The FDA requires its analysts to handle OOS results within the framework of the pharmaceutical quality system.
In today’s global economy, businesses making products that must adhere to health and safety regulations need to be aware of the differences in the rules for each country where they market those products.
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Many pharmaceutical and medical device brands market their products in both the United States and the United Kingdom. In the U.S., the Food and Drug Administration (FDA) sets the safety and quality standards for those products. The FDA’s counterpart in the U.K. is the Medicines and Healthcare products Regulatory Agency (MHRA).
However, the MHRA and the FDA have different regulations.
"Pharmaceutical companies must be familiar with these differences if they are marketing products in both the U.S. and the U.K.," said Abhijeet Mudholkar, senior project manager for Reckitt Benckiser Healthcare in New Jersey.
Mudholkar manages all new product development for Reckitt Benckiser Healthcare, which manufactures and markets analgesics, cough and cold, and skincare products. Earlier in his career, he actively participated in FDA and MHRA audits to represent the process validation and technology transfer activities for Reckitt Benckiser in India.
The regulatory landscape is constantly changing, so “pharmaceutical companies must remain vigorously up to date with amendments and new regulations so that they can make informed decisions,” Mudholkar said.
Regulatory agencies around the globe ensure product quality and patient safety by investigating test results classified as Out-of-Specification (OOS). These results fall outside of established acceptance criteria.
However, the FDA and the MHRA have slightly different definitions of OOS.
The FDA defines OOS results as those that fall outside the specifications or acceptance criteria established in drug applications, drug master files, official compendia, or by the manufacturer.
On the other hand, the MHRA defines OOS results as the ones that don’t comply with the pre-determined acceptance criteria established in drug applications, drug master files, approved marketing submissions, or official compendia or internal acceptance criteria, or fall outside of acceptance criteria established in official compendia and/or by company documentation such as raw material specifications or in-process/final product testing.
How do the two regulatory agencies investigate OOS results?
After the FDA identifies an OOS result, it conducts a preliminary assessment to determine if a clear testing error occurred. If so, the agency can invalidate the lab result. The MHRA also calls for an initial assessment to check for obvious laboratory errors.
Under FDA guidelines, if the lab result cannot be invalidated through the initial assessment, a full-scale investigation follows. This phase typically focuses on the laboratory procedures and processes. Similarly, the MHRA recommends a robust investigation, beginning with the laboratory where staff discovered the OOS result.
Suppose the FDA finds an OOS result isn’t due to a lab error. In that case, the investigation will expand to the manufacturing processes, raw materials used, and any other factor that could potentially impact the laboratory result. Under the MHRA, if analysts don’t discover lab issues, the probe also expands with a focus on manufacturing processes.
FDA guidelines allow retesting to confirm the OOS result, but the number of retests must be predefined and justified. The MHRA also permits retesting after OOS results. However, a passing result will not negate the initial OOS finding.
The FDA requires its analysts to handle OOS results within the framework of the pharmaceutical quality system. Corrective and preventative actions may be initiated at this step. The MHRA recommends that OOS results be handled within the quality system of the organization.
FDA guidelines state that the conclusion of an OOS investigation must be based on evidence gathered during the probe. If analysts can identify and correct the cause of the OOS finding, the product batch may still be released. However, if the reason for the OOS finding can’t be determined, the FDA may reject the batch. The MHRA has similar guidelines for concluding an OOS assessment and what actions should be taken next.
So far, the process sounds similar. However, here are some ways the two agencies differ:
- The FDA guidelines only mention OOS and outlier results investigations, while the MHRA also calls for Out of Trend (OOT)/atypical results investigations.
- FDA regulations do not refer to microbiological investigations, but under the MHRA, the process for those investigations is outlined.
- The FDA doesn’t cover stability OOS/OOT investigations, but the MHRA guidelines include this topic.
- FDA guidelines also don’t mention the 95% Confidence Limit concept for evaluating retesting results, but the MHRA uses this concept.
"Regulatory adherence is essential to consumer safety and trust," Mudholkar said. "Industry professionals who can navigate the compliance differences between nations are essential these days."
Written by Mary Pieper
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