A REVIEW: QUALITY RISK MANAGEMENT METHODS AND THEIR POTENTIAL APPLICATIONS
SONALI MAHAPARALE *, GAURI PHADTARE, MADHAVI KUCHEKAR, SNEHA WALASE
Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune-411044, Maharashtra, India.
ICH Q9 Quality risk management guidelines from the ICH provide an excellent high level framework for the use of risk management in pharmaceutical product development and manufacturing. This guidance was developed within the Expert Working Group (Quality) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product across the product lifecycle.”
(ICH Q9). Basic risk management facilitation methods (flowcharts, check sheets etc.) , Failure Mode Effects Analysis (FMEA) , Failure Mode Effects and Criticality Analysis (FMECA) ,Fault Tree Analysis (FTA),Hazard Analysis and Critical Control Points (HACCP) ,Hazard Operability Analysis (HAZOP) ,Preliminary Hazard Analysis (PHA) ,Risk ranking and filtering ,Supporting statistical tools these are well-recognized risk-management tools.
Keywords: QMR, risk assessment, methods of QRM, Potential applications.
ICH Q9 – Quality Risk Management provides an excellent high-level framework for the use of risk management in pharmaceutical product development and manufacturing quality decision-making applications. 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. Risk management has been part of the pharmaceutical industry for many years. The publication of ICH Q9 ―Quality Risk Management‖ in 2005 is having significant impact on pharmaceutical industry.
The FDA and other regulatory bodies, is embracing the Q9 concepts. ICH ―Q9 QRM is developed by the Expert Working Group (Quality) of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use which describes a model for a pharmaceutical quality system by providing principles and examples of tools for quality risk management and approach to identifying, scientifically evaluating and controlling potential risks to quality. In general Q9 provides high level guidance regarding identification, estimation, evaluation, controlling, monitoring and documentation of risk management process. The Q9 defines risk as the combination of the probability of occurrence of harm and the severity of that harm.
It is commonly understood that risk is defined as the combination of the probability of Occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each Stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm. In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and medical practitioners as well as government and industry, the protection of the patient by managing the risk to quality should be considered of prime importance 1.
Quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, inspection, and submission/review processes throughout the lifecycle of drug substances, drug products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging and labelling materials in drug products, biological and biotechnological products).
1.2 PRINCIPLES OF QUALITY RISK MANAGEMENT 2
Two primary principles of quality risk management are:
- The evaluation of the risk to quality should be based on scientific knowledge and Ultimately link to the protection of the patient; and
- The level of effort, formality, and documentation of the quality risk management process Should be commensurate with the level of risk.
Figure: 1 Integration of Quality risk management
1.3 INTEGRATION OF QUALITY RISK MANAGEMENT 3, 4: QRM is a process that supports science-based & practical decisions when integrated into quality systems such as: (as depicted in Figure)
- Quality defects investigations
- Auditing & Inspection
- Change Management
- Documentation and Training
- QRM PROCESS OVERVIEW 5, 6, 7, 8, 9
The QRM program consists of four major components:
- Risk Assessment
- Risk Control
- Risk Communication
- Risk Review
All the QRM methods (as described in Table: 1) should address the mentioned four basic components.
Table 1: The QRM Methods
|Quality Risk assessment||Quality Risk control||Quality Risk communication||Quality Risk review|
|Quality Risk Identification||Quality Risk reduction||Documentation and communication of result to stakeholders||Review events|
|Quality Risk Analysis||Quality Risk acceptance|
|Quality Risk Evalution|
2.1 QUALITY RISK ASSESSMENT 10, 11, 12
Quality Risk assessment is a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.” (ICH Q9)
Figure: 2 Overview of a typical quality risk management process
2.1.1 Quality Risk Identification: Risk identification shall consist of the use of information to identify hazards or potential risks. Information used to identify risk includes historical data, theoretical analysis, and informed opinions. The risk to be considered includes patient safety, product non-conformance, and fitness for use, specification and adulteration.
2.1.2 Quality Risk Analysis: During quality risk analysis a detailed understanding of the probability that the identified risk will occur shall be estimated. It can also include detect ability. The key activities to be performed during risk analysis include to understand the impact of risk, to rank the significance of risk (by scoring 1 to 5, where 1 = low & 5 = high), to calculate the risk score (Risk Score = Severity x Probability), colour code the risk based on score (define Red, Blue and Green bands e.g. acceptable risk = Green, unacceptable risk = Blue, Intolerable = Red).
2.1.3 Quality Risk Evaluation: Quality risk evaluation includes comparison of identified and analysed risk against pre-defined acceptance criteria and consideration of probability, severity and detects ability. The complete risk assessment shall result in an overall risk value expressed as either,
- A qualitative description of a range of risk using descriptions such as high, medium or low.
- A quantitative description of risk expressed numerically on probability scale of 0 to 100 percent.
2.1.4 Different Steps Involved In the Risk Assessment 13, 14
- Collect & organize the information.
- Formulate the Risk Question
- Choose Tool different tools include-
- Basic risk management facilitation methods (flowcharts, check sheets etc).
- Failure Mode Effects Analysis
- Failure Mode Effects and Criticality Analysis.
- Fault Tree Analysis.
- Hazard Analysis and Critical Control Points.
- Hazard & Operability Analysis.
- Preliminary Hazard Analysis.
- Risk Ranking & Filtering.
- Supporting statistical tools.
- Identify Risks Factors and Related Hazards
- Define the Risk Components &Scales
- Evaluate the risk for each hazard.
- Determine acceptability of risks
- Determine Action Threshold
- Apply the tool
2.2Risk control 5, 16, 17 : Risk control includes decision making to reduce and/or accept risks. The intention of risk control is to reduce the risk to an acceptable level. The amount of effort used for risk control should be proportional to the significance of the risk.
2.2.1 Risk reduction: Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds a specified level. Risk reduction might include actions taken to mitigate the severity and probability of harm. The implementation of risk reduction measures can introduce new risks into the system or increase the significance of other existing risks. Hence, it might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk after implementing a risk reduction process.
2.2.2 Risk acceptance: Risk acceptance is a decision to accept risk. For some types of harms, even the best quality risk management practices might not entirely eliminate risk. In these circumstances, it might be agreed that an appropriate quality risk management strategy has been applied and that quality risk is reduced to a specified (acceptable) level. This (specified) acceptable level will depend on many parameters and should be decided on a case-by-case basis.
2.3 Risk Communication: 18 Risk Communication is the sharing of information about risk and risk management between the decision makers and others. The output/result of the quality risk management process should be appropriately communicated and documented. The included information might relate to the existence, nature, form, probability, severity, acceptability, control, treatment, detestability or other aspects of risks to quality.
2.4 Risk Review: 19 Risk Review is the output/results of the risk management process should be reviewed to take into account new knowledge and experience. Once a quality risk management process has been initiated, that process should continue to be utilized for events that might impact the original quality risk management decision. Risk review might include reconsideration of risk acceptance decisions
- QUALITY RISK MANAGEMENT METHODS 20, 21, 22:
A key early step in the execution of a risk analysis is to determine the appropriate risk-assessment methods or tools. There is no single best choice for any given assessment process, and the selection of the appropriate risk methodology should be based on the depth of analysis required, complexity of the subject risk of concern, and the familiarity with the assessment tool.
3.1 Diagram analysis, Flowcharts, Check sheets, Process mapping, and Cause/effect diagrams:
Simple techniques that are commonly used to gather and organize data, structure RM processes and facilitate decision making. Potential applications are Compilation of observations, trends or other empirical information to support a variety of less complex deviations, complaints, defaults or other circumstances.
Eg. Cause and effect diagram of tablet hardness 23
Figure: 3 Cause and effect diagram of tablet hardness
3.2 Failure Mode Effects Analysis:
FMEA provides for an evaluation of potential failure modes for processes and
Their likely effects on outcomes and/or product performance. Once failure modes are established, risk reduction can be used to eliminate, contain, reduce, or control the potential failures. FMEA relies on product and process understanding. FMEA methodically breaks down the analysis of complex processes into manageable steps. It is a powerful tool for summarizing the important modes of failure, factors causing these failures, and the likely effects of these failures.
Figure: 4 Failure Mode Effects Analysis
3.3 Fault Tree Analysis:
The FTA tool is an approach that assumes failure of the functionality of a product or process. This tool evaluates system (or subsystem) failures one at a time but can combine multiple causes of failure by identifying causal chains. The results are represented pictorially in the form of a tree of fault modes. At each level in the tree, combinations of fault modes are described with logical operators (AND, OR, etc.). FTA relies on the experts’ process understanding to identify causal factors.Eg. Investigation of laboratory failure
Table: 2 Failure Mode Effects And Criticality Analysis: Calibration Of Equipment/Instrument)
|Potential failure mode||Potential effect||Contributory factors
|Current control measures|
|Deficient calibration practises /
Use of uncelebrated Instrument/ equipment for processing / testing
Ø Trained personnel for calibration activity.
Figure: 5 Investigation of laboratory failure
3.4 Hazard Analysis and Critical Control Points: 24
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and safety. It is a structured approach that applies technical and scientific principles to analyze, evaluate, prevent, and control the risk or adverse consequence(s) of hazard(s) due to the design, development, production, and use of products.
(Table: 3 Failure Mode Effects And Criticality Analysis: Blister Packing)
|Current control measures
Fault in product feeding station.
Wrong IPC loading on hopper.
Improper blister formation.
Empty/ partially filled blister
Less quantity of blister in final pack.
Wrong carton or Mix up of carton.
3.5 Hazard & Operability Analysis:
HAZOP is based on a theory that assumes that risk events are caused by deviations from the design or operating intentions. It is a systematic brainstorming technique for identifying hazards using so-called guide words. Guide words (e.g., No, More, Other Than, Part of) are applied to relevant parameters (e.g., contamination, temperature) to help identify potential deviations from normal use or design intentions. HAZOP often uses a team of people with expertise covering the design of the process or product and its application.
3.6 Preliminary Hazard Analysis:
PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure to identify future hazards, hazardous situations and events that might cause harm, as well as to estimate their probability of occurrence for a given activity, facility, product, or system. The tool consists of: (1) the identification of the possibilities that the risk event happens, (2) the qualitative evaluation of the extent of possible injury or damage to health that could result, (3) a relative ranking of the hazard using a combination of severity and likelihood of occurrence, and (4) the identification of possible remedial measures.
Figure: 6 Hazard Analysis and Critical Control Points
Figure: 7 Hazard & Operability Analysis
Figure: 8 Preliminary Hazard Analysis
Figure :9 Risk ranking and filtering
3.7 Risk ranking and filtering 25:
Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex systems typically involves evaluation of multiple diverse quantitative and qualitative factors for each risk. The tool involves breaking down a basic risk question into as many components as needed to capture factors involved in the risk. These factors are combined into a single relative risk score that can then be used for ranking risks. “Filters,” in the form of weighting factors or cut-offs for risk scores, can be used to scale or fit the risk ranking to management or policy objectives.
3.8 Supporting statistical tools :
Statistical tools can support and facilitate quality risk management. They can enable effective
Data assessment, aid in determining the significance of the data set(s), and facilitate more reliable decision making. A listing of some of the principal statistical tools commonly used in the pharmaceutical industry is provided:
- Control charts, for example:
- Acceptance control charts
- Control charts with arithmetic average and warning limits
- Cumulative sum charts
- Weighted moving average
- Design of experiments
- Pareto charts
- Process capability analysis
Figure: 10 Analysis of variables that may impact the coating process
- POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT
4.1 QRM as a part of development of a new drug product 26, 27:
To establish appropriate specifications, identify critical process parameters, and establish
Manufacturing controls (e.g., using information from pharmaceutical development studies
Regarding the clinical significance of quality attributes and the ability to control them during
To decrease variability of quality attributes:
- reduce product and material defects
- reduce manufacturing defects
The product lifecycle included the following technical activities for new and existing products:
- Pharmaceutical Development
- Formulation development
- Manufacturing process Development& scale‐up
Product and process knowledge should be managed from development through the commercial life of a product Knowledge management is a systemic approach to acquiring, analyzing, storing, and disseminating information related to products, mfg. processes, and components.
Figure: 11 Comparison of different spray nozzles and spray patterns
Knowledge Acquisition includes:
- Defining the Product Profile
- Public domain literature, patent review
- API attributes and limitations
- Definition of the DP manufacturing process
- Ranging the manufacturing process
Knowledge Analysis includes:
- Determining elements of intrinsic criticality, e.g. API attributes, process parameters,
- Risk analysis of the critical elements, e.g. FMEA, HACCP
- Defining a Control Strategy, e.g. integration of the process controls into facility QMS
Eg. Knowledge management and QRM- A Case Study Saxagliptin
Dipeptidyl peptidase IV inhibitor (DPP4) for Type II diabetes
- pKa = 7.2
- BCS Class III
Controlling Intramolecular Cyclization:
Cyclization Occurs in solid and solution state, Cyclization Accelerates with commonly used excipients, Cyclization Accelerates when processed under wet & dry granulation, Acidic environment stabilizes saxagliptin. Process Knowledge Acquired in Development and Transferred Forward to Production:
- Key Quality Attributes identified after risk assessment content uniformity potency
- Design space established using fundamental process understanding, modelling and Design of Experiments (DOE)
- A predictive model for CU and potency created for the Coating Step
Production Process was assessed for Criticality, Risk and Control. Applicable for either drug substance or drug product. When considering CPPs, determine what is critical and then how to control it.
4.2 Quality Risk Management for Equipment:
To determine appropriate product contact materials for equipment and containers (e.g., selection of stainless steel grade, gaskets, lubricants).
To determine appropriate utilities (e.g., steam; gases; power source; compressed air, heating,
Ventilation, and air conditioning (HVAC); water).
To determine appropriate preventive maintenance for associated equipment (e.g., inventory of necessary spare parts).
Qualification of equipment to determine the scope and extent of qualification of equipment and/or laboratory instruments (including proper calibration methods)
Eg. Failure Mode Effects and Criticality Analysis: Calibration of Equipment/Instrument
4.3 Quality Risk Management as Part of Materials Management:
Assessment and evaluation of suppliers and contract manufacturers
To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing, supplier quality agreements)
To assess differences and possible quality risks associated with variability in starting materials (e.g., age, route of synthesis).
Use of materials
To determine whether it is appropriate to use material under quarantine(e.g. for further internal processing).
To determine appropriateness of reprocessing, reworking, use of returned goods.
Storage, logistics and distribution conditions
To assess the adequacy of arrangements to ensure maintenance of appropriate storage and
Transport conditions (e.g., temperature, humidity, container design).
To determine the effect on product quality of discrepancies in storage or transport conditions
(e.g., cold chain management) in conjunction with other ICH guidance.
To maintain infrastructure (e.g., capacity to ensure proper shipping conditions, interim storage, handling of hazardous materials and controlled substances, customs clearance).
To provide information for ensuring the availability of pharmaceuticals (e.g., ranking risks to the supply chain).
4.4 Quality Risk Management as Part of Packaging and Labelling Design of packages
To design the secondary package for the protection of primary packaged product (e.g., to ensure product authenticity, label legibility).
Selection of container closure system
To determine the critical parameters of the container closure system.
To design label control procedures based on the potential for mix-ups involving different product labels, including different versions of the same label. For Eg. Failure Mode Effects and Criticality Analysis: Blister Packing
4.5 QRM application in product manufacturing operations 28
Effective QRM can facilitate the “How to do it?” and, therefore, ensure that the products will meet acceptable standards for safety, quality, and compliance. Among others, QRM methodology can support the following actions to assess and control quality risks:
- manufacturing process risks
- In-process sampling and testing controls
- Production planning
- Deviation and investigation management
- change management;
Laboratory control and stability studies:
- Out-of-specification results
- retest period and expiry date
- Method transfers;
Packaging and labelling:
- Design of packages
- Selection of container-closure system
- label controls;
Storage, transport and distribution:
- g. cold chain.
4.6 Quality Risk Management as Part of Laboratory Control and Stability Studies
- Out of specification results
- To identify potential root causes and corrective actions during the investigation of out of specification results.
- Retest period / expiration date
To evaluate adequacy of storage and testing of intermediates, excipients and starting materials.
4.7 Quality Risk Management as Part of Integrated Quality Management
Effective QRM can facilitate the decision on “What to do?” and, therefore, support better and more informed decisions. QRM should be integrated into existing quality system elements and related business processes and documented appropriately. Accordingly, the use of QRM can be beneficial across a broad spectrum of operations, e.g.:
Integrated quality management:
- Training and education
- Quality defects
- Auditing and inspection
- Change management and change control (includes equipment, facilities, utilities, control and IT systems)
- Continual improvement and corrective and preventive actions
Facilities, equipment and utilities:
- Maintenance and decommissioning of facility or equipment
- Hygiene aspects
- cleaning of equipment and environmental control
- Calibration and preventive maintenance
- Computer systems and computer-controlled equipment
Supplier, materials and contract service management:
- Assessment and evaluation of suppliers and contract manufacturers
- starting material
- Use of materials
- Logistics and distribution conditions
- From development to manufacturing
- During commercial manufacturing between sites
- From commercial manufacturing to product discontinuation.
4.8 Quality Risk Management as Part of clinical therapy 29,30,31,32:
Quality risk management aspect can be applicable to clinical therapy to identify and eliminate whatever risk comes during clinical therapy. Medication Therapy Management (MTM) can be used.
Defined as a distinct service or group of services that optimize therapeutic outcomes for individual patients.
- The 3 GOALS of MTM include:
- Improved medication understanding
- Adherence to medication therapy
- Detection of medication-related problems, including adverse drug reactions
- The 5 Core elements of MTM
- Provide a comprehensive or targeted medication therapy review
- Complete and update the patient’s personal medication record (PMR)
- Develop a medication-related patient-directed action plan (MAP)
- Intervene and/or refer when appropriate
- Document all services and interventions, communicate results encounter, and provide appropriate follow up.
Eg. Prevention of Risk due to particulate contamination in Infusion Therapy
Causes of particulate contaminations of IV fluids
- Undissolved particles/drugs
- impairment of microcirculation
- blockages of blood vessels
- damage to various organs
- Open ampoule or vial according to standards of care.
- Use filter straw for withdrawal of the infusion.
- In-line filter and infusion set filter prevent the infusion of particles into the patient.
- avoid glass ampoules
- use filter straws or filter needles
- incorporate appropriate filters into IV administrations
Ecoflac® plus: The state of the art IV solution container that offers safe and convenient application of all IV procedures from drug admixture to drug delivery. The superior properties of the resalable port membrane prevent coring of elastomeric particles when punctured with a needle or an infusion set.
Intrafix® SafeSet: IV set for safe and convenient infusions. A 15 μm particle filter prevents the infusion of particles. Using 15 μm particle filters in IV sets is recommended
in the international standards for infusion sets for single use in ISO 8536-4 (gravity) and in ISO 8536-8 (infusion equipment for use with pressure infusion apparatus).
Intrapur® and Sterifix® Infusion Filters
A whole range of filters for safe infusion therapy. Membranes of 0.2 μm and 1.2 μm separate particles and lipid macro micelles larger than the pore size of the filter.
Vented dispensing pins for safe and convenient fluid transfer with syringes. Particles such as undissolved lyophilisates in the fluid are retained due to the inbuilt 5 μm filter.
Sterifi x® filter straws
Filter straws for particle free withdrawal and filtration of fluids from ampoules. A 5 μm filter prevents the administration of glass particles, which can occur when ampoules are opened. The filter is already integrated in the hub of the straw.
Mini-Plasco® connect / Mini-Plasco®
The plastic ampoule offers small volumes of IV solution for drug preparations.
Low intrinsic particle load as Mini-Plasco plastic material does not produce such particles.
Can easily be opened without particle creation.
Figure: 19 Fault Tree Analysis of incorrect insulin drug administration
4.9 Quality Risk Management during drug administration:
Quality Risk Management also applicable during drug administration to identify and eliminate risk during drug administration. It is helpful to assure proper amount of drug is administered by proper way without any complaints. For e.g. Fault Tree Analysis of incorrect insulin drug administration
Quality Risk Management is a systematic process for evaluation, control, communication and review of risks to the quality of the drug product across the product lifecycle. Effective Quality Risk Management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks, and might affect the extent and level of direct regulatory oversight. Applying risk management to pharmaceutical industry should reduce the number of threats or minimize their impact through the consistent use of the tools/methods and periodic review. The output of the risk management supports to the organization to meets the defined goals towards protection of public health.
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