Could Granules be facing similar enforcement actions as Intas including an Official Action Indicated (OAI) inspection classification or a warning letter? Recent FDA inspection findings for Granules finished dosage form facility in Gagillapur, India, are strikingly similar to those found during a 2022 FDA inspection of Intas Pharmaceuticals, another large drug manufacturer located in India. Similarities include:

FDA Investigator – both inspection teams included Pratik Upadhyay, an FDA Dedicated Drug Cadre Investigator,
Multiple serious data integrity findings, and
Each company shut down manufacturing immediately following the FDA inspection. The Intas pause in manufacturing contributed to a shortage of cancer drug cisplatin.² The halt in production at Granules facility was temporary while the company reviewed FDA inspection findings.³ The effects on drug supply remain to be seen.

Subsequent to the 2022 inspection and 483 issuance, Intas was placed on Import Alert (Import Alert 66-40, “Detention Without Physical Examination of Drugs from Firms Which Have Not Met Drug GMPs”) and received an FDA Warning Letter, neither of which has happened to Granules. . . yet.

The ten-day inspection at Granules India Ltd took place between August 26 and September 6, 2024, resulting in a 26-page FDA form 483 with six detailed observations that call into question the safety and quality of the medicines the company produces and ships to the United States. More specifically, findings revealed the potential for serious microbial and drug cross-contamination of finished products and egregious data integrity issues, including manipulating and destroying GMP data.

The company submitted a response to the FDA on September 27, outlining the corrective actions and initiatives it is implementing to address the observations.

Granules India is headquartered in Hyderabad and manufactures active pharmaceutical ingredients, intermediates, and finished pharmaceuticals including highly potent compounds that it markets in more than 80 countries. It functions as a Contract Manufacturing Organization (CMO) and is among the largest global manufacturers of APIs for paracetamol, metformin, ibuprofen, guaifenesin, and methocarbamol, and sells numerous products in the U.S.¹

Details of 483 Findings

Using Redica’s Human Drug GMP and Data Integrity Labeling models, inspection deficiencies were mapped to detailed areas within the six Quality Systems plus data integrity (see What is “Quality and Regulatory Intelligence?”).

Twenty-four (24) distinct deficiency areas were found across four quality systems and data integrity in the language of the Granules India 26-page 483. The deficiencies areas are listed below and are grouped by quality system. Included for each area are a few examples of inspection findings taken from the 483. Facilities and Equipment, Data Integrity, and Production system observations were most prevalent.

Facilities and Equipment

Facilities and Equipment > Cleaning > Equipment > General
Facilities and Equipment > HVAC
Facilities and Equipment > Design > Sterile Filters
Facilities and Equipment > Facilities > Pest Control

Some non-dedicated manufacturing equipment has “not been appropriately cleaned” since its installation “several years ago.”
Material “indicative of potential bacterial and fungal and mold growth” was discovered inside the Air Purification Units
“Many sections of equipment were wet, leaking, and as a result corroded in multiple areas.”
Investigators observed “bird droppings and feathers on the APUs (b)(4) Ducts, (b)(4) water tank, cleaning skid, and the floors surrounding to Module (b)(4) ID (b)(4). The walls surrounding equipment were not secured enough in sections to prevent birds from getting inside the facility and stop dust and other environmental elements from damaging your equipment and facility.”

Data Integrity

Data Integrity > Data Destruction
Data Integrity > Testing into Compliance
Data Integrity > Data Manipulation
Data Integrity > System Controls
Data Integrity > Original Data
Data Integrity > Paper Records Control

“Investigators observed three (3) trucks full of scrap materials leaving from your facility at around 8:19 am. The inspection of scrap materials from these trucks revealed presence of large number of torn pieces of GMP documents such as analytical balance printouts, worksheets with handwritten documentation in ‘blue color indelible ball-point ink pen’ which were signed and dated along with large number of uncontrolled papers torn into pieces and crumpled having manufacturing and testing information. Similarly, during the walkthrough inspection of your QC laboratory, we observed cleaning personnel removing a large black color scrap bag from the area. The evaluation of this scrap bag revealed a large number of torn and few intact pieces of analytical balance printouts, pH meter printouts and some printouts similar to Karl Fisher (b)(4) test equipment.”
“Per your SOP No.: GIL-CQA-028, Titled: ‘Good Documentation Practices,’ Version: 03, Section: 5.37 ‘blue indelible ball-point ink pen’ is used for recording of GMP documentation. We also observed handwritten documentation in ‘green color indelible ball-point ink pen’ on large number of uncontrolled papers torn into pieces and crumpled having manufacturing and testing information.”
“Lack of Quality Unit oversight on employee practices of documenting GMP data on uncontrolled white paper and later disposing of these papers by tearing into pieces inside scrap bags.”

Production

Production > Contamination Control Lack of or Inadequate
Production > API > Cross Contamination
Production > Process Validation Inadequate or Missing
Production > Cleaning Validation or Verification > Swabs
Production > Sterile Products > Visual Inspection
Production > Process Monitoring > In-Process Sampling
Production > Sterile Products > Microbiological Contamination > General

A “potential risk for drug product cross contamination with other drug product active materials (drug substances)” that were manufactured using the same equipment
Swab sample testing of (b)(4)…showed unknown peaks, many of which had an area response several times higher than the known active peak, randomly eluting at different retention times in multiple swab samples tested by HPLC. These unknown peaks were not identified and accounted for… There is a potential that the unknown peaks could be due to active and degradant materials of drug product manufactured using the same equipment.”

Quality Unit

Quality Unit > Agency Notification > Field Alert
Quality Unit > Corporate Processes > Complaint Management
Quality Unit > Reviews and Approvals > CAPA > Inadequate
Quality Unit > Documentation > Procedures

“The complaint investigation was limited…”
CAPA “is inadequate to determine the risk to the drug products sold into the US market.”
“Your firm reported Field Alerts for some but not all drug products that are manufactured in module (b)(4) of (b)(4) block”

Laboratory

Laboratory > Method Validation
Laboratory > OOS / OOT
Laboratory > Stability > Stability Program

“Investigations pertaining to Out of Specification (OOS) and Out of Trend (OOT) investigations are not thoroughly investigated and the CAPA is inadequate to determine the risk to the drug products sold into the US market.”
“There was no justification provided for this provision to bypass failing test results at (b)(4) stage and continuing to use the failing (b)(4) (b)(4) batch # (b)(4) in manufacturing.”
“You (b)(4) only batches (b)(4) out of (b)(4) on long term stability which does not ensure the product performance for the remaining (b)(4) batches (b)(4) (b)(4) throughout the product shelf life until (b)(4).”

The Redica Systems Red Flag Model

Redica Systems has developed “Red Flag” risk models that weight quality and compliance risks across our data sources. The site Red Flag models assess the relative seriousness of events associated with the site including inspections.

Signals produced by the model, called “flags,” can be categorized as critical (red), major (orange), or minor (yellow). More flags indicate a higher potential for serious issues occurring. Each event is assigned a numerical value based on the severity of the event, such that the lower the cumulative score the better the compliance position of the manufacturing site.

For the Intas facility, mentioned above as having similar inspection findings to Granules, Redica’s analysis reveals multiple worsening compliance events since 2011. These risk flags indicated a high probability of a serious issue or enforcement action in the near term. In 2022, FDA and Health Canada inspected the facility leading to four critical outcomes (OAI, Warning Letter, and Import Alert from the FDA, and Non-Compliant standing from Health Canada). (See Figure 1., Red Flag Model Analysis of Intas). An in-depth analysis of the Intas warning Letter and the events leading up to it is available here.

Figure 1 | Red Flag Model Analysis of Intas

By contrast, Granules India’s inspection history shows low, successfully improving scores from 2009 until 2018 (Figure 2., Red Flag Model Analysis of Granules India). Minor and Major compliance events took the score from the Very Good to Poor category in just four years. It is not clear what changed.

Figure 2. Red Flag Model Analysis of Granules India

This points to an important difference between Intas and Granules India and their inspection history trajectory. Intas’ inspection history indicated a serious product or compliance issue was imminent – then the Import Alert and Warning Letter were issued.

Granules India, which has similar inspection findings, has a different history with far fewer major and minor flags resulting from its inspection history. Whether FDA issues an Import Alert and/or a Warning Letter is less clear and will depend not only on severity of the inspection findings but also on other factors including the strength of the company’s 483 response and the trust the company has gained with the agency during the inspection. Time removes all uncertainties, so we’ll keep a close watch on enforcement for Granules in the coming weeks.

References

¹ Drugs in the U.S. market that Granules holds the ANDA for: Gabapentin, Sertraline, Metformin, Metformin ER, Ibuprofen, Methocarbamol, Potassium Chloride, Potassium Chloride ER, Bupropion, Metoprolol Succinate, Pantoprazole, Venlafaxine, Esomeprazole, Losartan HCTZ, and Trazodone]. This spans 17 application numbers (ANDAs)

² https://www.nbcnews.com/specials/cisplatin-shortage-cancer-drug-chemotherapy-us/index.html

³ https://redica.com/wp-content/uploads/2024/11/GRANULES-Transcript-.pdf