Several Major Issues that Need to be Paid Attention to API Process Scale-up

The quality of the active ingredient of the drug, the bulk drug, largely affects the safety and effectiveness of the drug. In order to ensure the production quality of medicines and the safe use of medicines for the people, it is necessary to pay attention to the GMP on-site management of the raw material medicine production workshop. The GMP production workshop is of great significance to the effective implementation of production quality management and the production of high-quality drugs. When the production of APIs is to be scaled up from laboratory scale to industrial scale, it is necessary to pay attention to the problems that may exist when the API process is scaled up.

(1) Evaluation of availability of raw material intermediates

Before carrying out the scale-up reaction, the composition of the raw material intermediates should be checked to determine whether the expected profit can be obtained and the product with the expected yield and quality can be provided. The usability evaluation of raw materials and intermediates should pay attention to two combinations: analysis and testing combined with experimental verification; raw material evaluation and intermediate evaluation combined.

(2) Review of the production process route of API

Industrialization is the ultimate goal of the development process of APIs. The first consideration in route selection is whether it can be mass-produced industrially. In general, the unit reaction method and production process route should be basically selected at the laboratory stage. In the pilot scale-up stage, only specific process operations and conditions are determined to suit industrial production. However, when the selected process route and process reveal major problems that are difficult to overcome during the pilot scale-up, it is necessary to review the laboratory process route and revise the process.

(3) The process scale-up route should be as complicated as possible

The process development and scale-up should be as simple as possible. The simpler the process, the fewer opportunities for process errors. In actual operation, the more complex the process, the more difficult it is for operators to master, and it is also difficult to describe in detail through operating procedures. Simplification is not only from safety considerations, but also can reduce production cycles and reduce waste. Avoid reactions using very special equipment, or very dangerous reactions that require safety facilities, such as nitration, hydrogenation, etc.

The simplification of the process comes from the simplification of the reaction route, and the route with the least number of reaction steps is often the better route. In the process development stage, it is necessary to consider whether it is possible to avoid the separation of intermediates, to combine reactions, and to reduce the types and quantities of solvents used.

Medicilon is a CRO company dedicated to providing customers with fast and efficient services. Its unique “customized” pharmaceutical process research and development model also fully embodies this concept, enabling customers to obtain APIs as soon as possible for clinical research. Medicilon’s process R&D department has rich experience in process optimization and development of new, safe and environmentally friendly process routes, and is committed to helping customers develop stable, low-cost and suitable for large-scale production processes.

(4) The availability of equipment and the choice of material and type

Establish a GMP production workshop, implement effective GMP transformation technology in the pharmaceutical production process, and improve the actual core content of the workshop. The pharmaceutical design department clarifies the actual production level and determines the actual GMP production implementation standard requirements that are actually met. The 2010 version of the GMP has greatly improved the control requirements for the production of bulk drugs, especially sterile bulk drugs, and the requirements for production equipment have also been greatly improved.

The availability of equipment needs to be considered when the bulk drug process is scaled up. Six points should be noted for the evaluation of equipment availability: whether the mixing state meets the process requirements; what is the minimum feeding solvent of the reaction equipment; whether the heating medium has a temperature indicator and can be controlled in the process Within the required range; whether the temperature of the dripping point can be controlled (whether the dripping reaches a sufficient low temperature, whether the dripping is sufficiently diluted, whether the dripping position is at the maximum stirring point, whether the distribution of the dripping liquid meets the process requirements, etc.); Whether the cleaning and drying degree required by the process has been achieved; whether the reaction equipment has reached the sealing degree required by the process.

At the beginning of the pilot scale-up, the materials and types of the various equipment required should be considered, and whether they are suitable, especially the selection of equipment materials that contact corrosive materials.

(5) Examination of agitator type and mixing speed

Most of the reactions in drug synthesis reactions are heterogeneous reactions, and the reaction heat effect is relatively large. In the laboratory, due to the small volume of the material and the good mixing efficiency, the heat and mass transfer problems are not obvious, but during the pilot scale up, due to the influence of the mixing efficiency, the heat and mass transfer problems are prominently exposed . Therefore, during the pilot scale-up, the type of agitator must be studied according to the nature of the material and the reaction characteristics, and the influence of the stirring speed on the reaction law must be investigated. Especially in the solid-liquid heterogeneous reaction, the type of agitator that meets the requirements of the reaction must be selected And suitable stirring speed.

(6) Further research on reaction conditions

The best reaction conditions obtained in the laboratory stage may not meet the requirements of pilot scale-up. The main influencing factors, such as the feeding rate in the exothermic reaction, the heat transfer area and heat transfer coefficient of the reaction tank, and the refrigerant, should be conducted in-depth experimental research to master their changing laws in the pilot plant , In order to get more suitable reaction conditions.

(7) Determination of process flow and operation method

In the pilot scale-up stage, due to the increase of processed materials, it is necessary to consider how to adapt the operation methods of reaction and post-processing to the requirements of industrial production, especially to shorten the process and simplify the operation. Avoid heating after putting in all the raw materials and heating without stirring, and do not put solids into the reaction mixture that is refluxing or hot. This is a common operation in small trials, but it is difficult to achieve in production.

For those who are new to process amplification, perhaps the biggest surprise is that all operations take a long time. It is important to perform all stability assessments involving raw materials, intermediates and products before scale-up. Avoid reactions that must be quenched and separated immediately after the reaction.

(8) Quality control of raw and auxiliary materials and intermediates

Including: (1) determination of physical properties and chemical parameters of raw and auxiliary materials and intermediates; (2) formulation of quality standards for raw and auxiliary materials and intermediates. In addition, avoid ignoring the use of solvents. In the small test, solvents with good solubility and easy distillation and recovery may be used. But some of them need to be avoided in production. This includes all types of solvents, solvents with flash points below -18.

(9) Don’t ignore potential degradation reactions

Do not carry out the reaction within 50 of the known degradation temperature of the reactants to avoid the reaction out of control. In addition to calorimetric evaluation of exothermic reactions, self-accelerated degradation reactions also need to be investigated. This requires additional experiments, such as adiabatic reaction calorimetry (ARC). If the analysis believes that the reaction may produce potentially unstable and easily degradable products, corresponding calorimetric experiments should be carried out.

Some degradation reactions may proceed very slowly and cannot be identified by conventional tests. Even if it is lower than the initiation temperature, the reaction exotherm will still increase at a small rate. When the temperature is found to rise significantly, the decomposition reaction has already occurred.

The preparation of APIs can provide qualified APIs for pharmacology and toxicology research, preparations and clinical studies in the process of drug research and development, and provide detailed information for drug quality research. Therefore, it is of great importance to provide APIs preparation processes that meet industrial production. The establishment of a GMP production workshop for raw materials to comprehensively improve the on-site GMP management level of the raw materials production workshop provides a guarantee for the production of high-quality drugs.

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