It is FDA’s expectation that when observations are identified during an inspection that the firm will take a global view to remediation. This means that gap assessments are performed at all company sites to determine whether the same, or closely related, shortcomings may be found at other sites.
Remediation then is also expected to address the issues at all sites. This expectation is even more important if a firm receives a warning letter. Lupin Limited (India) seems to have come up short on both accounts.
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Lupin Limited’s Warning Letters
FDA issued a warning letter on September 10, 2019 to the Group President – CEO of Lupin Limited based on inspections at the Mandideep, Madhya Pradesh, India site that ended December 4, 2018. In the warning letter, FDA states:
- FDA has cited similar CGMP violations at two other facilities in your company’s manufacturing network. On November 6, 2017, we issued a warning letter to your facilities Lupin Limited, Goa, (FEI 3004819820) and Lupin Limited, Indore (FEI 3007549629).
- These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs are inadequate. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products you manufacture conform to FDA requirements.
Similarly, the 2017 warning letter was issued regarding inspections of the Goa, India and Indore, India sites and FDA commented that:
- FDA cited similar CGMP observations at these facilities in your company’s network.
- On March 11, 2016, Lupin Limited Goa, FEI 3004819820, was cited for, among other items, invalidating OOS results without thorough investigations.
- On January 23, 2015, Lupin Limited Indore, FEI 3007549629, was cited for, among other items, invalidating OOS results without thorough investigations.
- These repeated failures at multiple sites demonstrate that your company’s oversight and control over the manufacture of drugs is inadequate. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems and processes, and ultimately, the products manufactured, conform to FDA requirements at all your sites.
So, a common theme becomes evident where the firm first did not remediate inspection observations from 2015 and 2016 which resulted in a warning letter issued in November 2017 after additional inspections in April and May, 2017. And then, an inspection at a different site in 2018 resulted in yet another warning letter issued in September of 2019. And FDA notes the common features in all inspections and both warning letters in the above section.
It is interesting that neither warning letter notes imposition of an import alert, suggesting that FDA may feel the firm makes medically necessary products for which there aren’t ready substitutes. Let’s take a look at the common features among the inspections and the two warning letters (see Figure 1).
Figure 1: Comparison of Deficiencies
Both warning letters address management of OOS events as common problems at all three of the inspected sites. Ideally, the corrective actions from the first inspections in 2015 and 2016 should have resolved the issue at all Lupin sites and would have prevented the 2017 warning letter. This clearly didn’t happen.
Because the issues were not resolved, in response to the 2019 warning letter, the firm is asked to provide similar information and data to what was requested in 2017 regarding the management of OOS events.
The 2019 warning letter requests “A retrospective, independent review…” suggesting that FDA wants an outside firm to perform a very similar evaluation to what they asked the firm to perform in 2017. This clearly represents an escalation in what they expect from Lupin Limited. In the 2017 warning letter FDA “strongly recommend” that the firm engage qualified consultants to assist them in remediating their management of OOS events. Whether they did or not remains unknown, but they did not make the same recommendation in the 2019 warning letter, which is unusual.
Failure to correct inspection observations at all company sites, and then failure to correct the warning letter deficiencies at all company sites can have severe consequences for a firm. Although import alerts were not identified as consequences of the inspections and warning letters, it should be assumed that practices, particularly OOS management practices, at Lupin Limited sites will receive focused scrutiny from FDA.
In fact, at least four Lupin Limited sites have been inspected in 2019, including one of the sites which was the subject of the 2017 warning letter. Similarly, six sites were the subject of inspections in 2018, including the sites in Pithampur, India, and Mandideep, India.
It’s unlikely we’ve seen the end of enforcement actions against the firm. We’ll watch and update if additional actions are taken.
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