Process Validation Sterile Pharmaceutical Products

[Mohammed Huberty]

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This document is intended to provide guidance for the submission of information and data in support of the efficacy of sterilization processes in drug applications for both human and veterinary drugs. The recommendations in the guidance apply to applications for sterile drug products (new drug applications, new animal drug applications, abbreviated new drug applications, abbreviated antibiotic applications, and abbreviated new animal drug applications). These recommendations also apply to previously approved applications when supplements associated with the sterile processing of approved drugs are submitted. Information and data in support of sterility assurance may also be necessary in investigational new drug and investigational new animal drug applications.

I am pleased to inform you that a revised version of Guide 0006 entitled "Process validation: Aseptic Processes for Pharmaceuticals" is now available on the Health Products and Food Branch Inspectorate website at the following address:

This document has been revised to harmonize its content with version 2 of the Good Manufacturing Practices (GMP) Guidelines, 2002 Edition. No major changes to the requirements were made, therefore, consultation is not deemed necessary.

This document is intended to provide pharmaceutical dosage form manufacturers with guidance on the validation of aseptic manufacturing processes, as required in Division 2, Part C (Good Manufacturing Practices) of the Food and Drug Regulations , and in a manner which is acceptable to the Health Products and Food Branch Inspectorate.

Sterile Products may be broadly classified into two main categories, according to the manner in which they are produced: those which are sterilized after the product has been filled and sealed in the final container(s) ("terminally sterilized" products) and those where the sterilization stage (or stages) takes place before the bulk product is filled. In this latter instance, all subsequent processing (typically, the filling and sealing operations) must be conducted aseptically in order to prevent recontamination of the sterilized product.

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 (Probability of Survival approach).

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. Both are covered in this guide. The final section of this guide outlines documentation required to provide acceptable evidence that a given process has been thoroughly evaluated and is adequately controlled.

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.

Whilst this Guide is concerned only with the validation of ASEPTIC PROCESSES, it is crucial to the success of any such process that the product, materials, components etc. that are being handled/processed aseptically (e.g. bulk solution or powder; containers and closures) plus any equipment, vessels or surfaces (e.g. holding tanks, pipework, filling machines) which will or can come into contact with sterilized products/materials have themselves been previously sterilized by appropriate and validated sterilization processes. In any aseptic filling process, assurance of container/closure integrity is, of course, vital. Evidence that all this is so should be provided as part of the overall Validation Documentation (see Section 12).

2.2 Before Process Validation can commence there must be what may be termed an essential Prevalidation phase. This phase, in addition to such considerations as equipment specification, equipment design and equipment purchase, requires attention to Equipment Qualification.

2.3.1 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.

2.4 None of these various phases need to be considered as entirely "water-tight" compartments. The divisions have been defined as a matter of convenience in discussion. In practice there is likely to be some overlap, or merging, between the various components of Validation/Qualification. In addition, there are quite wide-spread variations in terminology and conception. Some consider "Qualification" and "Validation" as two separate, yet related activities. Others use the term "Validation" to embrace the overall activity of Prevalidation/Qualification PLUS Process Validation.

2.5.1 Prospective Validation applies to new processes and new equipment,where studies are conducted and evaluated, and the overall process/equipment system is confirmed as validated before the commencement of routine production.

2.5.2 Concurrent Validation applies to existing processes and equipment. It consists of studies conducted during normal routine production and can only be considered acceptable for processes which have a manufacturing and test history indicating consistent quality production.

2.5.3 Retrospective Validation applies to existing processes and equipment, and is based solely on historical information. Unless sufficiently detailed past processing and control records are available, retrospective validation studies are unlikely to be either possible or acceptable. For example, it would be necessary to establish that the process had not been modified and that the equipment was still operating under the same conditions of construction and performance as documented in the historical records. Maintenance records and process change control documentation would be necessary to support any such claim. Furthermore, the incidence of process failures, and records of rejects and/or reworking would need to be carefully evaluated for evidence of inconsistency in the process. Manufacturing, maintenance, testing and calibration data would all need to demonstrate process uniformity, consistency and continuity.

2.5.4 Concluding Note on Validation Terminology. While there is considerable variation in the understanding and use of the various terms discussed above, there is general agreement that the critical validation concepts are the following:

3.2 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.

3.4.12 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.

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.

4.4 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.

4.5 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.

4.6 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.

4.7 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.

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