Inadequate Equipment and Facility Design

Recommendation

17-19 September 2024

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GMP Compliance and Technology for the Manufacture of Oral Solid Dosage Forms

The inspection of the pharmaceutical manufacturer in Jordan which manufactures sterile OTC products and homeopathics as a subcontractor, already took place in August 2023. Due to the violations observed, the FDA has now issued a Warning Letter.

The FDA criticizes the lack of protection of the aseptic ISO-5 area and mentions among others the following design flaws

The FDA describes excessive and high-risk manual interventions during batch manufacturing and therefore unacceptable risks to product sterility. One batch required several hundred manual interventions!

• Product contact equipment on several lines was poorly protected and exposed to unacceptable environmental conditions for minutes.
• One container was not adequately covered and was exposed to the environment
• A hopper extended from ISO 5 (Grade A) into the ISO 7 (Grade B) environment and came into contact with the surrounding environment.

During aseptic assembly of sterile tubing, a poorly designed connection resulted in tampering where sterile tubing entered an ISO 7 environment and came into contact with non-sterile surfaces during operator manipulation. In addition, several small pieces of tubing were serially aseptically connected to reach the filling line, with each of these successive intermediate connections posing a significant risk of contamination.

The FDA found that the equipment did not consistently have suitable and smooth surfaces as required for good cleaning & sanitizing. For example, a hopper holder with exposed threads and hinges was observed.
The set-up of equipment in contact with the product was not carried out aseptically. For example, an operator placed his foot in the ISO 5 environment when transferring the sterile hopper to the aseptic line.
Overall, the FDA described the aseptic filling line, cleanroom layout, HEPA filter coverage, protection of ISO 5 areas, and the number and complexity of staff interventions as deficient.

In its Warning Letter, the FDA also criticized the required environmental monitoring

According to the FDA, the frequency of environmental monitoring is inadequate. There is no air monitoring of the ISO filling areas and the monitoring of surfaces and personnel is not frequent enough. However, personnel were observed performing critical procedures in the ISO 5 area of the aseptic line.

Microorganisms isolated during monitoring of the aseptic production areas were not routinely identified. According to the FDA, the lack of identification and sampling as part of the monitoring program provided insufficiently meaningful data on the microflora in the cleanrooms.
The company had stated that in the past two years there had been no alarms, tolerance or limit violations in environmental and personnel monitoring, media fill and testing of raw materials and finished products. However, during the inspection, the FDA found that there were more than 50 microbiological exceedances (including exceedances of the limits in the ISO 5 and ISO 7 areas). Regarding the data situation, the FDA writes that the laboratory data indicating that there are no microbial findings are not considered valid due to the significant breaches of data integrity and the overall reliability of the company's test results.

Behaviour of employees in the cleanroom and the aseptic techniques also criticized

Finally, the behaviour of the employees in the cleanroom and the aseptic techniques were also criticized:

• Use of forearms to directly touch and move the sterile equipment on the filling line
• Not wearing goggles 
• Crawling on hands and knees under aseptic line equipment
• Touching the uncovered eye area and personal cell phones
• Irregular disinfection of gloved hands

Another serious deficiency was the failure to sterilize equipment that comes into direct contact with the sterile product (e.g. hoppers, primary containers and closures). The pharmaceutical manufacturer had only cleaned and disinfected these.

The Warning Letter to the Jordanian pharmaceutical manufacturer can be found on the FDA website.