FDA Warning Letter to Lupin Tarapur (2022): Lessons for API Plants

In short: On 27 September 2022 the US FDA issued Warning Letter 320-22-25 to Lupin Limited’s API site at Tarapur, Maharashtra, after an inspection in March-April 2022. It cited weak equipment cleaning and cross-contamination control, poor control of genotoxic impurities, and failure to investigate critical deviations. This page summarises the letter in our own words and draws lessons for API manufacturers.

Letter details

The letter does not cite individual 21 CFR sections. Because the site makes API, the expectations are those of CGMP for API, described internationally in ICH Q7. FDA also warned that continued non-compliance could lead to refusal of admission of the firm’s articles into the US under section 801(a)(3) (21 U.S.C. 381(a)(3)), withheld approval of pending applications, and re-inspection. Lupin’s response of 25 April 2022 to the Form FDA 483 was judged inadequate.

What FDA cited

1. Cleaning procedures and equipment release

The firm had run risk assessments to see whether cleaning removes genotoxic impurities and residues carried over on equipment shared between products, including solvent recovery equipment. FDA found the assessments lacked data showing cleaning was effective. Points raised in the letter:

• two executed hypothesis-testing protocols on non-dedicated equipment found quantifiable genotoxic impurity close to its limit in four API batches made between 2019 and 2021 after a different API, with no further investigation;
• there was no documentation showing that the first batches after a changeover were made on the same equipment as the preceding product, and the specific equipment was not identified;
• contamination routes through shared solvent recovery equipment were not covered;
• two data sets conflicted (impurities quantified in one study, reported as not detected in the risk assessment) and the unfavourable data were set aside without scientific justification.

Dedicating solvent recovery tanks only during certain campaigns was not considered enough, as the cross-contamination risk remained.

FDA asked for an independent retrospective cleaning assessment, a CAPA plan, and a stronger cleaning validation programme that evaluates worst cases: more toxic or more potent products, products with low solubility in the cleaning solvent or that are hard to clean, difficult swab locations and maximum hold times before cleaning, plus change-management steps before new equipment or products are introduced.

2. Monitoring and control of process steps that cause variability

A specific process produced a genotoxic impurity at quantifiable levels, at an irregular frequency, in some batches of two APIs. Benchtop and commercial-scale studies had concluded purging was effective and no in-process monitoring was needed, yet commercial batches showed purging was not consistent, and the appearance of the impurity was not investigated. FDA expected either an upstream test (with spike and purge data showing the impurity below a stated fraction of the allowed limit) or a test for the impurity in the API specification, together with extra data supporting batch release. It also asked for the investigation and CAPA, a process capability analysis including special-cause variation, and the procedure for a risk-based review of all current products.

3. Failure to investigate critical deviations

During a cleaning verification protocol a swab result exceeded its limit, yet the final report stated that no deviations or out-of-specification results occurred and concluded that the cleaning was validated. FDA asked for a comprehensive assessment and remediation of the quality unit’s authority and resources (procedures, oversight, full batch review before disposition, approval of investigations) and a retrospective review of data used to qualify or validate API processes and of released materials within expiry.

Production status

Lupin had committed to suspend production of drugs for the US market at the site. FDA asked it to say whether it would resume and to notify FDA before doing so. The letter also asked the firm to contact CDER’s Drug Shortages Staff before any action likely to disrupt supply, and set a response time of 15 working days.

Lessons for your site

1. Prove cleaning, do not assume it. Use data-backed cleaning validation with worst-case products and locations, and verify the equipment history after changeover. See Principles of cleaning validation and Cleaning validation SOP.
2. Treat shared solvent recovery as a contamination route and assess it in the cleaning programme.
3. Do not disregard unfavourable data. If two studies disagree, investigate until the difference is explained scientifically.
4. Bench-scale purge studies do not replace commercial batch data for impurities with strict limits, such as genotoxic impurities; add controls where batches show variability.
5. Every limit excursion is a deviation. An OOS swab result cannot be absent from the final report. See OOS investigation guide.
6. Empower the quality unit to review batches fully and to approve investigations before decisions are made. For another recent example of quality-system failures, see the Aurobindo 2022 warning letter.

Where a site keeps records of such investigations and cleaning studies for a batch, retain them for at least 1 year after the expiry date of the respective product batch (EU GMP Part I Chapter 4 §4.11, or 5 years after QP certification if longer; 21 CFR 211.180(a)), longer if local law or the marketing authorisation requires.

Frequently asked questions

Does the letter cite specific 21 CFR sections?

No. It cites the FD&C Act (sections 501(a)(2)(B) and 801(a)(3)) and describes the deviations in plain terms; for API the relevant international benchmark is ICH Q7.

What is a genotoxic impurity and why does it matter in cleaning?

It is an impurity that can damage DNA and is therefore controlled at very low levels. Carry-over from shared equipment can bring such impurities into another product.

Is a warning letter a final penalty?

No. It is a notice that FDA expects prompt correction; unresolved issues can lead to import restrictions, withheld approvals and further action.

References

• US FDA, Warning Letter 320-22-25 to Lupin Limited, MARCS-CMS 633703, 27 September 2022: fda.gov.
• ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Step 4, November 2000), see section 2 (quality management), 5.2 (equipment cleaning): database.ich.org.
• European Commission, EudraLex Volume 4, Part I, Chapter 4 Documentation, Revision 1 (2011), §4.11: health.ec.europa.eu.
• United States, 21 CFR 211.180(a), current eCFR: ecfr.gov.