Guest Column | August 17, 2022

How To Avoid Form 483s For Biopharma Software Validation Failures

By LaToya Lee, Clarkston Consulting


The primary objectives of software validation1 are to ensure the safety and quality of the product, provide evidence that specifications conform to user needs and intended uses, and assure that software requirements can be consistently fulfilled. This makes software validation crucial for assurance of regulatory compliance. As pharmaceutical and biotechnology companies operate within a legislative environment that falls under the FDA, avoiding compliance violations is business critical.

The FDA issues a Form 483 if an inspector from its Office of Regulatory Affairs (ORA) encounters objectionable deficiencies during inspection. The form serves to communicate any observed violations of regulatory compliance standards. As of July 2022, approximately 100 FDA warning letters have been issued to pharmaceutical and biotechnology companies.  The Inspectional Observation Summaries2 released by the FDA reveal that most of the noncompliance in the GxP environment is due to:

  • data integrity failures
  • inadequate and/or unimplemented written procedures
  • deficiencies in investigations
  • substandard laboratory controls

Data Integrity Failures

The FDA requires that data be of the highest quality and integrity as well as scientifically valid and accurate. A Form 483 could be issued if there are concerns about data generated from nonclinical toxicity studies conducted at a testing facility, for example. This is a common problem that most pharmaceutical and biotechnology companies encounter, as they fail to ensure that their experimental data, observations of discrepancies, and discrepancy resolutions are accurately recorded and verified.

The FDA has increasingly made data integrity a focal point. It is therefore crucial your organization prioritizes data integrity in your system during software validation to ensure compliance.

Inadequate And/or Unimplemented Written Procedures

The FDA requires that organizations have readily available standard operating procedures as well as documentation that is in accordance with their established requirements for comprehensive, accurate, reliable, and consistent performance of their computer systems.

Procedures provide a structured environment for system processes, such as security, change control, system failure contingency plans, and data backup and recovery. Without establishing written procedures or following them accurately, mistakes abound, which jeopardizes product quality, data integrity, and accuracy. During inspection, the FDA may request documentation that proves that the software your organization is using is validated, that the proper procedures are in place, and that the software is being used accordingly. As such, companies must have adequate and implemented written procedures in place.

Deficiencies In Investigations

Testing is a GxP requirement, as it serves to confirm that system performance conforms with the business requirements. Inevitably, tests yield unexpected results. The FDA requires that an investigation into the root cause of the discrepancies, along with their corrective actions, be performed in a prompt and well-documented manner.

Deficiencies in investigations are another common problem that can have devastating consequences to product safety and efficacy and therefore lead to compliance violations. Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production3 is an FDA guidance document [Editor’s note: covered in this recent article] that gives a contemporary methodology on how to analyze test results that fall outside of the acceptance criteria.

Substandard Laboratory Controls

The FDA requires regulated companies to have established laboratory control mechanisms that ensure standards, specifications, test procedures, and sampling plans are scientifically sound and confirm product safety and efficacy. These mechanisms require periodic review and approval by the quality control unit.

Neglecting to do this can be a valid reason for a Form 483 issuance. Pharmaceutical and biotechnology companies should focus on performing risk assessments on product quality along with developing a remediation plan for the risks. They should also identify root causes of any variations to their established processes using data-driven and scientifically sound tools.

Tips And Recommendations To Avoid Form 483 Violations

  • Streamline company hierarchy: Enforcing laboratory mechanisms requires that the personnel responsible for quality assurance are empowered with the necessary resources to do their jobs and have the support of top management. Streamlining allows for quicker responses to risks, even when the risk exceeds the authority of the risk owners.
  • Develop document controls to ensure data integrity: Consider establishing a data integrity program and accompanying documentation that includes root cause analysis and remediation of any discrepancies in data integrity.
  • Develop a risk assessment traceability matrix (RATM): A RATM enables you to document any business and compliance risks that each of the requirements outlined in the user requirements specification might cause. This should be a cross-functional collaborative effort. When multiple workstreams get together in this manner, expect to have to manage competing priorities and business needs. The project management office (PMO) should account for these differences and manage the communication as well.
  • Build a repository of templates: Having a repository of templates for user requirements, functional specifications, operational qualifications, and performance qualifications can save time and ensure consistency and accuracy.
  • Digitize the laboratory: Consider investing in software tools for storing, documenting, analyzing, sharing, and managing experimental data in a digital form. Software such as laboratory information management systems (LIMS), electronic laboratory notebooks (ELN), laboratory execution systems (LES), and scientific data management systems (SDMS) are examples of applications that can be leveraged to digitize the lab.

The Importance Of Proper Software Validation

A Form 483 issuance can be a significant disruption to your company. Proper software validation – although a significant investment – will bring immense value to your organization. Software validation is not only critical for compliance but also for business growth and overall success. Proper software validation can help protect revenue streams, encourage organizational collaboration, and enable scaling up your operations. Investing in and properly validating software can help you realize your business’ short- and long-term goals and help prevent Form 483 violations.


  1. Lee, L., Dzinotyiwei, L. & Patterson, D. (2022, June 21). Best Practices for Software Validation in Life Sciences. Clarkston Consulting.
  2. U.S. Food and Drug Administration. (n.d.). Inspectional Observation Summaries.
  3. U.S. Food and Drug Administration. (2022, May). Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production - Level 2 revision.

About The Author:

LaToya Lee is an associate partner at Clarkston Consulting. With clients primarily in the pharmaceutical, biotech, and life sciences industries, Lee specializes in project and program management, as well as computer systems validation. She also has experience in business process development for and deployment of quality management systems, including laboratory information management systems (LIMS). She is adept in business process optimization, organizational efficiency, training development and execution, change management, and talent development. Lee has also served as a leader in diversity, equity, and inclusion for Clarkston, her clients, and peers.