Sterility assurance sterilization process

A product to be labelled sterile must be flee of viable microoiganisms. To achieve this, the product, or its ingredients, must undergo a sterilization process of sufficient microbiocidal capacity to ensure a minimum level of sterihty assurance (Chapter 20). It is essential that the required conditions for sterihzation be achieved and maintained through every operation of the sterilizer. 

For sterile products, particular attention should be paid to the choice of an appropriate method of sterilization. Wherever possible a terminal sterilization process should be applied to the product in its final container-closure system, as suggested in the Ph Eur. The preferred options include steam sterilization, dry heat sterilization, and irradiation using the Ph Eur listed conditions (saturated steam at 121°C for 15 minutes dry heat at 160°C for 120 minutes irradiation with an absorbed dose of not less than 25 kGy). Where these cannot be used, the application must include justification for the alternative procedure adopted on the understanding that the highest achievable sterility assurance level should be achieved in conjunction with the lowest practicable level of presterilization bioburden. There is guidance in the form of decision trees as to the preferred options for sterilization method to be applied ... 

Justifications for the use of nonstandard (i.e., nonpreferred or nonpharmacopeial) methods of sterilization may include the heat instability of the active ingredient or an essential excipient. The choice of a method based on filtration through a microbial retentive filter and/or aseptic assembly should be justified, and the appropriate in process controls (including bioburden controls on active ingredients, excipients, bulk solutions, process time constraints etc) discussed in detail in the application. Commercial considerations should not form part of the argument for the application of a nonstandard sterilization process. The highest possible sterility assurance level should be achieved. 

This procedure provides the information required to support the sterility assurance of the drug product (product name), USP, manufactured by ABC Pharmaceutical Industries. It references the FDA Guidance titled Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Dmg Products prepared by the Sterility Technical Committee of the Chemistry Manufacturing Controls Coordinating Committee of the Center for Dmg Evaluation and Research (CDER) and the Center for Veterinary Medicine (CVM) in November of 1994. 

Their use as an injectable warrants assurance of product sterility. Whereas the FDA-preferred heat-sterilization process is acceptable for total parenteral nutritional (TPN) emulsions, it could affect chemical as well as physical stability of emulsions containing therapeutic agents. Recently, data supporting the Liter sterilization of emulsions have been published. 

A product being validated for sterility should be associated with a characteristic D value for the micro-organism either most likely to contaminate the product or most resistant to the process used to sterilize the product. The employment of Bis in the validation of sterile products has the purpose of assuring that the sterilization process that causes a multiple log reduction in the BI population in the product will most certainly be sufficient in destroying all other possible viable contaminants. 

The complexity of the sterile filtration operation and the CGMP regulations require the validation of sterilizing filter systems. The validation of a sterile filtration operation can be complex, with many operational parameters and their interactions needing to be identified, controlled, and predicted for each end product to demonstrate that sterility is adequately achieved by the filtration process. In the commonly used steam sterilization process, the heat parameters are identified and in-process controls specified such that a level of sterility assurance can be reproducibly obtained. In steam sterilization, the important parameter of heat, measured by temperature, can be accurately measured and continuously monitored to ensure the operational integrity of the autoclave however, unlike steam sterilization, filtration sterilization cannot be monitored on a continuous basis throughout the process. 

Sterile radiopharmaceuticals may be divided into those which are manufactured aseptically and those which are terminally sterilized. In general, it is advisable to use a terminal sterilization whenever this is possible. Terminal sterilization is defined as a process that subjects the combined product/container/closure system to a sterilization process that results in a specified assurance of sterility [7], Since sterilization of solutions normally means autoclaving (steam sterilization), one must assure that the radiopharmaceutical product does not decompose when it is heated to temperatures above 120°C. Many radiolabeled compounds are susceptible to decomposition at higher temperatures. Proteins, such as albumin, are good examples of this. Others, such as 18F-fluodeoxyglucose (FDG), can be autoclaved in some formulation but not in others. 

The sterilization process for any equipment or supplies that are sterilized prior to introduction into the controlled environment must be validated, with sterilization records and verifications included in all product batch histories. Validation of sterilization equipment, alone, is not sufficient to assure sterility. Because the types of materials being sterilized, and the arrangement of articles within the sterilizer can effect results, standardized load configurations must be developed and validated. 

Even though the definition of sterility is an absolute condition, the effectiveness of the sterilization process can be determined by measuring the reduction of microbial population. Such measurements reveal the kinetics of microbial inactivation, and it is from the exponential nature of inactivation that the concept of sterility assurance level (SAL) is derived. This value... 

In pharmaceutical technology, to define an item as sterile, one must be able to demonstrate that on a statistical basis related to the processing conditions, no more than 1 in 10 units subjected to sterilization may be non-sterile. Therefore, the SAL (Sterility Assurance Level) of the product must be greater than (or equal to) 10 . The obvious consequence of this situation is that although the word sterile expresses an absolute concept, the word sterilized, understood as the result of an adequate sterilization process, has a probabilistic meaning. 

The principles behind the sterilization processes are described in Chapter 20. The choice of method is determined largely by the ability of the formulation and container to withstand the physical stresses applied during the sterilization process. All products intended for sterilization should be manufactured under clean conditions and therefore will be of low microbial content (bioburden) prior to sterilization. Under these conditions, the sterilization process will not be overtaxed and will generally be within the safety limits needed to provide the required level of sterility assurance (Chapter 20). The next section emphasizes parenteral products, but the practices described apply to many other types of sterile product. 

Underestimating the level of microbial contamination prior to the terminal sterilization process will lead to a miscalculation of the sterilization dose requirements to achieve the desired sterility assurance level. The bioburden must be maintained within certain limits to justify the chosen sterilization process. When a higher number of organisms or... 

Thus, for an initial burden of 102 spores an inactivation factor of 108 will be needed to give the required sterility assurance of 10-S (Fig. 20.3). The sterilization process will therefore need to produce sufficient lethality to achieve an 8 log cycle reduction in viable organisms this will require exposure of the product to eight times the D-value of the reference organism (8D). In practice, it is generally... 

Heat is the means of terminal sterilization that is preferred by the regulatory authorities because of its relative simplicity and the high sterility assurance that it affords. However, a significant number of traditional pharmaceutical products and many recently developed biotechnology products are damaged by heat, as are many polymer-based medical devices and surgical implants for such products alternative sterilization processes must be adopted. Whilst radiation is a viable option for... 

In well-understood and well-characterized sterilization processes (e.g. heat and irradiation), where physical measurements may be accurately made, sterility can be assured by ensuring that the manufacturing process as a whole conforms to the established protocols for the first three of the above headings. In this case the process has satisfied the required parameters thereby permitting parametric release (i.e. release based upon process data) of the product without recourse to a sterility test (see Chapter 19). 

Greater stringency is required for terminally sterilized products. Such environmental and process controls might seem overzealous, but it is better to minimize risk at all stages rather than to rely on final product testing (section 1). The lower the bioburden the easier it is to achieve the required sterility assurance level in the terminal sterilization process (Chapter 20). It is also important to exclude pyrogens and particulate matter that would not be removed by sterilization. 

Even when preservatives are included in single-dose presentations (as they often are), their efficacy against particular types of microorganisms can never be legitimately used as an excuse for tolerating in>process contamination by preservative-sensitive types. Nor can the inclusion of preservatives in products be used to shorten or reduce the intensity of sterilization processes applied to products or their containers to lower than normal levels of sterility assurance. Preservatives are supplementary, not intrinsic to industrial-scale processes of achieving sterility. 

The concept of sterility assurance invokes the idea of confidence. How confident should we be that an item is sterile AH three of the major pharmacopoeias now require assurance of less than 1 chance in 1,000.000 that viable microorganisms are present in a sterilized article or dosage fonn (10 probability of nonsteriiity). To obtain this assurance we must have good knowledge of the effects of sterilization processes on microbial populations. 

Chemical kinetics cannot be assumed for aseptic manufacture nonetheless, protection of items from microbiological contamination in clean rooms can never be perfect and may therefore be assumed to be subject to the laws of chance. The sterility assurance concept is certainly applicable to aseptic manufacture, but not in a manner directly comparable to terminal sterilization processes. 

In summary, there is always a finite probability of a survivor occurring, no matter the strength or duration of a sterilization process. In other words, absolute sterility, in the sense of total freedom from all viable life forms, can never be achieved in practice. The acceptance of exponential inactivation lunetics has led to two different approaches to the establishment of standards of satisfactory sterilization treatment, the inactivation factor approach and the sterility assurance level (SAL) approach. 

Doolan. P. T.. Dwyer. J.. Dwyer. V, M.. Filch, F. R., Halls. N. A and Tallentire, A. (1985). Towards microbiological quality assurance in radiation sterilization processing A limiting case model. Journal of Applied Bacteriology SSt jM)3-306. 

Sterilization by exposure to ethylene oxide is bounded by at least four variables gas concemratton, time of exposure, temperature, and humidity. It is also affected by product design, packaging design, and the composition of packaging materials. The shape, size, and materials of construction of individual sterilizers, the location of gas entry ports, and the presence or absence of forced circulation may all influence sterility assurance. There is no theory to describe these interactions. Validation and routine control of ethylene oxide sterilization processes boils down finally to the integration of all of these variables by reference to biological monitors. 

In making this proposal, the FDA recognizes that a dual standard of sterility a iunmee has been in operation. Terminal sterilization processes for parenteral pharmaceutical products are currently required to be validated to sterility assurance levels of 10 aseptic processes can only be demonstrated to achieve sterility assurance levels of 10. This is clearly an example of dual standards. Fuithefmore, to the FDA it appears to be fundamentally wrong for products that are quite capable of tolerating terminal sterilization to be manufactured asepti-cally. 

---