Validation sterilization processes

This chapter will discuss briefly the principles and applications of the various methods of monitoring and validating sterilization processes. 

ABC Pharmaceutical Industries information. The equipment preparation pages of the master batch record specify the validated sterilization processes to be employed in the preparation of the equipment for (product name) USP. Cycle sterilization parameters are defined along with attributes such as loading patterns and the mechanics of operating the sterilizing equipment. The following lists the sterilization cycles utilized for the equipment required in the processing of (provide product name) USP ... 

Steam sterilization is the method mostly used to sterilize freeze-dryers. High-quality, ultra-pure steam (water for injection standard USP XXII or PhEur equivalent) is used to achieve a minimum exposure of 121 °C for 30 min or the equivalent temperature-time combination for effective sterilization (Table 2.4.1). This method is easy to validate and is recommended by regulatory authorities as being reliable. The definition of sterilization is a validated process used to render a product surface free of all forms of viable micro-organisms (EN 556-1 2001). According to the authorities, a product or surface is only sterile when a validated sterilization process has been applied (EN 550, EN 552, EN 554, EN ISO 14160 and EN ISO 14937). 

The USP allows a very similar approach (termed overklH") to the determination of valid sterilization processes for compendial preparations ( a lethality input of 120 may be used in a typical overkill approach ). 

Dosage Forms and Product-Contact Components The object of aseptic manufacture is to bring a sterile dosage form and the finished presentation s presterilized product contact components together without contaminating them. Confidence of their sterility is of major importance. This means validated sterilization processes and low levels of microbiological contamination prior to their sterilization. 

All disinfection and sterilization processes for equipment should be validated, for preference using a microbiological challenge with an organism of appropriate resistance to the disinfectant, sterilant or sterilizing conditions. Once the required log reduction of the challenge organism has been achieved, physical and/or chemical parameters can be set which form the critical control points for the process. 

Berg, T., Humphreys, P., Phillips, B. and Scherz, B., Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation , PIC Publication PH 1/96. 

The purpose of this section of an application is to establish that the proposed manufacturing process is suitable and that it will yield consistently product of the desired quality. The concept is closely related to GMP and the detail of conventional manufacturing process validation may not be required. However, data will normally be required for nonstandard manufacturing processes (particularly nonstandard sterilization processes) and for those aspects of manufacture that are critical in terms of product quality, e.g., in the manufacture of modified-release products the quality, safety, or efficacy of which will be affected by the method of manufacture. 

Manufacturing validation data, which should aim to identify the critical process steps, especially for nonstandard manufacturing processes such as for new dosage forms, should be discussed in the development pharmaceutics section of the application. Validation data may be accepted based on closely related products. In-process control tests and acceptance limits should be included for any aspect where conformity with the finished product tests cannot otherwise be guaranteed (e.g., mixing, granulation, emulsification and nonpharmacopeial sterilization processes). 

The sterilization processes described in the Ph Eur are preferred, especially terminal sterilization in the final container alternative processes have to be justified. All sterilization processes will need to be described and appropriate in-process controls and limits included. Where Ph Eur prescriptions are followed, there should be a statement to this effect in the application. Most of this information should be discussed in the development pharmaceutics section. Reference is made to the specific guidelines on ethylene oxide sterilization and irradiation sterilization, which are discussed further below. The possibility of parametric release for terminal processes such as saturated steam and irradiation is mentioned (see below). For all sterile products there should be a sterility requirement included in the finished product specification regardless of the outcome of validation studies. 

The rules of steam sterilization are well described [2.15], including some guide-lines for the validation of the sterilization process. The special problems with the steam sterilization of closing systems for vial stoppers has been discussed above. Similar problems... 

Water system Cleaning practices Computer validation Process validation Test methods validation Sterilization procedures Stability evaluation... 

Appropriate procedures, designed to prevent microbiological contamination of compounded drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process. 

According to 211.113 Control of microbiological contamination, pharmaceutical manufacturers need written procedures describing the systems designed to prevent objectionable microorganisms in both nonsterile and sterile drug products. All sterilization processes used to manufacture parenteral drugs need to be validated. 

Description of the test functions required to qualify and validate the sterilization process after the change is made, as applicable... 

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. 

The lyophilizers are cleaned using a validated clean-in-place (CIP) cycle using hot WFI. After the cleaning process, a validated sterilization cycle is mn. The qualification of the steam sterilization cycle was performed during the operation qualification (OQ) of the lyophilizer. 

PDA guidance If the bulk drug solution is aseptically formulated from components that are sterilized separately, information and data concerning the validation of each of these separate sterilization processes should be provided. 

The D value is the determining factor if the death rate is, indeed, exponential, an assumption which is not necessarily always valid. Although only conditions which supply a single D value would be sufficient to completely sterilize a solution containing, say, one organism per unit volume, most heat sterilization processes are designed to administer 12D. This is an example of overkill and becomes more evident the fewer organisms there are in the untreated product in the first place. 

FDA Guidance for Industry on the Submission of Documentation for the Sterilization Process Validation in Applications for Human and Veterinary Drug Products (November 1994)... 

Process validation Inspection of the establishment to determine compliance with cGMP requirements and adherence to application requirements is a Field responsibility. CDER may request data to support validation of sterile processing operations for example, environmental monitoring, equipment validation, sterile fill validation, and associated sterile operations. 

Scale-up ensuring that installation qualification, operational qualification, performance qualification (IQ/OQ/PQ) activities are properly conducted These include cleaning validation, process validation, sterilization validation, and so forth, according to established corporate procedures. 

Sterile products have several unique dosage form properties, such as freedom from micro-organisms, freedom from pyrogens, freedom from particulates, and extremely high standards of purity and quality however, the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination. The emphasis of this chapter will be the validation of the sterilization processes responsible for achieving this goal. 

The D value is a single quantitative expression of the rate of killing of microorganisms. The D term refers to the decimal point in which microbial death rates become positive time values by determining the time required to reduce the microbial population by one decimal point. This is also the time required for a 90% reduction in the microbial population. Hence, the time or dose it takes to reduce 1000 microbial cells to 100 cells is the D value. The D value is important in the validation of sterilization processes for several reasons. 

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. 

These terms heretofore have been applied exclusively in the validation of heat-sterilization processes. The Z value is the reciprocal of the slope resulting from the plot of the logarithm of the D value versus the temperature at which the D value was obtained. The Z value may be simplified as the temperature required for a one-log reduction in the D value ... 

In sterile product manufacturing, five major steps are involved in approaching the validation of a sterile process. These are outlined below using thermal sterilization as the example process. 

Each validation process should have a documented protocol of the steps to follow and the data to collect during the experimentation. As an example, App. I presents a protocol for the validation of a steam sterilization process. 

With the main emphasis being the validation of a steam sterilization cycle based on the achievement of a certain reproducible value at the coolest part of the full batch load, procedures for validation of a steam sterilization process will now be discussed. 

As with any sterilization process, the first step in dry-heat sterilizer validation involves qualification of all the equipment and instrumentation used. This step includes examination and documentation of all utilities, ductwork, filters, and control valves or switches for the oven or tunnel unit, and the calibration of the instrumentation used in validating and monitoring the process. The instruments used are as follows ... 

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