Croatian Regulator Cites Indian Manufacturer for QA, GMP Violations

The Agency for Medicinal Products and Medical Devices of Croatia (HALMED) on Monday issued a statement of non-compliance to Indian active pharmaceutical ingredient (API) manufacturer Dhanuka Laboratories Ltd.

The notice was issued following an inspection of Dhanuka's Gurgaon, India facility conducted on 19 February 2016, during which inspectors discovered 32 good manufacturing practice (GMP) violations, including one critical violation involving Dhanuka's "weak" quality assurance (QA) system.

QA Issues and Actions

While the inspection was specifically linked to the manufacture of the antibiotic cefixime, HALMED says the issues uncovered related to the company's QA system could affect other products manufactured at the site, including the antibiotics cefdinir, cefuroxime and cefaclor.

"The QA system implemented on site, which related to the workshops that were engaged in the manufacture of cefixime, was found to be weak and not capable of proper design, planning, implementation, maintenance and continuous improvement of a system that allows the consistent delivery of products with appropriate quality attributes," the report states.

Due to the issues observed during the inspection, HALMED says EU regulators should consider removing the marketing authorization for affected Dhanuka products, and is banning the company from supplying further batches until the issues cited in the report are resolved.

Additionally, the European Dhanuka's certificate Directorate for the Quality of Medicines' (EDQM) Ad Hoc Committee has decided to suspend both cefixime (R1-CEP 2003-014-Rev 02) and cefuroxime axetil (R0-CEP 2011-173-Rev 00) based on the inspection findings.

Other Issues

Aside from the issues identified with Dhanuka's QA system, the inspectors cited the company for a number of other major GMP violations.

According to the inspectors, poor controls at the facility could have allowed for mix-ups of batches of cefixime that were derived from different production processes.

Inspectors also noted they could not rule out the possibility of product contamination in one of the centrifugation areas at the facility. "The rooms hosting the fluid bed dryers, as well as the dryers themselves, were found as not in accordance with [GMP] requirements because a contamination of the products openly handled in this area could not be excluded," the report states.

Additionally, the inspectors say they made "several observations with regard to the receipt, storage and dispensing of raw materials, key starting materials, intermediates and finished APIs … leading to the conclusion that a negative impact on quality cannot be excluded."

Lastly, the inspectors note that Dhanuka failed to implement a corrective and preventative action plan (CAPA) for observations related to the qualification of equipment at the facility made during a previous EDQM inspection. The inspectors say the company only addressed the qualification issues for specific equipment, rather than addressing the equipment qualification issues in a "holistic" manner.

Focus has reached out to Dhanuka for comment on the statement of non-compliance but the company has yet to respond.

EudraGMP