In order to routinely monitor particulates and micro-organisms in critical areas of a pharmaceutical manufacturing plant, more particularly in the aseptic processing areas, the environmental monitoring (EM) program has been designed, which comprises of viable and non-viable monitoring elements.
Viable or microbiological monitoring involves routine monitoring of the manufacturing environment for the presence of micro-organisms. Non-viable particulate monitoring measures the airborne particle count and provides information on the ongoing maintenance of the clean room air classification.
The methods used for microbiological monitoring include passive air sampling (settle plates), active air sampling (air sampler), surface sampling (contact plates and swabs) and personal sampling (finger plates/plates of gowns). The purpose of the microbiological environmental monitoring is to provide information on microbiological quality of the environment and to identify any potential contamination hazards. Following data analysis and trending, this information can be used to determine the microbial flora of the environment and to set action and alert limits based on historical data.
The implementation of an effective environmental monitoring program should involve a well-defined and documented sampling plan and associated standard operating procedure (SOP). The SOP should be periodically reviewed and revised if necessary. The key factors to be considered and documented within the environmental monitoring SOP should include sample locations, monitoring frequency, sampling technique, timing (during operation or at rest), action and alert limits and investigative and corrective actions to be taken when limits are exceeded.
When selecting sampling locations for an environmental programme, consideration should be given to the design of the area and to the process. According to the FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing-cGMP, Section A.11, monitoring locations that present the highest potential contamination risk to the product should be included in the monitoring programme.
Monitoring locations should be selected by assessing the critical activities taking place and the flow of personnel in the processing area to determine the most potentially high-risk contamination locations. Until recently, when establishing a microbiological monitoring programme, sample locations were often randomly selected using the grid approach for non-viable particulates as outlined in ISO 14644 series, clean rooms and associated controlled environments.
As per Clean room Management in Pharmaceuticals and Healthcare, p4233, this method involves applying a grid over the clean room plans and selecting sample sites at equal distances in each zone. This method of selection is inherently random and does not involve identifying locations which pose the greatest microbiological risk to the product.
Risk Assessment Tools
The most commonly used risk assessment tools to identify monitoring locations are Hazard Analysis Critical Control Points (HACCP) and Failure Mode Effect Analysis (FMEA) techniques. HACCP analysis involves the identification of critical control points in a process and the determination of methods to prevent and control the occurrence of hazards. As per ICH Q9 and Pharming Reviews No. 1 Current Perspectives on Environmental Monitoring (May 2010), Chapter 96, HACCP analysis typically involves a seven step process such as conducting a hazard analysis to identify sources of contamination, determining Critical Control Points (CCPs), establishing critical levels, setting up systems to monitor CCPs, Taking corrective actions when critical action limit deviations occur, having a record keeping system in place and establishing procedures to verify HACCP system is working correctly.
When using HACCP analysis to determine the sampling locations in an environmental monitoring programme, a thorough knowledge of the process and area is required. This activity should be conducted by a cross-functional team comprising representatives from operations, technical services, and quality control. All sources of contamination associated with the process and area should be listed in the hazard analysis stage with the aid of process/work flow diagrams. Potential sources of contamination include movement of personnel, air, entry points (areas within and around doors/airlocks), surfaces and equipment. These sources should be assessed and appropriately ranked depending on the severity and effect of the contamination hazard. FMEA may be useful as a hazard analysis tool at this stage also. FMEA involves the evaluation of potential failure modes for processes within a system of classification by severity or determination of the failure effects on the system.
The next step involves deciding which contamination sources need to be controlled and the level of control required. Critical levels and the most appropriate sampling methods to monitor the contamination hazard or their control should then be determined. The environmental monitoring program should be established with “alert” and “action” limits and determination of appropriate corrective actions when deviations occur. The effectiveness of the environmental monitoring program should be monitored by trending of resultant data and reassessment of hazards when necessary. The HACCP method should be fully documented in detail the steps and justify the rationale taken to select the monitoring locations. Key to the success of this activity is ensuring that a multi-disciplinary team is involved in the process with ‘buy in’ from the senior management team.
Using a risk based approach when establishing an environmental monitoring program drives a continual review of trends and a periodic re-assessment of the programme. This will contribute greatly to demonstrating control of the manufacturing environment and ensure that the EM program meets with regulatory requirements and expectations.
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