Cyclosporin API Quality Dispute Caused By the Specific Optical Rotation

cyclosporine-api-chemical-structure-estructura de la ciclosporina
Cyclosporine API Chemical Structure

Originally the quality dispute of Cyclosporine API has been over for quite a while, but I have been too busy to record this event, it happens that I have some spare time today so that I will write this story down as a remembrance of that event.

In March 2024, our customer imported one of our strong pharmaceutical raw materials (APIs) from our company: Cyclosporine (环孢素/Ciclosporina), the quality standard is that the purity is not less than (NLT) than 98%, also other testing items should meet the requirements of the United States Pharmacopoeia (USP) and Chinese Pharmacopoeia (CP) standards.

The quality of our Cyclosporine API, approved with NMPA (Chinese GMP), USFDA, and EMA, is consistent between batches, and our manufacturing process is very stable with better yields compared to our competitors, which makes it one of our most competitive APIs.

With the same quality levels, our price is slightly advantageous due to our higher yields, which is probably the main reason why we got this customer’s order.

Generally speaking, when an importer has purchasing plans, it is necessary to find several suppliers to comprehensively compare the quality and price, and then choose the right supplier for the final purchase.

After rounds of negotiations and several pre-shipment sample tests, we finally got the customer’s order, and the goods were shipped and delivered smoothly without any Customs issues. The customer did not raise any quality dispute within a month (Quality Dispute Period) after the arrival of the goods, and we thought that this order would end happily like one of our other orders.

But a few days later, we received a quality concern from the customer.

They questioned the quality of the cyclosporine API we just supplied. The reason is that although the customer did not find any problem after testing through the United States Pharmacopoeia (USP) testing method, the customer’s quality inspection department raised questions about the quality of our products after testing the cyclosporine’s specific optical rotation.

The following is the general process of the matter.

Cyclosporine API MOA by CP
Cyclosporine API MOA by CP

Chain of events

After the customer’s Cyclosporin API purchase order was confirmed, we prepared and shipped 5 batches in total in 3 working days.

After receiving the goods, our customer carried out the quality tests according to the USP standard at their earliest.

Two or three days later, according to their test results, all testing parameters complied. 

According to our contract, no objection to the quality of the product within one month after arrival means the quality of the product meets the standard.

However, just when both sides (The customer’s purchasing and we supplier) thought that this order was perfectly fulfilled, the customer’s quality control department raised a concern.

The issue was that when they tested the specific optical rotation (SOR), they found that the value of SOR was not consistent with their expectation, i.e. the specific rotation value was not proportional to the purity of cyclosporine, and then they had doubts about the quality consistency.

As we all know, specific rotation is an important parameter in the quality control of chemical substances, which is usually used to evaluate the chiral purity of certain molecules and their configurations. The customer’s QC department was very concerned about the configurations.

To address this doubt, the customer’s quality control department hoped that the supplier would give them an explanation.

环孢素-cyclosporine-ciclosporina-美国药典检测标准-MOA-by-USP40
Cyclosporine MOA by USP40

Our Investigation and Retesting

After receiving the customer’s quality concern, we immediately launched an investigation.

First of all, the quality of our Cyclosporine API meets the quality standards of the customer’s purchase contract, no doubt about that.

However, we still checked the production records and quality control process of these five batches to ensure that all production steps were meeting the regulations.

While we asked our customer to provide us with their specific rotation data, we also carried out the same tests 【Specific optical rotations @ 20 °C (c = 0.5 in methanol)】 with the samples of these five batches of cyclosporine.

Because we keep samples of every order, the seemingly insignificant samples are now put to great use.

When customers doubt the quality of our products, we will be able to have a sample of the same batch to test, which means there are traces to follow for any issues.

In the process of retesting, we found that each batch of specific optical rotation values does have some ups and downs, but the difference is not significant, the data are as follows:

Batch 1: – 192°

Batch 2: -186°

Batch 3: -186°

Batch 4: -185°

Batch 5: -191°

Upon further analysis by our Quality Department, we learned that the change in the product’s SOR does not directly reflect the purity of cyclosporine.

The SOR of a compound is affected by several factors such as the type of solvent, the concentration of the solution, and the temperature at which it is measured. Therefore, it is not applicable to determine the purity and assay of the drug by the consistency of specific optical rotation.

Relations between cyclosporine purity and Specific Rotation

Through detailed analysis and literature review, we conveyed the following points with the customer. 

1. All 5 batches of cyclosporine API samples are within the specific rotation range of the Chinese Pharmacopoeia (-185°~-193°), and there should be no quality doubts about cyclosporine APIs supplied.

2. The average value of all of our cyclosporine samples of 2023 is -188.6°.

3. We conclude that there is no direct correlation between cyclosporine’s Specific rotation and purity.

To summarize:

1. Factors affecting the Specific Optical Rotation:

Specific rotation is the angle of rotation caused by the optical activity of a substance as light travels through it.

Many factors affect the degree of rotation, such as the concentration of the solution, the type of solvent, and the temperature at which the measurement is made.

Small changes in these factors can lead to differences in the value.

2. Relationships between purity and SOR

Although the rotation value can reflect the purity of certain chemicals to a certain extent, it has no significant correlation with the purity in the case of Cyclosporine.

The purity of Cyclosporine is determined and measured by High Performance Liquid Chromatography (HPLC), and to control the content of its impurities.

On the other hand, the customer’s testing also confirmed our conclusion.

The client had to compare the samples from several cyclosporine suppliers, and the most outrageous thing was that the HPLC purity of the cyclosporine sample provided by one factory was around 90%, while the rotation value was still -188°, which was within the range of the Chinese Pharmacopoeia.

It can be seen that there is very little correlation between the purity of cyclosporine and the specific rotation value. It is not a good idea to define the quality of cyclosporine by the value of the specific rotation.

Story Summary

We shared our testing results in detail with our customer, explaining the reasons why the fluctuation of the specific rotation values and reiterating our quality control measures.

After listening to our QC department’s analysis of the relationship between rotation and purity, the customer expressed understanding and recognition, thus further endorsing the quality of our cyclosporine API.

This incident reminds us that when encountering customers’ objections to the quality of products, we must fully understand the essence of quality objections and the underlying logic of objections.

At the same time, we will further optimize our production process in the future, further improve the product yield, and control the content of impurities to the lowest range, so as to ensure that our customers have more confidence in our product quality.

good communication with your customers

Future improvements

To further enhance customer satisfaction, we plan to take the following measures:

1. Strengthen communication: 

We will have regular technical exchanges with our customers to introduce the update in our product quality control and testing methods, to enhance their trust in us.

2. Research and development: 

We will continue to pay attention to the latest research in the cyclosporine API production industry, improve and further optimize our cyclosporine production process, and lift our quality testing standards and methods to a higher level.

Through these efforts, we believe we can better serve our existing customers by providing APIs with higher purity, and maintain our reputation as a quality chemical supplier in China.

We try to add value to our customers

End Word

The quality of cyclosporine API is the core of our concern all the time.

In the face of quality dispute of our customers, we will, as always, analyze and solve problems scientifically and rigorously. We thank our customers for their trust and support, and look forward to continuing to bring them values.

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