Process Development and Manufacturing

The active ingredient of a potential product as it was identified in research is initially produced in minute amounts and by a process which in most cases is not acceptable for a pharmaceutical product or for large-scale production. Process development represents a link between research and manufacturing and adapts the research methods to the needs of production or develops new methods where necessary. Process developers must take multiple aspects into consideration (Table 7). Their task would be much easier, if researchers were aware of these aspects. 

In the worst case process development can imply that an entirely new procedure to obtain the active ingredient must be found and established. Frequently master seed stocks (cells, viruses, bacteria) must be newly generated and tested, since those from research are not suitable because 

Availability appropriate quantities, regular supply. Quality specifications and consistency (compliance with pharmacopoeia specifications if these exist). 

Freedom of adventitious agents, e.g. from human serum components or bovine serum  

Master seed cultures quality, documentation, suitability. 

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The line-chemical industry embodies a complex combination of physical assets, technologies, know-how and intellectual property (IP) that are geared to commercial process development and manufacturing. As opposed to process IP, there is in general little or no product IP owned by a fine-chemical company. Since the mid-1990s the marketplace has become much more competitive with a proliferation of independent players and the emerging strength from low-cost economies (see Chapter 14). 

Scale-up. Technology transfer lack of clear boundaries dividing research, process development, and manufacturing for protein products. 

Zhang GZ, Law D, Schmitt EA, Qiu Y. 2004. Phase transformation considerations during process development and manufacture of solid oral dosage forms. Adv. Drug Deliv. Rev. 56 371-390. 

At this time prime responsibility for the project was shifted from the Research Department to the Development Department under W.B. Nicholson. E.R. Behnke was given responsibility for molecular sieve sales, and I was made Manager of the Tonawanda Development Laboratory, responsible for molecular sieve applications, and in time, process development and manufacturing. 

Scarlett, J. A. (1996). Outsourcing process-development and manufacturing of rDNA-derived products. Trends Biotecbnol. 14, 239-244. 

Another important general objective which has been defined in the product profile may be the expected price limit for the production of the active ingredient or the formulated product. Specific tasks and measurable success criteria for process development and manufacturing, e.g. in terms of yields and recovery after purification, can be deduced from this price limit. Other very specific objectives and the majority of project tasks relate to specific registration requirements. 

Zhang, G.G. Law, D. Schmitt, E.A. Qiu, Y. Bauer, M. Bauer, J. Spanton, S. Henry, R. Quick, J. Dziki, W. Porter, W. Morris, J. Highleyman, L. Phase transformation considerations during process development and manufacture of solid oral dosage forms [Crystallization and solid state properties of molecules of pharmaceutical interest] Ritonavir an extraordinary example of conformational polymorphism Ritonavir manufacturing problems. Adv. Drug. Deliv. Rev. 2004, 56 (3), 371-390. 

As practitioners discover (or should soon discover), crystallization skills are paramount among the skills set of the bulk process development (and manufacturing) function. 

Over the last few years, an increasing number of pharmaceutical and biopharmaceutical companies have resorted to outsourcing activities in chiral synthesis, process development, and manufacturing. Dr. Peter Pollack demonstrates this strategy, provides useful pointers about the do s and don ts, and beautifully elaborates the risks and rewards inherent in outsourcing in the pharmaceutical industry. 

Whilst the application of continuous flow reactions is changing the way medicinal chemists are making and trying to identify lead bioactive compounds, the main impact of flow methods on green chemistry is in process development and manufacture, where the volumes of materials produced are far greater. 

Gramer, M.J. (2014) Product quality considerations for mammalian cell culture process development and manufacturing. Adv. Biochem. Eng. Biotechnol, 139, 123-166. 

These criteria are widely applied for the selection of conventional solvents in the process development and manufacturing. Nowadays, a new generation of solvents intervenes in the medicinal chemistry and pharmaceutical industry. These solvents have eco-friendly character and together with water compose an expanding family of green solvents [4-7]. 

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