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Quality Risk-Management Principles and PQRI Case Studies
The harmonized Q9 Quality Risk Management guideline from the International Conference on Harmonization (ICH) provides an excellent high-level framework for the use of risk management in pharmaceutical product development and manufacturing quality decision-making applications (1–2). It is a landmark document in acknowledging risk management as a standard and acceptable quality system practice to facilitate good decision-making with regard to risk identification, resource prioritization, and risk mitigation/elimination, as appropriate.
Recognizing the need to propagate and expedite holistic adoption of quality risk management across the pharmaceutical industry, the Product Quality Research Institute Manufacturing Technical Committee (PQRI–MTC) commissioned a small working group of industry and FDA representatives to seek out good case studies of actual risk-management practices used by large bio/pharmaceutical firms to share with the industry at large.
The working group spent approximately one year soliciting risk-management case studies from industry peers and contacts, and ultimately reviewed more than 20 of them. Each study was graded against six multiple criteria to assess applicability, usefulness, and alignment with ICH Q9. The highest graded case studies were measured against two additional criteria to ensure a balanced mix of examples for this report. Due to the size of a well-developed risk assessment, especially when applied to a complex problem or operating area, the presented case studies in most instances represent redacted versions of the actual assessments. Nonetheless, the provided summaries are effective in demonstrating the general thought process, risk application, and use of chosen risk methods.
As a byproduct of the working group's collaboration on risk-management practices, several common principles that reflect current industry and regulatory thinking emerged. These principles are aligned with, and in some instances expand beyond, those defined by ICH Q9 and are included in this report. In addition, several risk-management reference tools used by participating firms have been included as examples.
Principles and common practices
Core principles of quality risk management according to the ICH Q9 guideline include the following:
1. Compliance with applicable laws: Risk assessment should be used to assess how to ensure compliance and to determine the resulting prioritization for action—not for a decision regarding the need to fulfill applicable regulations or legal requirements.
2. Risk can only be effectively managed when it is identified, assessed, considered for further mitigation, and communicated. This principle embodies the four stages of an effective quality risk-management process as defined by ICH Q9: risk assessment (i.e., risk identification, analysis, and evaluation); risk control (i.e., risk reduction and acceptance); risk communication; and risk review.
4. Effective risk management requires a sufficient understanding of the business, the potential impact of the risk, and ownership of the results of any risk-management assessment.
5. Risk assessment must take into account the probability of a negative event in combination with the severity of that event. This principle also serves as a useful working definition for risk (i.e., risk represents the combination of the probability and severity of any given event).
Risk-assessment supporting tools
Risk trainers. In assembling this collection of case studies, the authors recognized the benefit of providing industry with additional background on core risk methodologies. Training tools for the application of risk ranking and filtering, FMEA, FTA, and HAZOP are available online with the web version of this article at PharmTech.com/PQRIstudies. These tools are meant to facilitate greater familiarity with the risk methodology used in each corresponding case study.
The PQRI–MTC Risk Management Working Group solicited and formatted a series of best-practice case studies aligned with ICH Q9 principles. The collected case studies demonstrate that there is a wide range of applications for the use of structured risk-management analysis to facilitate effective quality-decision activities. The studies demonstrate the baseline needed to choose the appropriate risk methodology for the targeted need, taking into account the degree of complexity and risk involved for the specific subject of concern. It is equally important to predefine the potential resulting risk categorizations so as to not be influenced by the assessment results in defining appropriate response actions. Finally, once risks have been appropriately assessed and prioritized, clear risk-mitigating actions must be defined, communicated, implemented and monitored for effectiveness.
Ted Frank is with Merck & Co; Stephen Brooks, Kristin Murray* and Steve Reich are with Pfizer; Ed Sanchez is with Johnson & Johnson; Brian Hasselbalch is with the FDA Center for Drug Evaluation and Research; Kwame Obeng is with Bristol Myers Squibb; and Richard Creekmore is with AstraZeneca.
*To whom all correspondence should be addressed, firstname.lastname@example.org
1. FDA Global Harmonization Task Force, "Implementation of Risk Management Principles andActivities within a Quality Management System" (Rockville, MD, 2000).
2. ICH, Q9 Quality Risk Management, 2005.
3. FDA, Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations (Rockville, MD, 2006).
4. FDA, "Risk-Based Method for Prioritizing CGMP Inspections of Pharmaceutical Manufacturing Sites–A Pilot Risk Ranking Model," (Rockville, MD, 2004).