Sterile pharmaceutical products aseptic processing

In the case of recombinant proteins intended for use in sterile pharmaceutical products, additional process controls on microbiologic aspects of analysis must be established and validated to ensure aseptic conditions throughout the manufacturing process. 

The purpose of open unidirectional airflow benches is to protect products from particulate contaminants by creating a controlled environment. These benches are used, for example, in electronic, biological, pharmaceutical, and food industries. It should be mentioned that within pharmaceutical production, aseptic sterile processes must be carried out in a Class 100 environment (U.S. Federal Standard 209 E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones). To avoid particle contamination in the bench, horizontal or vertical airflow with high-efficiency particulate air (HEPA)-filtered air is used. The air velocity is normally 0.4-0.5 ra s". Some examples of typical arrangements of open unidirectional airflow benches are shown in Fig. 10.51. 

In the Note for guidance and development of pharmaceuticals, the section on the manufacturing process stipulates clearly that, wherever possible, products intended to be sterile should be terminally sterilized in their final container. The methods of sterilization considered as terminal by the European Pharmacopoeia [5] are steam, dry-heat, gas or gamma-radiation sterilization. If terminal sterilization is not possible, sterilization filtration or aseptic processing are authorized but the choice must be fully justified. 

In addition to equipment, many processes/procedures undertaken during pharmaceutical manufacture are also subject to periodic validation studies. Validation of biopharmaceutical aseptic hlling procedures is amongst the most critical. The aim is to prove that the aseptic procedures devised are capable of delivering a sterile bnished product, as intended. 

The purpose of the second edition is to meet the need for a ready-to-use text on the validation of aseptic pharmaceutical production and to provide general information and guidelines. It is a compilation of various theories, sterilization variables, and engineering and microbial studies that can be used independently or in combination to validate equipment and processes. The concepts and methods presented in this edition are not intended to serve as a final rule. Reciprocal methods for achieving this purpose exist and should also be reviewed and consulted, if applicable. 

The manufacture of sterile products is universally acknowledged to be the most difficult of all pharmaceutical production activities to execute. When these products are manufactured using aseptic processing, poorly controlled processes can expose the patient to an unacceptable level of contamination. In rare instances contaminated products can lead to microbial infection resulting from products intended to hasten the patient s recovery. The production of sterile products requires fastidious design, operation, and maintenance of facilities and equipment. It also requires attention to detail in process development and validation to ensure success. This chapter will review the salient elements of sterile manufacturing necessary to provide acceptable levels of risk regarding sterility assurance. 

Agalloco, J., and Akers, J. (2006), Aseptic processing for dosage form manufacture Organization validation, in Carleton, F. J., and Agalloco, J. P, Eds., Validation of Pharmaceutical Processes Sterile Products, Marcel Dekker, New York. 

For pharmaceutical products and materials used in connection with aseptic manufacture, sterilization specifications apply to conditions of temperature and time, or Fq, or combinations of Fq, temperature and time to which the contaminating micro-organisms themselves must be exposed over the hold period of the sterilization process. In practice, this means actually within aqueous products, on the surfaces of rubber stoppers or metal machine parts, or within the folds of cartridge filters, etc. 

At present, the pharmaceutical industry regulatory requirements refer to isolators specifically in the context of the manufacture of sterile products. There is no reference to their role in broader areas of crosscontamination and operator safety control. Within Europe, the current EU GMP clearly states that isolators might produce improvements in sterility assurance of sterile products, and that aseptic processing manufacturing isolators should be placed in at least a Grade D surrounding environment. The Food and Drug Administration (FDA) requirements are less well defined, but it is likely that in equivalent circumstances, they would like to see an isolator located in a class 100,000 or M6.5 environment In Operation. ... 

As pharmaceutical products contain increasingly potent active constituents and as health, safety, and environmental protection issues increase in importance, isolators have been developed in many shapes and forms to permit thesafe weighing and subdivision of highly active compounds. The most sophisticated applications, such as the subdivision of bulk sterile active compounds, require that the isolator maintain aseptic processing conditions internally at the same time as satisfying the safety requirements. Fig. 2 shows an isolator device designed to allow a keg of potent... 

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... 

In the Federal Register of October 11, 1991, the FDA formally proposed that a rule should be established whereby aseptic processing of allegedly sterile pharmaceuticals should only be justifiable on the basis of the product being proven lo be unsuitable for terminal sterilization. On ratification of the rule and after a... 

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. 

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