USP<797>… It’s not “new”… but it must be “news” to you…

1. USP<797>… It’s not “new”… but it must be “news” to you… Kevin Robertson, PharmD, BCPS Inspector/Investigator Arkansas State Board of Pharmacy

2. No conflicts of interest to disclose

3. Pharmacist Objectives List commonly cited issues during recent USP<797> compliance inspections State the proper approach to beyond use dating assignment for “point of care activated systems” Explain the similarities and dissimilarities to USP<797> compliance between cleanrooms and compounding aseptic isolators Describe core components of an acceptable third party certification report

4. Technician Objectives Statecommonly cited issues during recent USP<797> compliance inspections Compare and contrast USP<797> compliance between cleanrooms and compounding aseptic isolators Understand the third party certification report

5. Commonly cited issues… so far...

7. Commonly cited issues • Cleaning and disinfection • Monthly cleaning is NOT occurring • Bins with loose materials (e.g., pieces of carboard) • Amount of items located in anteroom and/or buffer room • Computers, refrigerators, IV supplies, medications, etc

8. Commonly cited issues • Cleaning and disinfection • “Ready to use” products vs. “Not ready to use” products • Dating on mixed product • Buckets (PEC vs. SEC) • Dating on “not ready to use” products • Out of date “ready to use” products

9. Commonly cited issues • Cleaning and disinfection • Sterile water not being used with mixed germicidal detergents in PEC • Germicidal detergent not being used daily in PEC • Sporicidal agent used at a minimum of monthly (fungicidal ≠ sporicidal)

10. Commonly cited issues • Cleaning and disinfection • Use of gowns that are not cleanroom gowns • Lack of low lint wipes to dry hands • Fatigue mats – GET RID OF THEM

11. Commonly cited issues • Beyond use dating • Opened SDVs within the PEC, refrigerators, etc • Point of care activated systems • Multi-dose vial dated beyond 28 days

12. Commonly cited issues • SEC HVAC • Inadequate ACPH • Inadequate/Inappropriate pressure gradients • Classification of rooms (i.e., there is not such thing as “hall to chemo room”) • Room HEPA filter leak testing • Humidity excessive*

13. Commonly cited issues • SEC • No line of demarcation • Sink too small for adequate hand hygiene* • Return air return vents at ceiling height* • Numerous horizontal surfaces* • Exposed sprinkler heads* • Ceiling tiles not calked

14. Commonly cited issues • SEC • No pressure gauges for rooms • Pressure gauges not calibrated • HD room pressure too negative • Tacky mats in a conditioned room • Lack of interlock on pass-through* • Failures - LAFH vs. vertical workbench

15. Commonly cited issues • Medication storage • Cheap thermometer – Not calibratable* • Incorrect goal range for cold storage*

16. Commonly cited issues • Training • Yearly written exam on garbing, cleaning/disinfection, and aseptic technique (including those “supervising”) • Yearly validation of above • Gloved finger tip testing – Initial vs. annual

17. Commonly cited issues • Training • Appropriately matched media fill testing to match most complex mixture (e.g., ACD)

18. Commonly cited issues • Garbing • Makeup, artificial nails, etc in cleanroom • Lack of beard covers • Lack of nail picks for hand hygiene • Exposed skin (usually at the ankles)

19. Commonly cited issues • Garbing • Lack of waterless alcohol based hand surgical scrub • Donning sterile gloves properly • Lack of knowledge of why the line of demarcation is there…..

20. Commonly cited issues • Environmental monitoring • Inadequate third party certifier • CETA CAG-003-2006-11 • CETA CAG-002-2006 • PIC familiar with testing required and interpretation of results

21. Commonly cited issues • Environmental monitoring • Inadequate third party certifier • Report includes equipment used (model, last calibration, etc) • Lack of HEPA filtration testing • Lack of ACPH for each room • Lack of pressure differential for each room

22. Commonly cited issues • Environmental monitoring • Inadequate third party certifier • Lack of smoke testing UNDER DYNAMIC CONDITIONS • Viable sampling (air and surface) • Air: ISO5 environment —› 1000 L sample • Surface: Not the floor or walls

23. Commonly cited issues • Environmental monitoring • Viable sampling (air and surface) • Air & surface: Control, lot, expiration date of media • Air & surface: You tell the 3rd party certifier where to sample! • Air & surface: If you have a pass-through, it must be part of the sampling

24. Commonly cited issues • Environmental monitoring • Viable sampling (air and surface) • Don’t sample close to a sink (i.e., false positives)

25. Commonly cited issues • Compounding Procedure • sIPA use with “adequate frequency” • Too many items in the hood (e.g., pens, calculators, stickers, etc) • Inadequate sanitization of rubber stoppers

26. Commonly cited issues • Compounding Procedure • Filter sterilization: compatibility, volume limit, filter integrity (i.e., bubble test) • Extended dating beyond USP<797> • Sterility and pyrogen testing of each lot in addition to stability data

27. Commonly cited issues • SOPs • No action limits or thresholds for variances to stop compounding, investigate cause, trigger remediation, notify prescriber / patient / ASBP, etc • Directions for mixing germicidal detergents • Proper maintenance of tacky mats

28. Commonly cited issues • SOPs • Appropriate action levels for gloved finger tip / media fill testing • Appropriate action for failed testing in ISO5 environment: HINT… STOP COMPOUNDING UNTIL IT’S FIXED AND VALIDATED THAT IT HAS BEEN FIXED (ONE HOUR BUD)

29. Self-assessment question #1 • Which findings below is most likely to lead to non-compliance with USP<797>? • Lack of hands free soap dispenser • Use of tacky mats in controlled space • Excessive items in the compounding areas leading to inadequate cleaning/disinfection

30. Point of care activation systems

31. Extended BUDs • Supported by: • Stability (exact match preparation cited including concentration, excipients, storage device, etc) • Sterility testing (each batch) • Endotoxin testing (each batch)

32. Mini-Bag Plus

33. Mini-Bag Plus Manufactured by Baxter Compatible with 20 mm closure, single dose, powered drug vials Available in dextrose and saline Can be docked outside the pharmacy using proper aseptic technique Can be activated at point of care using proper aseptic technique Do not refrigerate assembled system prior to activation

35. Mini-Bag Plus • Manufacturer documents: • “..all Mini-Bag Plus container IV solutions should remain in the protective overwrap until ready for use…” • “..once assembled, the product should be used promptly…” • This does not support extended BUDs

36. addEASE

37. addEASE Manufactured by B Braun BCxx00 & N7995: Compatible with B Braun Partial Additive Bag (PAB) and xx mm vials or 250 mL EXCEL bag and 20 mm vials, respectively. Do not refrigerate assembled system prior to activation Can be docked outside the pharmacy using proper aseptic technique Can be activated at point of care using proper aseptic technique

38. addEASE • Manufacturer documents: • “..the chemical stability of the drug is not compromised during specified storage…” • “…the results of the testing verified the reliability of the connection…” • This does not support extended BUDs

39. Self-assessment question #2 • BUD extension beyond USP<797> is based on: • Stability data • Sterility testing (each batch) • Endotoxin testing (each batch) • All of the above

40. Sterile rooms vs. “gloveboxes”

41. CAI vs. CACI

42. Similar Considerations • Cleaning and disinfection • Areas within segregated compounding area (SCA) designated with LOD • Training and validation • Annual testing, media fill, gloved fingertip, etc • SOPs

43. Similar Considerations • Garbing • Must follow USP<797> UNLESS manufacturer documentation provided stating may be altered • Environmental monitoring • Pressure is ante-chamber etc • Temperature etc • Third party certification

44. Dis-similar Considerations • Environmental monitoring • Third party certification (CETA CAG-002-2006) • Certified to maintain ISO5 environment in non-classified environment under DYNAMIC CONDITIONS, including during transfer of product / product preparation

45. Dis-similar Considerations • Sink • Not within 1 meter of CAI/CACI • SCA • Located in low traffic area • Not close to unsealed windows/doors that connect to outdoors/construction site/warehouse/food preparation areas

46. Self-assessment question #3 • Which expectations below are similar between CSP operations using a “cleanroom” and a “glovebox”: • Sink placement • CETA criteria for 3rd party certification • Training and validation

47. Third party certification reports