1. Alternative Production Methods for WFI and Compendial Challenges Anthony Bevilacqua, Ph.D Mettler-Toledo Thornton April 5, 2011

2. Aqua Distillata (Distilled Water) Aqua distilleteur vasis permundis, donec ejus duo circiter trientes stillaverint. Aquam distillatum in lagena vitrea servato. “ Let water be distilled in very clean vessels until about two thirds have come over, which is to be kept in a glass bottle.” Printed in USP I (1820) by the Pharmacopoeia of the United States of America

3. USP History of WFI (continued) Based on data from a user, USP added RO as an acceptable WFI production method in USP XIX (1975) In spite of allowance, RO not widely adopted Many early design problems and microbial control issues, spotty success, validation difficulties Many advances in last decade - overcome historic problems Less problematic RO designs Other emerging technologies and heat-tolerant MOCs Better scientific understanding of endotoxin removal approaches Better scientific understanding of biofilm control

4. USP Water for Injection Monograph

5. WFI Method of Production – JP

6. WFI Method of Production – EP

7. Academic vs. Engineering Argument Academic - “Distillation is the gold standard, it works by inherently better separation methods” Engineer – “Don’t tell me how to make it, tell me the specifications you need it to meet” Water for Injection is the ONLY material in USP where it is prescribed “how to make it”.

8. EMEA Reflection Paper of WFI http://www.emea.europa.eu/pdfs/vet/qwp/2827108en.pdf

9. EMEA Microbiological Concerns

11. EMEA Conclusions

12. Response in PDA Letter - Vol XLIV (7) pp 15-16 Multiple responses (100%) reflecting a very negative opinion of specific comments of the EMEA position But comments were qualitative, not quantitative Comments indicated more data was needed

13. EDQM – Revisits Their Position

14. EDQM Survey

15. Results of survey are planned to be released in early 2011.

16. USP Pharm Water Perspective It is documented that there are Highly Purified Water systems in operation today by definition they do meet WFI requirements for chemical and microbiological tests It is “known” that there are Purified Water systems in operation today that meet WFI requirements – but not proven

17. USP Pharm Water Perspective It is not the final purification step that determines the water quality… It is not RO that is good or bad… …it is the entire water system and related supporting processes that determine the water quality It is NOT about RO, it is about the system.

18. What Specifically? Feedwater and microbial control methods Pre-treatment system design/sanitization Purification system design/sanitization System size, subloops, and distribution Water criticality relative to product

19. What Else? Sanitization methods Type(s) Frequency In-line microbial/endotoxin/purity controls Hours of operation/days of operation Usage – intermittent or continuous Cost – capital and operational And more

20. USP Survey Since it is the water system AND related processes… Let’s get data from industry to justify whether alternative techniques can produce WFI reliably and consistently Utilize the ISPE Critical Utilities COP to get the best available data.

21. EDQM Workshop

22. USP’s WFI Survey Needs to Reveal Factors Facilitating Reliable WFI Production Using Non- distillation Approaches Need to understand source water quality and consistency Need to understand purification & distribution system Design Maintenance Sanitization approaches Ongoing purification and microbial/endotoxin controls Excursion restoration approaches Specifications, Action, Alert and Typical Levels Need to understand system reliability and consistency Hoped to see survey responses representing long term system success WFI Survey probed attributes of these WFI systems Expected to see a few clusters of successful design configurations and approaches to purification, sanitization, controls – some surprises!

30. 8a. Are the above remedial distribution system sanitization parameters more extreme than routine sanitization parameters? No, 22, 76% Yes, 7, 24%

36. What’s Next? Summary of purification and control points necessary for reliable WFI production Discussion of survey descriptions of: Successful purification designs Successful purification train sanitization approaches Successful distribution designs Successful distribution sanitization approaches Successful distribution in-line controls Implications for the future of WFI production by non- distillation approaches

37. Logical WFI Purification and Control Points First, remove endotoxins from source water using Size exclusion using RO and/or UF (~10KD cutoff or less) Deionization removal (endotoxin is very negatively charged) Then, minimize biofilm colonization within purification train for the sake of Purification efficiency and operational cost Avoiding release of additional endotoxins Can control with sanitization and in-line microbial controls Finally, control biofilm and endotoxin in the distribution system Avoid/prevent release into distribution system from purification train Avoid/minimize biofilm growth and generation of endotoxins in loop Can control with sanitization and in-line microbial controls Can control with endotoxin polishing in loop (e.g., UF and DI)

38. Survey responses for Q13 and Q14 reveal system design and control approaches Presented here at a high level (still revealing) Purification unit operations used Purification train configurations used Purification train sanitization approaches used Distribution system sanitization approaches used Distribution system unit operations used Distribution system micro/endotoxin control approaches used Interpretation of what it all says about successful ways of making WFI other than by distillation

44. Years of Reliable Operation

45. Non-Distillation WFI Uses

46. Non-Distillation WFI Use Clusters

47. What Does All This Mean About Suitable Approaches to Generating WFI ? Some general Unit Op train pattern commonalities 1 or 2 pass RO + DI or EDI is common, but others also work Chem > HW > No RO+EDI sanitization, but all work With UF ≈ Without UF for last unit op, but both work Plain DI (no sani) without RO or UF (minority approach) also successful Bottom Line: Many approaches can work, likely with varying degrees of diligence to maintain control, but control nevertheless No such thing as fool-proof (even for distillation)!

48. What Does All This Mean About Suitable Approaches to Generating WFI ? Concerns essentially no different than with distillation-based WFI, however… Cost considerations, usually water not already hot, so ambient control measures more common/creative Micro/endo control/polishing in loop could be beneficial Use of high water purity (minority approach) also successful in controlling growth Loop sanitization approach commonality HW > Ozone ≈ Chem sanitization use, but all can work Multiple approaches >> Single approach >> No loop sani, but all can work

49. What Does All This Mean About Suitable Approaches to Generating WFI ? Ongoing in-line micro control/endo polishing Combo approaches >> Single approach >> No control unit ops, but all can work Most common combo is a UV sanitizer + MicroFiltration (0.1 or 0.2 µm rated) Bottom Line: Many approaches can work, with the systems having more control options likely needing less diligence in keeping the quality controlled No such thing as fool-proof!

50. Thank You! Dr. Anthony Bevilacqua, Head of R&D Mettler-Toledo Thornton 36 Middlesex Turnpike Bedford, MA 01730 USA +1 781 301 8642 anthony.bevilacqua@mt.com