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
State commonly 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Out of date “ready to use” products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
CETA CAG
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 )
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

51. Third Party Reports Must comply with appropriate CETA standards
CETA certified inspector
If not CETA certified, a comparison and determination the standards used is the same OR BETTER than the applicable CETA standards

52. Third Party Reports PEC (ideal to show calculations)
Equipment used make, model, last calibration, and expriation date of calibration
Airflow velocity supply average with “acceptable” limit stated for the environment tested
Average particle counts with “acceptable” limit stated for environment tested
Induction leak/backstreaming test results with “acceptable” limits stated
Airflow visualization test
HEPA filter integrity (leak) test results with “acceptable” limits stated
“PASS” or “FAIL” designation based on USP etc standards

53. Third Party Reports SEC (ideal to show calculations)
Equipment used make, model, last calibration, and expiration date of calibration
Average particle counts with “acceptable” limit stated for environment
ACPH from SEC HEPAs AND PECs (stated separately AND summed)
HEPA filter integrity test results with “acceptable” limits stated – Provide diagram showing each HEPA and corresponding number
If HEPA leaks detected, show on diagram and state if fixed or not while on site
“PASS” or “FAIL” designation based on USP etc standards

54. Third Party Reports ISO classification
ISO5 = less than 3,520 particles/M3
ISO7 = less than 352,000 particles/M3
ISO8 = less than 3,520,000 particles/M3
ISO5: PEC
ISO7: Anteroom and buffer room
ISO8: Anteroom for a non-HD buffer room

55. Third Party Reports Air changes per hour (ACPH)
Total CFM ÷ Room ft3 × 60 = ACPH
Example: room 12’W X 15’L X 8’H = 1440 ft3
941 CFM ÷ 1440 ft3 x 60 = 39.2 ACPH
ACPH: Minimum of 30 for ISO7 (only 50% UP TO 15 may come from PEC)

56. Third Party Reports Air changes per hour (ACPH)
ACPH: Minimum of 30 for ISO7 (only 50% UP TO 15 may come from PEC)
Example:
SEC: ACPH = 12
PEC: ACPH = 20
TOTAL DOES NOT EQUAL 32… It’s … 27 ACPH… FAIL for ISO7
Exception: HD room… NO recirculation from PEC

57. Third Party Reports Air changes per hour (ACPH) Pressure gradients
ACPH: Minimum of 20 for ISO8 (UNLESS it’s anteroom for a HD room – shared or not with a non-HD room)
Pressure gradients
Anteroom and non-HD buffer rooms
Positive 0.02”WC or greater

58. Third Party Reports Pressure gradients Facility pressure gauges
Non-HD HD buffer rooms
Negative 0.03 to 0.01”WC
Too negative pulls in contamination
Facility pressure gauges
Calibration

59. Third Party Reports HEPA filter testing Smoke test in PEC and SEC
New installation
Every 6 months
Smoke test in PEC and SEC
During dynamic conditions
PEC: If nothing to compound, MUST simulate

60. Third Party Reports Viable testing Surface AND air… not just one…
Documentation of appropriate growth media (e.g., TSApl)
Lot and expiration date of media
Control utilized

61. Third Party Reports Viable testing
Air sample: Minimum of 1000 L in PEC
Pass through: Must include

62. Self-assessment question #4
Key components of a third party certification report include:
ACPH for the SEC
HEPA filter leak testing for PEC and SEC
Pressure gradient for SEC
“PASS” or “FAIL” designation for each test
All of the above

63. Summary USP<797> last updated in 2008
What is new… Universal approach to inspection across the country
You must self-educate if you feel knowledge is inadequate
Know how to read and interpret 3rd party certification reports
Not all 3rd party certifiers are created equal