Risk-Based Environmental Monitoring Program 2
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Risk-based Environmental Monitoring Program 2 Presented by Ziva Abraham President Microrite, Inc. 5019 New Trier Avenue San Jose, CA 95136 Phone: 408-445-0507 Fax: 408-445-1236 Email: [email protected] www.microrite.com About the Presenter 3 Ziva Abraham is the President and Founder of Microrite, Inc., a California based consulting firm providing consulting and training services to pharmaceuticals, biotechnology, medical devices and in vitro diagnostics in the areas of quality assurance, quality control, microbiology, and validation. Ziva has over 35 years of academic, research, clinical and industrial experience in microbiology, and quality assurance. Ziva has received her Master’s Degree in microbiology with a focus on Mycology and has conducted research on developing microbial Insecticides using entomogenous bacteria and fungi for her Ph.D. degree. Her career also includes founding and managing clinical laboratories for Maccabi Medical in Israel. She has trained personnel from various industries in microbiology techniques and methods. She uses her extensive experience to teach why assessing risk of microbial contamination should be in the forefront of any company that has products for human/veterinary use. Her experience in clinical laboratories has provided her with the framework to understand the effects of microbial contamination in products from a patient safety perspective. Main Message 4 Environmental Monitoring is not an isolated activity; to develop a risk based environmental monitoring program, risk across the lifecycle of the facility, process, personnel and operations must be assessed utilizing pertinent knowledge! Quality Risk Management (QRM): concept: • Risk Management is NOT an Exercise!!! • Real-world risk must be considered and addressed • Risk Management should be: o Pragmatic o Scientifically Sound o Utilize Current Technology and Current Best Practices Learn from experience and from the mistakes of others! No single SME can be an expert in all aspects of Risk Assessment! Current Regulatory Expectations 5 GMP Annex 1 Manufacture of Sterile Medicinal Products: 2008, Drafts 2017 and 2020 FDA FDA: Guidance for Industry Sterile Drug Products Produced by Aseptic Processing -Current Good Manufacturing Practice:2004 Why a Risk Based Environmental Monitoring Program? 6 These risk assessments should be re-evaluated at defined intervals in order to confirm the effectiveness of the site’s environmental monitoring program, and they should be considered in the overall context of the trend analysis and the contamination control strategy for the site. • Facilities age • Barrier and cleanroom design and integration may not be optimal • Leaks in the room occur • Membranes tear • Filters get loaded • Gowns wear • Personnel leave Risk Assessment?? 7 FDA 483 Observation 8 Poor Aseptic Behavior 0ur investigator observed multiple poor aseptic practices during the set-up and filling of (b)(4) batch (b)(4). For example, during the aseptic filling of vials, an operator used restricted access barrier system (RABS) (b)(4) to remove a jammed stopper by reaching over exposed sterile stoppers in the stopper bowl. The RABS (b)(4) disrupted the unidirectional airflow over the stopper bowl, creating a risk for microbial contamination. After the operator removed the jammed stopper, the filling line was restarted, but the affected stoppers were not cleared. FDA 483 Observation 9 Our inspection also revealed poor aseptic processing operation behaviors. In response to this letter, provide: Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight during aseptic processing and other operations. Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide a risk assessment that covers all human interactions with the ISO 5 area, equipment placement and ergonomics, air quality in the ISO 5 area and surrounding room, facility layout, personnel flow, and material flow. Also include a detailed CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment. Understanding Contamination Sources and Risk 10 Without knowing the risk, risk cannot be monitored! • Using rating scales that are neither specific nor appropriate to a given situation • Perceived risk instead of understanding real-world risk • Not acknowledging uncertainty or missing important information • Neglecting to keep risk assessments current (reflecting current regulatory expectations) • Performing paper-based risk assessments without understanding systems, workflows and all possible sources of contamination • More about the presentation rather than the risk • One person performs the entire risk assessment? FDA 483 Observation 11 Aseptic garments worn in the filling area were also non-integral. “We observed 7 of (b)(4) sterile gowns with tears or holes; 8 of (b)(4) had loose threads. We observed 2 of (b)(4) sterile hoods with tears or holes; 12 of (b)(4) had loose threads. We observed 8 of (b)(4) sterile booties with tears or holes; 11 of (b)(4) had loose threads.” Procedure "Handling of Aseptic Area Garments" required production personnel to examine the garments for tears, holes, and loose threads, but our investigator found that these checks were not being performed. https://www.microrite.com/wp-content/uploads/2020/01/MICROBIOLOGICAL-FAILURES-DUE-TO-HUMAN- BORNE-CONTAMINATION-CLEANROOM-GARMENT-AND-MANAGEMENT-GAPS-2020v1.pdf Personnel 12 GMP/EU Annex 1-2020 Draft 4.7 There should be systems in place for disqualification of personnel from entry into cleanrooms based on aspects including ongoing assessment and/or identification of an adverse trend from the personnel monitoring program and/or after participation in a failed APS. Once disqualified, retraining and requalification should be completed before permitting the operator to have any further involvement in aseptic practices. 4:15 Clean area clothing should be cleaned in a dedicated laundry facility using a qualified process ensuring that the clothing is not damaged and/or contaminated by fibres and particles during the laundry process. Inappropriate handling and use of clothing will damage fibres and may increase the risk of shedding of particles. After washing and before packing, garments should be visually inspected for damage. The garment management processes should be evaluated and determined as part of the garment qualification program. Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided. Airflow visualisation studies should be considered as part of the operator’s training programme. How gowns affect EM results 13 • Gowns not correctly sized • Compromised gowns, such as fraying cuffs, open seams, etc. • No control on quality • No control over the number of laundries including detergents • Inappropriate storage of gowns • Inadequate gowning procedures Premises 14 GMP/EU Annex 1-2020 Draft 5.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, entry to which should be through changing rooms that act as airlocks for personnel and airlocks for equipment and materials. Cleanrooms should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and capable of evaluating the state of environmental conditions for cleanrooms, airlocks and pass-throughs used for material and equipment transfer. Premises 15 GMP/EU Annex 1-2020 Draft 5.12 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contaminant to the higher-grade areas. Where air movement is shown to be a risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns should be retained. The outcome of the air visualisation studies should be considered when establishing the facility's environmental monitoring program. Premises 16 GMP/EU Annex 1-2020 Draft 5.4 Grade B area: For aseptic preparation and filling, this is the background cleanroom for the Grade A zone (where it is not an isolator). When transfer holes are used to transfer filled, closed products to an adjacent cleanrooms of a lower grade, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the Grade B. Pressure differentials should be continuously monitored. Cleanrooms of lower grade than Grade B can be considered where isolator technology is used. Poor RABS Design 17 Aseptic Filling Operation: “Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and