Critical Differences Between a Form FDA 483 and Warning Letters

January 16, 2020

There are many publications and services that analyze the observations contained in Form FDA 483 documents issued to manufacturers at the close of an inspection by the U.S. Food and Drug Administration (FDA).  I won’t try to repeat that effort here in a blog post.  What I’d rather highlight are other extremely valuable sources of information from FDA with insights for inspection readiness and remediation, but they won’t come from analyzing Form FDA 483 content.

To get started, let’s understand exactly what information a manufacturer can expect to gleam from a Form FDA 483 – whether it was issued to the firm or whether the firm has an interest in taking a look at redacted Form FDA 483 issued to other manufacturers and available through Freedom of Information Act (FOIA) requests or commercial vendors.  The Form FDA 483 contains descriptions of observations made when in the investigator’s judgment (emphasis added by FDA) conditions or practices are significantly objectionable and would render the product adulterated or injurious to health (see Section 5.2.3 of the FDA Investigations Operations Manual (IOM) here).

It’s important to then understand what happens after the FDA has closed out the inspection at the manufacturer.  The investigator(s) have a specific amount of time to write the narrative report of the inspection, known as the Establishment Inspection Report (EIR) and have that report uploaded in the FDA compliance management database.

The EIR is designed to be written so that the findings of the inspection can be used for others to act on the information. That begins with a supervisory investigator in the Office of Regulatory Affairs (ORA) reviewing the inspection findings and recommending a facility classification and action (see FDA IOM Section 5.11 here).  The EIR and the field recommendation for the facility classification are next evaluated at the Center for Drug Evaluation and Research (CDER) by the Office of Manufacturing Quality (OMQ) and/or the Office of Pharmaceutical Quality (OPQ).

The review of the case uses a systematic risk-based framework and CDER makes a decision about two issues: (1) which of the observations and supporting information can be adequately used as violations or deviations of current good manufacturing practices (CGMP) for drug products and active pharmaceutical ingredients (API) which would render a product adulterated; and (2) what is the proper facility classification. Depending on those decisions, CDER will determine whether and what regulatory, administrative or enforcement action to take.

If FDA decides to issue a Warning Letter to a manufacturer after sifting and sorting through the case, the Warning Letter will have two very significant pieces of information for regulated industry that are not found in Form FDA 483 documents:

  • The CGMP charges for violations or deviations from CGMP for a drug product or API; and
     
  • Specific information requested by the FDA that will be necessary to develop as part of any successful response and remediation program.

After CDER has evaluated the case, the observations of the investigator(s) may also appear as charges in a Warning Letter. There may also be cases where only some of the observations are supportable as charges. And there can be cases where observations judged by the investigator to be less significant and communicated to the manufacturer verbally and not included as part of the Form FDA 483 are determined to be supportable as charges in a Warning Letter.

For all these reasons, the tracking and trending of the charges that appear in Warning Letter further refines the wider scope of Form FDA 483 observations.  There are several forums and publications where an annual overview of CGMP charges in Warning Letters is discussed, including participation by FDA. Metrics that track the disposition of observations listed on the Form FDA 483 to charges that appear on Warning Letters to fully understand how CDER is evaluating and prioritizing certain CGMP elements and systems are less often obvious but likely much more valuable for regulatory surveillance than an aggregate overview of the number and type of charges in Warning Letters.

What can be over-looked is tracking and trending the language in the Warning Letters that gives instructions to manufacturers about what information and steps are necessary as part of successfully remediating a violation or deviation.  This is valuable information that can be used as part of creating robust remediation programs – including drafting responses to Form FDA 483 observations as well as a Warning Letter – but can also be used as part of a feed-forward loop to test the robustness of CGMP systems that are in place and for inspection readiness programs.

To see how this works in practice, let’s have a look at two charges often cited in Warning Letters – violations related to process validation (21 CFR § 211.100(a)) and handling out of specification (OOS) investigations (21 CFR § 192) for drug products.  Over time, the FDA has developed more detailed and standardized language in Warning Letters when asking manufacturers to provide the agency with information related to showing remediation for each of these violations.

This strengthens the agency’s prior notice to firms, should act to improve a manufacturer’s ability to fully remediate the violation and reach voluntary compliance and prevent a firm from facing the prospect of recidivist observations on a follow-up inspection.  For a recent example of a Warning Letter that includes detailed language for requests related to remediating process validation violations, see here and here.  For a  recent examples of Warning Letters than include detailed language related to remediating OOS investigation violations see here and here.

It is certainly advisable to use every tool at your disposal for monitoring CGMP inspection trends by FDA, including surveillance of Form FDA 483 observations.  But since all Warning Letters are publicly posted, reading this mail from FDA with a critical eye on the charges vetted by CDER and scope of the remediation language will give a manufacturer better insight into how FDA is likely to act.

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