Analysis of Warning Letter issued to Brassica Pharma

Brassica Pharma Pvt. Ltd. (Brassica) is an India-based Contract Development & Manufacturing Organization (CDMO) that specializes in sterile semi-solids such as eye ointments and gels, pre-filled syringes, and dermatological and liquid oral products. Its past customers include Cipla and Cadila Pharma.

According to the company website, Brassica manufactures 250 different formulations, has been manufacturing sterile products for 20 years, and does business in 20 countries, including the U.S.

The company’s sterile manufacturing facility in Thane, Maharashtra, India was inspected between January 15 and 19, 2024, by FDA investigators Justin Boyd and Anastasia Shields.

The inspection resulted in an 18-page, ten-item 483.

Redica Systems’ GMP Labels highlighted 43 GMP deficiencies across four quality systems. Our models also gauge the criticality of the observations ranging from minor to critical. Here are those results:

As a result of the inspection, the firm was placed on Import Alert 66-40, “Detention Without Physical Examination of Drugs from Firms Which Have Not Met Drug GMPs” 11 days later, on January 30, 2024.

On February 12, 2024, the company announced a voluntary recall of eye ointment products “due to lack of sterility assurance at the facility noted during an inspection conducted by the FDA.”

On February 22, 2024, the company communicated to FDA its commitment to suspend manufacturing and distribution of all drugs for the U.S. market and agreed to voluntarily recall all drugs in current distribution in the United States.

On July 11, 2024, the FDA issued a ten-page warning letter to Brassica.

Review of Key GMP Labels

A high percentage (20%) of the GMP Labels in the Brassica 483 map to issues our models deem critical – specifically, observations around sterile products, such as deficiencies with process validation, a lack of effective barriers to microbiological contamination of the sterile products, and interventions during sterile drug manufacturing. These deficiencies indicate an unacceptable risk of microbial contamination of sterile products. The risk is heightened by a lack of validation of analytical methods used for sterility testing – in other words, there is no assurance that sterility breaches if they took place would be detected.

While the majority of the GMP Labels (58%) are in the Production system, nearly 20% mapped to deficiencies with Data Integrity – for example, fabricating test results for samples that were not collected or tested. Seven of the eight data integrity findings are classified as major and taken together are cause for serious concern.

The Laboratory system had nearly as many findings. Of particular concern were the ones around method validation, particularly validation of sterility methods and microbiological testing methods.

In the Facilities and Equipment system, the major finding was regarding the correct pressure differentials not being maintained between the Grade A filling area and the adjacent Grade D area. This is concerning in that airflow and pressure differentials are used to help ensure microbe-free environments for manufacturing sterile products.

Consider the following:

• the lack of validation of sterile processes, making them more prone to microbiological contamination
• the lack of validation of analytical methods to detect possible contamination
• the lack of systems to ensure appropriate pressure differentials between sterile manufacturing and adjacent areas, and
• the falsification of data such that testing documented as done was not performed

Taken together these inspection findings paint a picture of a manufacturing facility that should not be trusted to produce sterile drug products for human use.

Table 1. GMP Labels for Brassica 483

What Did the FDA Warning Letter Focus On?

In its July 11, 2024, warning letter to Brassica, the FDA focuses on the following key areas, listed in the letter as section headers, citing examples found on inspection. Next to each is the GMP Label and line number in Table 1 above that corresponds to the same issue identified in the 483 by our GMP Labels:

Table 2. FDA Warning Letter Sections Compared to GMP Labels

Regarding the CFR citations in the warning letter, the four CFRs FDA identified in the primary citations in the warning letter are all inferred by the GMP Labels, and three of the four were tagged more than once:

• 21 CFR 211.194(a) on laboratory records (tagged once)
• 21 CFR 211.113(b) on microbiological contamination (tagged 17 times)
• 21 CFR 211.42(c)(10) on design of facilities (tagged 3 times), and
• 21 CFR 211.67(a)(b) on equipment cleaning (tagged twice)

Conclusions

The Redica Systems GMP Labels identified issues in the Brassica 483 that were serious enough in aggregate to warrant FDA issuing a warning letter to the firm. The high percentage of major and critical observations on the 483 in combination with an import alert and recalls of all products in the U.S. market correctly led to the prediction that further enforcement action – in this case, a warning letter – would take place.

This case provides a good example of how Redica Systems customers can be forewarned of serious potential future enforcement actions targeted at pharmaceutical supply chain partners. This evidence helps pharma sponsors make better strategic partnership decisions.