History plays roles in two aspects: one, for us to avoid mistakes from happening again, just as the sayings go, "the overturned cart ahead is a warning to the cart behind", and "past experience, if not forgotten, is a guide for the future"; two, for us to promote the virtuous cycles of things, just as the sayings go, "be a worthy son to an able father", and "build on past achievements and open up the future". Now, let’s review the history of product recalls in the past decade!
The following pharmaceutical product recalls happened in the past, and the recent recall event was already more than three years from the present. This article aims to warn the future by discussing those recall events, to avoid similar events from happening again.
1. Sodium Fusidate for Injection (Fucidin): shards of glass were discovered in the product glass bottle;
2. Methotrexate Injection: a small batch of the product had shards of glass in the solution;
3. Risperidone Microspheres for Injection 25mg: sterility test result was positive;
4. Paroxetine hydrochloride formulation: concerns about the release of certain batches of contaminated APIs;
5. Specific batches of Recombinant Human Coagulation Factor VIII for Injection: valence deviation trend, high degradation rate;
6. Bacterial lysates: the product did not comply with the Good Manufacturing Practice for Pharmaceutical Products;
7. Ambroxol Hydrochloride Injection: the stability test of the reserved sample detected a high amount of related substance, however, all results were within the product quality standards;
8. Rabies Vaccine (Vero Cell) for Human Use, Freeze-dried: the bacterial endotoxin exceeded the provision of the related standard;
9. Hydrocortisone Acetate Eye Drops: the filling and other items did not meet the provisions of the related standard;
10. Fosfomycin Calcium Capsules: the product had a quality problem;
11. Puerarin for Injection: the product had a quality problem;
12. Compound Zinc Undecylenate and Triamainolone Acetonide Ointment: the production was suspected of violating the related regulation;
13. Xiaoer Tuire Oral Liquid: the product did not comply with the related provisions upon inspection;
14. Weikangling Capsules: the product did not comply with the related provisions upon inspection;
15. Compound Hepar Extractum Tablets (Capsules): the product was detected to have high chromium content;
16. Refined Coronary Tablets: the reserved sample was detected to have plant tissue;
17. Ferric Ammonium Citrate: high chromium content was detected in the scrap iron from the processing of the starting material 45# steel rod.
Let’s analyze the reasons for the pharmaceutical product recalls below:
Visible foreign matter: two recalls were caused by visible foreign matters. Visible foreign matter control is the most difficult among the control items in the production of injections, for which there are two reasons: one, it is difficult to find out the related factor; two, it is difficult to find out the true cause.
It is difficult to find out the related factor because once there is a factor affecting visible foreign matters in the production procedure, such factor will not cause each unit product to fail the visible foreign matter inspection, and it is very difficult to find out such factor in the sampling inspection. For other items, once such items are found, the related links can be locked on for checking; however, unlike them, visible foreign matters are affected by many production procedures, and once visible foreign matters are found, many production procedures need to be checked.
Shards of glass were the visible foreign matter leading to two recalls mentioned above, which was a reason easy to analyze. If it is white dots or other reasons, not only the related batches need to be recalled, but also the entire production line and the risks brought by the visible foreign matter to all batches need to be assessed.
Sterility: for non-terminal sterilization, nonconforming sterility of products is something difficult to control, however, compared to visible foreign matters, reasons for the nonconformance are relatively easier to find out.
Formulation recalls due to raw materials: two recalls above belonged to such kind of recall; wherein, the 17th recall event involved more than 40 downstream formulation manufacturers and even more batches; the 15th recall event was caused by the 17th recall event. Therefore, supplier management is a priority among priorities in quality management.
Stability investigation process: two recalls above belonged to such kind of recall. The occurrence of uncontrollable risks to product quality in the stability investigation process means that the stability of the product is very sensitive to external factors. Chinese manufacturers generally do not participate much in product development, and production and quality personnel are not quite clear about product quality attributes, therefore, enterprises are suggested to investigate more to reduce such kind of risk.
Filling: in terms of nonconforming filling, two aspects need to be considered in the production: one, the control means (precision); two, the detection means (precision).
Detection of plant tissue: the product involved in the recall event that belonged to such kind of recall was sugar-coated tablets; the existence of plant tissue means a problem with the extraction process or the existence of nonconforming material, plus the yield factor and the fluke mind with sugar-coating: it was not a product problem but a people problem.
Based on the above analysis, production and quality personnel must accomplish the followings to achieve good quality:
Sampling: it is a matter worth studying as to when to take samples and how many samples to take. For example, regarding filling and visible foreign matters, the beginning and the ending are the time when the filling is most unstable, and the filling will be very smooth and stable once the production starts, however, from employee’s perspective of thinking, they think the production only starts when the production is smooth and generally take samples when the production is smooth, which reduces the possibility of identifying problems. Except for a systematic reason (shards of glass), the products around the exploded bottle should have all been isolated, and samples should have been taken to identify the problem, however, this is usually ignored. Regarding the sampling quantity, when an exceptional situation occurs, whether to sample the quantity as usual or increase the quantity and increase how many are related to the specific circumstances of production, which we should pay attention to.
Material management: it is more than material balance and is also about material supplier management. Product quality assurance is about stability, therefore, do not easily change suppliers. Once the API, excipient or packaging material is changed, it will affect and even interrupt the production, leading to a deviation or exceptional situation.
Do not have the fluke mind: as the saying goes, "God is watching from above", pharmaceutical manufacturers shall be people-oriented and make pharmaceutical products with heart instead of the fluke mind.