Sterilization process development

A sterilization process may thus be developed without a full microbiological background to the product, instead being based on the ability to deal with a worst case condition. This is indeed the situation for official sterilization methods which must be capable of general application, and modem pharmacopoeial recommendations are derived firm a careful analysis of experimental data on bacterial spore survival following treatments with heat, ionizing radiation or gas. 

The F-value concept which was developed for steam sterilization processes has an equivalent in dry heat sterilization although its application has been limited. The Fh designation describes the lethality of a dry heat process in terms of the equivalent number of minutes exposure at 170°C, and in this case a z value of 20°C has been found empirically to be appropriate for calculation purposes this contrast with the value of 10°C which is typically employed to describe moist heat resistance. 

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. 

There are two EPARs for eyedrops. Specific issues considered for these include container composition and tamper evidence, the optimization of the formulation and manufacture, preservative and preservation issues, and justification for the use of nonterminal sterilization processes. Many of the points concerning active ingredients and excipients are similar to those discussed above. Changes in formulation during the development process (e.g., for carbomers or surfactants) are mentioned. Particle size controls for suspension products are discussed. 

Goodwin Biotechnology, Inc. (GBI) is a fully integrated GMP contract manufacturer of mammalian cell products providing process development (upstream and downstream) and cell banking through production, purification, and sterile fill. The downstream... 

Weuster-Botz, D., Aivasidis, A., and Wandrey, C., Continuous Ethanol Production by Zymomonas mobilis in a Fluidized Bed Reactor. Part II. Process Development for the Fermentation of Hydrolysed B-Starch without Sterilization, Appl. Microbiol. Biotechnol., 39 685 (1993)... 

Efficiency trails to develop Regarding sterilization process, in-process... 

Canned and bottled citrus juices are examples of products that are packed aseptically, and these processes have been used in the industry for many years. One of the newer processes for aseptic packaging employs a paperboard package that is sterilized with hydrogen peroxide prior to the form, fill, and seal operation. This process, developed by Tetra Pak Ab of Lund, Sweden, is in use in many parts of the world, but it has not yet been approved by the U.S. Food and Drug Administration for domestic use. 

The major concern with document linking to validation is with master batch records and SOPs. The defined ranges for the operating parameters (as established in development) as defined in the master batch record are confirmed to be satisfactory during the validation effort. There is no requirement, nor should there be, to establish on a commercial scale that success is possible at the extremes of these ranges. That type of confirmation is ordinarily restricted to developmental trials, in which the financial impact is less significant. The only common exception to this practice is in the validation of sterilization processes, in which the performance qualification efforts will oftentimes use worst-case conditions at or below the routine sterilization parameters. 

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. 

The use of radiation within a parenteral facility would have been considered unthinkable prior to the start of the twenty-first century. While y irradiation is typically a contracted service provided off-site, electron beam sterilization advances can make the installation of an in-house (and generally an in-line) system a real possibility. An in-line system would be utilized similarly to the gas/vapor systems described above for treatment of external surfaces for entry into either a clean room or isolator-based aseptic processing facility. The use of this same technology for terminal sterilization is also possible [1], Association for the Advancement of Medical Instrumentation (AAMI)/ISO 11137 provides widely accepted guidance on the development and validation of radiation sterilization processes. 

Yeast cells (Candida lipolytica) can convert n-paraffins to SCR The process developed by BP uses a continuous stirred tank reactor under sterile conditions. The SCP is harvested by centrifugation and then spray-dried. The mass balance equation (Eq. 9.4) shows that less heat is generated and that a little less oxygen is needed than for the methane process. 

Justification of the reliable achievement of SALs of 10 for particular pharmaceutical items treated according to particular specifications of temperature and time in particular sterilizers is predicated on the regularity and predictability of steam sterilization processes. The means of justification are through scientifically based development of sterilization specifications and sterilizer parameters, and through subsequent validation of the specified processes. 

The performance qualification (PQ) phase of validation follows the development of the sterilization specifications and of the sterilizer parameters which will deliver them. The purpose of PQ in steam sterilization of pharmaceutical products, equipment, laboratory media, and SIP systems is to confirm that the sterilization specification consistently achieves its intended purpose. The process is run using the parameters derived from process development on (usually) three separate occasions and tested for compliance with a variety of predetermined acceptance criteria. As a subset of PQ, the purpose of bio-validation is to confirm that the lethality expected from the process does not significantly deviate from what is expected. Biovalidation is a test of consistency. If the acceptance criteria are not achieved, there may be need for more process development. 

Data showing survival on some but not all of the Bis may be valuable in process development (particularly in the development of sterilization specifications and sterilizer parameters for porous and equipment loads), but would likely raise issues at regulatory inspection. The inference taken from having some survival could be that each item in the autoclave load is not being exposed to the same treatment. 

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. 

During development of the manufacturing process, an experienced microbiologist should be consulted as to the potential for microbial contamination of the product. Issues may include the selection of appropriate pharmaceutical ingredients, the ability of the manufacturing steps to control microbial contamination, the validation of sterilization processes, the cleaning and sanitization of process equipment, the adequacy of... 

Sterilization is a probability function. In the pharmaceutical industry, an item is deemed sterile if there is less than 1 chance in 1,000,000 that viable microorganisms are present in the sterilized article or dosage form. Therefore there is a 10 probability of non-sterility. In all sterilization processes, the inactivation of microorganisms develops as a first-order chemicalreaction, i.e., at a rate which is approximately logarithmic. ... 

A novel method for sterilizing glass containers with ozonized air has been developed. When used to replace a sulfur dioxide sterilization process, it resulted in substantial operating economies. Operation of a fully automatic soft drink plant is described. 

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