Aseptic filling, validation

Aseptic Filling Validation (Media Fill Studies)... 

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 ... 

ASEPTIC FILLING VALIDATION (MEDIA FILL STUDIES)... 

Aseptic filling validation (media fill studies) Cross-contamination control Computerized pharmaceutical system Quality assurance/control laboratory validation... 

Aseptic fill processes are validated by simulating production conditions and using a bacterial culture medium as the product. This process simulation test is commonly referred to as a media fill. ... 

Table 10 provides a list of considerations for ensuring that every aseptic process is appropriately simulated during a media fill validation exercise. 

The environment of an aseptic filling operation must be monitored and controlled. Environmental control begins with valid cleaning and sanitization procedures, then proceeds with adequacy of certified HEPA filtration and clean room procedures by personnel within the clean room, and is verified by environmental monitoring techniques. Such techniques include nonviable particulate... 

Validation of Aseptic Filling for Solution Drug Products, technical monograph no. 2. Philadelphia Parenteral Drug Association, pp. 16-21 (1980). 

While blending times and tablet press parameters may not be fully established for early phase clinical supply manufacturing of solid oral dosages, those variables have a much lower potential to directly affect product safety than sterility, endotoxin contamination, or objectionable types and levels of particulates do for sterile, parenteral clinical supplies. Because clinical supplies can be incompletely characterized, and are usually given to patients already in weakened conditions, those processes and their related validation data necessary to guarantee patient and product safety (e.g., sterilization and aseptic fill) are expected to be in place as early as Phase I clinical supply manufacture. ... 

If sterile product aseptic fill/Terminal sterilization Filter validation (if aseptic fill)... 

Alert and action levels for each parameter in each area or critical utility will be established based on the results from validation testing, compendia requirements, and cGMPs. Area or room limits will be based on the environmental data collected during the validation of the aseptic filling process validation. Specific action plans will be developed for addressing excursions beyond alert and action limits for each area or utility. 

For example, a company which experienced a customer complaint involving a large glass fragment in an aseptically filled powder vial introduced procedural preventive measures but concluded that the issue required automated vision inspection equipment. Once the corrective equipment was identified, a validation master plan detailed the key qualification elements for hardware, software, defect detection system, infeed/outfeed links, but also the specification requirements of the component and component quality, e.g ... 

Simulation trials (media fills) do not validate SALs for asepiieally filled products. The frequently encountered regulatory requirement for aseptic filling processes to be validated by simulation versus a standard of no more than 1 contaminated item in 1,000 items is not intended to imply that an SAL of 10 is satisfactory for these products. The SAL is a complex function of contamination rate and probability of survival the simulation trial measures only the first of these factors. SALs for aseptically filled products are in all likelihood much better than 10, only they are nonmeasureabie, and there is no basis or generally accepted theory to support extrapolation. 

Sterilization can be achieved by moist or dry heat, by ethylene oxide (or other suitable gaseous sterilizing agent), by filtration with subsequent aseptic filling of sterile final containers, or by irradiation with ionizing radiation (but not with ultraviolet radiation unless the process is thoroughly validated). Each method has its particular applications and limitations. Where possible and practicable, heat sterilization is the method of choice. 

Simulation process trials are used mainly to validate the aseptic filling of parenteral products that cannot be terminally sterilized. 

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