Integrating Safety Testing into Pharma Process Scale-up

Each process hazard should be mitigated with a defined basis of safety

By Swati Umbrajkar, Ph.D., Andrew J. Starkie, Ph.D., and Stephen M. Rowe, Ph.D., Chilworth Global

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Due to the novel nature of the materials being developed by pharmaceutical and fine chemical companies, all the information required for safe scale-up, storage, etc., is not readily available to the industry. The process lifecycle for a drug and fine chemical manufacture involves multiple stages. Once the chemical route and optimum process conditions have been defined, the scale-up process begins.

When scaling up a chemical process from the laboratory to the pilot plant, and then from pilot plant to plant/production scale, there is an appreciable increase in the risk posed by the process. In addition to the simple increase in the inventory of hazardous materials that are to be handled, there are changes in heat and mass transfer characteristics that may affect the progression of a reaction. Processes that are commonly most hazardous to scale-up are those associated with exothermic reactions (i.e., where heat is liberated during the reaction) and those which generate non-condensable gas.

In most cases, the process which is to be scaled-up will be complete, with a significant amount of existing physical property and thermochemical information pertaining to the thermodynamics and kinetics of the desired reaction (and defined deviations) and the fire and explosion properties of the process materials. The majority of this information will have been compiled prior to pilot-scale operations. It is critical, however, that these same data (and possibly some additional data) are available to enable safe scale-up to full-scale production.

In essence, each process hazard should be mitigated with a defined basis of safety. This should be a definitive safety measure (or collection of safety measures) which, when applied to a process, should either minimize the likelihood of an event occurring to an acceptably low level or, where this is not possible, provide a method for protection of personnel, the equipment, and/or environment from the manifestation of the event.

The scale-up of a chemical process will probably be collectively dependent on thorough study by a variety of individual groups within a company. Ideally, a multi-disciplinary team should be appointed to be responsible for each new process to be scaled-up (from laboratory-scale to full-scale). This team should include personnel from the following departments:

• Research
• Process development
• Safety
• Engineering
• Pilot plant
• Production (including possibly a process operator and a mechanic)
• Analytical

The attendance of a mid-level to senior manager is desirable, since this individual will be at an appropriate level to influence capital expenditure and keep track of development costs and timescales. A team leader should be appointed when the team is organized, and the leader would have responsibility for recording and feeding-back the team’s findings and compiling a process technology document (or similar scale-up manual for the process).

The concept of dividing project ownership among the individuals on the scale-up committee can be the most effective method of ensuring rapid and smooth transition through all of the stages of a process lifecycle. The integration of the skill bases of the individuals will also facilitate inter-departmental understanding and cross-fertilization of ideas, concepts and approaches. The same team should be reconvened to consider process developments or modifications, once full-scale production has been realized.

When a process is to be scaled-up, there are usually a number of potential hazards which must be considered via a strategic assessment procedure. With reference only to the thermal hazards posed by a reaction or process, the following six issues should be considered:

1) What are the thermal-stability characteristics of the process raw materials?
2) What are the thermodynamics of the desired chemical process and possible undesired reactions?
3) What are the kinetics of the desired chemical process and possible undesired reactions?
4) What are the thermal-stability characteristics of the intermediate process materials?
5) What are the thermal-stability characteristics of the process products and waste materials?
6) Are permanent non-condensable gases evolved at any stage of the process (or during material-handling operations)?

The questions posed by the issues above should have been fully considered prior to pilot-scale manufacture. The organization of safety studies varies significantly from company to company and, ideally, safety should be an integral part of the standard process-development stages. In reality, however, it is usually considered when a process is close to pilot-scale production.

The advantage of considering process hazards at a very early stage is that changes to the process can be made to minimize the hazards that are posed without having to re-validate or re-evaluate the process after safety problems have been corrected. There are a number of critical parameters which must be defined prior to any scale-up operations:

• What are the safe handling temperatures for the reaction starting materials, and the safe upper (and lower) temperatures for the intermediate and final process streams?
• Thermal stability trials should be conducted on all isolated process streams to provide information for establishing these parameters.
• What are the maximum and minimum allowable temperatures to effect the desired chemical conversion?
• If the temperature is too low, a semi-batch process may suffer from accumulation (i.e., the rate at which material is added becomes significantly greater than the rate at which the material is consumed by reaction).
• If the temperature is too high, the reaction rate will increase, and the rate of heat evolution may exceed the cooling capability of the reactor jacket and/or coils. In certain circumstances, elevated temperatures may trigger the onset of undesired (side) reactions or decompositions, yielding non-condensable gases.

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