Indian Sterile Manufacturer receives a second Warning Letter

In March 2017, the FDA published another Warning Letter to an Indian manufacturer in Goa due to GMP violations. The GMP deviations observed at Indoco Remedies Limited focus on the areas complaint handling, leaking of sterile products and the corresponding CAPA processing as well as on the non-compliance with quality agreements.

In the Warning Letter, the FDA depicts 1,500 complaints from 2012 to 2016 related to leaking, under-filled or empty bottles (of a sterile solution). In its root causes investigation, the company has indicated issues with the bottle within the filling process - e.g. when the bottle isn't correctly placed in the filling machine. Several manual interventions in the aseptic process were necessary, whereby defects haven't always been detected - particularly when cracks occur in the glass bottle under the cap. Moreover, such cracks may develop a few days after the filling process, as noticed in the investigation. Due to the high number of sustained complaints, the FDA has expressed doubts about the effectiveness of the company's processing of CAPAs. The company's reply mentions the use of a new test machine assuring 100% controlling which isn't sufficient for the FDA as defects occurring after the filling process cannot be detected (see above). An additional aggravating factor is that the company uses an "action level threshold" regarding the number of complaints before any measure is taken. Neither the criticality nor the risk to patients are taken into consideration.

The FDA therefore requests:

• A risk assessment of all lots of the sterile solution in the U.S. market
• A revision of the CAPA concept regarding the leaking defect
• An assessment of all other products to determine whether those can also be affected by the leaking defect
• Shipping studies with regard to the leaking defect
• A review of the suitability of the packaging components used for the process including an overview of the qualification status of the packaging suppliers
• Process capability studies with regard to capping
• Optimised procedures for complaints processing
• Improvement of CAPAs handling

Leaking issues had already been detected during a previous inspection. In 2011, the FDA discovered 17 complaints about leaking bottles and identified thereupon deficiencies in the manufacturing process control.

The FDA sees another critical deficiency in Indoco Remedies Limited not having informed a customer about the lots with quality defects as required in the Quality Agreement. The Indian manufacturer acts as a contract manufacturer for different medicinal product manufacturers. In the present case, Indoco Remedies Limited had not informed a customer although a number of complaints had been received concerning several charges with leaking, under-filled or empty bottles.

As already recommended in previous Warning Letters, the FDA advises the Indian company to engage a GMP consultant to remedy the GMP deficiencies.

For more details please see the original FDA Warning Letter to Indoco Remedies Limited.