All NewsBio/Pharma News
All PublicationsPharmTechPharmTech Europe
MarketplaceICH Q9 Revision: A Comprehensive Resource on Quality Risk ManagementPeer-Reviewed ResearchPharmTech ProductsPharma InsightsSponsored PodcastsSponsored VideosSponsored eBooksWhitepapers
Webcasts
All VideosAsk the ExpertBehind The HeadlinesBuy, Sell, HoldDrug Digest VideosDrug Solutions PodcastPeer ExchangeSexy ScienceTech Talk
Conference CoverageConference ListingEvents
Subscribe
AnalyticsAnalyticsAnalytics
Data and Artificial Intelligence
Dosage FormsDosage FormsDosage FormsDosage FormsDosage Forms
Drug DevelopmentDrug DevelopmentDrug DevelopmentDrug DevelopmentDrug DevelopmentDrug Development
ManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturing
OutsourcingOutsourcingOutsourcingOutsourcingOutsourcingOutsourcingOutsourcing
Quality SystemsQuality SystemsQuality SystemsQuality Systems
Spotlight -
  • Analytics
  • Dosage Forms
  • Drug Development
  • Manufacturing
  • Outsourcing
  • Quality Systems
IS1
  • Applied Clinical Trials

  • BioPharm International

  • Cannabis Science and Technology

  • Chromatography Online

  • Nutritional Outlook

  • Pharmaceutical Commerce

  • Pharmaceutical Executive

  • Pharm Tech

  • Spectroscopy Online

  • Turbo Machinery Magazine

AnalyticsAnalyticsAnalytics
Data and Artificial Intelligence
Dosage FormsDosage FormsDosage FormsDosage FormsDosage Forms
Drug DevelopmentDrug DevelopmentDrug DevelopmentDrug DevelopmentDrug DevelopmentDrug Development
ManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturingManufacturing
OutsourcingOutsourcingOutsourcingOutsourcingOutsourcingOutsourcingOutsourcing
Quality SystemsQuality SystemsQuality SystemsQuality Systems
IS1
  • Applied Clinical Trials

  • BioPharm International

  • Cannabis Science and Technology

  • Chromatography Online

  • Nutritional Outlook

  • Pharmaceutical Commerce

  • Pharmaceutical Executive

  • Pharm Tech

  • Spectroscopy Online

  • Turbo Machinery Magazine

    • Webcasts
    • Subscribe
Advertisement

News

Article

August 1, 2017

Pharmaceutical Technology

Pharmaceutical Technology-08-02-2017
Volume41
Issue 8
Pages: 38–41

Avoiding Investigational Failure/Discrepancy-Related Form 483 Observations

Author(s):

James Jardine,Walt Murray

Investigational failures and discrepancies can be avoided through the proper execution and documentation of investigations.

Sinart Creative/Shutterstock.com

Investigations-focused regulatory standards that apply to life-sciences organizations, such as FDA 21Code of Federal Regulations (CFR) 211.192, mandate that all deviations from written procedures must be thoroughly investigated and that the results of those investigations must be adequately documented. When life-sciences companies are unable to identify potential root causes and subsequently keep sufficient records of those events, their internal investigations are deemed incomplete by regulatory agencies.

A recent high-profile example of this occurred when FDA noted during a 2016 inspection that Busch & Lomb’s “written records of investigations into the unexplained discrepancies do not include the conclusions and follow-up” regarding the company’s investigations into its non-viable particle testing for aseptic filling lines (1). This investigational infraction, which resulted in the issuance of a Form 483 Investigational Observation from FDA, serves as an illustration that if a company does not perform its quality due diligence in the investigation of these types of events, such oversights could have long-lasting damage on a company’s reputation and its branded products, not to mention potentially catastrophic results for consumers.

The root of the problem

Figure 1. This diagram conceptualizes the depth required for thorough investigations. All the conceivable boundaries of an incident, nonconformance, deviation, or complaint regarding a quality event must be accounted for. All figures are courtesy of the authors.

The companies cited for these investigational failures are not alone. Historically, corrective actions and preventive actions (CAPAs) have been overused industry-wide as a part of the investigation process within the overall quality event management scheme. Even industry leaders have found themselves suffering from “death by CAPA” after cramming every quality event that occurs into their CAPA systems. It is becoming more evident that the key to effective and efficient investigations is to eliminate quality events as issues before escalating them from a correction to a corrective action. For this reason, the International Organization for Standardization (ISO) 9001 revised quality management standard has eliminated the term CAPA from its parlance and has now outlines separate processes for preventing action (PA) and nonconformance/corrective action (NCCA).

As referenced in FDA’s Quality Systems Approach to Pharmaceutical CGMP Regulations guidance, an “investigation” refers to the formal procedural process evaluation of a problem resolution (2). The Form 483 Investigational Observations issued most commonly for poor or ineffective resolutions are due to a poor or nonexistent investigation process by the offending -organization. All the data in the world won’t do any good if the process is inherently bad. By very definition, an investigation is the formal gathering of the factual boundaries of a problem or issue with the intention of uncovering clues which, by experiential treatment, are the source of generating the root cause (see Figure 1).

It should be noted that this investigational process demands the validation of action(s) to eliminate recurrence or proof that a plan of action will effectively address the resolution of an event. An action is not corrective if it cannot be proven to work on a repeatable basis and resolve the issue.

 

 

Finding out what you don’t know that you don’t know

CLICK FIGURE TO ENLARGE Figure 2. MasterControl quality event management/corrective action and preventive action (CAPA).

When done correctly and according to an established, proven process, an investigation can be as straightforward as following a road map. But, just like following a map, if you don’t know where you are, you won’t be able to figure out where you’re going. Figure 2 illustrates how a closed-loop quality event management system can act as a road map for investigations.

An investigation equation has three essential and interdependent components: clarification, decision making, and plan analysis.

Clarification. An investigation should start by thoroughly examining the input to clearly identify each respective issue of the event so that it may be completely addressed. These inputs come in the form of quality events such as customer complaints, deviations, nonconformances, out-of-specification incidents, and audits.

Decision making. The next potentially hazardous step where organizations can go wrong in their investigations is the decision-making phase where data are gathered and assessed. In this risk-based issue review phase an incident can be corrected or mitigated and closed, or a CAPA can be initiated, depending on what was discovered during the review. Each issue must be assessed for impact (negligible, minor, important, or critical) and frequency (rarely, frequently, or occasionally). Some issues may not be contained at the department level and must be escalated into a formal CAPA process. Different situations require different actions and, that being the case, the impact and frequency of the quality event can dictate what actions should be taken. A correction, for example, is ostensibly an immediate fix that can be made to eliminate an existing undesirable situation. For issues that can’t be resolved quickly, however, the company may carry out a series of corrective steps to determine the root cause(s) and prevent the reoccurrence of the problem(s).

Plan analysis. At the completion of the issue review phase, a documented plan analysis of the implementation is required, which gets back to the concept of knowing where one is in order to determine where one needs to be. The initiation of a CAPA marks the beginning of the third stage of a closed-loop quality event management system. The process of establishing corrective actions and preventive actions and effectiveness checks continues through this phase. It is during this investigational phase where root causes are conclusively determined, actions are implemented, and the event achieves closure once appropriate effectiveness checks have been finalized. Tracking and documenting these actions during this analysis phase is crucial to maintaining regulatory compliance.

Be aware, however, of an investigational truism that many working in regulatory environments have learned the hard way: for every solution, there is a cost. As such, several questions need to be taken into consideration when selecting the best action for eliminating a root cause:

  • Are multiple components needed to achieve complete removal of the problem?

  • Will the solution completely remove the root cause?

  • Is there a possibility that the solution will cause other problems?

Once these questions have been answered, the best course for resolving the quality event comes into focus.

During the course of the investigation process, the guiding principle behind all efforts should be to find out exactly what you don’t know that you don’t know. Otherwise, the bulk of your efforts will just be guesswork.

 

 

EQMS: The key to avoiding investigational failures and discrepancies

An organization’s ability to integrate data and documentation from investigations with the rest of the company’s overall quality system is the foundational element of efficient quality management. Life-sciences companies can dramatically simplify their investigations and documentation of quality events by implementing an enterprise quality management system (EQMS) software solution that automates the handling of every phase of the quality event investigation process, from initiation, investigation, and all the way through to closure. An EQMS software solution that provides forms and workflow routes optimized according to industry best practices can provide a repeatable methodology for guiding quality teams through every step of quality event evaluations and CAPA implementation (i.e., identification of the problem, investigation of root cause, correction of problem, and prevention of recurrence). Such systems can be invaluable tools for implementing and sustaining dependable, repeatable, and compliant closed-loop investigation management protocols. Some robust customizable EQMS solutions even include functionality that automatically handles quality events in accordance with scalable preconfigurations and triggers CAPAs whenever established thresholds are met.

Other investigation-centered benefits of EQMS software solutions include:

  • Automated routing, notification, delivery, escalation, and approval of CAPAs and all related documentation  

  • A central, secure repository for all documents pertaining to investigations

  • Connections to all departments, product lifecycles, and quality processes

  • Reduces duplicated efforts and data entry errors

  • Simplified tracking, trending, and report creation

  • Optimized quality processes and streamlined implementation of preventive measures.

Conclusion

Investigational failures and discrepancies can be avoided through the proper execution and documentation of investigations conducted by organizations that have the capability to securely maintain written records of their investigations within a central, audit-ready document management system. An EQMS can be integral to a life-science company’s ability to conduct and document investigations that meet even the stringent quality standards of global regulatory agencies.

References

1. FDA, Form FDA 483 Issued to Bausch & Lomb, Feb. 25, 2016. Accessed June 19, 2017.
2. FDA, Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations (CDER, September 2006). 

 

Article Details

Pharmaceutical Technology Europe
Volume 29, Number 8
July 2017
Pages: 38–41

Citation

When referring to this article, please cite it as W. Murray and J. Jardine, “Avoiding Investigational Failures and Discrepancies," Pharmaceutical Technology Europe 29 (8) 2017.

 

 

 

Download Issue PDF
Articles in this issue

Using QbD in Topical Drug Manufacturing
Using QbD in Topical Drug Manufacturing
Targeting Drug Delivery with ADCs
Optimizing Cell-Culture Media
Optimizing Cell-Culture Media
Gottlieb Tackles Opioids,  Drug Costs, and Innovation
Watson_Main.jpg
Larger Peristaltic Pumps Allow Scale-Up
A Look at Batch Record Review
Romanco_Main.jpg
Drying, Granulating, and Coating System Offers Modularity
PT0817_Spotlight_CharlesRoss200.jpg
Heavy-Duty Multi-Agitator Mixer
CDMOs: New Administration, New Frontier
sartobind_main.jpg
Single-Use Systems Expand Scale of Chromatography
Targeting Drug Delivery with ADCs
Targeting Drug Delivery with ADCs
Just the Pharma Facts, Please
Breaking Through Obstacles to Improve Drug Manufacturing
Breaking Through Obstacles to Improve Drug Manufacturing
The Role of Quality Standards for Biomanufacturing Raw Materials
The Role of Quality Standards for Biomanufacturing Raw Materials
Inside FDA’s Emerging Technologies Team with Team Chair, Sau Lee

Newsletter

Get the essential updates shaping the future of pharma manufacturing and compliance—subscribe today to Pharmaceutical Technology and never miss a breakthrough.

Subscribe Now!
Related Videos
A global supply chain map, visualizing the complex network of transportation routes and distribution centers | Image Credit: © venusvi - stock.adobe.com
Shortcut from point A to point B | Image Credit: © Olivier Le Moal - stock.adobe.com
Behind the Headlines, Episode 21: Waters-BD Merger, Merck’s $10B Bet, and Biotech’s Investment Frontiers
Wooden blocks spelling TARIFFS are placed on a map of North America, specifically over the United States and Mexico | Image Credit: © Rokas - stock.adobe.com
Simona Guidi, Associate Director, ProPharma
Tore Bergsteiner
Behind the Headlines, Episode 20: CAR-T Milestones, Abbvie and Eli Lilly M&A Moves, and More
Related Content
Advertisement
White House | Image Credit: © Zack Frank - stock.adobe.com
August 2nd 2025

Trump Sends Letters to 17 Leading Pharma Companies Outlining Most-Favored-Nation Drug Pricing Protocol

Patrick Lavery
If action is not taken within 60 days, the White House said it would “deploy every tool in our arsenal” to improve drug pricing practices for American patients.
Drug Solutions Podcast: Growth and Advancements in Fill/Finish
August 2nd 2025

Drug Solutions Podcast: Growth and Advancements in Fill/Finish

Felicity Thomas
In this episode, Hanns-Christian Mahler from ten23 Health chats about the advances in fill/finish.
Kratom or Mitragyna speciosa on natural background. | Image Credit: © wasanajai - stock.adobe.com
August 2nd 2025

FDA Seeks Scheduling Action to Control Harmful Kratom Plant Byproduct

Patrick Lavery
7-OH and the leaf of the kratom plant are not analogous, but as the former is a derivative of the latter, it has opioid-like qualities that make its susceptibility to abuse concerning.
Drug Solutions Podcast: All About Data: Looking at the EHDS in More Detail
August 2nd 2025

Drug Solutions Podcast: All About Data: Looking at the EHDS in More Detail

Felicity Thomas
In this episode, Alexander Natz from EUCOPE chats about the European Health Data Space.
automatic stainless steel pharmaceutical fermenter | Image Credit: ©gen_A - stock.adobe.com
August 2nd 2025

In-line UV Spectrometry Monitoring in Cleaning Validation

John Schallom Brian Bosso Paul Lopolito Katie Frey Amy Thanavaro
The authors performed interference and enhancement testing using a formulated alkaline and acid cleaner, as well as common biopharmaceutical process residues.
Glass vials for liquid samples. | Image Credit: ©nordroden - stock.adobe.com
August 2nd 2025

Flexibility Provides Solutions to Small-Batch Manufacturing Challenges

Susan Haigney
Modular process design, single-use technologies, and flexible filling lines are some of the ways manufacturers can combat challenges involved in small-batch manufacturing.
Related Content
Advertisement
White House | Image Credit: © Zack Frank - stock.adobe.com
August 2nd 2025

Trump Sends Letters to 17 Leading Pharma Companies Outlining Most-Favored-Nation Drug Pricing Protocol

Patrick Lavery
If action is not taken within 60 days, the White House said it would “deploy every tool in our arsenal” to improve drug pricing practices for American patients.
Drug Solutions Podcast: Growth and Advancements in Fill/Finish
August 2nd 2025

Drug Solutions Podcast: Growth and Advancements in Fill/Finish

Felicity Thomas
In this episode, Hanns-Christian Mahler from ten23 Health chats about the advances in fill/finish.
Kratom or Mitragyna speciosa on natural background. | Image Credit: © wasanajai - stock.adobe.com
August 2nd 2025

FDA Seeks Scheduling Action to Control Harmful Kratom Plant Byproduct

Patrick Lavery
7-OH and the leaf of the kratom plant are not analogous, but as the former is a derivative of the latter, it has opioid-like qualities that make its susceptibility to abuse concerning.
Drug Solutions Podcast: All About Data: Looking at the EHDS in More Detail
August 2nd 2025

Drug Solutions Podcast: All About Data: Looking at the EHDS in More Detail

Felicity Thomas
In this episode, Alexander Natz from EUCOPE chats about the European Health Data Space.
automatic stainless steel pharmaceutical fermenter | Image Credit: ©gen_A - stock.adobe.com
August 2nd 2025

In-line UV Spectrometry Monitoring in Cleaning Validation

John Schallom Brian Bosso Paul Lopolito Katie Frey Amy Thanavaro
The authors performed interference and enhancement testing using a formulated alkaline and acid cleaner, as well as common biopharmaceutical process residues.
Glass vials for liquid samples. | Image Credit: ©nordroden - stock.adobe.com
August 2nd 2025

Flexibility Provides Solutions to Small-Batch Manufacturing Challenges

Susan Haigney
Modular process design, single-use technologies, and flexible filling lines are some of the ways manufacturers can combat challenges involved in small-batch manufacturing.
About Us
Advertise
Contact Us
Editorial Info
Editorial Advisory Board
Do Not Sell My Personal Information
Privacy Policy
Terms and Conditions
Contact Info

2 Commerce Drive
Cranbury, NJ 08512

609-716-7777

© 2025 MJH Life Sciences

All rights reserved.