Contain Microbial Contamination: Achieve Compliance with Cleanroom Socks

Why cleanroom socks?

For decades, we’ve known that wearing cleanroom socks and adhering to proper gowning room protocol is an effective method for containing operator generated contamination, particularly in environments where microbial contamination is a concern. Since 2008, international good manufacturing practices (GMPs) have advocated for cleanroom socks.

Cleanroom Catastrophes Series: Contain Microbial Contamination and Achieve Compliance with Cleanroom Socks

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Why?

Operators are the #1 source of contamination in a cleanroom, and socks and footwear are a known hotbed of microbial contamination. If our goal with cleanroom gowning protocols is to control operator generated contamination, we should do everything we can to mitigate variables introduced to the environment by cleanroom operators.

What’s in Annex 1?

In August 2022, the European Union introduced GMP Annex 1 to prevent microbial, particulate, and endotoxin/pyrogen contamination in finished medical products. A significant update to past guidance and regulation includes the addition of cleanroom socks to the required facility garments that operators use. In fact, GMP Annex 1 takes it a step further to say that no street clothes are to be worn, “Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas.”

”Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas.”

The guidance continues, “Single or two-piece facility trouser suits or scrubs, covering the full length of the arms and the legs, and facility socks covering the feet, should be worn before entry to change rooms for cleanroom grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes.”

Who has to comply?

Since August 2023, European drug makers are required to comply with GMP Annex 1. Annex 1 has also been adopted globally via the Pharmaceutical Inspection Co-operation Scheme (PIC/S) and the World Health Organization. The United States Food and Drug Administration was also actively involved in the Annex 1 update.

Manufacturers licensed to sell pharmaceuticals and medical devices in the EU and PIC/S member countries must comply with Annex 1, regardless of country of origin. While the FDA has not revised its standards to reflect the same requirements as Annex 1, FDA inspectors may inspect facilities according to Annex 1 rules if the product is licensed for the EU or PIC/S countries. Despite this, some manufacturers are confused as to whether they need to comply with Annex 1.

I argue that there should be no confusion. The requirements outlined in Annex 1 contain the latest international regulatory thinking for contamination control governing medicinal products. It provides a baseline that considers a wide variety of facilities and environments where medical products are manufactured. It is important to understand this is a global GMP.

Many generics are produced outside of the US and Europe. We know that operators generate contamination. Sometimes it rains, floods or personnel step into a puddle on the way to work. Wet socks are a hotbed of microbial activity, so why not remove them from the equation? Operator’s socks are the remaining article of street clothing visible in the cleanroom, and the cleanliness of the clothing in the cleanroom should not be left up to operators as it becomes an uncontrolled variable in the contamination control strategy. First and foremost, wearing cleanroom socks is a simple and highly effective solution to manage risk and control contamination—avoiding any potential compliance issues is just an added benefit.

First and foremost, wearing cleanroom socks is a simple and highly effective solution to manage risk and control contamination —avoiding any potential compliance issues is just an added benefit.

I wish I could say that everyone felt the same way I do, but time and time again I hear manufacturers “rationalize” why they don’t have to comply.

Real-world practice: “GMP Annex 1 is not US FDA guidance, we don’t have to comply because we manufacture in the US.”

Reality: If you are licensed to sell your products in the EU or the member countries of PIC/S, you need to comply with Annex 1. Annex 1 is not a US FDA document, but the FDA was a contributor, and FDA inspectors may refer to your own SOPs that reference GMP Annex 1 when applicable.

The entire developed world has GMP standards with additional requirements that extend beyond the US FDA CGMP guidance. Just because the FDA has not updated its guidance yet to harmonize with Annex 1, does not mean that we haven’t proven that cleanroom socks help control operator generated contamination. Combined with the gowning protocols described in Annex 1, cleanroom socks ensure better quality and reduced risk to finished products—if they can play a role in avoiding facility shutdowns or product recalls, why not utilize them?

Real-world practice: “We’ve never had a problem before. We don’t think we need to change, and no one has told me we need to...yet.”

Reality: It is common for manufacturers to interpret the rules to justify why they don’t need to comply. However, requiring cleanroom socks mitigates risk and is far less costly than going the route of non-compliance, which can result in a lot of extra work, legal fees and trying to justify your actions to a foreign inspector.

Real-world practice: “Our operators follow hygiene standards and don cleanroom footwear before entering. Cleanroom socks are an unnecessary step.”

Reality: Removing all street clothes–even socks–and donning approved cleanroom products according to a gowning protocol helps achieve our goal—to contain operator generated contamination, which mitigates risk. Socks are a hotbed of microbial activity, and the many modes of transportation personnel use to get to work do have a significant and ranging impact on their cleanliness.

If you choose not to follow Annex 1 guidelines on cleanroom socks, some inspectors may accept a risk assessment report listing the methods the facility uses to control contamination. Along with the results of recent tests that show air particle and microbial counts within acceptable limits, inspectors may accept the plan. However, if inspectors come to your facility because of a contamination problem, it's unlikely they would accept the assessment and plan since you are technically non-compliant and experiencing consequential issues. The result could be costly fines and the associated cost of removing the contamination problem.

Real-world practice: “We’ve installed a hand and foot washing station in the gowning area and provide disposable socks for our employees.”

Reality: While this solution might be effective, it’s not an Annex 1 requirement. Annex 1 does not ask operators to wash their feet before entering the cleanroom. Annex 1 says, “Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas.” The cost of compliance—cleanroom socks—is far less expensive than an expensive foot-washing station.

Cleanroom socks control contamination and comply with Annex 1.

Annex 1 represents the latest scientific discovery in contamination control developed over the last two decades. It’s an international standard utilized in over 50 countries and considers the wide variety of facilities and environments where medical products are manufactured. Annex 1 is different from FDA CGMP, but if you are licensed to sell products in the EU or PIC/S member countries, you should comply with Annex 1.

Bottom line: The science points to reduced contamination when the operators' “street” socks are changed out for facility-approved cleanroom socks—regardless of Annex 1 compliance requirements, utilizing them has become a best practice. Will your facility be left behind?