How to Avoid Pharma’s Top 5 FDA Form 483 Triggers

The riskiest wager a pharmaceutical company can make is to gamble that its questionable quality practices will go unnoticed by the U.S. Food and Drug Administration (FDA). As proof, the agency has issued an average of 645 Form 483 reports to drug companies in each of the past five years. ⁽¹⁾

What Is FDA Form 483?

While you might hear it called by many names — “inspectional observation,” “Form 483,” or simply the dreaded digits “483” — an FDA Form 483 inspection observation report refers to the notice a company receives from the agency that highlights conditions found by FDA inspectors during routine observations that they’ve deemed to be objectionable.

The prevailing hope among ethical professionals in the industry is that errors resulting in Form 483s are most commonly due to oversight rather than sloppiness or fraudulence. Whatever the cause, however, the efforts to resolve these types of quality and accountability issues are indicators of the pharma industry’s integrity and commitment to safety.

If your organization hopes to evade painful and costly Form 483 outcomes, it’s worth taking the time to:

• Be aware of the most frequently occurring events that prompted the FDA to issue 3,229 inspectional observations to pharma companies over the past five years.
• Consider process improvements that can help thwart 483 in pharma environments.

The 5 Most Common FDA Form 483 Observations for the Pharma Industry

The following is an examination of the most commonly cited conditions that led to the issuance of Form 483s to drug companies last year (as summarized by the FDA in the most recent 12-month inspection period on record) accompanied by practical tips for avoiding them. ⁽²⁾ It’s important to note that while FY 2020 provided a smaller sample size from which trends could conclusively be derived (since fewer inspections were conducted during the height of the COVID-19 pandemic), the first four issues listed below consistently top the list of Form 483s issued to pharma companies year over year.

1. Discrepancies and/or Failures in Investigations (21 CFR 211.192)

The 21 CFR 211.192 guideline requires all deviations from written procedures to be thoroughly investigated and calls for adequate documentation of the results of those investigations. ⁽³⁾ If a pharma company is unable to identify root causes and document them sufficiently, the FDA regards their internal investigations as incomplete. Failure to attentively investigate quality events can have catastrophic consequences for a pharma company’s consumers, to say nothing of the long-term effects on product consistency, company reputation, and brand trust.

How to Avoid Observational Warnings for Investigational Failures:

Companies can dramatically simplify the investigation and documentation of quality events by implementing quality management system (QMS) software that automates the workflow of the entire corrective action/preventive action (CAPA) process — from initiation to investigation and all the way through to closure. Modern QMS solutions integrate CAPA-related data and documentation with other quality processes, which decreases the likelihood that information needed for investigations will slip through the cracks. Audit-ready written records of investigations can also be securely maintained within such a system, per compliance requirements.

2. Procedures Not in Writing or Not Fully Followed (21 CFR 211.22(d))

For a pharmaceutical company to provide evidence of compliance and commitment to safety, its standard operating procedures (SOPs) must be clearly written and maintained and modified in a timely and consistent manner. ⁽⁴⁾ SOP records must be centrally located and readily available to investigators. When employees aren’t given accurate or current written instructions for their tasks, or if they do not explicitly follow written instructions, mistakes and quality problems inevitably occur.

It’s easy for companies to slip into such predicaments when disparate, paper-based document control systems are in use, or if the systems aren’t capable of adequately tracking approvals, signatures, and audit trails. Up-to-date SOPs are more likely to go unnoticed if they’re trapped in disconnected, siloed systems, which leads to a greater likelihood of employees executing their tasks using outdated work instructions.

How to Avoid SOP-Related Observational Warnings:

A proven digitized system can automate the routing and delivery of SOPs, policies, work instructions, and other pertinent documentation to designated personnel while maintaining SOPs and other critical documentation in a secure, web-based repository. With digital systems, it’s easy to see who has changed a document and when updates were made, which helps ensure that only the most current versions of SOPs are in use. Digitization also simplifies the search for and retrieval of audit-ready documentation.

3. Unsound Laboratory Controls (21 CFR 211.160(b))

Pharma companies must ensure that the specifications, standards, sampling plans, and test procedures for assuring that drug products conform to standards of identity, strength, quality, and purity are scientifically sound and appropriate. ⁽⁵⁾ While laboratory control infractions are often caused by what may initially seem to be only minor issues (e.g., inter-departmental communication miscues, disconnected processes, etc.), they can have disastrous ripple effects on product consistency and reputation. Maintaining the integrity of laboratory controls requires the use of systems that effectively integrate multiple interrelated quality processes, particularly those critical to change control, nonconformance, document control, training, and CAPA.

How to Avoid Observational Warnings for Laboratory Control Failures:

An automated system that integrates related quality processes provides the most reliable means of maintaining sound laboratory controls. QMS software can connect every essential laboratory quality assurance process and prevent minor issues from snowballing into compliance failures. With digital, purpose-built solutions, companies gain the ability to automatically track documentation through collaboration, review, and approval steps and use it to apply timely controls where appropriate.

4. Absence of Written Procedures in Support of Production/Process Controls (21 CFR 211.100(a))

When deviations or other similar events are not adequately documented or tracked in pharma manufacturing environments, it’s impossible to pinpoint root causes and take the appropriate corrective and/or preventive actions. Many companies struggle to manage and control written procedures because the processes involved can be time consuming and cumbersome, especially if the organization is reliant on paper-based processes or if the documentation is scattered between multiple systems in different locales.

How Avoid Observational Warnings for Written Procedure Failures:

Pharma manufacturers can alleviate documentation inefficiencies by implementing a proven document management system with a track record of facilitating adherence to current good manufacturing practices (CGMP). A digital, connected system streamlines documentation management and simplifies how it is controlled. Purpose-built software provides automated revision control and ensures that old versions of documents are archived in an inspection-ready state. Any changes to production and process documentation can be initiated, escalated, and approved electronically, which provides greater assurance that critical documents are always going to the right person.

5. Lack of Appropriate Controls Over Computer Systems (21 CFR 211.68(b))

The FDA reported 57 instances of computer system control deficiencies in FY 2020, marking the first time the issue has cracked the list of the top five most observed Form 483 infractions. ⁽⁶⁾ This surge isn’t surprising, given the FDA’s increasing focus on data integrity and data management matters in general. It stands to reason that these types of data-related issues will only continue to get more attention from inspectors in the future, and trends indicate that data managed electronically via laboratory instrumentation and manufacturing batch records poses a particular ongoing concern to the agency.

How to Avoid Observational Warnings for Inadequate Computer System Controls:

Since Section 211.68(b) mandates that only authorized personnel may institute changes to master production, control, and other records, pharma companies must have reliable systems in place that prohibit interference by unauthorized users. ⁽⁷⁾ Organizations that rely on paper-based systems never have the assurance that only authorized users have altered records. With a proven electronic batch record (EBR) software system, access to records can be restricted as needed. Plus, if the software is cloud-based, authorized users have anytime/anywhere access to records, which maximizes efficiency.

To learn more about FDA expectations and how your organization can avoid the types of quality failures that lead to Form 483s, download the “Overcoming Pharma’s Top 6 Quality and Compliance Oversights” industry brief.

References:

1. “FDA FY2020 Drug Inspection Observations and Trends,” by Barbara Unger, Pharmaceutical Online, Dec. 9, 2020.
2. Inspection Observations page, FDA website, content current as of Nov. 24, 2020.
3. 21 CFR Part 211.192 – Production record review, revised as of April 1, 2020.
4. 21 CFR Part 211.22 – Responsibilities of quality control unit, revised as of April 1, 2020.
5. 21 CFR Part 211.160 – Laboratory Controls - General requirements, revised as of April 1, 2020.
6. Supra note 1.
7. 21 CFR Part 211.68 – Automatic, mechanical, and electronic equipment, revised as of April 1, 2020.