Equipment Design in the FDA's Focus

The current FDA Process Validation Guidance addresses qualification as Stage 2.1. Terms such as DQ, IQ and OQ, as used in Annex 15, do not appear there. However, the US FDA GMP regulations 21 CFR 210/211 include 21 CFR 211.63. This provision requires suitable design, adequate size and an appropriate location for equipment. The objective is to ensure that the equipment is suitable for its intended use and can also be appropriately cleaned and maintained. Using the example of a US-based API and medicinal product manufacturer, the FDA demonstrates what it expects from the practical implementation of 21 CFR 211.63.

What does the FDA expect with regard to 21 CFR 211.63?

The inspected manufacturer produces, among other things, sterile injectable medicinal products that are aseptically filled. The FDA clearly criticised one of the systems in use as being inadequately designed, monitored and maintained. Significant contamination in a storage tank was identified. The inspector discovered black plaques. It was also criticised that sealing tape had been used for repairs instead of sanitary fittings.

The Company's Response to the FDA's "Findings"

The company concerned responded to these "findings" by describing the black plaques in its response letter as biofilm, which it considered predictable and normal. The company also explained that ambient light could enter the tank, enabling photosynthesis on the tank walls. The company claimed that, as tests had shown, this would have no impact on the downstream process. Cleaning the tank was cited as a corrective action.

The FDA's Response

The FDA was far from satisfied with this. A simple cleaning is insufficient because it does not correct the fundamental design and maintenance deficiencies, according to the FDA. The FDA expressly states that such a tank must be designed so that it cannot become a source of microbial contamination. Testing alone does not compensate for design deficiencies.

The FDA therefore wants:

• A comprehensive third-party assessment of the system for the design, control and maintenance of the equipment
• A comprehensive assessment of the design, control and maintenance of the system concerned
• A comprehensive assessment of the system's weaknesses, with a summary of all deficiencies identified in the system. The summary should at least describe which system characteristics were assessed (construction materials, dead legs, slopes, stagnant areas, flow rate, unsuitable fittings)
• A validation report demonstrating how a suitably designed system was installed

It is hardly surprising that the Warning Letter recommends involving a GMP consultant. The FDA also recommends withdrawing a product from the market.

Conclusion: Although the terms DQ is not explicitly mentioned in the FDA Process Validation Guidance, the FDA expects such activity and also IQ and OQ .

You can find the full Warning Letter on the FDA website.