideline FAQs Q: If my customers don’t use the IPAC-RS Guideline, should I still follow its requirements? A: We encourage you to adhere to the Guideline’s requirements if you are an OINDP supplier. Many OINDP manufacturers will begin auditing against this Guideline, and you may find that potential customers expect/request that you follow the IPAC-RS Guideline. In addition, the Guideline provides clarity as to the GMP expectations for OINDP component suppliers, and may therefore be useful to you in designing/improving your processes.

34. IPAC-RS Guideline FAQs Q: Some of the component properties listed in section 7.3.1.1, Design and Development Planning, don’t apply to components produced by my company. What do I do? A: Notice that the list of component properties in Section 7.3.1.1 is prefaced by: “…the following relevant properties as deemed necessary by the customer or as applicable:” Only those properties applicable to your product, or deemed relevant by your customer need be considered. Many of the IPAC-RS sections of the Guideline allow for variation based on the needs of the supplier and the customer and based on the component in question.

35. IPAC-RS Guideline FAQs Q: This Guideline seems to require a lot of communication with customers. Why is this so necessary? A: OINDP components are critical to the functionality of OINDP devices, which are very complex. Therefore, it is critical that the supplier understand how the component will be used, and what the needs of the customer are. It is also important for the manufacturer to notify the customer of changes. Seemingly “insignificant” changes (e.g., change in cleaning agent, processing oil, or packaging) can significantly affect the functionality of the final OINDP device or its extractables/leachables profile.

36. IPAC-RS Guideline FAQs Q: Does the Guideline require suppliers to perform extractables testing? A: NO! The Guidelines notes that “Extractables testing should be performed by EITHER the OINDP manufacturer, OR the OINDP component supplier, OR the manufacturer with assistance from the supplier.” This should be decided jointly by the supplier and their customer. Extractables testing need only be done on critical components. The customer will identify these for the supplier.

37. IPAC-RS Guideline FAQs Q: How can I purchase a copy of the IPAC-RS Guideline? A: Contact Melinda Munos mmunos@gcd.com Tel. 202-230-5118 OR See www.ipacrs.com, which will post information on the Guideline in the near future.

38. IPAC-RS Guideline FAQs Q: Who do I contact if I have comments or questions about the IPAC-RS Guideline? A: Melinda Munos (IPAC-RS Secretariat) mmunos@gcd.com Tel. 202-230-5118

39. Conclusion and Next Steps

40. Conclusion OINDP components are critical to the quality and performance of OINDP IPAC-RS hopes that its GMP Guideline will be helpful in standardizing and clarifying quality expectations for OINDP component suppliers IPAC-RS expects that OINDP manufacturers will begin using the Guideline as an auditing standard for their suppliers The IPAC-RS Guideline does not replace supplier-customer communication and in fact emphasizes the importance of such communication

41. Next Steps U.S. Launch of Guideline and education/training of OINDP manufacturers and suppliers Consider development of an auditing service, certification process, or conversion of the Guideline to a Voluntary Consensus Standard

42. Questions?

43. Acknowledgements

44. IPAC-RS Member Companies Aradigm AstraZeneca Boehringer Ingelheim Eli Lilly GlaxoSmithKline INyX Kos Nektar Therapeutics Novartis Novo Nordisk Pfizer Sanofi-Aventis Schering-Plough

45. IPAC-RS Supplier QC Working Group Boehringer- Ray Oksala Ingelheim Eli LillyBen Dai Marcia Arentz KOSBarbara Falco, Chair NektarKenneth McCain* NovartisRainer Frueh Novo Nordisk Lisa Erdös Sanofi-Linda Nield Aventis PfizerSuzette McTigue Presspart*Bert Calvert Susan Hall Annette Thompson Schering- Michael Lusty* Plough ValoisValerie Leveque, Vice-chair WestFran DeGrazio Tom Gaspar *Former WG members

46. Reviewers FDA PQG OINDP Suppliers –3M –Bespak –Honeywell –Kinetics –Pfeiffer –Presspart –West –Valois

47. Special Thanks to Ashley McCreight (PQG) George Smith (FDA Office of Compliance) and Jon Clark (FDA Office of Pharmaceutical Science) IPEC and IPEA, particularly Art Falk and Irwin Silverstein The PQG, for this opportunity to present

48. Contact Information IPAC-RS Secretariat Melinda Munos mmunos@gcd.com Tel. 202-230-5118