The past four weeks have seen a flurry in publication of enforcement actions against pharmaceutical sites in China. In most cases the inspections supporting these actions were conducted a few months ago. Data integrity continues to be identified in most of these actions along with poor facility maintenance and repair which poses a risk to product contamination and cross contamination. FDA published warning letters to two sites in Hong Kong and the European authorities published three reports of non-compliance on the Eudra GMDP public page. We cover these five published actions below.
The French authorities determined that Minsheng Group Shaoxing Pharmaceutical Co. Ltd. does not operate in compliance with EU GMPs. The non-compliance summary report published December 28, 2015 is in regard to active substances. Eighteen total deficiencies were identified, two (2) were critical and related to data integrity and 4 were major.
- The first critical deficiency was associated with “falsification of source of API” because the API was represented as being manufactured in-house but was actually repackaged and relabeled after being received from a non-GMP Company.
- The second critical observation addressed an API that was manufactured as a CP grade but released as UPS grade without a full traceability of the testing activities.
- The four major deficiencies included: deficiencies in cleaning of equipment; deficient pipe design and instructions for transfer of the intermediate solution using nitrogen; hoses used for removing solvents were not identified, had no cleaning status identified and were stored on a dirty floor in an area of the facility not mentioned in the site layout; and yet another data integrity deficiency in that no procedures addressed audit trails nor were there any audit trails in place so it is impossible to determine whether chromatographic raw data were changed or deleted.
The authorities of the Czech Republic determined that the Hubei Hongyuan Pharmaceutical Co., Ltd. (Huanggang, China) is not in compliance with the EU GMPs. The inspection was conducted October 30, 2015 and the report published January 20, 2016. Two summary inspection reports are posted, one for the site which manufactures the APIs and one for the site which manufactures API intermediate(s).
- For the report regarding the sites where the API was manufactured: The inspection identified twenty-four (24) deficiencies, one (1) of which was critical, and ten (10) were major. Major deficiencies included the areas of data integrity, OOS result management, computerized system validation and documentation. The report indicates that the supplier should not be approved in any new or existing applications and that product should be recalled unless here are no available alternatives.
- Regarding the site where the intermediate(s) were manufactured: The sites stated they do not follow EU GMP. The summary report includes unusually harsh language: “The following observations were made and together categorized as critical: a. The manufacturing site and it’s equipment was found in a devastated state. b. Huge layers of dust and product indicated that no cleaning was applied to either the facility or the equipment, leading to an extreme risk of cross-contamination. c. The extremely bad shape of the facility and the equipment showed that no maintenance was in place. d. Almost none of the products seen was labelled. e. No batch manufacturing documentation could be seen.”
- The firm failed to implement adequate controls to prevent manipulation or omission of data. The firm then relied on incomplete data to make decisions on lot release. FDA sated “We observed systemic data manipulation across your facility, including actions taken by multiple analysts, on multiple pieces of testing equipment, and for multiple drugs.”
- Audit trails for HPLCs were disabled, testing were conducted, and then audit trails were enabled. During the time when audit trails were disabled, 80 injections were made for assay and impurity tests of validation lot stability studies. Raw data were also deleted.
- Microbiological testing showed problems with media quality. Several customers complained that their testing showed OOS results, inconsistent with those generated by the supplier. The firm attributed the difference in results to different test methods. FDA expressed concern about the number of these complaints.
- During the inspection an employee removed a thumb drive from a computer controlling an HPLC, and left the area. FDA requested the thumb drive and one was produced in ~ 15 minutes but there is no way to know whether this was the one removed from the computer associated with the HPLC.
Chan Yat Hing Medicine Factory (Hong Kong, China) received a warning letter dated December 15, 2015 based on an inspection ending July 8, 2015. The warning letter states that the firm did not respond with corrective actions for items identified in the form 483. The firm was placed on import alert on December 3, 2015 that included all drug and cosmetic products. The warning letter identifies only six (6) deficiencies with no specific examples to support them, but the abbreviated nature suggest to me that the firm does not have a solid understanding of GMPs and expectations for drug products sold in the US. FDA recommends they engage a third party consultant with appropriate expertise. Deficiencies include but are not limited to:
- The firm failed to test drug products for identity and strength of the active ingredient.
- The firm failed to ensure identity of purchased components including the API.
- The firm has no data to ensure products are stable through the identified shelf life. Procedures for production and process controls have not been established.
- The quality unit does not have written responsibilities, including investigation of OOS results.
- Failure to calibrate and maintain written records for a scale used to weigh components.