Discussion forum for Pharma Quality events, Regulatory Actions
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Five different facilities of Eugia across India and US were inspected by USFDA between December 2023 and May 2024. A subsidiary of Indian pharma major Aurobindo, Eugia manufacture sterile injectables, hormonal drugs and injectables, oncology drug products. All the facilities were issued USFDA 483s with seven to ten observations except for one facility which received three observations. Several observations across facilities were similar – Deficiencies in aseptic facilities, Aseptic operations, OOS investigations, Cleaning procedures, Control over computerised systems and equipment. Yet only one facility is issued a Warning letter and another facility was classified OAI (Official Action Indicated).
USFDA 483s to Eugia Facilities (December 2023 – May 2024) | ||||||
Inspection Closure Date | FEI Number | Facility | Country | City | Link to 483 | Regulatory Action |
05/03/2024 | 3009883410 | Eugia Pharma Specialities Limited | India | Bhiwadi | OAI | |
04/05/2024 | 3027357163 | Eugia Steriles Private Limited | India | Anakapalli | Â | |
02/29/2024 | 3011905047 | Eugia SEZ Private Limited | India | Polepally | Â | |
02/02/2024 | 3008461619 | Eugia Pharma Specialities Limited | India | Sangareddy | Warning Letter | |
12/22/2023 | 3015534630 | Eugia US Manufacturing LLC | USA | New Jersey | Â | |
Regulatory Actions – OAI, Warning letter
Objectionable conditions observed by investigators during FDA inspections are listed on a FDA Form 483 and issued to company’s management. Companies are expected to respond with corrective action plans. Based on the severity observations and the company’s response, the FDA may take further regulatory action. In cases of significant deficiencies, a company may be classified as Official Action Indicated (OAI) which mean FDA is recommending regulatory or administrative actions. When FDA identifies the observations to be significant violations of the federal requirements, and the response to the 483 and corrective actions are not satisfactorily, FDA may issue a Warning letter to the Firm. When facilities are classified OAI, what will be the next action – whether it will go on to more drastic actions like Warning letter, Consent Decree etc. or the facility will resolve the 483 observations without further regulatory actions will depend on the remediation actions taken.
Eugia Facilities’ Inspections
A review of the Eugia Form 483 observations show many similar observations across the five facilities:
Other observations include deficiencies in establishing inter – intra batch variability, lack of adequate equipment qualification, inadequate deviation handling, and insufficient change control processes. Each of these are major deviations from cGMP practices and have potential to impact quality and integrity of products. They need to be addressed through comprehensive corrective action plans that enhance both quality systems and production controls. The deviations require extensive investigation and impact evaluation to confirm whether products already distributed have been affected, potentially leading to remediation actions such as product recalls. Yet apparently it was not these deficiencies alone that led to more serious regulatory actions like a Warning Letter or OAI classification.
Warning Letter to Eugia’s Sangareddy Facility
The Eugia Sangireddy facility which was issued a Warning letter, had serious Data Integrity issues cited in the USFDA 483. Specific issues included:
Such violations cast doubt on the integrity of all data generated by the facility, making it difficult to conduct credible investigations or impact assessments. This leads to situations where potentially all distributed batches need to be considered suspect necessitating extensive remediation actions. Regaining regulatory confidence will require a comprehensive overhaul of the facility’s quality systems, quality management, management structure and control, relocation or replacement of personnel.
In the Warning letter issued to Eugia, FDA specifically notes that the response of the Firm did not adequately address how individuals responsible for data integrity lapses are removed from positions where they can influence cGMP data. The Warning letter also highlights that that incomplete records deprive the facility of the ability to adequately investigate deviations.
OAI Classification of Eugia’s Bhiwadi Facility
The Eugia Bhiwadi facility which was classified as OAI, didn’t record Data Integrity issues, but the facility had critical observations of lack of containment control procedures to prevent cross contamination. Key issues included:
Containment control deficiencies can directly impact product quality, especially in facilities dealing with cytotoxic or highly sensitizing products. Estimating the extent of impact by analytical means would not be possible as contamination cannot be expected to be distributed uniformly and potentially large number of batches could be impacted.
Conclusions:
GMP Inspection observations with critical system and procedural deficiencies require extensive investigation, evaluation of extent of impact on products manufactured and distributed and well-defined corrective actions. In cases where data integrity is compromised, the consequences are often more far-reaching, leading to Warning Letters or OAI classifications. This will require comprehensive overhaul of the Quality Management systems, Management structure and oversight, often under the oversight of third party consultants to regain the agency confidence. Deficiencies like deficient containment controls, especially in facilities handling highly sensitising, cytotoxic products have potential to affect large number of batches. Such deficiencies often lead to regulatory actions like OAI classifications and Warning letters if comprehensive remediation actions are not initiated.
Also read:
USFDA Warning letter to Eugia Sangireddy facility (August 2024).
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