Implementation of Enhanced Active Air Particle Counting. Jeffrey W. Weber Kalamazoo, MI May 5, 2015 PDA Midwest

Transcription

1 Implementation of Enhanced Active Air Particle Counting Jeffrey W. Weber Kalamazoo, MI May 5, 2015 PDA Midwest

2 Agenda Introduction Regulatory Aspects Case Study: Investigation Future Role: Elimination of settle plates

3 What is AFAAP? Auto-Fluorescence Active Air Particle Counting is a generic term for the following: Enhanced active air particle counters AAP with fluorescence detector for biologic fluorescent particles (and other auto-fluorescent compounds too) Laser-Induced Flourescence (LIF) Somewhat incorrect term that is more appropriate in analytical chemistry Aerosol Cytometry Accurate term, but potentially confusing.

4 Auto-Flourescent Unit CFU AFU Colony-forming unit (CFU) is a unit used to estimate the number of viable bacteria or fungal cells in a sample. Auto-Flourescent Unit (AFU) is a unit that reflects both size and fluorescence of the particle.

5 Technology Active air particle counter that simultaneously monitors biological fluorescence (ATP, NADH, picolinic acid), particle count and size information. Laser Path Air Path Interrogation Zone Fluorescence Detector Particle Size Detector

6 Commercial Systems BioVigilant IMD-Air TSI BioTrak PMS BioLaz

7 System Caveats Commercial systems do not replace any environmental microbiological testing; rather it is a risk reduction tool enabling sites to rapidly understand and correct variations in environmental control. Opportunity for improved process control, process understanding, and faster response Many of the applications can be performed with standard active air particle counters.

8 False Positive Signals Polymers, dead cells, pollen, some solvents Viable But Not Culturable (VBNC) microorganisms. Require sample capture to identify false positives Microorganisms Limitation of Growth Media ~ 0.1% 10 3 Culturable Microorganisms

9 System Roles HVAC reduction studies Investigations Commissioning and qualification of new areas. Release of areas back to manufacturing after shutdown and/or interventions Monitoring of shutdown activities

10 Roles Cont d Training & Evaluations Gowning (Shedders) Aseptic technique (aseptic training) Evaluation of Materials Particles from steam sanitized versus irradiated uniforms. Verification of non-shedding papers and cloths

11 Regulatory Perspective

12 Regulatory Summary Novel technology No chapters or specific guidance exists. USP <1223> EP PDA TR 33 Avoid settle plates AND enhanced active air particle unit. Applications for non-compendial roles

13 Annex I & Settle Plates USFDA does not discourage the elimination of settle plates. The EMA requirements for settling plates in Annex I requires the use of 55 and 90 mm settling plates in production areas. There is a large discrepancy between different Agencies EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex I Manufacture of Sterile Medicinal Products, 25 Nov 2008

14 Case Study: Viable and Non Viable Particle Assessment in Manufacturing Clara Hernandez-Robles, Luiz Cerciello, Francisco Morales, Joanny Salvas

15 Background The Manufacturing DS area failed consecutive micro testing for Room Air Viable Count Specification: NMT >200 cfu/ft^3 Initial OOL was environmental monitoring program after returning from year end shutdown. The HVAC was under increased monitoring in Monthly Basis because of the on going construction in adjacent area.

16 Background Several GMP cleaning and sanitization tasks including: Sporocide treatment (fogging with ozone) were performed in the room Additional sampling unsuccessful (3 consecutives days of <200 cfu/cubic foot)

17 Background Other Actions were taken such as : Air duct inspection and cleaning, Air handler inspection and cleaning, Chase cleaning. During the investigation, the room was identified to have negative pressure against the technical shaft and hallway by design for containment

18 Preliminary Results Screening Test Screening (Room Mapping) - mapping the room with 1 minute samples including near HVAC system and chases. Although higher counts were found close to the door, in the chase area and in the return. No specific cause was identified for the micro failure.

19 Preliminary Results Trending System operated overnight 16h at the micro monitoring locations. Sampling Protocol of Multiple Points was performed Significant increase in particles (viable and non viable) starting at 7:30 am, coincides with construction working shift of adjacent areas.

20 IMD-A Counts Overnight Room Sample normal sample point overnight Construction shift start >=0.5 >=5 bio

21 IMD-A Counts Overnight Monitoring in Hallway Hallway outside overnight Construction shift start >=0.5 >=5 bio

22 Overnight sample inside Chase 1 IMD-A Counts Chase Construction shift end Construction shift start >=0.5 >=5 bio 0

23 IMD-A Counts Weekend Trending Weekend monitoring of counts with the construction shift on Saturday, including decrease at lunchtime. Saturday construction shift start Construction shift lunch break Monday Construction shift start >=0.5 >=5 bio

24 Service Panel Access Door: Compressed air loto point Air comes through even when closed Access Door: Purified water Sometimes open during manufacturing process. Air comes through even when closed ~2 opening always open

25 Inter space from chases Both chases have openings to the inter space area above the room ceiling Solution: Create effective barrier between construction area and inter space above room

26 Investigation Conclusions Room Air Viable / Non Viable Count sampling points & chase correlate with construction activity. Room Mapping demonstrated: Air handling units don t appear to have an issue. Cleanest air was always near the air inlet to all rooms. AHU compensate efficiently cleaning air between periods of activity & inactivity Inter spaces (chases) may impact other rooms Micro vs. containment design constraints. Chases are always major point of particles infiltration.

27 Strategic Implementation: Reduction / Elimination of Settle Plates

28 BioPhorum Operations Group BPOG is a global collaboration of commercially active biopharmaceutical drug substance companies The BPOG Fill Finish community member companies include:

29 Why Eliminate Settle Plates? Non-volumetric, passive method No measure of air volume correlation Over represents larger particles Retrospective Information Results 3-5 days later All or none results entire lot is impacted Potential source of contamination Introducing personnel and media into controlled areas

30 Settle Plate Costs How much does a settle plate cost? $1 $5 One large pharma customer estimates each agar plate costs between $80.00 and $ per plate. This is growth promotion to final read. $25 $100

31 Annex I Plate Requirements EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex I Manufacture of Sterile Medicinal Products, 25 Nov 2008

32 Grade D Areas

33 Grade C Areas

34 Grade B Areas

35 Grade B/C/D Observations Data contains transient, non-reproducible events Door openings Personnel entering area All areas have rapid recovery after disturbances 70 seconds to 8 minutes

36 Grade A Areas

37 Grade A Implementation If 1 AFU in 5 min No action If 2 AFU in 5 min Inspect gloves, ports, and area (Annex I) If 3 or more AFU in 5 min Stop manufacturing Segregate material in isolator Full investigation USP <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments

38 Sample Capture Sample capture is required: False positives Viable But Non-Culturable Validation Verification

39 Implementation Gaps Statistical Alert / Action Limits for Grad B/C/D Quality Response How to address AFU limits? Product risk Comparability studies Regulatory Feedback BioPhorum Operations Group Industry Opinion Comfort with settle plates

40 Acknowledgements Joanny Salvas Esther Bellon Clara Roble-Hernandez Esther Bellon Amy McDaniel Steve Hammond Joep Timmermans Jeanne Mateffy

41 Questions?