Cyclosporine API Quality Dispute Caused By the Specific Optical Rotation
The quality dispute regarding Cyclosporine API (环孢素A) from one customer has been over for quite a while, but I have been too busy to record it. I have some spare time today, so I will write this story to remember that event.
In March 2024, our customer imported one of our strong pharmaceutical raw materials (APIs) from our company: cyclosporine.
The quality standard is that purity is not less than 98% (NLT).
Also, other testing items should meet the standards of the United States Pharmacopeia(USP) and the Chinese Pharmacopeia (CPh) s
The quality of our Cyclosporine API, approved by NMPA (Chinese GMP), the USFDA, and the EMA, is consistent between batches.
Our manufacturing process is highly stable, and our API yields are better than our competitors’, making it one of our most competitive APIs.
Our price is slightly more advantageous at the same quality level due to our higher yields, which is probably why we got this customer’s order.
Generally speaking, when an importer has purchasing plans, it is necessary to comprehensively identify several suppliers, compare their quality and prices, and then choose the right supplier for the final purchase.
After several rounds of negotiations and several pre-shipment sample tests, we finally received the customer’s order. The goods were shipped and delivered smoothly without any Customs issues.
The customer did not file any quality dispute within a month (Quality Dispute Period) of the goods’ arrival, so we thought that, like one of our other orders, this one would end happily.
However, 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 problems after testing using the United States Pharmacopeia (USP) method, the customer’s quality inspection department raised questions about the quality of our products after testing the specific optical rotation of cyclosporine.
The following is the general process of the matter.
Chain of events
After confirming the customer’s Cyclosporin API purchase order, we prepared and shipped five batches in 3 working days.
After receiving the goods, our customer performed quality tests in accordance with USP standards as soon as possible.
Two or three days later, according to their test results, all testing parameters complied.
According to our contract, no objection to the product’s quality within one month of arrival means the product meets the standard.
However, just when both sides (the customer’s purchasing department and we, the supplier) thought we had fulfilled this order perfectly, the customer’s quality control department raised a concern.
The issue was that when they measured the specific optical rotation (SOR), they found that the SOR did not align with their expectations; i.e., the observed rotation was not proportional to cyclosporine purity. Thus, they had doubts about the consistency of quality.
As we all know, specific rotation is an essential parameter in chemical quality control. It is key to evaluating the chiral purity and configurations of particular molecules.
The customer’s QC department was very concerned about the configurations.
To address this doubt, the customer’s quality control department hoped the supplier would provide an explanation.n
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 standards set by the customer’s purchase contract; there is no doubt about that.
However, we still reviewed the production records and quality control processes for these five batches to ensure all production steps complied with regulations.
While we asked our customers for their specific rotation data, we also carried out the same tests (specific optical rotations at 20 °C (c = 0.5 in methanol)) on samples from these five batches of cyclosporine.
Because we keep samples of every order, the seemingly insignificant samples are of great use.
When customers doubt the quality of our products, we can provide a sample from the same batch for testing, so there are traceable records of 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°
Our Quality Department further analyzed the situation and found that the change in the product’s SOR does not directly reflect cyclosporine purity.
Several factors affect a compound’s SOR, including the type of solvent, the solution concentration, and the temperature at which it is measured.
Therefore, determining the purity and assay of the drug by the consistency of specific optical rotation is not applicable.
Relations between cyclosporine purity and Specific Rotation
We conveyed the following points to the customer through detailed analysis and literature review.
1. All five batches of cyclosporine API samples are within the specific rotation range of the Chinese Pharmacopeia (-185°~-193°), and there should be no quality doubts about cyclosporine APIs supplied.
2. The average value of all of our cyclosporine samples in 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 rotation angle caused by a substance’s optical activity 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 you test.
Small changes in these factors can lead to differences in the value.
2. Relationships between purity and Specific Optical Rotation
Although the rotation value can reflect the purity of certain chemicals to some extent, it does not correlate significantly with cyclosporine purity.
The purity of Cyclosporine was determined by high-performance liquid chromatography to quantify its impurity content.
On the other hand, the customer’s testing also confirmed our conclusion.
The client had to compare samples from several cyclosporine suppliers. The most outrageous fact was that the HPLC purity of the cyclosporine sample from one factory was around 90%, while the rotation value was still -188°, which was within the range specified in the Chinese Pharmacopeia.
Very little correlation exists between cyclosporine purity and specific rotation. Therefore, it is not a good idea to define the quality of Cyclosporine by the value of the specific rotation.
Story Summary
We discussed our testing results with our customer in detail, explaining the reasons for the fluctuations in the specific rotation values and reiterating our quality control measures.
After listening to our QC department analyze the relationship between rotation and purity, the customer expressed understanding and recognition, further endorsing the quality of our cyclosporine API.
This incident reminds us that when we encounter customers’ objections to product quality, we must fully understand the essence of such objections and their underlying logic.
At the same time, we will further optimize our production process, improve product yield, and control impurity levels to the lowest possible level to ensure our customers have greater confidence in our product quality.
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 share updates on our product quality control and testing methods and to enhance their trust in us.
2. Research and development:
We will continue to monitor the latest research in the cyclosporine API production industry, improve and further optimize our cyclosporine production process, and raise our quality testing standards and methods.
Through these efforts, we can better serve our existing customers by providing higher-purity APIs and maintaining our reputation as a quality chemical supplier in China.
End Word
The quality of cyclosporine API is the core of our concern.
As always, we will analyze and solve problems scientifically and rigorously in response to quality customer disputes.
We thank our customers for their trust and support and look forward to continuing to bring them value.
Disclaimer:
This content is for informational purposes only and is intended for business-to-business communication within the pharmaceutical industry. It is not intended as medical advice. The manufacture, import, and use of API must comply with all applicable laws and regulations in the relevant country or region.
This blog post is informational only and does not constitute medical advice.
Always consult a healthcare professional before starting any new medication or treatment.
