Aseptic operation

The factors chosen were variations in vessel size, the effect of non-aseptic operation and medium recycle, and variations in recovery and drying procedures. 

Where floor drainage channels are necessary they should be open if possible, shallow and easy to clean. Connections to drains should be outside areas where sensitive products are being manufactured and, where possible, drains should be avoided in areas where aseptic operations are being carried out. If this cannot be avoided, they must be fitted with effective traps, preferably with electrically operated heat-sterilizing devices. 

Regardless of the methods used to obtain a clean air environment, unless the parenteral operator is made completely aware of the limits of laminar flow, uses careful, planned movements, and is wearing proper clothing, he or she can be a source of product contamination. Operator movement within aseptic rooms should be minimized. The rooms must be disinfected regularly and thoroughly before setting up for aseptic operation. 

To demonstrate the control of aseptic operations maintained by well-trained personnel, defined procedures, and appropriately designed equipment and facilities. Media filling in conjunction with comprehensive environmental monitoring will be conducted three times to demonstrate that the aseptic processing of lyophilized powder is functioning as intended. 

Section Val. 1600 describes 11 examples of how to prepare critical qualification and requalification reports related to aseptic operations and provides them as a proof of records to FDA for ANDA and ANDA file submissions. 

Section Val. 2000 describes the training needs of personnel involved in aseptic operations. 

Figure 9.1 Aseptically operated filling and closing lines for bottles and wide-mouth containers made of glass and plastics. (1) one-lane feed transfer (2) in-feed into bottle sterilisation unit (3) bottle sterilisation unit (4) discharge (5) two-lane transport of bottles to filler (6) aseptic 10-up inline filler (7) closing machine (8) discharge for closed bottles (9) fid punch and in-feed (10) aseptic module.

It should be established whether use of terminal sterilization or in-process sterilization with aseptic operation. When terminal sterilization is adapted for medical devices ISO standard fisted in references shall be referred. 

It is easily understood that if the aseptic operation is performed in a separated small space from which personnel have been completely excluded, the necessity for room classification based on particulate and environmental microbiological monitoring requirements may be significantly reduced. In other words, critical operations in an aseptic area should be performed in the smallest space, and intervention by personnel should be minimized by indirect means through the use of protective glove ports and/or half suits. Application of these methods can minimize the chance of contamination. Following are such systems currently in place to reduce the contamination rate in aseptic processing. 

Failure to establish yields or acceptable levels of rejects for both in-process and finished product Failure to conduct stability studies Manufacturing equipment not identified and/or qualified Inadequate training of employees working in aseptic operations Inadequate process change procedures Validation protocols that lack acceptance criteria Incomplete investigations of laboratory failures Failure to follow United States Pharmacopeia (USP) procedures for the bacterial endotoxin test... 

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... 

Personnel proficiency in aseptic operations must be firmly established before they are allowed to conduct critical aseptic process steps. Operators must master a number of relevant skills in order to be declared competent. The usual progression is from classroom training (CGMP, microbiology, sterilization, etc.) to relevant practical exercises (aseptic media transfers, aseptic gowning rehearsals) and ultimately to the core aseptic skills required (aseptic gowning certification, aseptic... 

Cleaning and Preparation. LFCB The LFCB should be allowed to run for at least 30 min before the commencement of aseptic operations. All work-zone accessible surfaces, with the exception of the filter-protective screen, should be cleaned and sanitized by application and recovery of a low-residuing, water-base disinfectant cleanser (household bleach or other hypochlorite solutions should not be used at any time... 

The cleanroom is normally constructed in an existing building or structure as a core unit, surrounded by supporting access and staging anterooms, service chases, and machine rooms necessary to support the aseptic operation, supply working materials, and remove finished products and waste materials without cross-contamination or interference with the critical work stream. 

Medium recycle (item 5) means that organic materials released from Methylophilus can build up in the medium. These are available for the growth of contamirrants. The process caimot be run at low pH to suppress the growth of contaminants as the organism itself requires a pH of about 7.0. Aseptic operating conditions are therefore required. 

To prevent dust from collecting, all ledges, doors and windows should fit flush with walls. Doors should be well fitting to reduce the entry of microorganisms, except where a positive air pressure is maintained. Ideally, all windows in manufacturing areas should serve only to permit light entry and should not be used for ventilation. In areas where aseptic operations are carried out, an adequate air-control system, other than windows, is essential. 

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