Research & Process
Development Facilities

API R&D of compounds derived via chemical synthesis presents many challenges and considerations that need to be identified, quantified, and solved. When a new and unique chemical moiety is first prepared, the synthetic route to its creation may be suitable in a research laboratory but it may be inappropriate and possibly dangerous to obtain additional significant quantities. This process of obtaining increasing quantities of a new drug substance encompasses the entire range of facilities and equipment from laboratory glassware for initial screening through large chemical reactors for commercial production.

Traditional research laboratories can generally synthesize micro-gram quantities of unique chemical materials using standardized small-scale glassware. However, if a newly discovered compound shows promise, more of it is required to sufficiently study its potential. Initially, the research laboratory prepares more of the material but will soon be overextended both in space and labor.

Bulk Raw Materials

Small quantities of liquid raw materials are typically charged via a drum or other small container. In small scale manufacturing, this is accomplished at the reactor level. In large-scale manufacturing, materials can also be charged from a charging floor located above the reactors. Bulk/large quantities of liquid raw materials are generally charged via pumps and hard piping from a tank farm in order to keep the systems tight. These liquids can be piped throughout the facility for charging into the reactors via hard piping, which can be very costly and require a large amount of space. A cost-effective solution that Parsons has employed has been to utilize a manifold concept.

A manifold room can be utilized for piping solvents to a fixed point such as a transfer panel. Using a spool piece or hose, the selected solvent can then be connected from a tank farm source tank directly to a reactor, and the transfer can take place.

Utilizing this method, any bulk solvent can be hard-piped to any vessel. Also, any vessel can be piped to any other vessel. The amount of piping to be installed in a plant can be significantly reduced while adding the benefit of increased flexibility.

Most major pharmaceutical companies at this point transfer the preparation of the material from research to chemical development. Some design issues to consider for chemical development facilities are:

Once the project is initiated, the chemical development group reexamines the research work and embarks on a comprehensive effort to develop a chemical synthetic route that satisfies upcoming clinical requirements and, if warranted, commercial needs. The preparation of the active substance provides a wide range of challenges. Facility design must allow for flexibility in operations while maintaining a high standard of personal and environmental protection. Superimposing the regulatory framework of cGMP compliance into this mix heightens project complexity, requiring a highly integrated design approach, and a substantial range of disciplines. Major areas of concern are:

• Environmental protection
• Equipment:
• Size or capacity
• Types and capability
• Material of construction
• Potential energy of the:
• Individual materials employed
• Various reaction mixtures
• Safety
• Suitability of the processing equipment
• Toxicity of the:
• SB
• Individual materials employed
• Intermediates produced

The traditional development of a viable process typically encompasses a series of scale-up executions starting in small glassware (e.g., 1 liter) in size and increasing in size as more material is required and more is learned about the process. In a laboratory setting, the work usually ends at the larger glassware (e.g., 22 liter size). Depending on material requirements and/or the maturity of the process, the process is transferred to a kilo laboratory or to a pilot plant for production of larger amounts of product.