Rouge is a Red Flag for FDA Inspections

Over the past decade, there has been an increased governmental focus on current Good Manufacturing Processes (cGMP) on the food, beverage, pharmaceutical and cosmetics industries. This has not just been limited to the United States’ FDA, but also the EU’s European Medicines Agency (EMA). On the American side of the Atlantic, this focus could be considered to have started in earnest with the Food Safety Modernization Act of 2011 (FSMA), which came into full effect at the beginning of 2020. This was followed by the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) which introduced similar regulations and requirements upon the manufacturers of beauty and personal care products.

For pharmaceuticals, however, the FDA’s focus on cGMP dates back to the Federal Food, Drug and Cosmetic act (FD&C Act) of 1938 which established the FDA. The term cGMP appeared later, as early as 1976 – a time when the FDA was part of the Department of Health, Education and Welfare. Section 501 (a)(2)(b) of the FD&C Act mandates that all drugs must be manufactured under cGMP. The standards applying to finished pharmaceuticals is located in Title 21 of the Code of Federal Regulations (CFR).  In the words of the FDA, “the regulations enable a common understanding of the regulatory process by describing the requirements to be followed by drug manufacturers, applicants, and FDA.” Title 21 has been constantly updated to keep up with advances in science and technology. Part 210 specifically deals with cGMP in Manufacturing, Processing, Packing, or Holding of Drugs.

Risk-Based Inspection Schedule

Part 210, along with parts 211, 225 and 226 gives the FDA the authority to establish the minimum cGMP for methods, controls and facilities used for the manufacture, processing, packaging and holding of a drug. This allows the FDA to conduct inspections to confirm compliance.

The FDA drug manufacturer inspection schedule has evolved over the years. All facilities involved in drug manufacturing must be registered with the FDA. With limited exceptions, these are subject to routine inspections for cGMP. As of 2005 the routine inspections are based on a Site Selection Model (SSM). In 2012, The Food and Drug Administration and Innovation Act (FDASIA) amended section 510(h) of the FD&D Act to change the SSM from a fixed minimum inspection interval to a risk-based SSM. This SSM is reviewed and updated annually by an internal FDA work group. Additionally, a “for-cause” inspection can be triggered when the FDA has reason to believe that a facility has quality control issues.

Red Alert

Besides the “for-cause” inspections, the majority of audits are regularly scheduled, the FDA also conducts unannounced audits. There are six risk factors that are taken into consideration in the SSM before an FDA inspector is sent out for a surprise inspection:

  1. Compliance history
  2. Inherent product risk
  3. Facility type
  4. Exposure
  5. The elapsed time since the last inspection
  6. Hazard signals

This last factor, a hazard signal, can invite deeper scrutiny once the inspector arrives on-site. The hazard in question, does not need to be spilled chemicals, it could be the simple presence of rouge (rust, typically red-orange in color) on the outside of the processing or storage equipment. Understandably, this is going to spark heightened interest in what the inner surfaces look like.

If an inspection turns up shortcomings, the inspector will issue a Form 483 listing the conditions that they feel indicate that a product might be adulterated and potentially be injurious. The inspector will go over the conditions cited with the firm’s management. The ball is then in company’s court to respond in writing to the FDA with their corrective action plan and then implement it in a timely manner.

Proactive vs. Reactive

No one truly enjoys the experience of an unannounced audit. But the difference between being proactive in planning for one as opposed to being reactive can be measured in more than just a feeling of dread, It can be measured in increased extra costs needed to swiftly develop the plan and bring the equipment into compliance.

The best way to pass an FDA audit – regardless of it being planned or unannounced – is to ensure that your equipment is prepared to pass an FDA audit to begin with. Among the first things an inspector will ask to see will be the maintenance records. A plant’s standard operating procedure that includes regular cleaning, and other services such as planned passivation will look better than one whose records show delayed maintenance. In addition, regular visual inspections by the internal Quality Assurance teams can turn up issues that can be addressed in a timely manner before they become serious issues.

Engaging Astro Pak to perform services to meet cGMP compliance requirements – either as part of regular maintenance, or after receiving a Form 483 notice – can greatly assist with FDA inspections. Astro Pak is very familiar with the specific FDA/cGMP compliant processes and chemistries for different industries. In fact, several members of Astro Pak’s senior leadership serve in the standards organizations that establish those best practices. During the service, technicians carefully document the processes and chemistries used in real time. When the service is done, the documentation is turned over to the facility. These should be included as part of the maintenance records presented to the inspector at the beginning of the audit. In the unfortunate situation where a Form 483 has been issued, these records will go a long way towards demonstrating remediation and compliance.

When it comes down to it, an FDA audit is a matter of “when” rather than “if”. Hoping one won’t happen is not a plan. Instead, a plan is making sure that the facility is ready when the auditor knocks on the door.

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Mary Cheng

Mary Cheng has been working in the high purity and precision cleaning industry for over 10 years. She currently serves as the Director of Marketing & Communications at Astro Pak where she oversees communications, branding, events, and digital marketing. Passionate about the customer experience, Mary excels at producing content tailored to the client's needs at each stage of their journey, from brand awareness to customer advocacy. She does this via cross functional collaboration with R&D, Sales, and operations to achieve technical accuracy and organizational alignment.

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