Pharmaceutical manufacturing operations

Company A is a major pharmaceutical manufacturer with worldwide operations. The U.S. Chemical Safety and Hazard Investigation Board (CSB) staff visited a site with both pilot-plant facilities and pharmaceutical manufacturing operations. The company is continually developing new and innovative chemistry, which results in frequent changes in the chemicals handled and manufacturing techniques used. 

Pharmaceutical manufacturing operations are inefficient and costly. The cost of low efficiency is generally not understood or appreciated (e.g., manufacturing costs far exceed those for research and development operations). Low efficiency is predominantly due to self-imposed constraints in the system (e.g., static manufacturing processes, focus on testing as opposed to quality by design, approach to specifications based on discrete or the so called zero tolerance criteria, a less than optimal understanding of variability, etc.). These constraints keep the system in a corrective action mode. 

Pharmaceutical manufacturing operations are inefficient and costly. Compared to other industrial sectors, the rate of introduction of modern... 

The cGMPs require manufacturers to have adequately equipped manufacturing facilities, adequately trained personnel, precisely controlled manufacturing processes, appropriate laboratory controls, complete and accurate records and reports, appropriate finished product examination, and so on. Current GMPs are not best practices rather, they establish threshold or minimum standards which must be satisfied in order for a pharmaceutical manufacturing operation to be compliant. 

Fourman, G.L., Mullen, M.Y., Determining cleaning validation acceptance limits for pharmaceutical manufacturing operations. Pharm Tech April 1993... 

This is an example of a rating system for a biologies or pharmaceutical manufacturing operation. The comprehensive assessment should cover all critical compliance systems (process validation, personnel training, change management system, etc.) and determine whether or not they meet FDA expectations and current industry standards. 

Amorphous substances are an important class of pharmaceutical materials that exhibit distinct physical and chemical properties. They are ubiquitous, and may be formed both intentionally and unintentionally during normal pharmaceutical manufacturing operations. The properties of amorphous materials can be exploited to improve the performance (e.g., bioavailability and dissolution rate) of pharmaceutical dosage forms, but these properties can also give rise to unwanted effects (e.g., physical instability) that need to be understood and managed in order for the systems to perform as required. 

In industry, the BSC is used to conduct small batch sterile-fill operations, manipulation (weighing and pouring), isolation of hazardous materials, and in QA/QC testing applications. All classes of BSC are encountered in pharmaceutical manufacturing operations for a wide variety of processing applications. 

The major difference between a biotechnological process and other pharmaceutical manufacturing operations is the need for a bioreactor (Fig. 8). These bioreactors may be required to produce expressed proteins utilizing bacteria, yeast, insect, or mammalian... 

FDA initiatives and other government regulations influence pharmaceutical manufacturing operations, including preformulation studies and quality control systems. These regulatory issues include the topics outlined below. 

Dolan, D., Naumann, B., Sargent, E., Maier, A., and Dourson, M. (2005). Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations. Regul Toxicol Pharmacol 43, 1-9. 

Because of the importance of product purity and the presence of toxic and biologically active constituents, pharmaceutical manufacturing operations must be very clean and closely controlled. Controlling air emissions is considered important to avoid the inadvertent contamination of products and to prevent occupational and community exposure to harmful substances. Using emission controls is also important... 

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