Sterile drug bulk production

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. ... 

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. ... 

Subpart C, Drug Compounding Faeilities. These are discussed further in the next seetion of this article. It also discusses bulk drugs and materials as well as the compounding of sterile products, radiopharmaceuticals, and products requiring special precaution such as the handling of penicillins. 

Regarding the components of bulk fermentation processes, the strain of the organism used to manufacture the drug substance for the clinical study should be compared with the strain to be used in commercial production. Strain identification includes microbiological, cultural, and biochemical characteristics. A comparison of the media composition and method of sterilization, sterilization parameters, and the pH of the medium after sterilization should be done. All fermentation stages, parameters, and conditions should be described in detail (i.e., temperature, pH) and documented. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

For the manufacture of sterile products please refer to Part Three, section 17. For the manufacture of active pharmaceutical ingredients (bulk drug substances) please refer to Part Three, section 18. 

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. 

Validation was initially introduced in the 1970s to the pharmaceutical industry as a means for more firmly establishing the sterility of drug products where normal analytical methods are wholly inadequate for that purpose. In following years, its application was extended to numerous other aspects of pharmaceutical operations water systems, environmental control, tablet,and capsule formulations, analytical methods, and computerized systems. Individuals working with bulk pharmaceutical chemicals (BPCs) were particularly reluctant to embrace validation as a necessary practice in their operations. Industry apologists explained this lack of enthusiasm... 

The first step in the manufacture of almost all freeze-dried products is the formation of a solution of the ingredients to be dried. Typically these solutions are sterile filtered, aseptically filled into containers, and freeze-dried. Some hydrophobic ingredients (e.g., the bulk drug or excipients) may... 

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