Analysis Of Main Points Of Process Scale-Up Of API

Many “accidents” encountered in the process of process scale-up can be predicted. If you can pay more attention to some details during the small test, do some simple experiments, and collect some data, it will be of great help to the future process scale-up.

The glass flask used in the test generally does not have corrosion problems (glass is not resistant to hydrofluoric acid and compounds that may decompose to produce fluorine, hot concentrated alkali). However, the compatibility of materials and materials in production must be considered, which is also the requirement of GMP for equipment selection. If you can consider doing a corrosion test of the material during the small test (adding stainless steel or other material test pieces to the reaction system), it will save time for equipment selection in the future. A simple measurement of the bulk density of the filter cake is beneficial to the estimation of the product filter cake volume and equipment selection in future production. The filtration speed has a certain relationship with the filter area and the thickness of the filter cake.

Part 1 Common Problems In Process Scale-Up

The most common problem in process scale-up is the change of reaction selectivity, which will affect the yield and purity of the product, which is mainly due to the inconsistent mixing effect and production of the small test. If the influence of the speed has been evaluated in the small test, the cause will be quickly found when a problem occurs. The reactors in the pilot plant are equipped with frequency conversion speed regulation, and appropriate adjustments can be made to determine the appropriate speed.

It is also common for new crystalline forms to appear during scale-up. During the scale-up, there will be problems in the separation of the product. The washing effect of the filter cake in the production cannot reach the level of the small test, and the impurities cannot be completely washed away. The filter, washing and drying three-in-one equipment with stirring can replace the centrifuge under certain process conditions. The three-in-one equipment can be directly added to the solvent for washing and beating after filtration, and the washing effect is better than that of the centrifuge.

Another reason for the scale-up problem is the influence of production operation time. It is necessary to carry out experiments on the influence of time extension on products in small experiments. In actual production, due to the prolongation of the distillation time, the product is decomposed and side reactions occur many times.

The reason for the amplification problem is that the reaction mechanism is not understood, crystallization and mixing are the three most common reasons. In the following, we can see that although there are many problems related to mixing and heat transfer, the fundamental lies in the understanding of chemistry. In addition to the main reaction, what side reactions will occur? What conditions will promote the occurrence of side effects? What changes during zooming in? How would these changes affect the selectivity of the reaction? In actual production, the heat transfer conditions of the current reactor can basically not be changed (the local supercooling/heating can be reduced by controlling the temperature difference between the heating, cooling medium and the system in the kettle, and the speed of heating/cooling), and the mixing can be achieved by rotating speed and paddle Type selection is improved.

Part 2 Key Points Of Establishing Process Scale-Up System

1 Teamwork In Process Scale-Up

A stable, scalable process can only be achieved through the close cooperation of different professionals. Chemists have a deep understanding of how variables affect product quality. Process engineers have a better understanding of what operations are not feasible or safe in production. Also, as mentioned earlier, there are many tests that chemists can do early in process development. Such as drying and distillation experiments, record physical parameters such as pressure and density of the system.

2 Principles Of Process Development And Operation

Regardless of the size of the company, some basic rules need to be established to ensure the safe transfer of small-scale processes to kilogram laboratories and pilot plants. Establish clear and strict procedures and documentation required for small tests, resist pressure, and strictly enforce them even under time constraints. These materials include production operating procedures, and there are three batches of small-scale tests carried out according to these operating procedures, at least one batch adopts and produces the same specifications of raw materials. Cleaning validation protocol to avoid the possibility of cross-contamination. Process safety analysis data. Although the above requirements will affect “efficiency”, under strict implementation, there have been no serious accidents and failed batches for many years.

3 Process Test Equipment Ledger

Establish the operation and maintenance log of the main equipment (reactor, filter, dryer, pump, etc.) of the kilogram laboratory and pilot plant. Include batch records, cleaning records, validation records and other maintenance records.

4 Sample Database

Establish a sample database, collect and organize the data of each sample (product, wet filter cake, distillate, process by-product). Including production batch number, collection time, analysis results, etc. These data have important reference value, and the collection and arrangement can ensure that the data will not be lost. For research and regulatory reasons, it is often necessary to reanalyze these samples for confirmation, and a constant mass calculation can be performed.

5 Sample Storage

With the establishment of the sample database, it is necessary to set up a special sample room to store samples, pay attention to dryness, avoid light, and low temperature. It is important to have a system in place so that the samples you need can be quickly found when you need them.

6 Fixed Process

Identify and resolve relevant issues prior to trial production. Changing processes at the last moment before scale-up is dangerous. May cause accidents and safety problems.

7 Process Risk Assessment (Hazop Analysis)

Risk assessment should be carried out before trial production of new technology. An assessment team should be composed of personnel from different departments to conduct a detailed review of the entire process safety and preventive measures. There is no 100% safe process, but according to the evaluation results, corresponding measures can be taken to avoid or reduce safety accidents.

8 Determining The Reaction Energy

Insufficient awareness or recognition of the hazards of exothermic reactions can be a major cause of serious injuries and accidents. The heat transfer area per unit volume of the reactor in production is much smaller than that of the small test flask. The heat transfer area of the 500ml flask is about 0.02㎡, while the 4000L reactor only has a heat transfer area of 10.7㎡.

Safe scale-up therefore requires calorimetric or similar experiments. For the work in this area, we are gradually attracting our attention. Although no serious accidents have occurred, punching materials in production have occurred from time to time. In the small test stage, it is necessary to avoid the use of compounds containing high-energy functional groups (such as compounds containing multiple amine groups, tetrazole, hydrazine hydrate), the reactions that may generate free radicals and the reactions that generate gas should be given enough attention, and in the process Describe clearly when transferring.

9 Establish Production Operating Procedures

Needless to say, the importance of production operating procedures is to ensure the timeliness of the procedures and minimize text errors. Using “copy-and-paste” when editing documents can bring convenience, but it can also lead to unintentional errors. This is also the importance of repeating the experiment in the small test according to the process regulations.

10 Raw Material Control

The experiment uses industrial-grade raw materials, and conducts small-scale experiments on all raw materials before expanding production. In this way, if the enlargement is unsuccessful, the cause of the raw material can be directly eliminated. In addition to the chemical purity of raw materials, physical properties also have an impact on the reaction, such as the particle size of solid materials.

11 Seize The Opportunity To accumulate Process Data

To prepare for pilot production requires a lot of labor, time and money. Many times, however, only limited data is collected. That’s why it’s important to take advantage of every production opportunity you can to learn. A detailed sampling and analysis plan can assist in performing mass balance calculations, identifying unexpected by-products and addressing other possible scale-up issues. Every process stream (including waste) is weighed and sampled. There is no other opportunity to collect as much data as the pilot test!

All observations should be recorded and isolated intermediates and samples should be retained for future use. Take advantage of the opportunity to collect as much scale-up data as possible and conduct a detailed summary analysis of production in a report for future reference. Verification is required during production transfer. Prior to this, trial production is required to familiarize yourself with the process and determine process regulations and operating procedures. If the trial production goes well, the verification time will also be shortened. The success of the trial production depends on the in-depth research on process issues in the early stage of small test research and development and pilot test stage.

Part 3 Process Scale-Up Summary

In the process of process amplification, strictly abide by the process flow formed in the small test process, and do not change it at will; strictly record the realization phenomena and process parameters in the process of process scale-up, and form important original data. In the process of process scale-up, experience is very important, and there are many excellent references worth learning and adopting.