A quality plan is a blueprint for business success and regulatory compliance.
If you are a biopharmaceutical professional, it is nearly certain that you work in a regulated environment. Making regulatory compliance a core business system and adapting a comprehensive quality plan can help you achieve superior business advantages.1
Understanding FDA's new regulatory approach to inspections, the Quality System Inspection Technique (QSIT), and incorporating it into site and corporate quality plans can improve the speed, efficiency, and consistency of both routine and preapproval inspections (PAIs).
QSIT is a systems-based approach to inspections and enforcement. It shifts the regulatory focus from specific product and process issues to assessing the strength of the supporting systems that manufacturers use to prevent and resolve difficulties. This holistic approach broadens the scope of inspections. Thus, inspections potentially can have significant business impact not only on individual products at a site, but also on all products controlled by the same quality systems.
Consistent implementation of QSIT is long overdue and a significant step forward for regulators. FDA is finally progressing towards a standardized inspection approach, which previously and all too often depended upon an individual investigator's knowledge, interests, or capabilities. QSIT training is now "part and parcel" of all investigator training, requiring certification in FDA's level II curriculum.2
QSIT requires investigators to follow a predetermined regimen for conducting inspections. Understanding the FDA investigation process is a powerful tactic for industry in designing quality plans. The main task for investigators utilizing QSIT is determining if the facility has defined and functional quality systems and processes, and if it maintains compliance with current Good Manufacturing Practices (cGMPs). Timely management notification and review of quality issues are necessary to these systems. This places ultimate responsibility for compliance at the feet of upper management and corporate directors.3
The Center for Drug Evaluation and Research (CDER) defines and groups QSIT into six major systems aligned to the GMP regulations provided in 21 CFR Parts 210 and 211. The major quality systems are:
Identification of the relevant business systems and their relation to CDER-defined quality systems is the foundation for integrating QSIT into your overall quality systems. Identification of the system owner clarifies roles and assigns responsibility. Associating internal and external standards and supporting documentation with these systems helps identify compliance and enhancement gaps. Once gaps and opportunities are identified, they can be prioritized and organized into a comprehensive quality plan and managed to completion by a quality management team.
Table 1 shows the working matrix of business systems, QSIT systems, and documentation categories. Note that the quality system is one of the six QSIT-defined quality systems.
Table 1. Quality Systems Organization
The six major quality systems are the foundation for both full and abbreviated inspections. A full inspection requires evaluation of at least four of the QSIT-defined systems, whereas abbreviated inspections only require review of two systems. Companies that have previously demonstrated noncompliance or have a pending PAI will usually undergo the full inspection. Firms that have compliant histories and those that have recently been inspected (such as contract manufacturers who were recently inspected for different clients) may receive an abbreviated inspection. The quality system is part of every inspection.
Compliance investigators may, with district office concurrence, reduce a full inspection to an abbreviated inspection. This may sound like good news, but it usually indicates that the firm has failed early in the inspection process, or that one or more QSIT systems are significantly out of control, and FDA does not intend to expend the time and resources to complete an inspection of the remaining systems. This is part of QSIT's approach, which aims for faster results. Whenever the quality system portion of an inspection fails, the inspection is terminated, and the agency contemplates regulatory action.
Let us take a closer look at quality systems. Ask any number of experts to define quality systems and how they are used, and you will receive a varied response, both within and between industries and within individual facilities in the same company. Even FDA, CDER and the Center for Devices and Radiological Health definitions differ. Trade and professional organizations also differ slightly. The International Conference on Harmonization, the American Society for Quality, and the World Health Organization have similar, yet distinctly different definitions. Within companies, the definition may vary, and the interpretation often is unclear. One thing is certain-the industry is required to define appropriate quality systems to support specific business and customer needs.
FDA is finalizing its definition of quality systems. The current draft, which will probably be release next month reads, "A quality system is a formalized business practice that defines management responsibility for organization, structure, processes, procedures and resources needed to fulfill product or service requirements, customer satisfaction and continual improvement."4 Each of the six QSIT quality systems identified by CDER contains several subsystems within the scope of this definition.
FDA mandates that one of the investigator's first tasks is "to ask for a copy of the firm's Quality Policy, and high-level Quality System Procedures (including Management Review Procedures), Quality Manual and Quality Plan."4 Therefore, it is necessary to have a well-defined set of quality systems that are known and used throughout the enterprise and support all aspects of cGMP activities.
Figure 1. Integrating QSIT into Quality Plans
An earlier article cautioned, "Defining operational specific quality systems requires careful thought and consideration and demands nurturing and support as the systems evolve."5 Don't be satisfied with the lowest common "regulatory required" denominator. Too many long-term, critical decisions address merely meeting the regulatory requirements, rather than adopting the best quality and business strategy to drive leadership and competitive advantage. Quality systems designed to exceed FDA requirements provide unmeasured dividends for the enterprise. No enterprise has achieved lasting success and growth by lowering quality standards to minimum regulatory requirements.
Since the QSIT inspection requires a review of the site's quality plan, a regulated site should have a good one. The quality plan — as an effective, living document — should transcend the policy boundaries outlined in a quality manual, while supporting those principles and strategies.
The quality plan is required to fulfill product or service requirements, customer satisfaction and continual improvement. Progressive leadership also demands that quality systems support product design and functional specifications, meet regulatory requirements, and delight customers, while continuing to improve processes and efficiencies and simultaneously reduce the cost of goods.
A quality plan is the basis for understanding, prioritizing, organizing, and setting the direction for all compliance and quality-improvement efforts at a site. Utilizing a quality plan as a strategic remediation tool has been successful in resolving severe regulatory actions including the lifting of a warning letter.6
All identified improvement opportunities such as internal and external audits, inspections, quality engineering studies, Six-Sigma activities, cost of quality results, and long-range improvement plans should contribute to site quality plans. Anything related to compliance or cost that can improve the product or process should be included. The quality plan is the blueprint for corrective action, compliance, and quality enhancement projects. It also is a surrogate awareness tool, demonstrating to FDA and customers that leadership is aware of quality issues and has a definitive plan and timetable to correct deficiencies. The quality plan has great potential for gaining credibility with FDA, and fits well into the QSIT model for system evaluation and compliance.
Quality plans consist of two main sections. One is usually a narrative describing the capabilities, scope, strategies, and general outline of the site including mission, responsibilities, customers, expectations, and products. The second section of the quality plan details and categorizes gaps, contains action plans for correction,and addresses their relation to existing standards or regulations. Each actionable item has an owner or sponsor, estimated cost, targeted completion date, and can be managed using a tracking number. See Table 2 for a sample of quality plan contents.
Table 2. Sample of Quality Plan Content
An additional benefit of the quality plan is that it can help direct individual and departmental objectives. Once the quality plan is approved, all management levels will see clearly the reporting period's objectives and whether they were met.
Incorporating and consolidating multiple inputs for compliance, product, and processes into a comprehensive, prioritized site-quality plan at individual manufacturing or development sites benefits both their compliance and business competitive status. This plan is supported and executed locally by a quality management team (QMT), which shares those objectives with a corporate QMT. The corporate QMT strategically addresses global issues, shares the learning from individual sites, and communicates that information to all sites throughout the enterprise. Compliance and improvement efforts are driven by the quality plan diagrammed in Figure 1, resulting in enhanced, more efficient business processes and a strategic business advantage.
The quality plan needs an owner with clout or it will fail. The group in charge of executing the plan is the QMT. Staff it with the highest management available at a manufacturing site: the technical or process development director, plant or manufacturing manager, operations manager, and quality manager. The quality team at the corporate level would include the senior leadership of manufacturing, quality assurance, and operations. Leadership must emanate from positions of power and responsibility and include representatives from all of the departmental stakeholders.
The value of the QMT is to have leadership from technical, compliance, and business groups focused on the strategy, issues, and prioritization of the elements within the quality plan. QMT leadership must supply the resources required to accomplish the plan's objectives. While the plan can act as a repository for quality issues, it is incumbent upon the QMT leadership to keep the number of active projects within reason and within reach. Focusing on the "Top 20" can be a realistic approach, and, as those items are completed, new items can take their place. Administration of the schedule and topics can be, and probably should be, contracted to either an outside project management group or internal administrative functionaries.
A responsible site QMT can best serve the enterprise by managing all local quality plan issues, while the corporate QMT provides leadership on multilevel and global issues such as the corporate strategy for computer validation, Part 11 activities, and requirements for designing and maintaining the quality systems used throughout the enterprise. The QMT provides a forum for discussion and support of the quality plan and ensures it is regularly reviewed, updated, and executed and is a living document driving closure to quality issues.
Utilizing a common approach for appraisal, such as one incorporating QSIT methodology, and having well-defined quality systems that are applicable and supportive of the enterprise provides a foundation for a solid business and compliance position. A proactive, meaningful corrective action plan that drives product and process enhancements and is executed with upper management support through quality management teams provides a lasting advantage over an unstructured approach.
The rate of change in today's environment is phenomenal, and all companies need systems for dealing with change. Integrating QSIT into a quality plan can provide a common language, metrics, and knowledge-transfer between sites. It has the power to affect local system improvements and to have a positive impact on the global enterprise. To gain the most from QSIT, findings can be incorporated into larger systems and the overall business plan. Understanding how QSIT fits into the larger picture can bring competitive and regulatory advantages to those who implement it.
Congress and the general public became critically concerned about the safety, purity, and efficacy of the food and pharmaceutical supply after the 9/11 terrorist attacks. The number of domestic establishments that FDA is required to regulate exceeds 120,000. Annual imports to the US number nearly 8 million shipments of FDA-regulated products from about 500,000 foreign manufacturers. Many of their facilities have never received an FDA inspection.
The agency is also being ordered by Congress to address even more complex issues including bioterrorism, mad cow disease, foreign pharmacy imports, counterfeiting, product diversion, and tampering.
FDA is hiring over 4,000 employees in the Office of Regulatory Affairs including CSOs, (Consumer Safety Officers), CSIs (Consumer Safety Inspectors) and OCI agents (specially trained investigators in the Office of Criminal Investigation).9 The field investigators who conduct inspections are being trained to focus on protecting public health and ensuring that the food and pharmaceutical industries are in compliance with laws, regulations, guidance documents, and policies. Most of these standards are well written and understood; however, many are not and are subject to the interpretation not only of industry, but also of FDA and its individual agents.
Of special interest to the biopharmaceutical industry is the ongoing transfer of responsibility for many CBER-regulated (Center for Biological Evaluation and Research) products to CDER. Both CDER and CBER are incorporating QSIT into their regulatory enforcement process.10
The FDA continues to modify regulatory strategies to ensure a safe and efficacious supply of pharmaceutical products for the American public in the face of new threats and constraints.11 Meanwhile our business, social, and political atmosphere continues to place extremely high demands on the biopharm and pharmaceutical industries as they strive to bring innovative, life-saving drugs to ill patients. While the efforts put forth by our regulators and industry should be congruent, they often are viewed from different paradigms, resulting in defensive and reactive modalities. The result is a diversion of efforts and detraction of limited resources from the business at hand.
The QSIT approach was devised in late 1997, when a team at CDRH reengineered the inspection process for quality-system (GMP) inspections within regulated facilities. In early 1998, an inspection technique was proposed, and submitted for public comment and methodological validation. The program, inspector training, and compliance guidance document were implemented in late 1999.
The QSIT approach was designed to encompass both comprehensive and limited inspections of medical device manufacturers. The procedure for the medical device industry was based on seven subsystems of the quality system regulation (21 CFR, Part 820). Four were chosen as the top subsystems: management controls, design controls, corrective and preventive actions, and production and process controls.5
In 2001, FDA piloted an adapted version of the CDRH QSIT program at CDER, the unit that oversees most human drug applications and where inspections originate. The CDER regulatory approach recently became even more meaningful for the biopharm industry, since many of the CBER registrations and pending Biological License Applications are being transferred from CBER to CDER. FDA's primary focus is to promote faster, more-efficient inspections and, based on preliminary metrics, more-effective inspections as well.12 Better inspections translate into faster new drug approvals or denials and a quicker route to enforcement action, when that is warranted.
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2. German, G. FDA, director division of human resources development and ORA U, telephone conversation May 2004.
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4. Pauls L. FDA, CDER Director, Office of Executive Programs, QA Staff. Telephone conversation, March 2004.
5. FDA. Quality systems inspections reengineering; Available at URL: www.fda.gov/cdrh/gmp/gmp.html.
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8. Baumgarten A. Keynote address. QSIT Seminar American Society Quality, FDC Section. 2002 Nov. Des Plaines, IL.
10. Ralston, D. Quality systems for the 21st century: Team Biologics Inspections. Presented at California Separation Science Society 8th symposium on the interface of regulatory and analytical sciences for biotech health products. 2004 Jan 6. Washington, DC.
11. Noferi J, Arling E, Dillon R. Homeland defense: protecting the pharmaceutical supply chain in the new paradigm. American Pharmaceutical Outsourcing 2003; Feb:2-5.
12. Noferi J, Arling E, Worden D. Beyond QSIT. Biopharm 2002 April; 15(4):40-46, 67.