It is recognized that aseptic processes play an important role in rendering sterile formulations which cannot be terminally sterilized. However, terminal sterilization, in particular using moist heat processes, is considered to be the method of choice in the manufacture of sterile products due to the enhanced sterility assurance which it affords. Manufacturers who choose to manufacture a sterile product without terminal sterilization must be prepared to justify this decision by demonstrating that the product cannot be terminally sterilized, even under less severe autoclave cycles tailored to the bioburden of the batch.

The two most common pharmaceutical applications of aseptic processing methods are (a) the filling of liquid products following sterilization by filtration and (b) the filling of previously sterilized bulk powder products. It is assumed that, throughout, manufacturing and control operations are conducted in accordance with the principles of Good Manufacturing Practice, both in general and in specific reference to Sterile Products manufacture.

Installation Qualification, that is demonstrating and certifying that a piece of equipment is properly installed, is provided with all necessary services, subsidiary equipment and instruments, and is capable of performing in accordance with its basic design parameters.

Operational Qualification, consists of demonstrating that the equipment will perform consistently, and within pre-defined limits, as specified and installed.

Protocol development
Each stage in the validation of the overall process should proceed in accordance with a pre-established and formally approved, detailed, written protocol, or series of related protocols. Prior to the commencement of the studies, written change control procedures should be established, which will prevent unauthorized changes to either the process itself, or to the study protocol, and restrict change during any stage of the study until all relevant data are evaluated.

Protocols should have a Title, Date and a unique Identification or Reference Number. They should be formally authorized/approved by person(s) with the competence and authority to do so. It should specify the objectives and scope of the study. Like, a clear and precise definition of the process, equipment, system or sub-system which is to be the subject of the study, with details of performance characteristics.
- Installation and qualification requirements for new equipment.
- Any up-grading requirements for existing equipment, with justification for the change(s) and a statement of qualification requirements.
- Detailed, step-wise statement of actions to be taken in performing the study (or studies).
- Assignment of responsibility for performing the study.
- Statements on all test methodology to be employed, with a precise statement of the test equipment and/or materials to be used.
- Test equipment calibration requirements.
- References to any relevant Standard Operating Procedures (SOPs).
- Requirements for the content and format of the report on the study.
- Acceptance criteria against which the success (or otherwise) of the study is to be evaluated.
- The personnel responsible for evaluating and certifying as acceptable each stage in the study, and for the final evaluation and certification of the process as a whole, all as measured against the pre-defined acceptance criteria.

Personnel
As with all process validation studies, documented evidence of the relevant experience and training of the personnel involved in conducting the studies should be maintained. However, because the personnel actually performing the aseptic processing (both during the course of any validation studies, and in routine operation) can, and do, have so crucial an effect on the quality of the end-product, it is appropriate and necessary to consider both these aspects of personnel involvement.
- Appropriately qualified personnel should ensure that the protocol and the testing methodology are based on sound scientific principles and that all studies are properly evaluated and certified.
- All personnel conducting tests should be trained and experienced in the use of the instruments, measuring devices and materials used.
- Engineering/maintenance personnel should be fully trained and competent in the operation and maintenance of the machines, equipment, and air control systems involved.
- Although modern automated and barrier techniques may reduce contamination risk, the significance of the "human factor" in all aseptic processing operations cannot be over-stressed. For the results of any validation studies themselves to be valid, it is essential that the risk represented by so potentially random a variable as a human operator is kept as much under control as is possible. That is, steps must be taken to reduce the risk and to minimize the variability.
- This in turn means that any operators involved in performing an aseptic processing operation which is the subject of a validation study should adopt the same techniques, disciplines, and standards of hygiene, clothing and behaviour as in normal routine manufacture. The converse also applies: if operators conduct themselves, during routine production, in manner which is different from their behaviour etc. during the validation studies, then conclusions drawn from the validation will be invalid.
- It is therefore vital that all personnel involved in aseptic processing operations are trained in, and fully understand, the concepts and principles of GMP, and the relevant elements of microbiology. They must understand the importance of personal hygiene and cleanliness, and be made fully aware of the possible hazardous consequences of product contamination.
- Operators should be provided with suitable Clean Room clothing and trained in appropriate gowning technique. The type of clothing to be worn, and the "scrub-up" and gowning process should be defined in written procedures, available to the operators, and preferably displayed in the changing room. The same clothing/gowning standards should be observed during validation studies as in routine production, and vice versa.
- The maximum number of personnel permitted in the Clean Room during normal routine production should also be present in the Clean Room during any validation test runs.
- At all times, operators should be encouraged to report any infections, open lesions or any other conditions which could result in the shedding of abnormal numbers of particles or microorganisms. As with routine manufacture, no person thus affected should be present in the Clean Room during validation test runs.
- As in routine production, Clean Room operators involved in validation studies should be microbiologically monitored by taking test samples from gloves, gowns and facemasks.
- Normal routine process documentation should specify and record the numbers and types of operator interventions that are permitted during processing, and in what circumstances. A similar series of interventions should occur during any validation test runs. Details should be provided as part of the overall validation documentation .

Data review and certification
All information or data generated as a result of the study protocol should be evaluated by qualified individuals against protocol criteria and judged as meeting or failing the requirements. Written evidence supporting the evaluation and conclusions should be available.
- These evaluations should be made as the information becomes available.
- If such an evaluation shows that protocol criteria have not been met, the study should be considered as having failed to demonstrate acceptability, and the reasons should be investigated and documented.
- Any failure to follow the procedure as laid down in the protocol must be considered as potentially compromising the validity of the study itself, and requires critical evaluation of the impact on the study.
- The final certification of the validation study should specify the pre-determined acceptance criteria, against which success or failure was evaluated.

Laboratory
All laboratory tests (including physical, chemical and microbiological determinations) should be performed by a competent laboratory, suitably equipped, and staffed with personnel properly trained and qualified to carry-out the test procedures assigned to them.

Detailed authorized, written procedures defining the relevant, validated methodology should be available for all laboratory tests which are to be carried out during the course of the study. These procedures should be referenced in the study protocol.

If any external laboratory facilities are used, a system should be in place for determining the competence of these laboratories to carry out the tests required. This requirement should be referenced in the study protocol.

All measuring/recording/indicating instruments employed in the studies should be adequate for the purpose, in terms of range, accuracy, reproducibility etc.. They must be calibrated in accordance with pre-defined written procedures before any validation studies are commenced.

Records of each calibration should be maintained, and should form part of the overall validation documentation.

For the conclusions drawn from any qualification/validation studies themselves to remain valid during routine production, all controlling and recording instruments must be subjected to a written maintenance and calibration program.

Clean room standards
Although prior to their being sterilized, products, materials, containers, components, closures etc. may be handled/processed in a lower (for example, Grade C) Clean Room environment, subsequent to the sterilization stage(s) all aseptic processing operations should be conducted under local Grade A ("work station") protection, within a general (or "background") Grade B Clean Room environment. However, if certain specialized automated or barrier techniques are employed to provide the localized protection, a lower background environmental standard may be acceptable, provided that process validation studies demonstrate the attainment of an acceptable level of sterility assurance. (Grades A, B and C are as defined in the table for the "Basic Environmental Standards for the Manufacture of Sterile Products" in the Sterile Products section of the current version of the "Good Manufacturing Practices". ).

For the results of any validation studies to have valid relevance to routine production, they must be conducted under precisely the same environmental conditions as used, or intended to be used, during normal routine production.

Confirmation and Certification that the room and the work station(s) do, in fact conform to the specified Environmental Standard may be considered as forming part of the Installation Qualification phase. To this end, the following basic work should be carried-out on the initial commissioning (or "Qualification") of a new Clean Room installation:

Equipment qualification
A wide range of different types of mechanized equipment may be used in various aseptic processing operations. Before any process validation studies may be commenced, it is necessary that all such equipment be properly qualified, in both Installation and Operational terms, and that this qualification be certified. It is clearly outside the scope of these guidelines to detail Installation and Operational requirements for every possible item of equipment. The essential requirements are that the equipment be confirmed as Qualified before any subsequent studies can be considered valid.

Revalidation
Following initial aseptic process validation, media-fills and process simulations should be repeated to an extent, and at a frequency, which will depend on the occurrence of events or changes which may bear upon the potential microbial hazard to the process and product. Significant modifications to equipment or facilities, changes in personnel, undesirable trends in environmental monitoring results, and sterility test failures may all indicate an immediate need to implement a full process validation protocol (i.e. minimum of 3 consecutive successful media-fill runs) with the facility in question taken out of service until any problems have been resolved, and the results of the three media-fills have been evaluated and found acceptable.

In the absence of any significant changes, or of any other events giving cause for concern, then a minimum re-test frequency should be twice per year per operator shift or team, for each process line. For single shift operations, the minimum frequency should be 3 times for each process line per year.

- (Pharmaceutical Manufacturing)