Gambling that questionable quality processes will go unnoticed by the FDA is the riskiest wager a pharmaceutical company can make. As proof, in the past decade the agency has issued an average of more than 665 Form 483 Inspectional Observations to drug companies every year. While ethical professionals will maintain hope that 483-worthy errors are more often due to negligence than to deception or fraudulence, matters of quality and accountability will always be barometers of the pharmaceutical industry’s integrity and commitment to safety. If you wish to evade FDA warning pitfalls, it’s worth your while to examine the most common triggering events that led to the issuance of 691 warnings to drug companies last year and delve into some potential remedies that can help thwart 483s in pharma environments in the future.
Here are the top five reasons Form 483s were issued to drug companies last year (as summarized by the FDA in the most recent 12-month inspection period on record) and a few related tips that describe how to steer clear of them.
For a pharmaceutical company to prove to the FDA that it is operating within the bounds of compliance and is committed to safety, its standard operating procedures (SOPs) must be clearly written, and maintained and modified in a timely and consistent manner. Records of those procedures must be centrally and readily accessible to investigators. Quality problems and/or accidents inevitably occur when employees of a pharmaceutical product research organization and/or manufacturer do not have current or accurate written instructions for their tasks or if they do not explicitly follow written instructions.
In a recent inspection, one notable pharmaceutical company was issued a Form 483 for these types of SOP deviations when the FDA noted that its “responsibilities and procedures applicable to the quality control unit (were) not fully followed.”[i] Pharma companies easily slip into these procedural predicaments when their document control systems are paper-based, dispersed between multiple locations, or if the company does not sufficiently track approvals, signatures, and audit trails. Critical up-to-date SOP documentation is more likely to get lost in systems that are disconnected, and employees have a much greater probability of executing their job tasks using outdated work instructions in these instances. Manual and paper processes and geographic barriers can further complicate the already time-consuming processes of collaborating on, updating, or approving new or revised documents.
The no-brainer solution for evading written procedure-related 483s is to implement an automated document management system. Whether such a solution is fiscally viable or not, though, depends on the organization’s resources. It would be a mistake to discount such a solution for purely financial reasons, however, as there are many affordable options on the market whose value and resourcesavings far outweigh up-front cost considerations.
An electronic 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. It is also befitting to invest in a system that can provide the ability to search for, easily retrieve, and continually maintain audit-ready documentation. Change control and audit trail functionality—other extraordinarily beneficial functions to consider—can dramatically enhance visibility into quality activities. Such functionality makes it easy to see who has changed which document and when they did so, which helps ensure that only the most current version of a document is in use. Format agnostic systems are also especially advantageous, as they have the added advantage of handling any type of file used by the organization, regardless of the software application of origin.
Pharmaceutical 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. Failure to do so can be devastating, as was the case when a 483 Observation led to a warning letter to Emcure Pharmaceuticals for its failure to establish such laboratory controls due to unreliable environmental and personnel monitoring.[ii] While these types of infractions may be caused by what can seem at the time to be only minor issues (i.e., disconnected quality processes, inter-departmental communication miscues, etc.), they can have dreadful ripple effects on company reputation or product consistency. To maintain the integrity of controls, a pharma company must have systems that effectively integrate multiple quality processes, such as those critical to change control, nonconformances, document control, employee training, audits, and corrective and preventive actions (CAPAs).
As with tip No. 1, an automated system is the most reliable means of nullifying these quality shortcomings. When implemented correctly, an electronic quality management system (EQMS) will streamline every critical process related to laboratory quality assurance and prevent initially insignificant-seeming issues from falling through the cracks. An EQMS can automatically track documentation through collaboration, review, and approval steps and be used to apply controls where appropriate. Once generated, laboratory control information can be securely maintained in an EQMS’ centrally-accessible document repository where it can be maintained in an audit-ready state. Also, it is far simpler to manage quality information (i.e., deviations, nonconformances, equipment calibration records, CAPAs, audits, change control data, etc.) electronically rather than with printed files or hybrid paper/electronic systems.
All deviations from written procedures must be thoroughly investigated, according to the 21 CFR 211.192 guideline, and the results of those investigations must be adequately documented. If a pharmaceutical company is unable to identify potential root causes and make sufficient record of them, their internal investigations will be viewed by the FDA as incomplete. Such was the case when the FDA inspectors recently observed that Bausch & Lomb’s “(w)ritten records of investigations into unexplained discrepancies do not include the conclusions and follow-up” in regards to the company’s investigations into non-viable particle testing for aseptic filling lines.[iii] Bausch & Lomb may have been able to resolve these issues without significant financial or quality penalties, but if a pharmaceutical company is not attentively investigating these kinds of quality events, the consequences can be catastrophic for consumers, not to mention that long-term damage can be inflicted on a company’s reputation and its products.
The investigation into and documentation of quality events is drastically simplified with an EQMS that enables an organization to automate the management of the entire CAPA process, from initiation to investigation and all the way through to closure. By integrating data and documentation from investigations with the entire quality system, a configurable EQMS could trigger a CAPA whenever a quality event occurs at a predetermined threshold. Robust EQMS offerings even include preconfigured best-practice forms and workflow routes that can guide quality teams through every step of a CAPA implementation (identification of the problem, investigation of root cause, correction of problem, and prevention of recurrence). Written records of investigations can also be securely maintained within such a system, per compliance requirements.
You’ve probably played the “Telephone Game” where a phrase is passed from person to person verbally to show how even the simplest bit of information can quickly become incomprehensively distorted. Similarly, when production events or deviations are not adequately documented or tracked in pharmaceutical manufacturing environments, it is impossible to determine a root cause and take the appropriate corrective and/or preventive action. Catalent Pharma Solutions was saddled with a recent 483 Observation after insufficiencies in its quality control unit were discovered after the FDA found that quality events had been reported by phone or email rather than documented via a formalized means.[iv] Catalent is not alone—many pharmaceutical companies similarly struggle with managing and controlling documents because the processes involved can be time consuming and cumbersome, especially if the organization is relying on paper-based systems or if documentation is scattered between multiple systems in different geographic locations.
While it’s the responsibility of every individual pharmaceutical company to get procedures down in writing, an EQMS can streamline how that documentation is managed and simplify how it is controlled. Manufacturers can alleviate these burdens by implementing a comprehensive and reliable document management system that is designed to facilitate adherence to current good manufacturing practices (cGMP). In addition to providing a collaboration workspace for creating procedures and other vital documentation, an EQMS can provide automated revision control and ensure that old versions of documents are archived in an audit-ready state. Any changes to a document can be initiated and approved electronically, and audit trail and change control functionality is built into the system. Document approval, collaboration, and escalation can be routed by document type, which guarantees that all documents go to the right place every time.
Drug product sterility is paramount to the protection of consumer safety. Regulation 21 CFR 211.42(c)(10)(iv) requires pharmaceutical companies to establish adequate systems for monitoring environmental conditions in aseptic and other similar types of processes. Once established, such systems are most effectively monitored with a quality management solution that has the capability to integrate all quality processes. Without the assistance of an integrated solution, support costs are increased and vital environmental monitoring information gets disconnected in quality contexts. It’s reasonable to conclude that most, if not all, of the 83 environmental control-related observations issued by the FDA in the last 12-month period on record could have been avoided by the utilization of a holistic, integrated quality management system.
The safety and sterility of a pharmaceutical company’s environmental system can be assured if it incorporates tools and methodologies that have a demonstrated track record of effectively determining root causes and enables appropriate corrective actions to be taken whenever environmental safety factors are jeopardized. An integrated quality management system should effectually automate and unite CAPA, audit, and other quality monitoring processes. Process integration can help alleviate unnecessary work whenever environmental issues are detected. Effective reporting and analytics processes—another function that can be enhanced with a reliable automated system—can give managers more visibility into potentially problematic systems and help them make data-based decisions before a minor quality event turns into a widespread adverse issue.
All of the leading reasons for pharma-related Form 483s explored above, as well the aforementioned tips on avoiding such infractions, are excerpted from a white paper titled “Ten Most Common Reasons for FDA 483 Inspectional Observations in Pharmaceutical Environments,” which is available for free here.
James Jardine is a content marketing specialist at MasterControl. He has covered regulatory environments, quality management and life science industries for more than a decade and has a bachelor’s degree in journalism from the University of Utah.
[i] Retrieved from FDA website http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-orgs/documents/document/ucm525311.pdf. Accessed 22 November 2017.
[ii] Retrieved from FDA website http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm489735.htm. Accessed 22 November 2017.
[iii] Retrieved from FDA website http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-orgs/documents/document/ucm516150.pdf. Accessed 22 November 2017.
[iv] Retrieved from FDA website http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-orgs/documents/document/ucm496233.pdf. Accessed 22 November 2017.