Not surprisingly, there was still an accident. Hengrui's Warning Letter was still present as promised. This will be a sensation. As for the 483 defects in Hengrui's early stage, in fact, after reading it, the author also made analysis and communication with many big players in the pharmaceutical industry. Warning the arrival of Letter may be a matter of time, there is still a chance to reply after all. As a research and development enterprise, Hengrui is a landmark pharmaceutical enterprise in our country and a leader in our pharmaceutical industry. As an industry practitioner, I feel a little heavy. As one of the consulting companies promoted by going overseas, we have helped many companies complete inspections and successfully go to the U.S. market. We also hope that through our efforts, the level of the pharmaceutical industry will be improved. Further improvement.

(FDA Warning Letter Source: FDA official website)

Reflection 1: Many of our pharmaceutical companies regard entering the US market and entering the FDA as the most difficult step. Then, it seems to be a smooth road.

Whether, we think the hardest hurdle has passed. But on the contrary, there are still many things we need to do, "it is easy to fight, but it is difficult to sit down". Recently, when we helped Lotus, the largest pharmaceutical company in Taiwan, to carry out FDA project services, the company's general manager gave some different views. He believes that the PAI test will actually be easier, and it may be more difficult to re-check. Because what you are facing is the mentality adjustment of the enterprise's own managers, and the enterprise managers lack the "original intention", more and more product batches, including deviation, OOS and various data, will also be greater challenges.

The simplest thing to do is to record the quality. For Data Integrity, recently some customers are asking "why not use Data reliability, it is all data reliability". Because Integrity also has a meaning, is "good faith".

For example, it is mentioned in 483 and warning letters. "Our inspections documented serious quality assurance (QA) deficiencies, such as the discovery of discarded original CGMP records in bags under the vehicle and nearby trash cans, and your production manager's unrestricted access to blank production batch records and other CGMP files without a QA issuance. Your QA department has not fulfilled its basic responsibility to supervise and control the adequacy and reliability of all CGMP data in your factory. In addition, your QA department is responsible for ensuring that your staff understands and adheres to batch distribution procedures and data integrity principles." The behavior here is not Hengrui's senior management thinking, but for FDA inspection, this is no longer a technical problem. This is not data reliability, but another meaning of Integrity, integrity risk. When we inspected some enterprises, we found, for example, "it takes 10 minutes for materials to enter the buffer airlock, 10 minutes each time; The result of calibration is 10.00kg each time." In essence, it is a truth. What about the actual data?

Reflection two: advanced computerized system management is a double-edged sword.

Many of our companies want to go to various systems, but our technicians and grassroots managers are not aware of the risks. "Your production manager repeatedly accessed and printed uncontrolled blank copies of production records, medium filling records, visual inspection records, process verification batch records, and cleaning verification records saved on their computers or through your document management system. When a production employee reports an" error "in a record, the production manager prints a blank copy and has the employee transcribe the information on the new record and discard the old record. There is no guarantee that the archived data is original or accurate."

We have also recently audited some enterprises that have passed the EU FDA project in the United States, and found that many enterprises have a good understanding of the new CSV system, including our QA personnel, who think that I have a CSV system and I don't have to worry about it. However, there is no more inspection and prevention for system audit, system errors and personnel operation.

The CSV system means that we have completely exposed ourselves and your actions are firmly recorded, especially when the prosecutor starts to suspect you. Sometimes, when we are not ready, "millet rifle" is also a good choice. What we need is not only machine guns and cannons, but also the promotion of our core team. Otherwise, the gun is aimed at enemies or friends.

Reflection three: about the design of the plant and facilities, and aseptic transfer considerations.

We sometimes think that a company has passed the FDA in doing so, or passed my last inspection. For example, the sterilization of rubber plugs, the transfer of appliances, including the test of airflow manifold, etc. When I communicated with an FDA inspector in November 23, she said that the FDA would arrange about 2 weeks of off-the-job training every year. The theme was about equipment and facilities. I think there are two advantages here: one is to promote American equipment, and the other is to let the inspector know the risks of these equipment and facilities.

There is a saying that is quite right: "Hunters can miss many opportunities, but for prey, they can be proud many times, but as long as they miss once, they will not have another chance."

In the 483, it is mentioned:

"You lack a smoke study to demonstrate the airflow transitioning between the Class A and Class B areas outside the filling machine. A thorough smoke study is essential to evaluate and qualify your aseptic processing operations and to ensure proper implementation of the required design remedies."

"A) Product contact equipment includes (B)(4), rubber plugs, (B)(4) sterilized without proper packaging, and not covered when transferred from the Class A cart to the RABS. In the workshop in the filling room (B)(4), there is no physical separation between the-level area (outside the RABS) and the B- level area (the rest of the room). The airflow visualization study did not include the transition between Class A and Class B."

"The physical separation between the-level and B- level classification areas is insufficient to ensure the proper conditions for the sterile production of sterile drugs in your facility. For example, the" transition "A-level area on both sides of the (B)(4) traditional filling machine is where production employees transfer (B)(4) sterile equipment for assembly, and (B)(4) where vials of medicine are used in (B)(4). The transitional Class A area and the surrounding Class B area are only separated by (B)(4). This design does not provide adequate protection and may compromise the sterility of (B)(4) medicines and sterile equipment."

I remember when I was helping an enterprise in southwest China to conduct FDA inspection, we did about 2:30 a.m. three days before the inspection teacher came to help them finish the airflow manifold. Because I think that's a big risk. What we want is that the airflow manifold is not to watch movies, but to be able to express the CCS pollution risk of the product.

Of course, regarding the transfer and protection of appliances, I think this needs to be considered from the perspective of design. We may know now that Enterprise A has no breathing bag, no laminar flow car, Enterprise B has no laminar flow car, Enterprise C has rubber plugs directly entering Class A bottlers, and Enterprise D has a single-layer breathing bag. They have all passed FDA. Why can't we pass? Why? Why do we eat warning letters? There is a lot of logic behind the design. Partners who like the tweet can add our public number or Liu's WeChat.

Reflection four: enterprise senior management should participate in data integrity, how to participate?

Tieguai Liu (author) mentioned this issue when doing data integrity training (review) for a listed company in Jiangxi. I think the enterprise is very determined, but there are still many inexplicable data integrity problems.

Questions to be considered when replying to Hengrui 483 and warning letter projects. If our response does not make the prosecutor think that senior management is involved, how can we participate. Then this reply will not impress our prosecutor.

For similar problems, I have dealt with two cases in the southwest region. In the European and American concepts, high-level participation will be crucial to the outcome, but in China, it is often a mere formality. Because our senior officials spend a lot of time dealing with government affairs or some external affairs. However, there is a lack of continuity and attention to the quality management within the enterprise. In fact, we can also understand the difference in our quality culture. It is a struggle between ideas.

"Describe how senior management and executive management support quality assurance and reliable operations, including but not limited to providing resources in a timely manner to proactively resolve emerging manufacturing/quality issues and ensure continuous control status."

For Hengrui's warning letter, Hengrui missed three opportunities:

For the first time, when the incident happened, there was no emergency plan, no drills, and no personnel were arranged to give the inspector an in-depth CAPA measure in time. This is the best time. For example, when the inspector conducts FDA inspection reports every day, conduct an in-depth investigation of the situation at that time to find the root cause, and formulate an effective measure. Three times, effective measures. This matter may not necessarily 483, but how to do it, if interested partners can contact Tieguai Liu. For this matter, railway Liu is not all wise after the event. Tieguai Liu has experienced a similar Case to help enterprises avoid disaster.

The second time, the morning before the end of the inspection, this is the best opportunity. We must seize the opportunity. This is the last day of the prosecutor's report because of the time difference in the United States. The reply here must add the height of the management, otherwise, it will be pale.

The third time, 483 the handling of the reply letter. This time, we must think about it. The most difficult point this time lies in the integrity of the data, but where is it at all? As long as we can solve the doubts of the examination teacher, we can still bring the dead back to life. After many FDA inspections, it was found that one rule is to check the teacher, which is actually too troublesome. For example, you will find that FDA has very few defects. This is why the inspector thinks you can pass, so he writes a few symbolically, even zero defects, and gives them directly. Because in the end, when they arrive at the review center, the more defects they have, the more things they will do themselves. Therefore, if we have to deal with it through warning letters, it is better to deal with it through 483. If we can pass 483, we might as well solve it on the spot. In fact, the story back to the origin, the scene to solve. Some regret, or rather regret.

I hope this regrettable event can inspire Hengrui to set sail again, as China's pharmaceutical aircraft carrier, leading everyone to a better glory in biopharmaceuticals! There is no disrespect to the enterprises involved in the article. If there is any, please understand!