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Adverse observations on domestic facilities: Tackling the USFDA regulatory heat

Following observations by American drug controller, Strides Shasun & Cadila Healthcare for their Bengaluru and Matoda facilities, respectively, sent detailed responses which included admitting to faults and revising SOPs & hold-time study approach, among others.

Written by Deepak Patel | New Delhi | Updated: November 21, 2017 12:06:28 am
US Food and Drug Administration, Strides Shasun & Cadila Healthcare, Indian drug manufacturers, dr reddy’s laboratories, novartis india, ranbaxy laboratories, sanofi india, strides shasun, indian express news, business news Many Indian companies are still facing the US drug regulator’s heat.

On November 7, Lupin announced that it has received a warning letter from the US Food and Drug Administration (USFDA) for its Goa and Indore facilities, with its shares on the BSE tanking by about 17 per cent after the news broke. Earlier, on June 16, Ipca Laboratories announced that the USFDA had barred the entry of the company’s products into the US market from three of its Indian plants because of non-compliance with manufacturing norms. While many Indian companies are still facing the US drug regulator’s heat, some have begun the arduous process of course-correction to assure the American drug regulator about quality and manufacturing practices.

The Indian Express has reviewed the detailed responses sent by two Indian drug manufacturers, Strides Shasun for its Bengaluru (Anekal Taluk) facility and Cadila Healthcare for its Matoda (Sanand) facility on the USFDA observations, following which the US regulator has accorded clearances to these plants. Responses of the two companies list the number of procedural improvement measures which they took to allay USFDA concerns: admitting to faults in their processes that were identified by the USFDA; revising old standard operating procedures (SOPs) or creating new SOPs to deal with those faults; initiating remedial measures for the faults that were pointed out by the USFDA inspector just verbally; conducting retrospective review of ‘legacy’ equipment; revising hold-time study approach of the company and submitting documented proofs of all remedial measures.

Hold-time studies establish the time limit for holding the materials at different stages of production so that they remain in good condition.

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 reasonsfor the fall has been adverse observations of the USFDA on the domestic facilities of Indian pharma companies.

Strides Shasun response

The USFDA inspected the Bengaluru (Anekal Taluk) manufacturing facility of Strides Shasun Limited between May 22 and May 26 this year. A drug inspector from the Indian drug regulatory authority Central Drugs Standard Control Organisation (CDSCO) participated as an observer on all days of inspection.

Many persons from the senior management of the company, including chief operating officer P V S Ramaraju, chief quality officer Umesh Kale and chief information officer A Lakshminarayanan, were present during this inspection to answer queries of USFDA inspectors. Once the inspection was over, the USFDA made three adverse observations through Form 483. In response to these observations, Strides Shasun sent a 10-page response letter dated June 16. The two USFDA inspectors — who did this inspection — noted that the firm is manufacturing products such as Calcitrol capsules, Dutasteride capsules and Ergoclaciferol capusles. Calcitrol is used to increase calcium levels in the body; Dutaseride is used to treat enlarged prostate and hair loss; Ergoclaciferol is a man-made form of Vitamin D.

In the establishment inspection report (EIR), which was written by the two USFDA inspectors, it was noted: “The firm has received several complaints relating to these commercial products. Although the firm conducted investigations into the manufacturing process, these investigations did not arrive at the actual root cause to take the appropriate corrective actions. The deficiency relating to complaint investigations for the ‘capsules sticking’ is described under Observation 1 in the Form 483.” The first observation of Form 483 stated: “Written records of investigation into unexplained discrepancies do not always include the conclusions and follow-up.” An FDA Form 483 is issued to firm management at the conclusion of an inspection when investigators have observed any conditions that in their judgment may constitute violations of US drug laws.

In its response to the first observation, the company stated in its June 16 response that it has revised its complaint management procedure to include “trending of all complaints so as to ensure that suitable corrective actions, as necessary, are initiated”. To address concerns raised in first observation, it also revised its two SOPs titled “Process Validation” and “In-Process Checks in Manufacturing”.

Strides Shasun did not answer the queries sent by The Indian Express.

In the second adverse observation, it was stated that there is no scientific rational or data to support the sampling plan Strides Shasun uses for testing certain capsules. In its response to USFDA, the company stated that it has revised its sampling plan “during process validation and routine manufacturing and making it more comprehensive with scientific rationale”

In the third adverse observation, the USFDA inspectors stated that the company has failed to establish hold times; where hold times have been established the batch sizes for studies do no represent those of commercial batches. The company revised its complete hold time study approach to address this adverse observation. On September 1, 2017, Strides Shasun announced that it has been given the EIR — which is issued if the facility is deemed acceptable — by the USFDA.

Cadila Healthcare response

The USFDA inspected the Sanand (Matoda) manufacturing facility of Cadila Healthcare Limited in between January 16 and January 24 this year. During the inspection, the USFDA inspector made one observation through Form 483. Moreover, three items were discussed verbally by the USFDA inspector during the closeout of the inspection. The company did not inform the BSE about these observations. “Regarding the point on notifying the exchanges, the company has several plants and various regulatory authorities have periodic inspection of the same. Depending on the price sensitivity or material impact of the observation, the company notifies the stock exchanges,” the company spokesperson told The Indian Express.

In response to Form 483 observations, Cadila Healthcare Limited sent a 9-page response letter dated February 10, 2017. In response to the verbal comments made by the USFDA inspector during January audit, Cadila Healthcare Limited sent a total 13-page response letter dated September 12, 2017. The Matoda site, which is located inside of a Special Economic Zone (SEZ), manufactures pharma products for the US market only.

The one observation pointed out in the Form 483 was: “The responsibilities and procedures applicable to quality control are not in writing and fully followed.” In its response, the company stated that it has revised its SOP dealing with this observation and has re-trained its employees. All the documents related to these remedial measures were submitted as proof with the USFDA.

The first verbal comment submitted by the USFDA inspector was: “Manual integration parameters should be detailed. The firm had working draft when I discussed this.” Chromatography is one of the major process required for pharmaceutical analysis and manual integration is one subset of this process. In its response letter, Cadila Healthcare told the USFDA that it has prepared and implemented a new SOP titled “Good Chromatographic practices” to deal with this first comment.

The third verbal observation was that the firm should consider a longer period of activity for ‘performance qualification (PQ)’ and the firm can compile the data to show it later. PQ is the final step in qualification processes for equipment, and this step involves verifying and documenting that the equipment is working properly within a specified working range. Rather than testing each instrument individually, they are all tested together in PQ as part of a partial or overall process. The company stated that it has taken the following corrective action:”Retrospective review for all other legacy equipment of Matoda site…shall be completed by April 2018.” Moreover, the company revised its two SOPs to deal with this verbal observation.

Cadila Healthcare announced on August 29 this year that the USFDA has issued the EIR for Matoda facility. However, to the specific query on whether they also follow the revised SOPs for drugs that are manufactured for domestic consumption, both Cadila Healthcare and Strides Shasun did not respond.

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