For decades, the pharmaceutical industry has managed its business by focusing most of its resources on the next blockbuster drug. With changes in regulations, declines in drug approvals and a shift toward developing high value biologics, today’s manufacturers must begin to refocus and address current processes, practices and systems, and take a hard line on improving their overall quality and compliance efforts. This article will explore how one company determined the health of its quality manufacturing systems by assessing its current quality systems, developed Key Performance Indicators and learned best practices to address and resolve all high risk areas. With more than 50 percent of Form 483 observations and warning letters citing Corrective Action/Preventive Action (CAPA) deficiencies, we will provide tips for developing effective CAPAs and define CAPA Effectiveness.
And, with the FDA’s request for more authority to ensure the public’s safety, we will discuss Change Management, including elements of the system and industry challenges. Lastly, we’ll explore Management Review, providing examples of FDA warning letters to highlight current industry issues and reasons why the manager is no longer the manager.
A Quality System is the organizational structures, processes, procedures and resources used to manufacture pharmaceutical products in accordance with applicable regulations. This entails quality planning, quality control, quality assurance and quality improvement for achieving consistent product quality. The objective of a Quality System is to achieve product realization, establish and maintain a state of control and facilitate continual improvement across the different lifecycle stages. The major components of a products lifecycle are pharmaceutical development, technology transfer, commercial manufacturing and product discontinuation.
Key Elements to a Quality System
The elements of a Pharmaceutical Quality System, as described in International Conference on Harmonization (ICH) Q10 Pharmaceutical Quality System Guideline, outline the effective quality systems for the pharmaceutical industry. The systems are designed to be used throughout each stage of the products lifecycle. The Quality System consists of these four key elements: Process Performance and Product Quality Monitoring, Corrective Action and Preventive Action (CAPA), Change Management, and Management Review of Process Performance and Product Quality.
I. Process Performance and Product Quality Monitoring System
A process performance and product quality monitoring system ensures that pharmaceutical companies are operating in a state of control. The system should provide assurance that the processes and controls produce products with safety, efficacy and quality. These systems include risk management, statistical tools, quality control, process excellence tools, supplier/material management, internal/external source review and validation.
An example of a process performance and product quality monitoring system are Key Performance Indicators (KPIs). The following case study illustrates how one company benefitted from outsourcing a quality systems assessment to determine the state of their Quality Systems.
The Benefit of KPIs in a Global Quality System
Overview: A consulting firm was retained by a mid-sized global pharmaceutical company to assess their current quality systems and develop Key Performance Indicators (KPIs) to determine the health of their quality manufacturing systems. A scorecard was developed to monitor the performance of the quality system in terms of achieving the set targets. The client company’s Global Quality Assurance (GQA) organization proactively retained the consulting firm to provide ongoing compliance support for KPI/Metrics evaluation and remediation, as well as overall compliance support in the following areas: Regulatory Intelligence Vendor Management Internal Audits Stability Program.
Scope: The assessment required an understanding of the client company’s existing quality systems, as well as federal and international manufacturing regulations and guidances. The assessment involved several quality systems within the Global Supply Chain. The consulting firm used the DMAIC methodology of Define, Measure, Analyze, Improve and Control to improve the Quality System.
Methodology: During the project, the following key activities for KPI/Metric review were performed:
1. On-site Assessment of the following:
- Corrective Action Preventive Action (CAPA) System
- Deviation/Investigation System
- Change Control System
- Complaint Program
- Training Program
- Internal Audit Program
- Documentation Management System
- Stability Program
- Supplier Control Program
2. A thorough Data System Review of every existing electronic system that is capturing data.
3. Based on Data Review, a Score Card for the Quality System was developed, highlighting statistical targets as well as industry standard targets based on historic performance.
4. A Global Dashboard to provide an overall score indicating compliance risk level for their total quality system.
5. Weekly Global Supply Chain Status Meeting discussions with leadership team to ensure clear communication regarding project progress as well as remediation of issues.
6. Monthly Senior Executive Leadership presentations for the executive board regarding KPI/Metrics progress.
7. Quality System remediation plans for high-risk areas discovered within the quality system.
Deliverables: The consulting firm provided the observations made as a result of the assessment activities during a review with the client company’s key stakeholders in the project. After the review, the firm provided the complete set-up of the dashboards for each quality system and the global dashboard, which included all calculations and targets. The firm also provided an action plan outlining best practices to address and resolve all high risk areas in a timely, compliant fashion which later resulted in the firm implementing the client-approved action plan.
Benefits: The client has benefited from the assessment conducted in the following ways:
1. The client company has external, independent confirmation outlining areas for improvement to minimize business and compliance risks that may exist within the current quality system.
2. The client company has recommendations and action plans to remediate identified compliance gaps or risk areas in the quality systems.
3. The global client company has received recommendations for improvements based on both U.S. and international standards.
4. The client company is in line with the two principals outlined in ICH-Q9 (Quality Risk Management) which state that the risk to quality should be based on scientific knowledge.
5. The client company now has developed and can monitor effective control systems for process performance and product quality as stated in ICH-Q10.
II. Corrective Action and Preventive Action System
Once a company has a system in place that identifies and monitors gaps in its system, a systematic approach should be taken to handle those issues. This leads us to the next element of the Quality System, Corrective Action and Preventive Actions (CAPAs). CAPAs are the systematic investigation of the root cause of non-conformities in an effort to mitigate the issue or prevent their recurrence. In recent years regulatory agencies have focused heavily on CAPAs during regulatory inspections.
A company must have a robust CAPA system to ensure regulatory compliance, organizational effectiveness and operational efficiencies. A CAPA should address areas of nonconformance and strategies to stop issues from recurring. The three critical elements of a successful CAPA system include development of a proper CAPA system, monitoring and analysis to ensure that the CAPA system is compliant and performing appropriately and a continuous improvement plan to eliminate or mitigate nonconformities or the potential of nonconformity. So how does a company develop a CAPA system?
Developing a CAPA System
As a regulatory requirement, the CAPA process must consist of the following key elements:
- Having documented procedures in place to define how an organization will track the records;
- Performing an investigation to determine the root cause once a nonconformance has been identified;
- Identifying the corrective and/or preventive actions after the root cause has been determined;
- Having an established and approved action plan
- Implementing the action plan;
- Having actions that support continuous improvement within the CAPA;
- Having mechanisms in place to allow monitoring and analyzing of all CAPAs;
- Completing all documentation and proper notifications;
- Evaluating the effectiveness of the actions performed after implementation.
These steps are vital for a CAPA System to be successful. The content of the CAPA should address the nonconformity; the actions must be documented and recorded; and the actions should be monitored and tracked for common root causes. The goal of the CAPA System is to show continuous improvement within the defined processes that govern the operations of an organization.
Monitoring and Analysis: In order to assure that the CAPA System is compliant and performing appropriately, the CAPA System must have a monitoring process. To effectively monitor the process, a company must select appropriate measurements to show that the corrective action always addresses the root cause of the problem.
One way to assure that the established CAPAs are appropriate is to have KPIs in place, as noted above in the first element of the Quality System. KPIs will alert management of the effectiveness of the CAPAs and also determine if additional actions are needed. The running of KPIs against the data may be a continuous or periodic process depending on the source/availability of the data. The overall monitoring process should be routinely reviewed to assure continued suitability.
There are several tools that can be used for the measurement and analysis of the data against established parameters. The analysis will allow a manufacturer to identify nonconformity (or potential nonconformity), and identify areas that may need further investigation. In this way the manufacturer is able to fully establish a preventive action process, allowing them to address a potential problem before impacting the product. The analysis can be performed using several methods, such as analytical tools, a team of experts or process owners.
The use of statistical tools will help the manufacturer to identify any sources of variation, determine if the CAPA has truly remedied the problem, and potentially assist in the decision making process.
Continuous Improvement: The purpose of making continuous improvements to a CAPA process is to eliminate or mitigate nonconformity or the potential of nonconformity. There have been many observations issued by regulatory agencies to manufacturers that state there is a failure to establish a verification process to show the adequacy of the established CAPAs. Therefore, in order to establish CAPAs that will address nonconformity, a strong investigation process must be established, which includes a strong root cause analysis of the problem.
A. Root Cause Analysis
B. Identify and Verify Actions - CAPA Action Plan
C. Implementing the CAPA Action Plan
D. CAPA Effectiveness
E. Management Review
III. Change Management System
A plausible definition for change management is the act of handling or controlling something that passes from one state to another. Any time a change to a Quality System is being considered, there are certain steps that must be taken in order to determine the risk involved with the change and how it may impact the product. These steps are called the Change Management system, the third element of the Quality System. This system ensures continual improvement is undertaken in a timely and effective manner while providing assurance that the improvement does not adversely affect the quality of the product. When a change is required, the change management system should address the risk of the change, the safety, and the performance. The change management system should include the quality risk assessment, justification for the change and a proper evaluation by appropriate subject matter experts. After implementation, the effectiveness of the change, and its regulatory impact, should be assessed by qualified individuals.
Challenges in Change Management
Today, many companies struggle with change management systems. Companies lack effective resources when managing the different aspects within the change system. In addition, many companies have difficulty documenting the change and evaluating its effectiveness. However, it seems that completing the risk assessment and implementing the change comes as routine for many.
Some changes require regulatory submissions and cross site/ cross department approvals. Depending upon the frequency of the occurrences, one cannot effectively evaluate the change in a timely manner. Companies who are outsourcing or contract manufacturers must notify the proper audience for the changes. The resources assigned to the change may have been eliminated or changed since the creation.
These examples support the necessity for companies to ensure that the change management system must be monitored and reviewed at consistent intervals. The process must have contingency for closure, which may include a risk assessment for legacy items. Each change management system should include the quality risk assessment, experts, evaluation of the change, and traceability of the change.
IV. Management Review of Process Performance and Product Quality
The fourth element to the Quality System is Management Review of Process Performance and Product Quality. The management review system assures the process performance and product quality are managed properly throughout the products lifecycle and ensure that opportunities for improvement, such as training, are identified. Regulatory inspections and audit result are evaluated in this system as well as product quality reviews, customer complaints and CAPA effectiveness.
Regulatory agencies take a hard approach to assessing the compliance of Quality Systems within a pharmaceutical company to ensure the safety and efficacy of the products being produced. If the FDA determines that a company has a poor quality system in any way, they will inform that company and the public of all the details.
You’ve Been Warned
The Food and Drug Administration (FDA) is required to conduct regular inspections of manufacturing companies. As those of us in industry are well aware, these inspections can be some of the most difficult and heavily scrutinized inspections that your company will endure. Many companies are finding out that they are not well prepared for these inspections and this is causing a significant increase in the number of Form 483s (Notice of Inspectional Observations) being issued by the FDA. Recent news stated that “through November 2, 2011, the FDA had issued 9,052 483s, approximately 215 more 483s than the same time period in 2010, roughly a 2.4% increase…the FDA was expected to issue roughly 10,690 483s for 2011. That’s one 483 every 50 minutes”
. Below are excerpts of warning letters issued by the FDA .
- “Your firm’s failure to investigate these customer complaints is a serious deviation from CGMP. It is your responsibility to ensure that drugs manufactured at your facility are produced in compliance with CGMP. This includes establishing adequate systems to detect such quality issues before a product is distributed, and promptly implementing corrective measures to prevent recurrence.”
- “Your quality unit fails to conduct and document regular product quality reviews for the (b)(4) produced to verify the consistency of the process….The inspection revealed that the quality unit does not perform an annual evaluation of the process to ensure that it remains in a validated state.”
- “Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.”
- “Your response acknowledges that your facility “was not up to the mark of FDA....” and that corrective and preventative actions are needed, but are not completed at this time. We recommend that you conduct a complete and extensive evaluation of your overall quality and manufacturing controls to ensure that all APIs manufactured at your facility meet the quality and purity characteristics they purport to possess. We highly recommend that you hire a third party auditor with experience in detecting data integrity problems, who may assist you in evaluating your serious CGMP deviations. Your firm’s broad-based CGMP compliance issues will require significant remediation and substantial investment of time and resources. Among the areas needing global attention include but are not limited to facility improvements, process validation, complete and accurate manufacturing procedures, training programs, quality unit effectiveness, and an overall effective quality system.”
Why the Manager is No Longer the Manager
A company’s quality system is only as good as the people managing those systems. If a company does not have a culture of compliance coming from top management down, the systems are likely to fail which could lead to misbranded or adulterated products that could be injurious to the consumer health. If these products make it to market, the consequences carry a heavy price to be paid. What happens to the manager in these instances?
Does it matter whether an incident is the result of an accident or intent to harm? To answer these questions, many different things can happen to the responsible party and it does not matter whether there was intent to harm. The price to pay varies depending on the severity of the incident. In some cases, the top managers are fired from the companies or debarred from industry. However, under the Food, Drug & Cosmetic Act (FDCA), a corporate official, in addition to a corporation, may be prosecuted for violations of the Act.
The FDCA prohibits the causing of adulteration or misbranding of any drug, food, cosmetic or medical device in interstate commerce and causing the introduction or delivery for introduction into interstate commerce of an adulterated or misbranded product. The penalties associated for violations of the Act are a misdemeanor charge with up to one year in prison and/or a fine of up to one-thousand dollars for the first offense. A second violation of the Act or a first conviction that shows intent to defraud results in a felony charge with up to three years in prison and/or a fine of up to $3,000.
In conclusion, the Quality System must continually improve in order to remain compliant and be able to efficiently produce quality products. A continuous improvement plan is a formal process for the review of the Quality System. Improvements can be made through an assessment of KPIs which will show the status of critical quality elements such as documentation management, product stability, internal/external audits, product quality reviews and customer complaints. As regulations and best business practices in industry change, monitoring or implementation of these changes into the Quality System will ensure that the organizational structures, processes, procedures and resources used to manufacture pharmaceutical products remain in compliance throughout the product lifecycles; pharmaceutical development, technology transfer, commercial manufacturing and product discontinuation.
1. FDAzilla Blog website / FDA Issues 483 Every 50 Minutes in 2011
2. Food & Drug Administration / Warning Letters 2011