A July 29 to August 2, 2024, FDA inspection of API manufacturer Global Calcium Pvt. Limited, in Hosur, Tamil Nadu, India, revealed that blatant data falsification and manipulation continue to take place at factories that supply drugs to the U.S. market.

The five-day inspection by FDA investigators Justin Boyd and Teresa Navas resulted in a seven-page, six-observation FDA Form 483, with two of the observations and four of the seven pages focused on data integrity.

A salient feature of the inspection findings is that egregious data falsification practices were taking place under the direction of the Plant Manager and Production Head. It also found that products were shipped to the U.S. market without Quality Assurance review and approval.

According to the Global Calcium website, the company manufactures over 150 products in multiple therapeutic segments, including Antipsychotic, Antifungal, Antidepressant, Antihypertensive, and Anticonvulsant drugs that it ships to the U.S. and worldwide.

Management Instructs Employees to Falsify Records

The primary observations around manipulation and falsification of production and control records are best illustrated by direct quotes from the form 483:

“The Production Head stated that he directed employees to create batch records and supporting records including cleaning records and equipment use logs for activities that did not actually occur…”

“The Plant Manager stated that he used Microsoft Excel to generate plans with dates, production start and stop times, sampling dates, and product weights to instruct employees how to create these records for activities that did not occur.”

“Production employees…participated in the creation of these batch records, cleaning records, and equipment logs for activities that did not occur.”

“All Microsoft Excel files present on the Plant Manager’s computer, where the plans for fabricating batch records were created, were deleted by the Production Head on the evening of July 29, 2024 [the day the inspection began], preventing additional plans that may have been present on the computer from being reviewed during the inspection.”

QA Was Complicit

By regulation, in a pharmaceutical manufacturing plant, the Quality Assurance Unit has the responsibility to remain independent, ensure that Good Manufacturing Practices (GMPs) are followed, and act in an oversight role to ensure the quality of product leaving the facility and integrity of the data supporting manufacturing and product release. According to FDA, that did not happen at Global Calcium.

For example, an Injection API batch was shipped to the U.S. without QA review and approval. A review of the batch record showed conflicts between the data in the batch record as compared with equipment use logs and cleaning records.

In addition, FDA investigators observed that, “QA issues duplicate equipment use logs and cleaning logs with the same issuance number. These duplicate logs are used in creation of records that document activities that did not occur. QA subsequently reviews and approves both sets of contradictory records.”

A detailed examination of the batch records, cleaning records, and equipment logs produced overwhelming evidence of their manipulation and fabrication.

Other GMP Issues Found

Other problematic deficiencies FDA investigators Justin Boyd and Teresa Navas observed during the inspection were in the areas of stability testing, setting product impurity profiles, maintenance of the facility and equipment, and investigation of deviations:

Stability program: 2023 yearly stability samples could not be located. Other 24- and 48-month time point samples, as required by internal SOP could not be located. There were no stability protocols describing the handling of stability samples. Stability testing methods have not been shown to be stability indicating.
Impurities: Established impurity profiles for products destined for the US market were deemed “inadequate.”
Facility and equipment: Characterized as “not maintained in a manner that prevents contamination of APIs by other materials.” For example, unidentified liquids were seen dripping from pipes in manufacturing areas.
Deviations: Not investigated and noted in the batch records

Key Takeaways

Complete fabrication of data and records under the direction of senior manufacturing management along with a complicit QA department means that no data or products coming out of the Global Calcium facility in Hosur, Tamil Nadu, India should be marketed anywhere. The company’s actions border on criminal behavior.

It is surprising that FDA has not yet issued an import alert for this company. It is all but certain that a warning letter will be forthcoming.

It is worth noting that a five-day FDA inspection in February 2019 by John Mistler resulted in a three-page, four-item 483 that also found data integrity shortcomings.

According to that 483, “The firm does not follow good documenting practices to ensure control over all loose GMP documents. The firm’s Quality Assurance uses a Loose Sheet Request Log for issuance of required and additional test parameters used to support release of APIs (active pharmaceutical ingredients) intended for distribution to the US, such as (b)(4)~~~~~~~Injection. These loose sheet GMP documents are authorized to be issued in multiples and without identification of specific lots or batches. The firm has not established a formal control process for reconciliation of these GMP documents and good documentation practices are not always followed.”

This suggests that data integrity issues FDA observed 5 years earlier were not rectified but instead became even more widespread and egregious.

If this company had been one of your supply chain partners, would you have been aware these issues were taking place?

What is the Compliance History of Your GMP Partners?

It is critical to perform due diligence on potential supply chain partners and conduct regular compliance audits to identify potential issues before they result in a warning letter. Audit both your owned and operated manufacturing sites, as well as those of your key suppliers like CMOs/CDMOs. Use of Vendor Quality Monitoring tools like Redica Systems can provide key data points like a Vendor Risk Score™.