Environmental monitoring, sterility

The other document that the FDA will probably want to review during the course of the PAI is the validation master plan. It is important to note that at the very least a validation protocol must be in place at the time of the inspection (unless it is a sterile product, then full validation must be completed). The validation master plan should cover the cleaning, environmental monitoring, sterilization (when necessary) process, analytical, and computers. The role of validation in PAI has been reviewed in detail by Nash [5]. 

An anaerobic condition exists if there is need for sterile inert gas to break the vacuum on the chamber and remain in the container after sealing. The use of anaerobic medium (e.g., alternative fluid thioglycolate medium) would be appropriate where the presence of anaerobic organisms has been confirmed in either environmental monitoring or, more likely, during end product sterility testing. 

Where anaerobic organisms have not been detected in the environmental monitoring or sterility testing, lyophilizer process simulation tests should utilize TSB and air. 

The incubation period should be not less than 14 days per procedure. An incubation temperature in the range of 20 to 35°C may be used depending upon information gained from the environmental monitoring (during routine production, sterility testing, and media filling). 

The biochemical profile of the contaminant can then be compared to that of microorganisms obtained from the sterility tests and bioburden and environmental monitoring programs, in order to help identify the potential sources of the contaminant. 

This document contains information related to the liquid aseptic fill operation used in the manufacture of (product name), USP, at ABC Pharmaceutical Industries located at (provide postal address). Additional information to support the liquid aseptic filling validation includes but is not limited to environmental monitoring and controls, as well as product-specific testing such as bioburden and sterility testing. The main subsections are ... 

Media fill failures are investigated in accordance with manufacturing site SOPs. The investigation may include, but is not limited to, a review of the aseptic fill data, review of the environmental monitoring data, review of the component sterilization results, review of all intervention activities, and identification of the contaminants found. Also, additional media fills may be performed to demonstrate that the area and processes are under aseptic control. If the system cannot be shown to be under control, product produced subsequent to the media fill failure on that fill line will be placed under management review for final disposition. 

ABC Pharmaceutical Industries routinely monitors the microbial content of the air, inanimate surfaces, personnel, water systems, and product component bioburden. Microbiological monitoring of these areas generally reflects on the efficiency of cleaning and sanitization procedures and employee practices. Continuous environmental monitoring provides the assurance that product is produced by a controlled process that will maximize the sterility and quality of the manufactured sterile product. 

All microbiological isolation techniques used for the environmental monitoring shall be validated and, in addition, media shall be examined for sterility and for growth promotion as indicated next. 

Environmental monitoring is more critical for products that are asepti-cally processed (intensive monitoring) than for products that are processed and then terminally sterilized (normal monitoring). As manual interventions during operation increase and as the potential for personnel contact with the product increases, the number of sampling points increases. 

Additional tests in response to adverse trends or failures in the ongoing monitoring of the facilities or process, such as (1) continued critical area environmental monitoring results above the action levels or (2) an increased incidence of product sterility tests failures or to evaluate changes to procedures and practices, such as... 

A contaminated container should be examined carefully for any breach in the container system. All positives (from integral containers) should be identified to at least genus and to species whenever possible. The identification of contaminant should be compared to the database of the organisms recently identified. The biochemical profile of the contaminant can then be compared to that of microorganisms obtained from the sterility tests and bioburden and environmental monitoring programs, in order to help identify the potential sources of the contaminant. 

If media-fill contaminant is same as sterility test contaminant increase media-fill vial quantities and routine filling environmental monitoring to identify the source of contamination. Review environmental data obtained during line set up. 

If sterility test contaminant is same as media fill environmental contaminant increase routine environmental monitoring (in the same location) and number of media-fill vials to conform. 

If media-fill environmental contaminant is same as sterility test contaminant and if routine environmental contaminant is same as sterility test contaminant check environmental monitoring methods and techniques closely for problems. Review personnel practices, gowning, sanitation, and sterilization. 

Process validation Inspection of the establishment to determine compliance with cGMP requirements and adherence to application requirements is a Field responsibility. CDER may request data to support validation of sterile processing operations for example, environmental monitoring, equipment validation, sterile fill validation, and associated sterile operations. 

Housekeeping An important component of environmental control are the housekeeping activities utilized to clean the facility external to the controlled environments. Aseptic operations utilize a series of protective environments to protect the sterile field. Controls on the surrounding unclassified areas are an important part of the overall control scheme for sterile manufacturing. These unclassified areas support sterile operations in a variety of ways, and it is important to conduct activities therein that assist in the environmental control. Routine housekeeping, periodic sanitization, and even occasional environmental monitoring may be appropriate to... 

There are items that must be transferred into the aseptic processing area that cannot be treated within a sterilizer/oven. These include portable tanks, electronic equipment, and containers of sterile materials (ready-to-use items, sterile powders, environmental monitoring media, etc.). Air locks, pass-throughs, and similar designs are employed in which the exterior surfaces of the items are disinfected. The disinfection process may be completed by personnel outside and/or inside the aseptic area depending upon the specifics of the design. 

TR 11 Sterilization of Parenterals by Gamma Irradiation, 1988 TR 13 Fundamentals of an Environmental Monitoring Program, 2001 TR 22 Process Simulation Testing for Aseptically Filled Products, 1996 TR 26 Sterilizing Filtration of Liquids, 1998... 

To paraphrase the Hippocratic Oath, the first rule of environmental monitoring should be to do no harm. Sampling in a effort to detect microorganisms should not increase the potential for contamination of sterile materials. 

Installation and certification of laminar air flow areas where sterile air is provide via high-efficiency particulate air (HEPA) filters Environmental monitoring of the facility, equipment, water, and personnel for strict microbiological and particulate control... 

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