Regulatory Focus™ > News Articles > The Tip of the Iceberg: What Lurks Beneath the 483

The Tip of the Iceberg: What Lurks Beneath the 483

Posted 23 March 2015 | By Marlene S. Bobka Sharon DeGrove Bishop, RAC 

The Tip of the Iceberg: What Lurks Beneath the 483

Regulatory intelligence is at the heart of every well-informed regulatory decision, and is integral to maximizing effectiveness and influence for the regulatory professional. The Regulatory Intelligence Quotient is a regular exploration of regulatory intelligence topics by thought leaders in the field. Want to learn more or suggest future topics? Contact us at asksofie@graematter.com.

At the end of a grueling week spent sitting in a conference room with an investigator from the US Food and Drug Administration (FDA), you may end up with an FDA Form 483 listing the inspectional observations that the agency has cited as potentially deficient.

That form, while important, actually captures little of what occurred during that week – which areas of the facility the investigator toured, what types of documents were reviewed and who was interviewed. A person reading the 483 from another manufacturer’s inspection will learn very little about the inspection just from looking at that single form. But for anyone seeking insight into the elements involved, there’s a wealth of intelligence available for each FDA inspection, including the documents and areas reviewed, personnel involved and potentially even notes indicating what the investigator was thinking during the course of the week.

Behind each 483 lies a distinct chain of events, carrying lessons and insights for drug, device and biologic firms. The circumstances behind a 483 can vary widely, and, when known, can be of value to firms preparing for an inspection, characterizing the style and specialized interests of specific FDA investigators, and carrying out due diligence into potential suppliers, joint venture partners and merger or acquisition targets.

What You Can Learn from a Form 483

What can we learn when we take a deeper dive into the regulatory records documenting inspections when we look at the files held in FDA desk drawers?

We selected an inspection of a clinical investigator’s studies, who, under contract, was conducting the blood draws needed to study the pharmacokinetics of new products.  This type of inspection is of interest to drug, biologic and combination product developers, as well as device manufacturers whose proposed product comes into direct contact with the patient. The 483 for this inspection consists of only one observation:

“An investigation was not conducted in accordance with the investigational plan.

Specifically, four out of six consecutive subjects did not have the required 2-hour time-point blood draw for a pharmacokinetic (PK) study on August 22, 2009. This failure to perform the study procedure, was due to the use of a staffing grid or schedule which failed to include the required 2-hour time-point blood draw.”

The observation is of interest, certainly, but many firms may benefit from more in-depth information.

The Information Behind a 483

Via FOI Services, we obtained the records available for this inspection under the Freedom of Information Act. In addition to the 483, we received the Establishment Inspection Report (EIR), a typed summary of the investigator’s notes and a copy of the handwritten investigator notebook.

The EIR offered a fairly comprehensive look into the inspected clinical investigator’s facilities and operations, including:

  • the firm’s inspectional history
  • the names and titles of upper management and study employees
  • the types and numbers of records reviewed
  • the rationale behind the possibly objectionable conditions discussed that did not appear on the 483
  • a summary of the discussions held between the site staff and the FDA investigator

Several additional points of interest are described in the EIR narrative. In fact, the EIR reveals some issues that, while not cited in the 483, certainly warrant consideration. These issues included:

  • “The key-card controlled drug storage room was left open and unattended during the pharmacy tour. Investigational drug for this study was out on the table in that room…”
  • “The Study Procedure Manual (SPM) was not received from the sponsor and the site started the study without this manual…”

The Value of Notes and Diaries

Digging deeper, we found that the investigator's notes and diary were also available. These records can offer additional detail and even reveal investigator uncertainties or on-the-edge judgment calls as well as present the direct chronology of events as they transpired during the week. These can be used as training tools for any firm with similar products or processes and are excellent models for mock audits.

In this case, the FDA investigator’s notes and diaries offer considerable additional information:

  • Which areas of a firm were inspected, and when?
  • Why did a particular point rise to the level of a 483?
  • Were there instances of items of discussion that did not appear on the 483?
  • What did the investigator note to him/herself as essential to examine?

The notes and diaries include checklists of items the investigator looked into, as well as questions raised in the course of the inspection on areas where the investigator wanted further information.

The notes also reveal an unresolved discrepancy in product accountability. Drug accountability record retention deficiencies were noted in the prior inspection of the facility, so this issue might well have been elevated, but this discrepancy was not noticed until after the inspection was complete … and therefore was not cited on the 483.

The EIR lists names of all persons interviewed and all responsible parties, as well as their place within the organizational structure for the facility – again offering a realistic model to prepare for inspections. Insight into the investigator’s thinking can be found in surprising ways, such as a “note to self” that the investigator made. Where else could you find this type of behind-the-scenes gem?

An Untapped Resource

Industry members have access to this unparalleled and little known wealth of intelligence.  So don’t make the titanic mistake of seeing only the tip of the iceberg … use these resources to help you get the full picture.

This and many other types of valuable information are available from FDA by using the Freedom of Information Act; a link to instructions for submitting a request are included in the bottom menu of each page of FDA’s website. Keep in mind that your FOIA request is a matter of public record and turnaround time may be quite slow. Third-party requests and collections of already-released FOIA documentation are available from private firms, including FOI Services at www.foiservices.com.

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