Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).
One of the more difficult processes to inspect and one which has presented considerable problems over the years is that of the manufacture of sterile bulk drug substances. Within the past several years, there have been a number of batches of sterile bulk drug substances from different manufacturers which exhibited microbiological contamination. One manufacturer had approximately 100 batches contaminated in a 6 month time period. Another had approximately 25 batches contaminated in a similar period. Other manufacturers have had recalls due to the lack of assurance of sterility. Although the Inspection Guide for Bulk Drug Substances provides some direction for the inspection of the sterile bulk drug substance, it does not provide the detailed direction needed.
In the manufacture of the sterile bulk powders, it is important to recognize that there is no further processing of the finished sterile bulk powder to remove contaminants or impurities such as particulates, endotoxins and degradants.
As with other inspections, any rejected batches, along with the various reasons for rejection, should be identified early in the inspection to provide direction for the investigator. For example, lists of batches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. Because some of the actual sterile bulk operations may not be seen, and because of the complexity of the process, it is particularly important to review reports and summaries, such as validation studies, reject lists, Environmental Monitoring Summary Reports, QA Investigation Logs, etc. These systems and others are discussed in the Basic Inspection Guide. This is particularly important for the foreign sterile bulk drug substance manufacturer where time is limited.
In the preparation for a sterile bulk drug substance inspection, a flow chart with the major processing steps should be obtained. Generally, the manufacture of a sterile bulk substance usually includes the following steps:
1. Conversion of the non-sterile drug substance to the sterile form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer).
2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.
3. Aseptic isolation of the sterile substance by centrifugation or filtration.
4. Aseptic drying, milling and blending of the sterile substance.
5. Aseptic sampling and packaging the drug substance.
These operations should be performed in closed systems, with minimal operator handling. Any aseptic operations performed by an operator(s) other than in a closed system should be identified and carefully reviewed.
In addition to the impurity concerns for the manufacture of bulk drug substances, there is a concern with endotoxins in the manufacture of the sterile bulk drug substances. The validation report, which demonstrates the removal, if present, of endotoxins to acceptable levels, should be reviewed. Some manufacturers have commented that since an organic solvent is typically used for the conversion of the non-sterile bulk drug substance to the sterile bulk drug substance, that endotoxins will be reduced at this stage. As with any operation, this may or may not be correct. For example, in an inspection of a manufacturer who conducted extensive studies of the conversion (crystallization) of the non-sterile substance to the sterile drug substance, they found no change from the initial endotoxin level. Organic solvents were used in this conversion. Thus, it is important to review and assess this aspect of the validation report.
In the validation of this conversion (non-sterile to sterile) from an endotoxin perspective, challenge studies can be carried out on a laboratory or pilot scale to determine the efficiency of the step. Once it is established that the process will result in acceptable endotoxin levels, some monitoring of the production batches would be appropriate. As with any validation process, the purpose and efficiency of each step should be evaluated. For example, if the conversion (crystallization) from the non-sterile to the sterile substance is to reduce endotoxins by one log, then data should support this step.
Since endotoxins may not be uniformly distributed, it is also important to monitor the bioburden of the non-sterile substance(s) being sterilized. For example, gram negative contaminats in a non-sterile bulk drug substance prior to sterilization are of concern, particularly if the sterilization (filtration) and crystallization steps do not reduce the endotoxins to acceptable levels. Therefore, microbiological, as well as endotoxin data on the critical components and operational steps should be reviewed.
Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control. Because sterile bulk aseptic facilities are usually larger, problems with pressure differentials and sanitization have been encountered. For example, a manufacturer was found to have the gowning area under greater pressure than the adjacent aseptic areas. The need to remove solvent vapors may also impact on area pressurization.
Unnecessary equipment and/or equipment that cannot be adequately sanitized, such as wooden skids and forklift trucks, should be identified. Inquire about the movement of large quantities of sterile drug substance and the location of pass-through areas between the sterile core and non-sterile areas. Observe these areas, review environmental monitoring results and sanitization procedures.
The CGMP Regulations prohibit the use of asbestos filters in the final filtration of solutions. At present, it would be difficult for a manufacturer to justify the use of asbestos filters for filtration of air or solutions. Inquire about the use of asbestos filters.
Facilities used for the charge or addition of non-sterile components, such as the non-sterile drug substance, should be similar to those used for the compounding of parenteral solutions prior to sterilization. The concern is soluble extraneous contaminants, including endotoxins, that may be carried through the process. Observe this area and review the environmental controls and specifications to determine the viable and non-viable particulate levels allowed in this area.
Sterile powders are usually produced by dissolving the non-sterile substance or reactants in an organic solvent and then filtering the solution through a sterilizing filter. After filtration, the sterile bulk material is separated from the solvent by crystallization or precipitation. Other methods include dissolution in an aqueous solution, filtration sterilization and separation by crystallization/filtration. Aqueous solutions can also be sterile filtered and spray dried or lyophilized.
In the handling of aqueous solutions, prior to solvent evaporation (either by spray drying or lyophilization), check the adequacy of the system and controls to minimize endotoxin contamination. In some instances, piping systems for aqueous solutions have been shown to be the source of endotoxin contamination in sterile powders. There should be a print available of the piping system. Trace the actual piping, compare it with the print and assure that there are no "dead legs" in the system.
The validation data for the filtration (sterilization) process should also be reviewed. Determine the firm's criteria for selection of the filter and the frequency of changing filters. Determine if the firm knows the bioburden and examine their procedures for integrity testing filters.
Filters might not be changed after each batch is sterilized. Determine if there is data to justify the integrity of the filters for the time periods utilized and that "grow through" has not occurred.
In the spray drying of sterile powders, there are some concerns. These include the sterilization of the spray dryer, the source of air and its quality, the chamber temperatures and the particle residence or contact time. In some cases, charring and product degradation have been found for small portions of a batch.
With regard to bulk lyophilization, concerns include air classification and aseptic barriers for loading and unloading the unit, partial meltback, uneven freezing and heat transfer throughout the powder bed, and the additional aseptic manipulations required to break up the large cake. For bulk lyophilization, unlike other sterile bulk operations, media challenges can be performed. At this point in time, with today's level of technology, it would seem that it would be difficult to justify the bulk lyophilization of sterile powders (from a microbiological aspect). Refer to the Guide for the Inspection of a Lyophilization Process for additional direction regarding this process.
Seek to determine the number and frequency of process changes made to a specific process or step. This can be an indicator of a problem experienced in a number of batches. A number of changes in a short period of time can be an indicator that the firm is experiencing problems. Review the Process Change SOP and the log for process changes, including the reason for such changes.
Equipment used in the processing of sterile bulk drug substances should be sterile and capable of being sterilized. This includes the crystallizer, centrifuge and dryer. The sanitization, rather than sterilization of this equipment, is unacceptable. Steriliza
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