Anhui Bayi Chemical Industry Co. Ltd. — EU GMP NCR (EudraGMDP) Findings

During the inspection 1 critical and 7 major deficiencies were found: Critical: 1 The inspection revealed a substantial number of severe GMP violations in various areas. This indicated not only a substantial lack of GMP knowledge by the firm, but also a shortfall of QA oversight. Together with the repeated statement of the firm's management that the firm manufactures chemicals and is not involved in GMP activities, which violates the firm’s own commitment to follow EU GMP as outlined in the above-mentioned CEP application, a significant impact on the quality of the N-1 intermediate p-aminophenol and a negative impact on the final API paracetamol cannot be excluded. Major: 2 Contamination of the firm’s final product, i.e. the intermediate p-aminophenol (PAP), was certain based on the condition of filter cloths and the dilapidated state of the areas surrounding the four air inlets. Two of them are located in a small room on the roof which supplies the air that is to be heated up and used to dry the wet PAP cake in a continuous drying process. The other two are located outside, protected only by a roof, and supply the air for the transport of dried PAP. Before transporting the dried intermediates, the air passes through an air handling unit (AHU). The contamination was evidenced as follows: a. One filter cloth of each set of air inlets showed substantial damage/large gaps. As a consequence, air from the outside environment came into direct contact with the product to be dried. The firm later explained that the cloths were intentionally destroyed to ensure enough air supply in case the filters became clogged. b. All four ceilings above the inlets released paint flakes. The two inlets located in the rooms were in a horizontal position; therefore, large paint flakes could be found on the intact parts of the filter cloths. c. Bins full of dust and dirt, brooms, etc. were found in close proximity to one air inlet, protected only by a room. Considering the enormous amount of air needed for the drying operation, this particulate matter could be sucked onto the filter cloths causing clogging or, in the case of damage, further distribution towards the AHU. Another risk factor contributing to a potential negative impact on the air being filtered is the limited protection of the air inlet itself by a roof made only of corrugated steel. Therefore, particles from the wind, dust and dirt accumulated on the roof could contribute to the clogging of the filter. d. According to the design drawing shown, a 3rd filter should be installed in the AHUs. This was not the case for the AHU that was opened. The other major 6 deficiencies include: - insufficient maintenance resulting in serious contamination and corrosion of the plant and equipment; - improper change management lacking sufficient level of detail, retrospective risk assessments missing major risks, and lack of evaluation of effect of major changes on the quality of the product; - major flaws in the company’s approach to process validation resulting in the process being considered non validated; - alarms generated by the automatic process control room can lack proper assessment, and an overview of alarms are not available to QA during batch release. Action taken/proposed by the NCA: Suspension or voiding of CEP (action to be taken by EDQM) The manufacturer was removed as manufacturer of active substance intermediate from CEP 2000-124 for Paracetamol. Others The clients using the intermediate 4-aminophenol (para-aminophenol), the intermediate of Paracetamol, from ANHUI BAYI CHEMICAL INDUSTRY CO., LTD. to synthesize paracetamol, and the MAHs of the finished products using this paracetamol, should assess the potential impact on their finished product considering product quality and risk to the patient. This should in particular include an assessment of the risk of any foreign matter in Paracetamol based on the potentially contaminated intermediate 4-aminophenol.