Environmental Monitoring in the Cell Processing Laboratory What to do with the data?

Transcription

1 Environmental Monitoring in the Cell Processing Laboratory What to do with the data? Shelly Heimfeld, Ph.D. Fred Hutchinson Cancer Research Center Seattle Cancer Care Alliance ISCT President Somatic Cell Therapy September 26, 2006

2 SCCA/FHCRC Cellular Manufacturing Apheresis Cellular Product Collection Cellular Therapy Laboratory Routine Cellular Processing Minimal Manipulation e.g. RBC Depletion, Cryopreservation, Cell Selection Cellular Processing Facility Cellular Processing under IND Extensive Manipulation e.g. Gene Therapy, Expansion, Activation, Vaccines cgmp cgtp

3 Cellular Therapy Laboratory GTP

4 Cell Processing Facility GMP

5 Facilities Cleaning and Sanitation Facility shall be maintained in a clean, sanitary, and orderly manner. Detailed procedures for cleaning and sanitation, including cleaning schedules, shall be established. Cleaning and sanitation activities shall be documented.

6 Cleaning of CPF Daily cleaning occurs only in suites with active production. Weekly cleaning consists of floor mopping only, using a two bucket method for cleaning. Monthly cleaning involves floors, ceilings, walls, carts, and exteriors of equipment. Cleaner agents are rotated weekly between a low ph and high ph phenolic agent. Quaternary cleaning agent used on door handles and windows. Cleaning is primarily by an outside vendor that has undergone training by CPF personnel and has experience in cleaning of controlled environments.

7 Environmental Control and Monitoring Always Subject to Interpretation Where environmental conditions might have an adverse effect upon the product, the following systems shall be in place to monitor and control: Temperature and Humidity. Ventilation and Air Filtration. Environmental Testing for Organisms.

8 Aspects of an EM Testing Program Sampling for: 1. Non-viable air (particulates) 2. Viable air (microbial) 3. Surface (microbial) 4. Personnel (microbial)

9 Airborne Particulate Classification International Organization for Standardization (ISO) Class Name Particles equal to and larger than 0.5 µm SI U.S. Customary (m3) (ft3) M M M M M3 1, M , M4 10, M4.5 1,000 35,300 1,000 M5 100,000 2,830 M5.5 10, ,000 10,000 M6 1,000,000 28,300 M ,000 3,530, ,000 M7 10,000, ,000 * Adapted from ISO 14644, Clean rooms and controlled environments-part 1: Classification of air cleanliness, and Part 2: Specifications for testing and monitoring.

10 R o o m Minimum Requirement for EM Sites Site Class Cellular Processing Facility Sq. footage Reqd # Sites[1] Nonviable Sites Air Viable Sites Surface Sites (floor) # DE310 Entry 10, Vestibule DE530 Hall 10, Surface Sites (work) DE532 DE534 DE536 Processing 10, Suite 3 BSCs Processing 10, Suite 3 BSCs Processing 10, Suite 2 BSCs DE538 Vestibule 10, DE540 BSL-3 10, BSCs DE544 Exit 10, Vestibule DE546 Anteroom 100, [1] Determined by the following equation: # sample locations = area/square root of classification Square root of 100,000 (class 100,000 or MC) = 316 Square root of 10,000 (class 10,000) = 100

11 CPF EM RODAC Surface Monitoring Sample Locations

12 CTL EM RODAC Surface Monitoring Sample Locations

13 Recommended Testing Frequency (USP) Sampling Area Class 100 or better room designations Frequency of Sampling Each operating shift Supporting areas immediately adjacent to Class 100 (e.g., Class 10,000) Other support areas (Class 100,000) Each operating shift Twice/week Potential product/container contact areas Twice/week Other support areas to aseptic processing areas but non-product contact (Class 100,000 or lower) Once/week Reference: USP 28-NF 23 <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments.

14 Action Limit Recommendations Viable and Non-viable Particulates USP Class CFU per Cubic Meter of Air* CFU per Cubic Foot of Air* CFU per Contact Plate SI U.S. Customary Surfaces Glove Personnel Clothing & Garb M Less than 3 Less than M5.5 10,000 Less than 20 Less than (10 floor) M ,000 Less than 100 Less than (30 floor) *A sufficient volume of air should be sampled to detect excursions above the limits specified, using a Slit-to-Agar Sampler or Equivalent

15 Corrective Action for EM Excursions When action levels for microbial or non-viable particulates are exceeded, documentation review and investigation are required. 1. Investigation includes: A. Review of area maintenance documentation. B. Sanitization documentation. C. Changes in environmental conditions (e.g. temperature). D. Training status of personnel involved. 2. Investigations are conducted to determine root cause.

16 Corrective Action for EM Excursions 3. After investigation, actions taken may include: A. Re-training of personnel. B. Additional EM sampling at increased frequency. C. Additional sanitization. D. Identification of contaminant(s) and possible source. E. Evaluation of current SOPs. F. Additional product testing. 4. Corrective and preventive actions are initiated. 5. All investigations and rationale for course of action are documented and included as part of the overall quality management system. 6. Based on QA review of investigation and testing results A. Acceptability of operations or products processed during that condition may be ascertained.

17 QA Product Impact Assessment How do we connect the EM data to the cells? During investigation, QA determines if there has been a potential impact on product(s): Possible Actions required: Review manufacturing records Increase product sterility testing Repeat sterility testing for product(s) under concern Quarantine products Discard products

18 (1) Type of EM excursion: Scenarios Non-viable Particulates exceed action level: A. Adjacent laboratory support area B. BSC Assume 10 products processed during the time between last measurement and excursion. 5 Allogeneic PBSC infused fresh 1 URD DLI (multiple aliquots cryopreserved) 4 Autologous PBSC cryopreserved What would you do? 1. Notify recipient, attending, risk management, others? 2. Repeat sterility testing for products under concern? 3. Quarantine products? 4. Discard products?

19 (2) Type of EM excursion: Scenarios Viable Particulates exceeded action level: A. Adjacent laboratory support area B. BSC (1 week for first results, another week for ID testing) Assume 50 products processed during the time between last measurement and excursion. 25 Allogeneic PBSC infused fresh 10 Allogeneic DLI cryopreserved 15 Autologous PBSC cryopreserved What would you do? 1. Notify recipient, attending, risk management, others? 2. Repeat sterility testing for products under concern? 3. Quarantine products? 4. Discard products?

20 (3) Type of EM excursion: Scenarios Surfaces Testing exceeded action level: A. Floor B. Work Bench support area C. BSC Assume 50 products processed during the time between last measurement and excursion. What would you do? 20 Allogeneic PBSC infused fresh 10 Allogeneic DLI cryopreserved 15 Autologous PBSC cryopreserved 5 Products under IND, now in CPF for T-cell T cloning 1. Notify recipient, attending, risk management, others? 2. Repeat sterility testing for products under concern? 3. Quarantine products? 4. Discard products?

21 (4) Type of EM excursion: Scenarios Personnel Testing exceeded action level: A. Exterior Clothing B. Gloves Assume 50 products processed during the time between last measurement and excursion. What would you do? 20 Allogeneic PBSC infused fresh 10 Allogeneic DLI cryopreserved 15 Autologous PBSC cryopreserved 5 Products for Phase III registration study 1. Notify recipient, attending, risk management, others? 2. Repeat sterility testing for products under concern? 3. Quarantine products? 4. Discard products?

22 Conclusions? Cell Processing Clinical/Research Support GTP/GMP Regulations

23 References 21 CFR Parts 1271: cgtp for Human Cell, Tissue, and Cellular and Tissue-Based Products ISO 14644: Cleanrooms and controlled environments Part 1: Classification of air cleanliness Part 2: Specifications for testing and monitoring ISO 9001, third edition , Quality Management Systems Requirements. International Organization for Standardization: 7.1 Planning of Product Realization ISO Part 1: Biocontamination Control General Principles ISO Part 3: Biocontamination Control of Surfaces MIL-STD Product Cleanliness Levels and Contamination Control Parental Drug Association (PDA) Technical Report No. 13: Fundamentals of a Microbiological Environmental Monitoring Program USP 28-NF 23. <1116> Microbiological Evaluation of clean rooms and other controlled environments.

24 Acknowledgements Kimberly Boyt Haj Chana Karen Edward Cindy Green Victoria Lake Melodee Smith CPF Manager CTL Manager Consultant Consultant Regulatory Trials Office Apheresis Manager