HVAC and Risk Management RACI Meeting 7 th December Agenda. Design. Project Management. Context. Qualification. Construction

Transcription

1 HVAC and Risk Management RACI Meeting 7 th December 2011 Dr Stephen Firmer Asia Pacific Consultants Pty Ltd Agenda Context Project Management Design Construction Qualification Routine Control /Potential Audit Questions 2 1

2 Context Other people can discuss tools DrS Firmer RACI Meeting 7th Dec Context GMP Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively. 4 2

3 Project Management Some of the Generic Risks for a Project Technology Potential for design flaws Planning/Scheduling Lead time estimates Organizational resources Economic Budget, cost control Scope Scope creep Procurement Capacity at Vendors etc Commissioning and Startup Timing, interface with any ongoing operations Health Safety and Environment Site accidents 5 Wrong Technology? Slide 6 3

4 Project Management Some of the Generic Risks for a Project Technology Potential for design flaws Planning/Scheduling Lead time estimates Organizational resources Economic Budget, cost control Scope Scope creep Procurement Capacity at Vendors etc Commissioning and Startup Timing, interface with any ongoing operations Health Safety and Environment Site accidents 7 HVAC Design General considerations Flow of material and personnel Minimizing contamination/ sources Open versus closed equipment Clean rooms versus Isolator technologies Dedicated or Segregated facilities / equipment Process requirements etc Detail What if analysis in design of control system 8 4

5 As Built At Rest 9 In Operation 10 5

6 HVAC Design Risk Potential areas for impact on Critical Process Parameters (CPP) Temperature Relative Humidity Particle Count at rest Total Particle Count in use Clean up time (in use to at rest) HEPA performance (capture of contaminants) Air change rates/airflow volumes Pressure differentials Turbulent vs Unidirectional airflow Microbial viable particles (airborne or surfaces) 11 HVAC Design Risk Potential modes of failure Airflow failure Filter Failure Failure of Temperature Control Failure of Humidity Control Failure of different AHUs or parts of the system resulting in imbalances 12 6

7 Typical OSD HVAC 13 Construction Making sure that what gets built is what is on the drawing 14 7

8 Dr S Firmer Dr S Firmer Pictures RACI Meeting 7th Dec 2011 Pictures RACI Meeting 7th Dec

9 Qualification For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualified may include: Temperature Relative Humidity Supply air quantities for all diffusers Return air or exhaust air quantities Room air change rates pressures (pressure differentials) airflow patterns particle counts clean-up rates Unidirectional flow velocities Containment system velocities HEPA filter penetration tests Microbiological air and surface counts where appropriate Operation of de-dusting (vacuum systems) Warning/alarm systems (where applicable) 17 Routine Control Potential audit questions How do you prevent contamination by air? How did you decide on the points to be included for qualification/requalification? How do you decide if requalification of the HVAC system is necessary (change control and unplanned maintenance)? What alarms do you consider critical and how do you challenge them? How do you assess system deviations? 18 9

10 FDA Warning letters WL: , November 1, 2010 (India) b. Your investigation into an incident involving IV bag filling rooms and Laminar Air Flow (LAFs) losing positive pressure is inadequate. For example, During the production of the bag filling room and LAFs -intended to provide a constant flow of clean air out of the work area to prevent potentially contaminated air from entering -lost positive pressure.. your firm rejected only the bags filled after 9:30 am until the line was stopped, despite the fact that. the last acceptable positive pressure was at 9:21 am. The deviation report.adequate rationale for not rejecting all the bags at risk. Specifically the reason for not rejecting the bags filled after 9:21 am was because the microbial environmental monitoring results were within acceptable limits. This approach, however, is unacceptable because the loss in pressure may also have affected the accuracy or reliability of the environmental monitoring results; there is, thus, no assurance that all bags filled after 9:21 am were unaffected by the loss of positive pressure,. Slide 19 FDA Warning letters WL: , June 21, 2011(India) 2. Your firm has not established or followed appropriate written proceduresdesigned to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R (b)]... b. The technician performing the air sampling held the probe close to the HEPA filter facerather than. as specified in section 4.5 of your written procedure SOP/QC/049. During the inspection, the investigators were provided with retraining records for technicians performing active air sampling. Your responses and corrective actions.. failed to indicate the disposition of exhibit batches that were manufactured during the time when personnel and air sampling monitoring was inadequate. Provide information on the disposition of these batches. Slide 20 10

11 FDA Warning letters WL: , May 12, 2010 (Venezuela) Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R (c)]. For example, a) Your firm lacked an adequate assessment of the crosscontamination risksposed by the manufacture of several potentially hazardous compounds... Deficiencies were observed in the shared manufacturing areas where you manufacture potentially hazardous compounds and sterile ophthalmic drug products. You should ensure that a documented justification and a welldesigned contamination prevention strategy has been put in place to minimize the possibility of contamination. FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination.. Slide 21 FDA Warning letters WL: , May 12, 2010 (Venezuela) continued continued b) There was no documentary evidence of in-situ air pattern analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Please note that proper design and control prevents turbulence and stagnant air in the critical area... c) You do not have a procedure or documentation for monitoring differential pressure within the aseptic processing areas... Pressure differentials between cleanrooms should be monitored continuously throughout each shift and frequently recorded. All alarms should be documented and deviations from established limits should be investigated. Slide 22 11

12 FDA Warning letters WL: , October 29, 2010 (UK) Your firm has not established separate or defined areas or such other control systems to prevent contamination during aseptic processing [21 C.F.R (c)]. For example, a. There is no documentary evidence of in-situ air pattern analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Your firm failed to demonstrate that the appropriate design and controls are in place to prevent turbulence and stagnant air in the critical area. It is essential that you evaluate airflow patterns for turbulence that can act as a channel for air contamination. The studies should be well documented with written conclusions, and should include an evaluation of the impact of aseptic manipulations (e.g., interventions) and the equipment design. b. Your aseptic processing control systems and operations do not provide assurance that the production rooms and equipment maintain aseptic conditions. Additionally, your environmental monitoring practices do not include adequate routine examination of the facilities and equipment to ensure that possible contaminants can be detected. Slide 23 FDA Warning letters WL: , March 26, 2010 (France) During the filling of validation batches., you obtained OOL results for the non-viable particle (NVP) count of 0.5 μm and 5.0 μm particles, but did not adequately investigate these results. In batch. the monitoring data for non-viable particles reported a maximum value of 10,319 particles. This result was obtained in a critical area class 100 (ISO 5) where the recommended limit for 0.5 μm particles is 3250/m3 particles. You failed to investigate these NVP excursions and determine the impact on product quality or its possible relation to the higher particulate content observed... During the inspection, your firm provided the investigator a copy of procedure /1 NVP Monitoring. This procedure was made effective on June 18, 2009, approximately seven months after you manufactured the validation batches. Slide 24 12

13 FDA Warning letters WL: , February 9, 2011 (Germany) 2. Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R (c)]. For example, a) The airflow velocity inside critical areas of the aseptic processing operationsof was found unacceptable by FDA. The documentary evidence of in-situ air pattern analysis (e.g., smoke studies) reviewed during the inspection confirmed this condition. With respect to aseptic processing in critical areas, you should be able to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Please note that proper design and control prevents turbulence and stagnant air in the critical areas. It is crucial that airflow patterns are evaluated for turbulence that can act as a channel for contamination, and that any deficient conditions are addressed. Slide 25 FDA Warning letters WL: , January 31, 2011 (Israel) 2. Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during drug manufacturing [21 C.F.R (c)]. For example, your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potentially hazardous compounds. Your facility contains shared manufacturing areas where you produce potentially hazardous compounds in multi-product equipment that are high powder generating operations, including. Your firm should ensure that a documented justification and well-designed contamination prevention strategy is in place to minimize the possibility of contamination. To achieve proper product protection,. We recognize that you are in the process of developing a risk management program for control of cross-contamination of the products produced at the..(osd) plant. However, you did not submit. We also recognize your commitment to finish the risk assessment.. Please provide us with any update on your timeline, and the identification of resources allocated to address this issue. Please also include in your risk analysis, procedures and data addressing the following potential routes for cross-contamination: mix-up, retention, mechanical transfer, and airborne transfer. Slide 26 13

14 Summary HVAC and Risk Management No one way to do things It all depends on: Type of products and materials Product range Campaign sizes Cleaning procedures Facility Design, age, changes Monitoring results (OOLs) etc 27 References ICH Q9 Briefing Pack 2006 WHO Technical Report Series, No. 937, 2006 Annex 2 Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms ISPE Good Practice Guide. Heating, Ventilation and Air Conditioning (HVAC), Tampa, Fl, International Society for Pharmaceutical Engineering, ISPE Baseline pharmaceutical engineering guides, Volume 2. Oral solid dosage forms, 1st ed. Tampa, Fl, International Society for Pharmaceutical Engineering, PICS Aide Memoire document PI September 2007 Inspection of Utilities Brett Schroeder et al, RiskManagement A Key Requirement for Project Success, Pharmaceutical Engineering, Vol 31 No 1, 2011 FDA website

15 Thank You Slide 29 15