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Quality assurance units are interwoven throughout the biopharmaceutical enterprise and provide support to sustain operations. Most importantly, they must have the capacity and leadership to adapt to change.
Change, rather than stability, engulfs us. In the wake of changing FDA enforcement practices, stricter post-Enron governance regulations, increased threats from pharmaceutical counterfeits, and a precarious world situation, there are endless demands for the reinvention and re-invigoration of business processes and the systems that support them. Maintaining a viable compliance posture is even more critical to the success of biopharmaceutical quality assurance (QA) units. Our responsibility to customers is enormous and our efforts worthwhile. We are legally and morally responsible for the safety and efficacy of products throughout the supply chain, from development through manufacture to delivery to the consumer. This is not a simple task, especially in an industry where the process is the product.
In the June 2002 issue of this magazine, the authors described their experiences in creating an effective biopharm QA unit and the challenges they faced in the environment of two merging corporations.1 Those challenges included understaffed quality assurance and regulatory organizations, increasing regulatory scrutiny, a complex and disparate supply chain, conflicting efforts between regulatory and quality needs, and advancing technologies that increased the pressure on all parties involved. We focused on building a robust organizational structure that stressed individual qualifications linked with strong communication tools.
Table 1. Biopharmaceutical QA units have some level of influence over these five supply chain touchpoints.
Overall, we succeeded. We lifted a complex, multisite warning letter at an international manufacturing site,2 shepherded a successful multisite EMEA and FDA preapproval inspection,3,4 and saw the approval and launch of our first therapeutic protein to integrate proprietary antitampering and anticounterfeiting technologies.5
The positive results experienced over the last year confirmed our design assumptions, strategy, and execution plans. However, the real test of any organization is when it is stressed, when normal operating parameters are challenged. Just as chaos theory posits that a butterfly flapping its wings in Brazil can cause tornadoes in Texas, small changes in an operating environment can have an impact and implications far beyond the realm of a single decision maker.
In an ecosystem, complex and dynamic relationships create a synergistic, operational system. Similarly, the ecosystem of a biopharmaceutical QA unit consists of many direct and indirect, dependent and interdependent relationships; change in one area affects the others to some degree.
Our industry is inherently dynamic. Technology, regulatory, and business paradigms that worked yesterday may well be obsolete today. Biopharmaceutical QA units, which are interwoven throughout the enterprise, must have the capacity to adapt to new information and reallocate resources accordingly. The inter-relationships in an ecosystem, or touchpoints in the biopharmaceutical model, produce varying results (Table 1). The quality of these results depends on the operating environmental conditions (that is, stress), adequacy of design and philosophy, and effectiveness of leadership.
What Makes Quality in Biopharma Different?
There are many kinds of stress. We are all familiar with work overload, long hours, and new product launches. Assuming that a robust organizational design and adequately trained and competent personnel exist, such factors should be manageable by any QA unit. Catastrophic stress, however, can cause failure.
Changes, large or small, internal or external - such as interruptions to the commercial supply chain, negative regulatory compliance action, and loss of customer satisfaction or business practice enhancements - amount to catastrophic stress when there are no systems and processes to address them. Merger and acquisitions activity, inlicensing, outsourcing, and continuous change in the supply chain (such as technology transfer issues and changes to the active pharmaceutical ingredient or at fill and finish sites) are challenges to QA units. As technology and regulations continue to develop and evolve, regulatory posture and company policies, procedures, and guidelines will change and impact the QA unit and the structure it supports. Personnel and management changes (including responsibilities, philosophy, or skill sets) may appear subtle on the surface but have significant impact on the organization.
The Process Is the Product
External changes, outside the biopharmaceutical enterprise's control or influence, also present challenges for QA units. For example, FDA is moving to incorporate the process analytical technology (PAT) initiative and quality systems inspection technique (QSIT) into their processes, transfer responsibility for many products previously regulated by the Center for Biologics Evaluation and Review to the Center for Drug Evaluation and Review, and address new concerns regarding counterfeiting, diversion, and bioterrorism. FDA needs to move quickly, so it has increased hiring for enforcement staff, modified it's training programs, and developed a risk-based approach to monitoring and enforcement. National expertise is being implemented for specified inspections, and a higher level of expectations for compliance is in force. QA leadership will need to factor these variables into their operating models.
Demands placed upon organizations in urgent, stressful environments draw on the full panoply of human abilities: cognitive, physical, emotional, organizational, and cultural. These demands often push the limit of people's ability to function. Therefore, leadership must provide strength and depth. It must also be able to quickly respond in the dynamic biopharmaceutical environment. We must ask: At what point can operations fail? What are the limits of existing systems? What changes can be made to strengthen performance? And at what point does the collective say, "Just get it done."
Here, quality leadership provides the most value to the enterprise. QA leadership needs to be proactive, leading the way for the enterprise in all matters relating to quality and compliance issues and not waiting for leadership outside the group to take action. It must develop the sensitivity to quickly detect or intuit changes in the operating environments, and, specifically, it must be aware of changes that may upset the QA ecosystem, know where to look for these changes, and determine their potential impact. Quality leadership also needs to have processes in place that can quickly discern the real and potential changes between "business as usual" (BAU) and the stress situations that affect the QA unit's ability to deliver results. These leaders must determine if a gap exists between the design of the QA units in the BAU mode and the support required when internal and external changes are occurring.
Other Quality Resources
The systems paradigm6 helps QA leaders determine which parts of the organization are designed to detect and analyze threats to the status quo. Once identified, efficiencies can be derived that enable the analysis of inputs (such as funding, raw materials, and human capital), and new processes can be developed to generate and sustain the desired level of compliance, maintain capability, and provide competitive advantage.
In this industry, policies, standards, guidelines, and standard operating procedures (SOPs) dictate organizational design and support. Generally, they assume a normal operating environment with time to plan activities, balance resources, and identify and correct errors before they create unmanageable problems. However, emerging challenges, disruptive technologies, and threats are changing that paradigm. Leading organizations need to move to proactive systems and process development to identify immediate needs and prepare for the future. Today's managers must be able to absorb damaging information, re-assess situations, and formulate new courses of action quickly and correctly. Paramount is the need to consider interactions between organizational and technical structures that facilitate the rapid assessment of risk and execution of decisions.
Clearly, it is critical that leadership identify stress factors requiring organizational changes and take proactive steps. This is best accomplished by designing into the organizational infrastructure the ability to determine the existing robustness and design of the QA unit, measure that robustness against existing or potential changes occurring in the internal and external environment, and develop a gap analysis and remediation plan. People must be empowered to visualize the future.
Engineers use fragility curves to determine failure modalities. The concept of a fragility curve implies that a structure does not fail all at once, but is subject to strains and stresses that accumulate until the structure loses viability and collapses. Their objective is to learn how and where to reinforce vulnerable points to absorb probable levels of stress from environmental changes. Biopharmaceutical QA units are similarly subject to stresses and strains and can lose viability and collapse or no longer function effectively.
However, almost no attention is given to measuring an interorganizational system's capacity to function under severe stress. At present, there is no viable measure of organizational fragility curves for QA units.
Because biopharmaceutical QA units are in the business of risk management, they are not designed to have the personnel, infrastructure, or resources required to give full support, clarity, and attention to every detail of activity. The capacity of an organization to mitigate risk and respond to change depends on its ability to assess its own vulnerabilities, monitor its own performance, and mobilize resources in response. All members of organizations share risk - whether they contribute to the circumstances that create risk or not - but the biopharmaceutical QA unit should lead the enterprise, monitoring the potential impact of internal and external changes and bringing proactive resolutions and corrective action to management's attention.
The concept of shared risk is critical to effective management. Therefore, communication is a critical function of the organization, including the capacity to access, store, transmit, receive, and comprehend information as events unfold. This function is social and depends on the communications infrastructure and the cognitive functions of individuals who receive and act (or fail to act) on that information. Embracing change must become a core process.
Biopharmaceutical QA units have unique challenges facing them. Industry leadership needs to be aware of all the internal and external changes occurring, and assess how those changes will affect the QA unit structure supporting the enterprise. Communication within the organization is essential for leading and maintaining a competent, capable biopharmaceutical QA unit. Being aware of the strengths of the existing systems, the potential for changes affecting those systems, and proactively managing change (by adjusting the QA unit construct to ensure continued support) increases the probability of success of any biopharmaceutical operation. A successful endeavor will usually include a plan for failure as well as for success. A skilled leadership can intuit the changes and make the necessary adjustments for today's challenging regulatory and business environment.
1. Arling E, Dillon R, Noferi J. Creating effective biopharmaceutical QA/QC organizations.
2. Noferi J, Arling E, Dillon R, Blomqvist M. You have failed. a case study in warning letter remediation. BioPharm International 2002; 15(11).
3. Noferi J, Arling E, Servin E. A case study of the preapproval inspection. Biopharm International 2003; 16(3).
4. Managing the inspection: exploring new technologies. FOCUS 2003; 8(11).
5. Homeland defense: protecting the pharmaceutical supply chain in the new paradigm. American Pharmaceutical Outsourcing 2003; 4(1).
6. Noferi J, Arling E, Worden D. Beyond QSIT. Biopharm 2002; 5(4).