Sterile pharmaceutical products manufacture

ABC Pharmaceutical Industries routinely monitors the microbial content of the air, inanimate surfaces, personnel, water systems, and product component bioburden. Microbiological monitoring of these areas generally reflects on the efficiency of cleaning and sanitization procedures and employee practices. Continuous environmental monitoring provides the assurance that product is produced by a controlled process that will maximize the sterility and quality of the manufactured sterile product. 

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. 

The purpose of this book is to help practitioners in the field who manufacture sterile products, pharmaceutical products, and medical devices to understand what needs to be done to achieve sterility. It is not intended for experts in specific sterilization technologies indeed, that would necessitate a multivolume, multiauthor work. 

Pharmaceutical products are used in a variety of ways in the prevention, treatment and diagnosis of disease, hi recent years, manufacturers of pharmaceuticals have improved the quality of non-sterile products such that today the majority contain only a minimal microbial population. Nevertheless, a few rogue products with an unacceptable level and type of contamination will occasionally escape the quality control net and when used may, ironically, contribute to the spread of disease in patients. 

Areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate level of microbial and particulate cleanliness four grades (Table 22.1) are specified in the Rules and Guidance for Pharmaceutical Manufacturers and Distributors (1997), defined by measures of airborne contamination (Table 22.2). Environmental quality is substantially influenced by the air supplied to the manufacturing environment. 

It is quite rare that the composition or the packaging of an ophthalmic pharmaceutical will lend itself to terminal sterilization, the simplest form of manufacture of sterile products. Only a few ophthalmic drugs formulated in simple aqueous vehicles are stable to normal autoclaving temperatures and times (121°C for 20-30 min). Such heat-resistant drugs may be packaged in glass or other heat-de-formation-resistant packaging and thus can be sterilized in this manner. The convenience of plastic... 

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. 

According to 211.113 Control of microbiological contamination, pharmaceutical manufacturers need written procedures describing the systems designed to prevent objectionable microorganisms in both nonsterile and sterile drug products. All sterilization processes used to manufacture parenteral drugs need to be validated. 

The required information as outlined in sections IV and V of the EDA Guidance is in boldface type, followed by ABC Pharmaceutical Industries information. It is submitted in the ANDA file for the manufacturing of (product name) USP. Other sections of the Guidance (sections I to III) pertain to the Guidance s introduction and terminal sterilization processes. 

This document contains information related to the liquid aseptic fill operation used in the manufacture of (product name), USP, at ABC Pharmaceutical Industries located at (provide postal address). Additional information to support the liquid aseptic filling validation includes but is not limited to environmental monitoring and controls, as well as product-specific testing such as bioburden and sterility testing. The main subsections are ... 

ABC Pharmaceutical Industries is located (provide postal address). ABC Pharmaceutical Industries manufactures sterile pharmaceutical dosage forms in strict compliance to the cGMP, United States FDA guidelines. ABC Pharmaceutical Industries is supplying its products to its customers around the world. 

The purpose is to develop a guideline to validate the efhcacy of the sterility test method for a specihc product or material. The similarity of the validation approach with the other pharmaceutical manufacturers shall be considered coincidental due to the similarity of operations and the nature of the work. 

Edwards, L. M., Childers, R. W. Hydrogen peroxide vapor sterilization Applications in the production environment. In. M. J. Groves and R. Murty, eds. Aseptic Pharmaceutical Manufacturing II Applications for the 1990s. Buffalo Grove, IL Interpharm Press, pp. 415-466 (1995). 

The nature of the primary contaminating product—The nature of the primary potentially contaminating product refers to how the product is administered to the patient. Is the product a finished pharmaceutical dosage form or is it a precursor or chemical intermediate that will be used as a starting material by other companies to manufacture finished products Are the products sterile or nonsterile What is the route of administration of the product (e.g., oral, topical, intravenous, ophthalmic) The answers to these questions will dictate the actual calculations to be used to determine acceptable limits. 

The concept of validation came up in the 1970s in association with sterilization procedures and was extended to all steps of pharmaceutical manufacturing procedures. Validation means proving that any and all procedures, processes, equipment, material, operations, and systems comply with the expected performance. Well-planned and well-conducted validation studies constitute GMP principles once they guarantee a consistently safe and efficacious final product. Validation is important for companies, first for QA, and also for cost reduction, decreasing failures, rejection, reworks, recalls, and complaints. The positive aspect of validation is an increase in productivity, as a consequence of a well-controlled process. Validation is required by the regulatory agencies of many countries. 

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. 

Pharmaceutical Products and Materials for Aseptic Manufacture—Sterilization Specifications... 

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. 

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