Terminal sterilization products, process

Process Flow, Variables, and Responses Terminal Sterilization Products... 

This raises a second question of how much confidence must one have to claim sterility The answer to this question, for terminally sterilized products, is that there must be no more than one chance in a million that viable contaminants survive in any one unit. This is called a sterility assurance level (SAL) of 10 . The answer for aseptically filled products is that the SAL must be as close to 10 as is technically possible, with the proviso that thedegree of protection given to the process must afford no more than one chance in a thousand of any one unit becoming contaminated. This is called a contamination rate of 10 , and unlike the SAL it relates only to the protection given to the process and not to the potential for contaminants surviving or proliferating in actual products. ... 

Injectable products, ophthalmic products, and inhalation solutions Pharmaceutical ingredients Purified water Manufacturing environment Products As above Loop and taps daily Every shift in critical aseptic processing areas Every batch with the exception of terminally sterilized products approved for parametric release... 

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. 

Manufacturing operations for sterile products are divided into two groups, one where the product is sterilized terminally, that is at the end of processing after it has been sealed in its container, and the other where some of the processing must be conducted aseptically. For terminally sterilized products, a grade C environment is usually... 

PROCESS FLOW, VARIABLES, AND RESPONSES TERMINAL STERILIZATION PRODUCTS... 

Process flow, variables, and responses terminal sterilization products... 

The effect of the autoclave cycle, i.e., fill, heat-up, peak dwell and cool down, on the theoretical chemical stability of compounds intended for IV injection has been investigated by Parasrampuria et al. (1993). Assuming first-order degradation kinetics, i.e., hydrolysis, the amount of degradation was calculated for any point during the above process. Although the results were calculated for first-order kinetics, the authors estimated that the calculations were applicable to other reaction orders, i.e., zero and second. Acceptable reasons for not proceeding with a terminally sterilized product are as follows ... 

Products can be manufactured as sterile by different methods known as aseptic processing and terminal sterilization. Aseptic processing involves passing the ophthalmic solution through a 0.2 pm filter in order to rid the solution of all bacteria. The solution is then filled into sterile ophthalmic containers under sterile conditions. This assures a sterile product. 

SALs for terminally sterilized products are substantiated (validated) by extrapolation of measurable responses of microbial populations at sub-process treatment levels to process treatments that ought to be providing the specified nonmeasureabie SALs. Extrapolation can only be justified when a response takes a regular form and can be supported by theory. This is clearly the case for the kinetics of inactivation of microbial populations. 

The approach to achieving sterility in a finished product can be achieved in two different ways. The first is aseptic processing and the second is terminal sterilization. Aseptic processing will be discussed here, as terminal sterilization is favored as a more certain method as it eliminates any potential contamination during processing. 

The first two categories, clarifying and crossflow filters, have been very well developed and optimized for use in biotechnology and standard wastewater treatment applications. Equipment is easily available for these applications, whether as small 0.2 micron sterilizing filter used to terminally sterilize 100 ml of product solution, or a small 500 ml crossflow filter used to concentrate a small amount of antibody solution. Many vendors of this equipment to wastewater treatment applications have their origins in the CPI (Chemical Process Industries), and have incorporated many of the scale-up and optimization properties developed in much larger units used in large scale chemical production. As a result, these two filtration unit operations are one of the most optimized and efficient used in wastewater treatment. 

Sterilization of the finished drug delivery formulation is an important consideration often overlooked in the early design of lactide/glycolide delivery systems. Aseptic processing and terminal sterilization are the two major routes of affording an acceptably sterile product. Both of these methods are suitable for products based on lactide/glycolide polymers if proper care is exercised in processing or selection of the treatment procedures. 

One can see by the complexity of these types of manufacturing procedures that much care and attention to detail must be maintained by the manufacturer. This sterile manufacturing procedure must then be validated to prove that no more than 3 containers in a lot of 3000 containers (0.1%) are nonsterile. Ultimately, it is the manufacturer s responsibility to ensure the safety and efficacy of the manufacturing process and the absence of any adverse effect on the product, such as the possible formation of substances toxic to the eye, an ever-present possibility with gas sterilization or when using ionizing radiation. For ophthalmic products sterilized by terminal sterilization (sterilization in the final sealed container, e.g., steam under pressure), the sterilization cycle must be validated to ensure sterility at a probability of 106 or greater. 

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. 

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 ... 

The Ph Eur mentions the possibility of parametric release for certain terminal sterilization processes (saturated steam, dry heat and irradiation) where sterilization parameters can be accurately monitored and recorded and controlled. Much of the information in the two draft documents relates to parametric release of sterile products, but the possibility of parametric... 

The required information as outlined in sections IV and V of the EDA Guidance is in boldface type, followed by ABC Pharmaceutical Industries information. It is submitted in the ANDA file for the manufacturing of (product name) USP. Other sections of the Guidance (sections I to III) pertain to the Guidance s introduction and terminal sterilization processes. 

Environmental monitoring is more critical for products that are asepti-cally processed (intensive monitoring) than for products that are processed and then terminally sterilized (normal monitoring). As manual interventions during operation increase and as the potential for personnel contact with the product increases, the number of sampling points increases. 

Changes in dry heat depyrogenation processes for glass container systems for products that are produced by terminal sterilization processes or aseptic processing. 

In step 5, the qualification stage, the critical issue is that the protocol for IQ/OQ of the equipment and the facility include the established method and acceptance criteria. The IQ/OQ report should include the maintenance program to keep the equipment in good condition for reproducibility of the product. For qualification of the equipment and process for terminal sterilization, the following standards should be referred to ISO 13408-1 [6] and 11138-1 [7] for general issues, ISO 11134 [8] and 11138-3 [9] for moist heat sterilization, ISO 11135 [10] and 11138-2 [11] for ethylene oxide sterilization, and ISO 11137 [12] for radiation sterilization. 

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