Environmental Monitoring: How Much is Enough? A. Lynn O Donnell, PhD

Transcription

1 Environmental Monitoring: How Much is Enough? A US U.S. Perspective Lynn O Donnell, PhD Director Cell Therapy Laboratory

2 What is required? FDA 21 CFR Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products Sec Facilities. (a) General. Any facility used in the manufacture of HCT/Ps must be of suitable size, construction, and location to prevent contamination of HCT/Ps and to ensure orderly handling of HCT/Ps without mixups. You must maintain the facility in a good state of repair. You must provide lighting, ventilation, plumbing, drainage, and access to sinks and toilets that are adequate to prevent the introduction, transmission, or spread of communicable disease. (b) Facility cleaning and sanitation. (1) You must maintain any facility used in the manufacture of HCT/Ps in a clean, sanitary, and orderly manner, to prevent the introduction, transmission, or spread of communicable disease.

3 What is required? FDA 21 CFR Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products Sec Facilities. (c) Operations. You must divide a facility used in the manufacture of HCT/Ps into separate or defined areas of adequate size for each operation that takes place in the facility, or you must establish and maintain other control systems to prevent improper labeling, mix-ups, contamination, cross-contamination, and accidental exposure of HCT/Ps to communicable disease agents.

4 What is required? FDA 21 CFR Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products Sec Environmental control and monitoring. (a) Environmental control. Where environmental conditions could reasonably be expected to cause contamination or cross- contamination of HCT/Ps or equipment, or accidental exposure of HCT/Ps to communicable disease agents, you must adequately control environmental conditions. Where appropriate, you must provide for the following control activities or systems: (1) Temperature and humidity controls; (2) Ventilation and air filtration; (3) Cleaning and disinfecting of rooms and equipment to ensure aseptic processing operations; o and (4) Maintenance of equipment used to control conditions necessary for aseptic processing operations.

5 What is required? FDA 21 CFR Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products Sec Environmental control and monitoring. (c) Environmental monitoring. You must monitor environmental conditions where environmental conditions could reasonably be expected to cause contamination or cross-contamination of HCT/Ps or equipment, or accidental exposure of HCT/Ps to communicable disease agents. Where appropriate, you must provide environmental monitoring for microorganisms.

6 The James Cell Therapy Lab Hospital-based processing laboratory Rapid growth, 25%-50% last year 500 products processed per year, 400 other procedures (infusions, research samples, cell sorts for chimerism) i Staff size currently 4 technologists, 1 Manager, shared Quality Manager

7 The James Cell Therapy Lab Mostly HPC, Apheresis and HPC, Marrow with minimal manipulation CD34 enrichments on IDE and IND Manipulated products manufactured by companies (DCs, MSCs) store, thaw, wash only Pancreatic islets under IND

8 The James Cell Therapy Lab HOOD ASEPTIC PROCESSING AREA GENERAL PROCESSING AREA C R F TESTING AREA LABEL ING AREA OFFICE STORAGE AREA OFFICE HOOD 500 sq ft, semi-divided, U-shape Typical hospital lab facility

9 Environmental Control General - Existing Key card added to existing key access Accoustic ceiling tiles Supply storage loosely controlled wherever space could be found HOOD ASEPTIC PROCESSING AREA HOO D GENERAL PROCESSING AREA STORAGE AREA TESTING AREA LABE LING AREA OFFICE OFFICE General - Improvements Removed master key access only Security has master Installed vinyl clean room ceiling tiles No cardboard boxes beyond the blue areas

10 Environmental Control HVAC - Existing HOOD GENERAL LABE 100% fresh air PROCESSING TESTING LING ASEPTIC AREA AREA AREA PROCESSING HEPA filtered at air AREA handler (entire hospital) STORAGE AREA Pneumatic controls Facilities checks & changes filters as needed HVAC - Improvements Set to positive pressure and air exchanges at 10-15/hr Digital controls & new mixing box better temp control Facilities contracts out quarterly measurement of air exchanges & positive pressure HOO D OFFICE OFFICE

11 Ready to Begin Environmental Monitoring Program but How? Information for clean rooms for pharmaceutical manufacturing Federal Standard 209E - Airborne Particulate Cleanliness Classes in Clean Rooms and Clean Zones Long been the only classification definitions Per cubic foot Class 100, Class 10,000 International Organization for Standardization produced 10 standards documents related to clean rooms ISO Switch to metric per cubic meter Class 5, Class 7 3 new classes 2 cleaner and 1 dirtier

12 Compare Classifications for Particles > 0.5 μmm FS 209E ISO Metric (per ft 3 ) (per m 3 ) (per m 3 ) Class 100 Class 1000 Class 10,000 Class 100, ISO 5 3,530 M ISO 6 35,300 M4.5 10,000 ISO 7 353,000 M ,000 ISO 8 3,530,000 M6.5

13 Other Sources United States Pharmacopeia Chapter <797> Pharmaceutical Compounding Sterile Preparations Processing CT products in functionally closed systems is much like sterile compounding by pharmacies Fairly specific guidelines for facility design, environmental controls, ISO class, operations and environmental monitoring

14 Environmental Monitoring Getting Started t Purchased particle counter for nonviable particles APC Plus from Biotest Purchased air sampling device for viable particles RCS Plus from Biotest impaction onto agar strip

15 Environmental Monitoring Getting Started t Wrote validation plan to gather data Weekly nonviable particles > 0.5 μm BSCs at rest (static) and during use (dynamic) Facility in processing, storage and testing areas 1-2 minute sampling time 2-4 times per month viable particles BSCs at rest (static) and during use (dynamic) Facility in processing, storage and testing areas 1 m 3 (= 1000L) sampled Incubate strips at C for 3 days

16 Environmental Monitoring Getting Started t Gathered validation data May 2006 April 2007 Evaluated validation data quarterly Graphed particle counts vs. time Look for trends, exceeds classification levels Graphed particle count distribution Look for normal or negative exponential distribution Alert and action levels are set differently depending on the distribution

17 Environmental Monitoring Validation Results Weekly Particle Counts Support Areas Processing Areas 1,000,000 Weekly Particle Counts - CTL NON-Processing Areas ISO Class 5 (100) ISO Class 6 (1000) ISO Class 7 (10,000) Labeling Area Storage Area 1,000,000 Weekly Particle Counts - CTL Processing Areas ISO Class 5 (100) ISO Class 6 (1000) ISO Class 7 (10,000) Processing Area Aseptic Processing Area 100,000 10,000 1, ,000 10,000 1,000 Nonviable Particles (>0.5um/m3) Particles (>0.5um/m3) /29/2006 5/6/2006 5/13/2006 5/20/2006 5/27/2006 6/3/2006 6/10/2006 6/17/2006 6/24/2006 7/1/2006 7/8/2006 7/15/2006 7/22/2006 7/29/2006 8/5/2006 8/12/2006 8/19/2006 8/26/2006 9/2/2006 9/9/2006 9/16/2006 9/23/2006 9/30/ /7/ /14/ /21/ /28/ /4/ /11/ /18/ /25/ /2/ /9/ /16/ /23/ /30/2006 1/6/2007 1/13/2007 1/20/2007 1/27/2007 2/3/2007 2/10/2007 2/17/2007 2/24/2007 3/3/2007 3/10/2007 3/17/2007 3/24/2007 3/31/2007 4/7/2007 4/14/2007 4/21/2007 4/28/2007 4/29/2006 5/6/2006 5/13/2006 5/20/2006 5/27/2006 6/3/2006 6/10/2006 6/17/2006 6/24/2006 7/1/2006 7/8/2006 7/15/2006 7/22/2006 7/29/2006 8/5/2006 8/12/2006 8/19/2006 8/26/2006 9/2/2006 9/9/2006 9/16/2006 9/23/2006 9/30/ /7/ /14/ /21/ /28/ /4/ /11/ /18/ /25/ /2/ /9/ /16/ /23/ /30/2006 1/6/2007 1/13/2007 1/20/2007 1/27/2007 2/3/2007 2/10/2007 2/17/2007 2/24/2007 3/3/2007 3/10/2007 3/17/2007 3/24/2007 3/31/2007 4/7/2007 4/14/2007 4/21/2007 4/28/2007 Nonviable Date Date Mean=37,475, Max=221,000 Mean=23,700, Max=159,000 NEVER exceeded ISO 7 (Cl 10,000) 000)

18 Environmental Monitoring Validation Results Set alert and action limits - distribution of data points matters If Normal Distribution Alert Level = mean + 2SD Action Level = mean + 3SD If Negative Exponential Distribution Alert Level = mean x 3.0 Action Level = mean x 4.6 Ref. Booth, A. Environmental Monitoring Practices and Regulations for the Sterile Manufacturer.

19 Environmental Monitoring Validation i Results Processing Areas Nonviable Particles Viable Particles Frequency to to to to to Particles / m3 Frequency to to 8 8 to to to 20.8 CFU / m3 Negative Exponential closer to Normal BSCs both viable & nonviable VERY low counts - Negative Exponential

20 Alert & Action Limits NONVIABLE PARTICLES / m 3 Area Alert Action Processing Areas > 71,000 > 109,000 BSC > 1000 > 3000 VIABLE PARTICLES - CFU/ m 3 Area Alert Action Processing Areas > 18 > 22 BSC > 1 > 2

21 Alert & Action Limits Action if Exceeded If between Alert and Action Limit Repeat count if repeat is below alert done If repeat is between alert & action repeat daily x3, notify QA If repeat is above action notify QA If over Action Limit Repeat daily x3, notify QA If ALL repeats are below alert done If ANY repeats are between alert & action notify QA If ANY repeats are above action notify QA hood out of service

22 Continuing EM Program Weekly Particle Counts - CTL Processing Areas Processing Areas ISO Class 5 (100) ISO Class 6 (1000) ISO Class 7 (10,000) 1,000, ,000 10,000 1, Nonviable Particles (>0.5um/m3) 10/1/ /8/ /15/ /22/ /29/ /5/ /12/ /19/ /26/ /3/ /10/ /17/ /24/ /31/2007 1/7/2008 1/14/2008 1/21/2008 1/28/2008 2/4/2008 2/11/2008 2/18/2008 2/25/2008 3/3/2008 3/10/2008 3/17/2008 3/24/2008 3/31/2008 4/7/2008 4/14/2008 4/21/2008 4/28/2008 5/5/2008 5/12/2008 5/19/2008 5/26/2008 6/2/2008 6/9/2008 6/16/2008 6/23/2008 6/30/2008 7/7/2008 7/14/2008 7/21/2008 7/28/2008 8/4/2008 8/11/2008 8/18/2008 8/25/2008 9/1/2008 9/8/2008 9/15/2008 9/22/2008 9/29/ /6/ /13/2008 Date

23 Continuing EM Program Weekly Particle Counts - CTL Biological Safety Cabinets (hoods) ISO Class 5 (100) ISO Class 6 (1000) ISO Class 7 (10,000) Hood 1 Hood 2 1,000, ,000 10,000 1, Repeat count 8000, Hood out of service, call repair Motor failing, replaced 10/1/ /8/ /15/ /22/ /29/ /5/ /12/ /19/ /26/ /3/ /10/ /17/ /24/ /31/2007 1/7/2008 1/14/2008 1/21/2008 1/28/2008 2/4/2008 2/11/2008 2/18/2008 2/25/2008 3/3/2008 3/10/2008 3/17/2008 3/24/2008 3/31/2008 4/7/2008 4/14/2008 4/21/2008 4/28/2008 5/5/2008 5/12/2008 5/19/2008 5/26/2008 6/2/2008 6/9/2008 6/16/2008 6/23/2008 6/30/2008 7/7/2008 7/14/2008 7/21/2008 7/28/2008 8/4/2008 8/11/2008 8/18/2008 8/25/2008 9/1/2008 9/8/2008 9/15/2008 9/22/2008 9/29/ /6/ /13/2008 Nonviable Particles (>0.5um/m3) Date

24 CONCLUSIONS A robust EM program is capable of detecting failing environmental control Our EM program was not terribly challenging g to establish It takes time to get sufficient data points If you don t have alert and action limits set, what s the point? We have not done surface monitoring except for in-process for islet isolations