As we sit at home on our computers attending meetings on Teams or Zoom, each of us is dealing with this crisis in our own way. Our world is being fundamentally changed by a virus we don’t fully understand and can’t control. We are wondering how this will impact our careers, our income, our families or our plans for the future. It is also a time when we should reflect upon how we have done things and how we can do them more effectively.
In the pharmaceutical industry, and now in the rapidly developing world of biotechnology and personal medicine, we continue to follow a compliance methodology to ensure quality that has barely changed in 60 years. Companies establish processes and implement quality systems based on their interpretation of the published regulations.
Regulators then conduct document reviews and site audits for approval. Following approval, regulators return for periodic audits to ensure continued compliance to regulations. Lack of compliance results in audit findings that require remediation, inadequate responses may result in more severe warnings, and ultimately if findings are not addressed, they may lead to injunction or removal of product from the market.
Industry’s response has also remained consistent, responding with corrective actions, including revisions to procedures, personnel changes, additional training, and often hiring third-party consultants to help draft responses and bring their expertise to identifying and implementing the changes required. The result of these efforts should be a growing number of companies that consistently and sustainably produce quality product that meet the requirements and expectations of regulators charged with protecting the public.
Failure to Comply
The actual results tell a different story. If one reviews just the FDA’s data for observations and trends, the only conclusion is that the situation is worsening with more FDA 483 observations being delivered each year along with an increasing number of warning letters when the agency is not satisfied with the company’s responses to their investigations.1
Clearly there may be many contributing factors to these findings. Changing technologies, globalization, changing workforce demographics, automation, regulatory changes, improved analytical capabilities and data integrity issues are but a few potential contributors to continuing gaps in quality and compliance. One underlying theme raises a significant question: Despite companies investing hundreds of millions of dollars in third-party remediation consulting, often at the direct recommendation of regulators, has there been a measurable improvement in industry’s overall ability to sustainably comply with quality regulations? If we use the metrics published by the FDA as an effectiveness check, the answer is that despite a significant investment by industry in corrective and preventive actions, we have not properly addressed the root cause of the problem.
Who then do we blame for the lack of desired impact on sustainable compliance? If we look at most remediation consulting engagements, we can quickly see that the responsibility of establishing the goals are shared between the consulting firm and the company’s management. It is at the initiation of the project that a clash exists between short-term goals, deliverables and the achievement of a sustainable solution. Company executives are confronted with pressures from top management or investors to demonstrate an aggressive response to regulators concerns within the mandated 15 business day response period (for FDA),2 and consulting management is enticed by the prospect of large numbers of consulting hours and revenues to address these concerns.
However, achieving a sustainable solution requires a more nuanced approach to evaluating and developing a comprehensive program to address the true systemic gaps and root causes that led to the audit findings.
In most cases the result is a focus on the audit response commitments, modifying procedures, retraining personnel and eliminating quality system backlogs in deviations, change controls and corrective and preventive actions. Completion of these activities are demonstrated in quality metrics and both the consulting firm and their client can point to a measurable win. At this point getting traction to identify and address the root causes for the issues that led to the audit findings is difficult because top management no longer faces any external pressure and the continued expense of consulting support is not as defensible as during the initial “crisis.” The result can be seen in the pharmaceutical press with reports of companies, both domestic and international, receiving repeat observations in followup audits by regulators.
Breaking the Cycle
In defense of all involved, the industry (including regulators, company quality personnel and industry consultants) has attempted to solve the issues interfering with the development of sustainable cultures that can achieve and maintain quality and compliance. Conferences led by industry groups, articles in a multitude of professional journals and publication of guidance by the FDA and other regulators have all attempted to address the issues. But the problem persists and some different approaches to quality and utilization of consulting support in our industry need to be explored.
Start at the Top
The culture of every organization starts with its leadership. Leaders in every organization are ultimately guided by the financial return they deliver to investors or shareholders. In many organizations the board of directors or private equity owners are unfamiliar with the value that a robust quality system can deliver by avoiding delays, rejections and time lost managing events in the quality system. They may only become aware when problems are identified that impact supply or regulators deliver negative findings. This can be avoided by utilizing the advice and direction of senior quality experts that are unaffiliated with their organization and whose input is not tied to any performance criteria that would influence objective assessment of the organization’s needs. As advisors on strategy and structure to the board and senior operational management, these consultants can support an ongoing dialog and full transparency to ensure decisions taken by the organization have had a balanced evaluation of risk versus reward before a crisis mandates expensive remedial actions. These quality advisors can be recruited and selected in the same manner as any board member with selection based on knowledge, experience and the ability to provide balanced advice, coaching and mentoring.
Strengthen Consistency of Product Release
In the United States, product release is governed by internal company procedures that may be comprehensive or may allow subjective interpretation of data to allow companies to compromise on standards for release when under financial or time pressures. Further, the structure of quality organizations has led to a lack of personal accountability or capability as evidenced by FDA data that the most cited compliance failure in 483 citations during 2019 was related to part 211.2(d) Procedures applicable to the quality unit shall be in writing and shall be followed.3 Here we must remember that in the United States and other countries outside of the European Union, where the legal responsibilities of the “qualified person” are detailed in European Directive 2001/83/EC,4 there are no statutory requirements defining the qualifications or personal responsibilities of the individual who makes the ultimate decision on the quality of a product prior to release for clinical or commercial distribution.
As most of us sit at home and reflect on what changes this pandemic will cause, should regulators consider an alternate approach? Could a statutory system be developed to better ensure the quality of released product by building on the EU approach and requiring the personnel making release decisions to complete a prescribed certification course, potentially with specialization in Biotechnology, Medical Devices or Aseptic Production. Could this system also define these individuals’ personal accountability and give them independence from inappropriate influence in their decision making.
Companies following this approach could be rewarded with a reduced frequency of regulatory audits or completion of self-audits in lieu of third-party audits.
This approach may not eliminate the need for consulting support to remediate compliance or quality gaps, but it may help strengthen the credibility and influence of the quality leadership in addressing potential quality or compliance gaps.
Close the Education/Training Gap
Despite the continued adoption of automation in our industry, the human factor still represents the greatest risk to product quality. Errors in executing SOPs, poorly qualified or maintained equipment and lack of expertise to troubleshoot problems when they arise are all continuing sources of deviations in our processes. Mastering and maintaining any skill requires a person to understand the how and why of performing the activity and requires the opportunity to perform it with sufficient frequency to maintain the capability. In today’s employment market, especially in the rapidly growing biotech and personal medicine sector, the ability to train and retain personnel is very challenging. Companies need to develop programs that permit individuals to efficiently learn the how and why at their own pace and have sufficient time to practice and demonstrate their skill in a safe environment before being assigned to actual production responsibilities. Utilizing read and understand or on-the-job training as primary education and training approaches is simply not sufficient. The use of computer-based training, supplemented with virtual reality (VR) and augmented reality (AR) experiences, is growing in our industry and is already in use in other critical industries (e.g. nuclear energy).5
Here again, the proper use of experienced consultants as mentors and trainers as supplements to other training tools can be an effective use of the experience and skills they can bring to an organization.
Remediation Consulting – The Right Way
When proactive approaches have not been taken or have not been aggressive enough and remediation is required, achieving a sustainable solution requires a more nuanced approach to evaluating and developing a comprehensive program to address the true systemic gaps and root causes that led to the audit findings. That is not to dismiss the need for developing a rapid and efficient response to regulatory findings. Today’s system still requires responses in a relatively short time frame (e.g. 15 business days for the FDA). This is where the differences in consulting firms emerge.
The compliance-oriented firms bring expertise on regulations and procedures and often have team members that have compliance experience with the FDA. Their focus is on response to the regulatory observations and making the changes that respond to those deficiencies. Their goal is to submit an appropriate response and to ensure these observations will not be repeated in future audits. Often this is achieved by large numbers of consultants, usually under the direction of client management, writing or rewriting SOPs as well as conducting and writing investigation reports to address existing backlogs in quality systems. But this approach is writing a prescription for the symptoms without diagnosing and treating the underlying disease.
The alternative is consulting firms that can be characterized as change-oriented with a focus on quality. These firms may support the urgent response needs of the organization but only if it is accompanied by a broader independent program supported by top management. It must be an effort that brings in expertise to comprehensively examine the true root causes of the quality or compliance failures including the culture, organizational design, individual management capabilities, data systems or process deficiencies, then allows them to identify and implement solutions working side by side with internal line management. The side-by-side work with line management must include a clear objective for partnering and mentorship to develop an internal capability to maintain sustainable solutions after the consulting firm has left the site. Treating and curing the disease and eliminating the underlying issues that prevent the creation of a sustainable process for producing quality product should ultimately be the purpose of remediation consulting.
The Path Forward
At this unique time in our history, facing a challenge that all of us must face together, we are being given a chance to stop and take stock in the processes we have been following and question whether there is a better way. The data regarding our failure to build a process for an efficient and effective quality product in the biotech, pharmaceutical or medical device arenas says that there should be a better way.
Whether you are a company executive, regulator or consultant, now is the opportunity to begin a dialog on dramatically changing our processes and creating a path forward that uses our resources in the optimal way. The need for remediation is an indication of failure, and the better way must be to proactively utilize all available resources to build organizations and systems capable of meeting the demands and opportunities of a post-pandemic world.
We welcome everyone who would like to participate in this dialog, whether industry executive or SME, regulator or consultant to post your comments on LinkedIn or contact me on twitter at @MikelevittQxP or just e mail me at email@example.com and I will work to get as many voices heard as possible in the coming weeks and months.
- Unger, Barbara. FDA FY2019 Drug Inspection Observations and Trends. Pharmaceutical Online, 6 December 2019; www.pharmaceuticalonline.com
- Department of Health and Human Services, Docket No:FDA 2009-N-0335, Review of Post Inspection Responses, Federal Register/Vol.74, No. 153, Tuesday, 11 August 2009.
- The FDA Group LLC, 2019 FDA Warning Letter & Inspection Observation Trends, Blog Post, 20 December 2019; www.thefdagroup.com
- Directive 2001/83/EC of the European Parliament and the Council of 6 November 2001 on the community code relating to medicinal products for human use (Section 27). Official Journal L311, 28/11/2001 pages 0067-0128.
- Nichols, Greg. Meltdown Averted: How VR Headsets are making nuclear plants safer, ZD Net, 15 August 2019; www.zdnet.com