FDA Warning Letter to Shilpa Medicare (2020): OOS and Complaints

In short: On 9 October 2020 the US FDA issued Warning Letter 320-21-01 to Shilpa Medicare Limited for its Unit-IV site at Jadcherla, Telangana. FDA found weak out-of-specification (OOS) and complaint investigations, and missed Field Alert Reports. QA and QC staff can use it as a case study in investigation quality and CAPA.

Letter at a glance

This page paraphrases the letter. Read the full text on the FDA website.

Provisions cited

Observation 1: Investigations did not reach a supported root cause (21 CFR 211.192)

FDA said the firm did not investigate OOS results and complaints thoroughly enough to identify root causes or to put effective corrective and preventive actions (CAPA) in place. It also described this as a repeat finding from the 2017 inspection. Examples in the letter:

• Tablet impurity OOS (2019). The Phase I investigation confirmed the result and found no cause, and an unknown peak next to the impurity peak was not properly examined. The peak was put down to sample contamination or column load without evidence. After the HPLC column was reconditioned, other batches were retested and passed, the batch with the original OOS was retested several times, and it was released on a passing result. FDA found the column theory unproven and the column history and method performance unevaluated.
• Injection assay OOS (three batches, 2018 to 2019). Each was attributed to analytical error, such as a stock solution preparation error, and released on retest results. FDA noted there was no scientific evidence for the lab error, CAPA was mostly analyst retraining without effectiveness measures, and the production side of the investigation was not comprehensive.
• Sealing defect complaint. A vial closure separated from the vial. The batch had a sealing-machine breakdown and loose seals during filling, yet it was released. FDA said the release was not justified, including for vials filled before the breakdown was noticed.
• Foreign particle complaints. The firm blamed the end user’s device without enough data, so FDA considered the complaints not properly evaluated.

FDA asked for an independent assessment of the whole investigation system (deviations, OOS, complaints, failures), a CAPA programme review, a market action plan, and a retrospective independent review of invalidated OOS results for US products. It pointed readers to its OOS guidance.

Observation 2: Complaint handling (21 CFR 211.198(a))

The firm’s own procedure said severe complaints should be treated as critical. Complaints about particles and possible loss of vial integrity, which could indicate loss of sterility, were classified as minor and had no CAPA, even though the customer treated some as critical. FDA found the explanation inadequate and asked for an independent review of the complaint programme and of complaints on in-date batches.

Field Alert Report violation (21 CFR 314.81(b)(1)(ii))

Holders of approved applications must report significant chemical, physical or other deterioration of a distributed product within three working days. FDA listed eight particle-related complaints between December 2017 and December 2018 for an injection where the firm decided no initial Field Alert Report was needed.

FDA’s closing points

• A strong recommendation to engage a qualified consultant (21 CFR 211.34), while stating management remains responsible for compliance.
• A request for a written response within 15 working days.
• A warning that FDA may withhold approval of new applications or supplements listing the firm, and may refuse admission of articles from the site under section 801(a)(3) of the FD&C Act.
• A request to contact FDA’s drug shortages staff before any action likely to disrupt supply.

Lessons for QA and QC teams

1. Do not close an OOS as “analytical error” without evidence. A lab cause needs documented proof, and if none is found the investigation must extend to manufacturing. See OOS investigation Phase I and Phase II.
2. Retesting is not a route to a pass. Repeated column reconditioning and retests until the result passes is the pattern FDA criticised. See FDA’s approach to failing laboratory results.
3. Classify complaints by risk, not by convenience. Particles and seal integrity in a sterile product point to possible sterility loss.
4. Measure CAPA effectiveness. Retraining alone, with no effectiveness check, was not accepted. See CAPA step by step.
5. Know the Field Alert clock if you hold or support US applications.

Frequently asked questions

Who signed the letter? The Director of CDER’s Office of Manufacturing Quality, Office of Compliance.

Is a Warning Letter a final enforcement action? No. It tells the firm about violations and asks for a prompt response. Continued non-compliance can lead to further action such as approval withholding or import refusal.

What does a Field Alert Report cover? Significant quality problems in distributed products of approved applications, such as contamination or significant deterioration, reported within three working days.

Where can I find the OOS guidance FDA mentions? FDA’s guidance Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, Revision 1 (May 2022), on fda.gov.

References

1. US FDA, CDER. Warning Letter 320-21-01 (MARCS-CMS 607877) to Shilpa Medicare Limited, 9 October 2020. fda.gov warning letters database.
2. US FDA. 21 CFR 211.192, 211.198 and 211.34; 21 CFR 314.81(b)(1).
3. US FDA. Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, Revision 1 (May 2022).