Exports by the Indian pharmaceutical industry to the US — its biggest market — grew around 28 per cent in 2015-16. However, in 2016-17, the growth in exports plummeted to just 1.3 per cent. One of the major reasons for the fall has been adverse observations of the United States Food and Drug Administration (USFDA) on the domestic facilities of Indian pharma companies. While a majority of Indian drug manufacturers are still grappling with such adverse observations, some have begun a process of course-correction to successfully deal with them.
The Indian Express has reviewed the detailed responses sent by two major manufacturers, Glenmark Pharmaceuticals for its Ankleshwar facility and Sun Pharmaceutical for its Mohali facility, to the USFDA observations, following which the US regulator gave clearances to these plants. Their responses list the number of procedural improvement measures — starting with admitting to most faults in their processes and then revising the number of standard operating procedures (SOPs) to deal with those faults, alongside training employees in the new SOPs, creating new global policies for the companies’ quality systems and operating systems and submitting documented proofs of all these remedial measures — which they took to allay the USFDA concerns.
“Other companies that are currently facing similar issues with the USFDA are trying to emulate these kinds of steps. Half way measures do not go down well with the USFDA and the Indian companies need to show their absolute intention — through documentation as well as action — to resolve all the issues raised by the regulator. Otherwise, the audit and adverse observations will never stop,” said a Mumbai-based pharma analyst on the condition of anonymity.
Sun Pharma response
The USFDA inspected the Mohali manufacturing facility of Sun Pharma between November 7 and November 16 last year. During the inspection, it made seven major observations through its Form 483. In response, Sun Pharma sent it a 40-page letter on December 8, 2016.
“We … have established a new global documentation system and hierarchy to improve and sustain quality across our manufacturing network. Nine new global policies — the highest level of Sun document hierarchy — were established, including a definition of Sun quality system, as well as policies for major operating systems such as laboratory controls, production, research and development, and cGxP (Current Good X Practice) computer systems. Additionally, 28 global quality standards are in place…currently, 23 out of the 28 have been implemented at Mohali, and implementation of the remaining is in progress,” Sun Pharma stated in its letter.
Since 2013, Mohali facility had been under the USFDA import alert, which means that this facility was not allowed to export its products to the US. Ranbaxy Laboratories, which owned the Mohali facility, was sold to Sun Pharmaceutical in 2015.
In one of its observations to Sun Pharma, the USFDA inspector had stated: “On November 10, 2016, during the laboratory tour I interviewed the analyst who performed the IR (infrared) identification analyses and he stated that he performed the IR identity test without being trained in the IR identification of the finished product test of (specific) tablets.” The inspector then added that the firm “failed to train and qualify the analyst in the IR identification” of the tablets.
In its response, Sun Pharma “acknowledged” that the analyst was “not specifically trained in the IR identification for (specific) tablets at the time he performed testing on May 23, 2016”. The company then went on to explaining to the USFDA how the IR test for this specific tablet is different from normal IR test. The company did its own investigation and it concluded “that the probable cause of the failure was analyst error”.
As a corrective action, the company revised its SOP on this issue and re-trained and re-qualified its analysts on specialised identification techniques. All data generated by the aforementioned analyst was reviewed for discrepancy. The company, however, did not find any “discrepancy, out of specification (results) or deviations” in the data. Moreover, “all of the data generated during the period January 2014-October 2016 for identification testing performed for (specific) tablets using IR technique was reviewed”. As a proof, the company sent all the related documents on this issue — revised SOP, track-wise out-of-specification record and revised test procedure — to the USFDA.
The company took similar detailed actions to deal with other issues raised by the USFDA. It informed the USFDA about these through the letter. Satisfied with the company’s response on March 13 this year, the USFDA lifted the import alert imposed on its Mohali manufacturing facility and removed the facility from the official action initiated (OAI) status.
Sun Pharma did not respond to the queries sent by The Indian Express.
Exports to the US by Indian pharmaceutical companies have been on a rise for more than a decade. “The exports are mainly driven by the cost advantage that India has. The share of exports to the US in total pharma exports from India which was 25.4 per cent in 2012-13 increased to 33.1 per cent in 2016-17,” CARE Ratings stated in its July 2017 report.
Glenmark Pharma response
The USFDA inspected the Ankleshwar manufacturing facility of Glenmark Pharma between December 12 and December 16 last year. During the inspection, the USFDA made four adverse observations through Form 483. In response, the company sent a 42-page letter on January 3, 2017.
In one of its observations, the USFDA inspector had stated: “The QA (quality assurance) department is not involved in the review and release of raw materials tested in the QC (quality control) laboratory. Raw materials are tested and released by the QC department as per (its specific) SOP.”
In response, Glenmark Pharma went on to explain the role of QA and QC departments in detail. It also told the USFDA that their
roles are defined as per their respective SOPs. The company admitted that QA is involved in qualifying the vendors “before procurement of any raw material”. Therefore, as a corrective action, it revised its SOPs to include the responsibility of release of raw material to QA unit.
“As per the revised procedure, the QC reviewer shall submit the analytical documents along with supporting documents to QA reviewer. The QA reviewer shall review the complete data. QA Manager/Designee shall check the accuracy and adequacy of results to release the batch of raw material,” Glenmark Pharma stated. The company added: “The new responsibility to QA unit is being addressed by making one group of personnel responsible for review and release of raw material.”
In another observation, the USFDA inspector stated that “buildings used in the manufacturing of API (active pharmaceutical ingredient) drug products are not maintained in a good state of repair”. The inspector then talked about “chipped corners”, “cracked paint” and walls that are “not evenly plastered and painted”.
In response, Glenmark stated that it has acknowledged the USFDA’s observation and “would like to confirm that adequate procedures have been implemented across the site to maintain clean room condition during manufacturing of product”. It then went on to say that “each specific observation made during the objection was rectified”. Photographs of the clean room of the plant were attached with the letter of the company. It also changed various SOPs, so that this problem does not occur again. Moreover, the company also implemented a SOP through which stated that the QA team was also involved in the inspection of clean room “during each product change over”.
In response to the queries of The Indian Express, Glenmark spokesperson stated: “Glenmark would like to state that its Ankleshwar plant received the EIR (establishment inspection report) in March 2017. The EIR is issued by the FDA only if it finds the facility to be deemed acceptable.”
However, to the specific query on whether they also follow the revised SOPs for domestic production, both Sun Pharmaceutical and Glenmark Pharmaceuticals did not respond.