Process Validation Parenterals production

These major limitations demonstrate that reliance on end-product sterility testing alone in ascertaining the sterility of a parenteral product may lead to erroneous results. One purpose of validation in the manufacture of sterile products is to minimize this reliance on end-product testing. Three principles are involved in the validation process for sterile product. 

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. 

Filled containers of parenteral products should be inspected individually. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eyesight checks, with spectacles if worn, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. 

Most purified and WFI systems, including RO and UF systems, have the potential for the development of endotoxins. If the final excipient is purported to be pyrogen free or sterile, or will be used in preparing parenteral products, validation of the system to control endotoxins should be conducted and routine testing of the process water for endotoxins should be performed (preferably by the LAL method). 

Simulation process trials are used mainly to validate the aseptic filling of parenteral products that cannot be terminally sterilized. 

Utility systems such as water for injection (WFl). clean steam, clean-in-placc (CIP) solutions and sterile process air must be similarly proven. Also the building system itself has to be validated. Many bioprocess operations which contain potentially hazardous materials are operated in closely-controlled negative pressure enclosures with filtration of exhaust ventilating air. Sterile and particularly parenteral products arc processed in clean rooms which are maintained at positive pressure with filtered incoming air. Validation of building control systems and of personnel changing facilities and systems of work are necessary to meet CMP requirements. Manuals for formal test procedures are required to validate these activities. 

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. 

Extensive use of in-process controls and assessments where true validation is not yet possible or required (as required for parenteral and sterile products)... 

While blending times and tablet press parameters may not be fully established for early phase clinical supply manufacturing of solid oral dosages, those variables have a much lower potential to directly affect product safety than sterility, endotoxin contamination, or objectionable types and levels of particulates do for sterile, parenteral clinical supplies. Because clinical supplies can be incompletely characterized, and are usually given to patients already in weakened conditions, those processes and their related validation data necessary to guarantee patient and product safety (e.g., sterilization and aseptic fill) are expected to be in place as early as Phase I clinical supply manufacture. ... 

Plasma-derived therapeutic proteins are parenteral biologies that are purified on an industrial scale. All biologies derived from human sources, such as plasma, carry the risk of viral contamination. Thus, in order to market a medicinal product derived from human plasma, manufacturers must assure the absence of specific viral contamination. Virus validation studies are performed to evaluate the capacity of a manufacturing process to remove viral contaminants. Virus clearance across three different terminal inactivation steps, low pH incubation of immunoglobulins (IgG), pasteurization of albumin, and freeze dry/dry heat treatment of plasma-derived products (Factor VIII and Protein G), is discussed in this article. The data show that, like all other upstream virus reduction steps, the methods used for terminal inactivation are process and product dependent, and that the reduction factors for an individual step may be overestimated or underestimated due to inherent limitations or inadequate designs of viral validation studies. 

Clearly, physical stability is of critical importance for emulsion formulations, and care must be taken to ensure not only that the product itself is physically stable but that any infusion solutions which may be prepared by dilution of the emulsion are also physically stable over the required period of time. In addition, parenteral emulsions should be able to withstand the stresses associated with moist heat sterilization. Alternatively, if this cannot be achieved, it may be possible to prepare an emulsion aseptically from sterile components, provided the process can be suitably validated. For a good introduction to the formulation and preparation of IV emulsions, the reader is referred to Hansrani et al. (1983). 

The excipient manufacturer must document the sanitizing of critical processing equipment such as centrifuges and dryers. Any manipulation of sterile excipients post-sterilization must be performed as a validated aseptic process. This is particularly important for those excipients which are not further sterilized prior to packaging into final containers. In some instances, the compendial monographs may specify that an excipient which does not meet parenteral grade standards be labelled as not suitable for use in the preparation of injectable products. Ethylene oxide is sometimes used for the sterilization of powders. The manufacture should validate that the ethylene oxide exposure does, in fact, produce a sterile product. 

As unnecessary IPC s may reduce the awareness and discipline of the personnel it is important to consider carefully whether IPC s are really necessary in order to control the quality of the product. An example is the preparation of an all-in-one parenteral nutrition admixture wherein the aqueous part has to be checked for clarity, because precipitates or particulate matter cannot be seen after the fat emulsion is added. Another reason for the use of an IPC is to control critical process steps when no final quality control of the product is possible. An example of this is the control of the application of nitrogen for making ampoules oxygen-free after the filling process, because the laboratory is unable to measure the oxygen content in each ampoule. This IPC is based upon the conclusions from the validation of the oxygen replacement process. 

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