WHO's Position on the Import Alert for a Chinese API Manufacturer's Products

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The Chinese API manufacturer Qinhuangdao Zizhu Pharmaceutical Co., Ltd received a Warning Letter after an FDA inspection end of last year. This Warning Letter contains a list of serious violations of GMP. The deficiencies observed primarily cover the handling of data in the area of quality control (data manipulation, audit trail feature disabled, missing access controls, repeated analyses until the desired results be achieved) and the inappropriate exercising of the QC's responsibilities with regard to the release of products (incompletely filled in, unapproved batch records). The Warning Letter presents an impressive list of 17 items criticised and required by the FDA. The company now has to submit a lot of documents and statements to convince the FDA that the deficiencies observed during the inspection are corrected sustainably. Only when this is done, the Import Alert set in March this year will be repealed (an "Import Alert" entitles the FDA to block the further transport of goods within the US American borders without any further investigation).

Already before the issuance of this Warning Letter, the WHO published on its "Prequalification of Medicines Website" a statement on the Import Alert for products of the company Qinhuangdao Zizhu Pharmaceutical. The reason for this rapid and strong reaction of the WHO was a conflict due to this Import Alert with extensive and maybe even global consequences which can be described as follows:

In the course of the prequalification programme for APIs, representatives of the WHO's prequalification team (PQT) inspected the production sites of Qinhuangdao Zizhu Pharmaceutical in October 2015. The inspectors also discovered violations of the GMP-compliant handling with data and several minor deficiencies. After the company's responsible persons had communicated the CAPAs, the inspection was closed out and the site was classified as "compliant". The report is publicly accessible like any other inspection report of the PQT.

The objective of WHO's prequalification programme is to assess the quality, safety and efficacy of APIs and finished products with regard to the GMP-compliance of their production. The indication of those products concerns diseases particularly prevalent in the developing countries like HIV/ Aids, tuberculosis, malaria, diarrheal diseases among children as well as reproductive health. Products with the prequalification status are listed and are used by international official procurement agencies as a guide for the bulk purchase of medicinal products to be used in medicinal programmes in such countries. Quality control laboratories can also apply for a prequalification.

Qinhuangdao Zizhu Pharmaceuticals' prequalified products according to the WHO inspection were the hormones Mifepristone, Ethinylestradiol and Levonorgestrel, all of which are used in reproductive medicine. Root of the problem is: the last of the aforementioned is the only API the WHO classified as prequalified at all. The fact that due to the FDA inspection, Qinhuangdao Zizhu Pharmaceuticals' products are now placed on import alert, led to a precarious situation; US based official procurement entities can for now no longer obtain medicinal products containing the API Levonorgestrel from this source.

In its statement, the WHO lists the following measures as "WHO action and advice":

• Consultation between Qinhuangdao Zizhu Pharmaceuticals and the FDA in order to find a solution for the problem.
• Close cooperation with the manufacturers of finished medicinal products containing Levonorgestrel with the goal of identifying alternatives for the API.
• Appeal to manufacturers of Levonorgestrel preparations to undertake comprehensive quality controls on shipments of said API supplied by Qinhuangdao Zizhu Pharmaceutical.
• Scheduling of a de novo inspection at the site of Qinhuangdao Zizhu Pharmaceuticals.
• Frequent updates of the current situation.

The WHO points out that there have been no quality problems in relation to Levonorgestrel tablets in the market so far. Therefore, the prequafilied status of Levonorgestrel and the two other preparations remain until revoked; international official procurement agencies may still include products from this source in their purchases.