Key details that are easily overlooked during the scale-up of the synthesis process

Many “accidents” encountered in the process of amplification can be predicted, if you can pay more attention to some details of the small test, do some simple experiments, collect some data on the future process amplification will be of great help. This post, Arborpharm will share with you about the key details that are easily overlooked during the scale-up of the synthesis process.

The glass flask used in the test, there is generally no corrosion problems (glass is not resistant to hydrofluoric acid and may decompose to produce fluorine compounds, hot concentrated alkali). However, the compatibility of materials and materials in production must be considered, which is also the GMP requirements for equipment selection. If the small test can be considered to do a material corrosion test (in the reaction system to add stainless steel or other materials test piece) will save time in the future equipment selection.

Simple measurement of the cake density, for future production for the product of the estimated volume of the cake and equipment selection, filtration speed and filtration area, the thickness of the cake have a certain relationship.

1.2 Typical amplification problems

The most common problem in process scale-up is a change in reaction selectivity, which affects the yield and purity of the product, mainly due to inconsistencies between the mixing effect of the pilot plant and the production. If the effect of rotational speed has been evaluated in the small trial, the cause will be found quickly when problems occur. The reactors in the pilot plant are equipped with variable frequency speed control, which can be adjusted appropriately to determine the appropriate rotational speed.

It is also common for new crystalline forms to appear in the scale-up.

In the amplification, the separation of products can also be a problem, the production of the washing effect for the filter cake is not up to the level of the small test, impurities can not be completely washed away. Filtering washing and drying three-in-one equipment with agitation, in some process conditions can replace the centrifuge, the use of three-in-one equipment can be filtered directly after the addition of solvent washing and pulping, washing effect is better than the centrifuge.

Produce another reason for the amplification problem is the effect of production operation time, small test it is necessary to carry out experiments on the effect of time extension on the product. In actual production, due to the prolongation of distillation time, resulting in product decomposition, the occurrence of side reactions occurred many times.

Zooming in on the causes of the problem, lack of understanding of the reaction mechanism, crystallization and mixing are the three most common causes. In the following we can see that although many of the problems are related to mixing and heat transfer, the root of the problem lies in the understanding of the chemistry – what side reactions occur in addition to the main reaction? What conditions promote side reactions? What changes in amplification? What are the effects of these changes on reaction selectivity? In production practice, the current heat transfer conditions in the reactor are basically unchangeable (you can control the temperature difference between the heating and cooling medium and the kettle system, and the heating/cooling rate to minimize local overcooling/heating), and the mixing can be improved by the selection of the rotational speed and paddle type.

2.1. What needs to be done in scaling up

1. Teamwork

A stable, scalable process can only be obtained through close cooperation between 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.

At the same time, as mentioned earlier, there are many tests that a chemist can perform early in the development of a process. For example, experiments on drying and distillation, recording the 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 ground rules need to be established to ensure the safe transfer of small pilot processes to the kilo lab and pilot plant.

Establish clear, strict protocols and documentation that need to be provided by the pilot plant, and resist the pressure to follow them to the letter, even when there is a time limit to do so. This information included the production protocol and there were three batches of small pilot tests conducted according to this protocol, with at least one batch using the same specification of raw material as the production. Cleaning validation program to avoid the possibility of cross-contamination. Process safety analysis information.

Although the above requirements may affect the “efficiency”, under strict implementation, there have been no serious accidents or failed amplification batches for many years.

3. Equipment account
Establishment of operation and maintenance logs for major equipment (reactors, filters, dryers, pumps, etc.) in the kilo lab and pilot plant. Include batch records, cleaning records, validation records, and other maintenance records.

4. Sample database

Establish a sample database to collect and organize data for each sample (product, wet filter cake, distillate, process by-products). Including production lot number, collection time, analytical results. This data is an important reference value, and collecting and organizing it ensures that it is not lost. For research and regulatory reasons, it is often necessary to re-analyze these samples to determine, at the same time, can be carried out quality constant calculation.

5. Sample preservation
With the establishment of the sample database, it is necessary to set up a special sample room to preserve samples, pay attention to dry, light, low temperature. It is important to establish a system to facilitate the need to quickly find the required samples.

6. Fixing process

Determine and solve the problems before trial production. Changing the process at the last minute before scale-up is dangerous. It can lead to accidents and safety problems.

7. process risk assessment (hazop analysis)
Risk assessment should be performed before trial production of a new process. An assessment team from different departments should be formed to review the entire process safety and precautionary measures in detail.

There is no such thing as a 100% safe process, but based on the results of the assessment, appropriate measures can be taken to avoid or minimize safety incidents.

8. Determination of reaction energy
Insufficient awareness or failure to recognize the hazards of exothermic reactions can be a major cause of major injuries and accidents. The heat transfer area per unit volume of the reactor in production is much smaller than that of a small test flask. 500ml flask has a heat transfer area of about 0.02 square meters, while a 4000L reactor has a heat transfer area of only 10.7 square meters.

Therefore safe scale-up of the reaction requires calorimetric or similar experiments. For this aspect, it is gradually attracting our attention. Although no serious accidents have occurred, flushing in production happens from time to time. Compounds containing high-energy functional groups (e.g., compounds containing multiple amine groups, tetrazolium, hydrazine hydrate) are to be avoided in the small pilot stage, and reactions that may produce free radicals and reactions that produce gases are to be given sufficient attention and described clearly in the process transfer.

9. Establishment of production procedures

The importance of the production procedure needs no explanation, but it is important to ensure that the procedure is up to date and to minimize typographical errors. The use of “copy and paste” when editing documents brings convenience, but can also lead to unintentional errors. This is also why it is important to repeat the experiments in accordance with the process protocols for small trials.

10. Raw materials

Industrial grade raw materials are used for the experiments and all the raw materials are tested in small trials before scaling up. This way, if the scale-up is not successful, the cause of the raw material can be eliminated directly. In addition to the chemical purity of the raw materials, the physical properties also have an effect on the reaction, such as the particle size of the solid material.

11. Seize the opportunity
A great deal of labor, time and money is required to prepare for pilot production. Often, however, only a limited amount of data is collected. That’s why it’s important to take advantage of every production opportunity to learn as much as possible. A detailed sampling and analysis plan can help complete mass balance calculations, identify unanticipated by-products and address other amplification issues that may arise. Every process stream, including waste, must be weighed and sampled. There is no other opportunity to collect as much data as in a pilot plant!

All observations should be recorded, and separated intermediates and samples should be retained for backup. Take advantage of the opportunity to collect as much scale-up data as possible and perform a detailed summary analysis of the production to form a report for future reference.

Validation is required when production is transferred. Before that, trial production is required to familiarize with the process and to determine the process and operating procedures; if the trial production goes well, the validation time will be shortened. If the trial production is smooth, the validation time will also be shortened. The smoothness of the trial production depends on the in-depth study of the process problems in the preliminary small-scale research and development and pilot stage.

2.2. What to avoid in amplification

1. Avoid complexity

Keep the process development and scale-up as simple as possible. The simpler it is, the less chance of process errors. In practice, the more complex the process, the less likely it is to be mastered by the operator and the more difficult it is to describe in detail through operating procedures.

Simplicity is not only a safety consideration, but also reduces production cycles, waste, etc. Avoid reactions that utilize very special equipment. Or very dangerous reactions that require safety facilities, such as nitrification, hydrogenation, etc.

The simplification of the process comes from the simplification of the reaction route, often the route with the least number of reaction steps is the best route. At 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.

2. Avoiding reheating all feedstocks

One of the most dangerous operations in the process is to add all the reactants together and then heat up the reaction. Similarly, do not add the catalyst after the final feed. The danger is that once the reaction mixture reaches the reaction temperature and starts to react, there is no way to stop it. Some reactions are highly exothermic and will warm up to higher and higher temperatures on their own. If the boiling point of the mixture is reached it will boil or even wash out. Some feedstocks degrade at higher temperatures and the degradation is self-accelerating and more exothermic than the reaction itself. Switching and cooling down is also not as convenient and quick as in small trials when the reaction needs urgent cooling.

Of course for reactions that are already understood and determined to be safe, a single input of feedstock is acceptable. However, it should be prohibited for the first scale-up of the process.

The most common control of exothermic reactions is to use a dropwise addition of a reagent, the duration of which depends on the heat of the reaction and the heat transfer capacity of the reactor. When dropping, it is important to avoid the accumulation of raw materials, which can cause sudden reactions. It is necessary to drop at a suitable temperature to ensure that the drop reacts immediately, as in the case of the format reaction.

3. Avoid heating without stirring

Heat transfer in the reactor in production mainly relies on stirring. In addition to ensuring safety, good agitation reduces the temperature difference inside the kettle, allowing for more accurate temperature readings. Generally the kettle wall temperature will be a little higher than the center of the system, which can cause local overheating, product decomposition or coking, and ultimately affect the yield and quality. Stirring should also not be stopped until the reaction is complete and cooled to a safe temperature.

For example, an accident occurred due to a strong exothermic reaction between an organic amine and sulfuric acid. According to the process, the amine needed to be added slowly to the hot sulfuric acid under vigorous stirring, and the reaction was a biphasic system. One day the operating employee changed and started adding the amine without turning on the stirring, and the amine settled to the bottom of the reactor without reacting. A little later another employee realized that the stirring was not on and started the stirring, at which point all the materials reacted instantly resulting in an explosion.

4. Do not ignore potential degradation reactions

Do not react within 50°C of the known degradation temperature of the reactants to avoid uncontrolled reactions. In addition to calorimetric evaluation of exothermic reactions, degradation reactions that can be self-accelerating need to be examined. This requires additional experiments such as adiabatic reaction calorimetry (ARC), which should be performed if the analysis suggests that the reaction may produce potentially unstable and labile degradation products.

Some degradation reactions may be so slow that they cannot be recognized by conventional tests. Even below the initiation temperature, the exotherm of the reaction will still increase at a very small rate, and by the time the temperature is found to have risen significantly, the decomposition reaction has already occurred.

When an API plant in China was carrying out a diazotization reaction, the operator closed the steam valve during the holding phase and left his post to eat, which led to a rise in reaction temperature and decomposition of the diazonium salt due to an internal leak in the steam valve. As no one was on duty, the temperature rise was not detected in time. When the workers on duty returned to their posts and realized that the temperature had risen abnormally, the reaction could no longer be controlled, and an explosion eventually occurred, destroying the whole workshop.

5. Avoid adding solids to the reaction mixture.

Do not put solids into a reaction mixture that is refluxing or hot. This is a common operation in small trials, but difficult to achieve in production. Split dosing is used to control the reaction and is easily accomplished in small trials. However, in the production of solid material is bound to open the manhole, kettle solvent vapors already in the kettle will form an explosive gas mixture with air. If the material reaction is very fast, it will lead to the material spraying out of the manhole (a similar accident occurred when casting sodium hydrogen).

An improvement would be to consider adding the solids first, then the solvent. However, changing the feeding order may affect the selectivity of the reaction. Alternatively, the solids could be dissolved and added, or even formed into a slurry before being pressed into the reactor.

If it is not possible to change the process, engineering considerations need to be made on how to perform the dosing under confined conditions. This has been trying to improve, such as the use of vacuum feeding, but there is not yet an economic, good and generally applicable solution, especially for some corrosive, highly toxic products and poor fluidity of solid raw materials and intermediates.

6. Avoid evaporation to dry

The operation of using rotary evaporation to concentrate the material to dryness is very common for small trials. However, most reactors on the shop floor have a minimum stirring volume of about 10 – 20%. When the liquid is concentrated to the end, it is inevitable that the material will be heated without good agitation. The hazards of heating without stirring have already been mentioned. This can cause safety and quality problems. When evaporation to dryness is for solvent replacement, the operation of concentrating to dryness can be avoided by evaporating to a certain volume and then adding the latter solvent with repeated tows, but this depends on the relative volatility of the two solvents and whether they are azeotropic or not. A more efficient way is to use “constant volume distillation”.

Concentration to dry is a common process in our production, and if the process provided in the pilot process is concentrated to dry, it will be followed in production. Concentration to dry may be easy, but it is uncontrollable, there is no standard of measurement, and it is only when there are subsequent problems with yield and quality that it becomes apparent that the previous step may not have been dry enough. There have been instances of broken stirring shafts, incomplete solvent replacement leading to lower yields, and poor stirring after concentration to quench the washout. Therefore, it is necessary to consider whether there is a better process to realize this in R&D.

7. Avoid underestimating process time

Probably the biggest surprise for someone who is new to process scale-up is that all the operations take so long. It is important to perform a stability assessment of all the raw materials, intermediates and products involved prior to scale-up. Avoid reactions that must be quenched and separated immediately after reaction.

8. Avoid neglecting solvent use

Solvents with good solubility and easy distillation recovery may be used in small trials. However, some of them need to be avoided in production. This includes all class I solvents, those with flash points below -18°C. Hexane has a flash point of -23 ℃, and poor conductivity, generally foreign companies in the production of prohibited the use of heptane instead. However, due to cost issues, there are still used in some processes. Dichloromethane is less toxic than other chlorinated alkane solvents (chloroform, dichloroethane, etc.), but still try to avoid the use of methyl tert-butyl ether, toluene can be used in some processes instead.

9. Avoid neglect of quenching and extraction

Many amplification problems originate in the post-treatment process. Therefore it should receive as much attention as the reaction. Avoid layering the top layer as a waste solution. Extraction is often the step with the largest solvent volume, and the solvent used for extraction should be minimized in order to increase the capacity per unit volume. As the amount of solvent increases, the delamination and discharge times increase and emulsification may intensify. In weak acid/base environments, prolonged extraction and separation times may lead to hydrolysis of compounds containing readily hydrolyzable functional groups.

When an API intermediate is scaled up to 80 tons/year, one of the extraction steps requires 2000 L of solvent extraction twice for a total of 4000 L of solvent, and the solvent transfer takes three to four hours.

Ethyl acetate, a common extraction solvent, is prone to hydrolyze to produce acetic acid in acidic/alkaline environments, thus making the system more acidic. Instead of isopropyl acetate or butyl acetate, which are more stable, the solvent can be used.

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