Sterile Bulk Production

The preparation of BPCs, which must be sterile upon completion of their synthesis and purification, is a common activity in the pharmaceutical industry and increasingly common in biotech processes. The validation of sterile BPCs represents 

The predominant method of sterilization for BPCs is by membrane filtration. This filtration will require validation in accord with regulatory expectations. Adaptations to the common filter validation methodologies may be required for certain solvents and/or antibiotic solutions. Subsequent to the filtration step, the succeeding unit operations must be carried out using facilities, equipment, and methods designed to prevent the ingress of microorganisms. The remainder of this section reviews considerations relative to sterile BPC preparation under these constraints. 

Central to understanding much of what is presented below is recognition that BPCs, whether intended to be sterile or not, are primarily produced in closed systems in which the reaction, separation, and purification unit operations take place. A joint PDA/PhRMA task force has defined a closed system as  

Closed systems provide for complete separation between the environment in which personnel (uniformly accepted as the primary source of contamination in aseptic environments) are located from that in the materials are processed. Theoretically, if a sterile BPC could be processed in its entirety within closed systems, there would no possibility of microbial contamination. In marked contrast to the closed system is the open system , perhaps best defined by what it is not. Essentially, an open system lacks one or more of the features of a closed system, thus leaving it vulnerable to the potential ingress of contamination. One substantial issue associated with these definitions is establishing that a system remains closed over the length of the production campaign. 

Environmental classification—The environments in which sterile BPC production is executed can vary with the degree of closure provided by the equipment. Closed systems as described earlier have been successfully operated in Class 100,000 (EU Class D) or unclassified environments. Systems that are open are generally located within Class 100 (EU Class A) where product is exposed, and surrounded by Class 10,000 (EU Class B or C). 

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This chapter focuses on the preparing and filling of injectable solid bulk pharmaceutical formulations. The material presented is general in nature but with references to direct the reader to more in-depth treatment of the subject matter. Coverage includes sterile bulk product preparation. 

The products utilized for testing subsection shall include a listing of the items used for OQ test function runs and items utilized for sterilizer bulking during test function runs. 

Plain condensed milk or concentrated milk has the same standard of identity in the United States as evaporated milk, except that it is not given additional heat processing after concentration. This product is shipped in bulk containers and is perishable. Technology is available to produce it in a sterile or almost sterile manner, and its extended shelf life gives it a potential, but as yet undeveloped, market as a source of beverage milk. Whole milk can be successfully concentrated up to 45% total solids, and these higher concentrations have found some use in the bulk product market. 

Manipulation of the A, FT, and />, values in Eq. (11) will naturally produce different values of B. Accordingly, if it is desirable that B be as low as possible, this may be accomplished in one of three ways (1) reducing the bioburden A of the bulk product, (2) increasing the equivalent exposure time FT, or (3) employing a micro-organism with a lower D value at the specified temperature. Since option 3 most likely is impossible, as the most resistant micro-organisms of a fixed D value must be used in sterilizer validation, one must either employ techniques to assure the lowest possible measurable microbial bioburden prior to sterilization or simply increase the sterilization cycle time. 

Final product isolation in a form suitable for further processing into the final dose form of the pharmaceutical, e.g., as a tablet or an injectable solution. Secondary production of this type is sometimes done in a separate facility, with the raw material referred to as the bulk product or, more recently, the active pharmaceutical ingredient. Examples of unit operations at this stage of processing include lyophilization, precipitation, or crystallization followed by solid isolation using filtration and drying techniques. In some cases, the final product must be produced in a sterile form, which introduces additional complications when selecting suitable process equipment. 

EBRS for bulk production (granulation, ointment, syrup, and sterile solution manufacturing)... 

The conduct of aseptic processing validation ordinarily requires the use of a microbiological growth medium in lieu of the product. The PDA/PhRMA joint task force of Validation of Sterile Bulk Processes has outlined some process simulation methodologies which do not... 

The bulk production of sterile drug products such as antibiotics, corticosteroids, insulin, and certain biotechnology products requires that a number of processes be carried out under aseptic conditions. These processes can be evaluated in a manner adapted from those employed for aseptic filling processes. A joint PDA/PhRMA task force has developed the definitive guidance document on this subject. ... 

The most widely used solvent for SVIs is water for injection (WFI), USP. As a solvent, WFI is used in preparing the bulk solution (compounding) and as a final rinse for equipment and packaging preparation. WFI is prepared by distillation or reverse osmosis, although only distillation is permitted for sterile water for injection, USP. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products... 

A suitably sized solution preparation system similar to that mentioned under the previous sections can be used to provide material for bulk freeze drying. (Since product solutions can be sterile-filtered directly into the final container, microbial and particulate exposure will be minimized.) The sterile solution is subdivided into trays and placed into a sterilized freeze dryer. Aseptic transfer of sterile product in trays to the freeze dryer must be validated. After tray drying, the sterile product is aseptically transferred through a mill into suitably designed sterile containers. The preparation of sterile bulk material is usually reserved for those cases where the product cannot be isolated by more common and relatively less expensive crystallization methods. Due to recent advances in this field, a freeze drying process should be considered as a viable option. ... 

Water is used in sterile bulk operations for final rinsing of equipment, tanks and other items used in final compounding, processing and filling of sterile drug products. The quality of water must meet the requirements of the USP Water for Injection. Among the most important of these requirements are extremely low (e.g. 0-2 CFU) coliform bacterial counts. Water for Injection outlets are sampled daily in large amounts (>500 ml). Appropriate culture media, temperatures and times for incubation of water samples are selected for enumeration of bacteria. ... 

For sterile Filtration of ophthalmics and small-volume parenteral products it is not unusual to Find several Filters mounted in series. For instance a compounded bulk product may be Filtered through the wall from a dean area into an aseptic filling room. In these cases there are usually two filters mounted in... 

Figure 1. Enzyme Membrane Reactor (EMR) for bulk production - schematic representation. 1, ultrafiltration module 2, peristaltic pump 3, septum 4, sterile filter 5, metering pumps 6, reactor loop (ther-mostated) pHI, pH indication TIR, temperature indication and regulation PI, pressure indication.

The interval between the washing and drying and the sterilization of components, bulk-product containers, and equipment, as well as between sterilization and use, should be as short as possible and subject to a time-limit appropriate to the validated storage conditions. 

Sterile filling would not normally be regarded as part of packaging, the bulk product being the filed, but notthe finally packaged, primary container. 

Components, bulk-product containers, equipment, and any other articles required in a clean area where aseptic work is in progress should be sterilized and, wherever possible, passed into the area through double-ended sterilizers sealed into the wall. 

In this environment bulk product formulated from starting materials of lowest practicable biological load is filtered to reduce or eliminate this load and filled (or dried and filled) into clean or sterile containers. Sterilisation is carried out under closely controlled and validated conditions. Additional precautions against contamination are taken with products that are not sterilised in their final containers. 

ASEPTIC PROCESS (procede aseptique) A method of produdng a sterile product in which sterile bulk drug or sterile raw materials are compounded and assembled with sterile packaging components under Grade A or conditions. 

Following cleaning and sterilization, components, bulk-product containers and equipment are handled in such a way that they are not re-contaminated. The stage of processing of components, bulk-product containers, and equipment is properly identified. 

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