513
The purpose of this annex is to provide a general overview of and references for some of the
514
primary tools that might be used in quality risk management by industry and regulators. The
515
references are included as an aid to gain more knowledge and detail about the particular tool.
516
This is not an exhaustive list. It is important to note that no one tool or set of tools is applicable
517
to every situation in which a quality risk management procedure is used.
518
It is neither always appropriate nor always necessary to use highly formal quality risk
519
management methods and tools. The use of less formal quality risk management methods and
520
tools can also be considered acceptable. See Chapter 5 for guidance on what constitutes
521
formality in quality risk management.
522
I.1 Basic Risk Management Facilitation Methods 523
Some of the simple techniques that are commonly used to structure risk management by
524
organizing data and facilitating decision-making are:
525
• Flowcharts;
526
• Check Sheets;
527
• Process Mapping;
528
• Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram).
529
I.2 Failure Mode Effects Analysis (FMEA) 530
FMEA (see IEC 60812) provides for an evaluation of potential failure modes for processes and
531
their likely effect on outcomes and/or product performance. Once failure modes are
532
established, risk reduction can be used to eliminate, contain, reduce or control the potential
533
failures. FMEA relies on product and process understanding. FMEA methodically breaks down
534
the analysis of complex processes into manageable steps. It is a powerful tool for summarizing
535
the important modes of failure, factors causing these failures and the likely effects of these
536
failures.
537
Potential Areas of Use(s)
538
FMEA can be used to prioritize risks and monitor the effectiveness of risk control activities.
539
FMEA can be applied to equipment and facilities and might be used to analyze a manufacturing
540
operation and its effect on product or process. It identifies elements/operations within the
541
system that render it vulnerable. The output/ results of FMEA can be used as a basis for design
542
or further analysis or to guide resource deployment.
543
I.3 Failure Mode, Effects and Criticality Analysis (FMECA) 544
FMEA might be extended to incorporate an investigation of the degree of severity of the
545
consequences, their respective probabilities of occurrence, and their detectability, thereby
546
becoming a Failure Mode Effect and Criticality Analysis (FMECA; see IEC 60812). In order
547
for such an analysis to be performed, the product or process specifications should be
548
established. FMECA can identify places where additional preventive actions might be
549
appropriate to minimize risks.
550
Potential Areas of Use(s)
551
FMECA application in the pharmaceutical industry should mostly be utilized for failures and
552
risks associated with manufacturing processes; however, it is not limited to this application.
553
The output of an FMECA is a relative risk “score” for each failure mode, which is used to rank
554
the modes on a relative risk basis.
555
I.4 Fault Tree Analysis (FTA) 556
The FTA tool (see IEC 61025) is an approach that assumes failure of the functionality of a
557
product or process. This tool evaluates system (or sub-system) failures one at a time but can
558
combine multiple causes of failure by identifying causal chains. The results are represented
559
pictorially in the form of a tree of fault modes. At each level in the tree, combinations of fault
560
modes are described with logical operators (AND, OR, etc.). FTA relies on the experts’ process
561
understanding to identify causal factors.
562
Potential Areas of Use(s)
563
FTA can be used to establish the pathway to the root cause of the failure. FTA can be used to
564
investigate complaints or deviations in order to fully understand their root cause and to ensure
565
that intended improvements will fully resolve the issue and not lead to other issues (i.e. solve
566
one problem yet cause a different problem). Fault Tree Analysis is an effective tool for
567
evaluating how multiple factors affect a given issue. The output of an FTA includes a visual
568
representation of failure modes. It is useful both for risk assessment and in developing
569
monitoring programs.
570
I.5 Hazard Analysis and Critical Control Points (HACCP) 571
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability,
572
and safety (see WHO Technical Report Series No 908, 2003 Annex 7). It is a structured
573
approach that applies technical and scientific principles to analyze, evaluate, prevent, and
574
control the risk or adverse consequence(s) of hazard(s) due to the design, development,
575
production, and use of products.
576
HACCP consists of the following seven steps:
577
(1) conduct a hazard analysis and identify preventive measures for each step of the process;
578
(2) determine the critical control points;
579
(3) establish critical limits;
580
(4) establish a system to monitor the critical control points;
581
(5) establish the corrective action to be taken when monitoring indicates that the critical
582
control points are not in a state of control;
583
(6) establish system to verify that the HACCP system is working effectively;
584
(7) establish a record-keeping system.
585
Potential Areas of Use(s)
586
HACCP might be used to identify and manage risks associated with physical, chemical and
587
biological hazards (including microbiological contamination). HACCP is most useful when
588
product and process understanding is sufficiently comprehensive to support identification of
589
critical control points. The output of a HACCP analysis is risk management information that
590
facilitates monitoring of critical points not only in the manufacturing process but also in other
591
life cycle phases.
592 593
I.6 Hazard Operability Analysis (HAZOP) 594
HAZOP (see IEC 61882) is based on a theory that assumes that risk events are caused by
595
deviations from the design or operating intentions. It is a systematic brainstorming technique
596
for identifying hazards using so-called “guide-words”. “Guide-words” (e.g., No, More, Other
597
Than, Part of, etc.) are applied to relevant parameters (e.g., contamination, temperature) to help
598
identify potential deviations from normal use or design intentions. It often uses a team of people
599
with expertise covering the design of the process or product and its application.
600
Potential Areas of Use(s)
601
HAZOP can be applied to manufacturing processes, including outsourced production and
602
formulation as well as the upstream suppliers, equipment and facilities for drug substances and
603
drug (medicinal) products. It has also been used primarily in the pharmaceutical industry for
604
evaluating process safety hazards. As is the case with HACCP, the output of a HAZOP analysis
605
is a list of critical operations for risk management. This facilitates regular monitoring of critical
606
points in the manufacturing process.
607
I.7 Preliminary Hazard Analysis (PHA) 608
PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or
609
failure to identify future hazards, hazardous situations and events that might cause harm, as
610
well as to estimate their probability of occurrence for a given activity, facility, product or
611
system. The tool consists of: 1) the identification of the possibilities that the risk event happens,
612
2) the qualitative evaluation of the extent of possible injury or damage to health that could
613
result and 3) a relative ranking of the hazard using a combination of severity and likelihood of
614
occurrence, and 4) the identification of possible remedial measures.
615
Potential Areas of Use(s)
616
PHA might be useful when analyzing existing systems or prioritizing hazards where
617
circumstances prevent a more extensive technique from being used. It can be used for product,
618
process and facility design as well as to evaluate the types of hazards for the general product
619
type, then the product class, and finally the specific product. PHA is most commonly used early
620
in the development of a project when there is little information on design details or operating
621
procedures; thus, it will often be a precursor to further studies. Typically, hazards identified in
622
the PHA are further assessed with other risk management tools such as those in this section.
623
I.8 Risk Ranking and Filtering 624
Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex
625
systems typically requires evaluation of multiple diverse quantitative and qualitative factors
626
for each risk. The tool involves breaking down a basic risk question into as many components
627
as needed to capture factors involved in the risk. These factors are combined into a single
628
relative risk score that can then be used for ranking risks. “Filters,” in the form of weighting
629
factors or cut-offs for risk scores, can be used to scale or fit the risk ranking to management or
630
policy objectives.
631
Potential Areas of Use(s)
632
Risk ranking and filtering can be used to prioritize manufacturing sites for inspection/audit by
633
regulators or industry. Risk ranking methods are particularly helpful in situations in which the
634
portfolio of risks and the underlying consequences to be managed are diverse and difficult to
635
compare using a single tool. Risk ranking is useful when management needs to evaluate both
636
quantitatively-assessed and qualitatively-assessed risks within the same organizational
637
framework.
638
I.9 Supporting Statistical Tools 639
Statistical tools can support and facilitate quality risk management. They can enable effective
640
data assessment, aid in determining the significance of the data set(s), and facilitate more
641
reliable decision making. A listing of some of the principal statistical tools commonly used in
642
the pharmaceutical industry is provided:
643
• Control Charts, for example:
644
- Acceptance Control Charts (see ISO 7966);
645
- Control Charts with Arithmetic Average and Warning Limits (see ISO 7873);
646
- Cumulative Sum Charts (see ISO 7871);
647
- Shewhart Control Charts (see ISO 8258);
648
- Weighted Moving Average.
649
• Design of Experiments (DOE);
650
• Histograms;
651
• Pareto Charts;
652
• Process Capability Analysis.
653
654
ANNEX II: QUALITY RISK MANAGEMENT AS PART OF INTEGRATED QUALITY
655
MANAGEMENT
656
This Annex is intended to identify potential uses of quality risk management principles and
657
tools by industry and regulators. However, the selection of particular risk management tools is
658
completely dependent upon specific facts and circumstances.
659
These examples are provided for illustrative purposes and only suggest potential uses of quality
660
risk management. This Annex is not intended to create any new expectations beyond the current
661
regulatory requirements.
662
II.1 Quality Risk Management as Part of Integrated Quality Management 663
Documentation
664
To review current interpretations and application of regulatory expectations;
665
To determine the desirability of and/or develop the content for SOPs, guidelines, etc.
666
Training and education
667
To determine the appropriateness of initial and/or ongoing training sessions based on
668
education, experience and working habits of staff, as well as on a periodic assessment of
669
previous training (e.g., its effectiveness);
670
To identify the training, experience, qualifications and physical abilities that allow personnel
671
to perform an operation reliably and with no adverse impact on the quality of the product.
672
Quality defects
673
To provide the basis for identifying, evaluating, and communicating the potential quality
674
impact of a suspected quality defect, complaint, trend, deviation, investigation, out of
675
To facilitate risk communications and determine appropriate action to address significant
677
product defects, in conjunction with regulatory authorities (e.g., recall).
678
Auditing/Inspection
679
To define the frequency and scope of audits, both internal and external, taking into account
680
factors such as:
681
• Existing legal requirements;
682
• Overall compliance status and history of the company or facility;
683
• Robustness of a company’s quality risk management activities;
684
• Complexity of the site;
685
• Complexity of the manufacturing process;
686
• Complexity of the product and its therapeutic significance;
687
• Number and significance of quality defects (e.g., recall);
688
• Results of previous audits/inspections;
689
• Major changes of building, equipment, processes, key personnel;
690
• Experience with manufacturing of a product (e.g., frequency, volume, number of
691
batches);
692
• Test results of official control laboratories.
693
Periodic review
694
To select, evaluate and interpret trend results of data within the product quality review;
695
To interpret monitoring data (e.g., to support an assessment of the appropriateness of
696
revalidation or changes in sampling).
697
Change management / change control
698
To manage changes based on knowledge and information accumulated in pharmaceutical
699
development and during manufacturing;
700
To evaluate the impact of the changes on the availability of the final product;
701
To evaluate the impact on product quality of changes to the facility, equipment, material,
702
manufacturing process or technical transfers;
703
To determine appropriate actions preceding the implementation of a change, e.g., additional
704
testing, (re)qualification, (re)validation or communication with regulators.
705
Continual improvement
706
To facilitate continual improvement in processes throughout the product lifecycle.
707
II.2 Quality Risk Management as Part of Regulatory Operations 708
Inspection and assessment activities
709
To assist with resource allocation including, for example, inspection planning and frequency,
710
and inspection and assessment intensity (see "Auditing" Section in Annex II.1);
711
To evaluate the significance of, for example, quality defects, potential recalls and inspectional
712
findings;
713
To determine the appropriateness and type of post-inspection regulatory follow-up;
714
To evaluate information submitted by industry including pharmaceutical development
715
information;
716
To evaluate impact of proposed variations or changes;
717
To identify risks which should be communicated between inspectors and assessors to facilitate
718
better understanding of how risks can be or are controlled (e.g., parametric release, Process
719
Analytical Technology (PAT)).
720
II.3 Quality Risk Management as Part of development 721
To design a quality product and its manufacturing process to consistently deliver the intended
722
performance of the product (see ICH Q8);
723
To enhance knowledge of product performance over a wide range of material attributes (e.g.,
724
particle size distribution, moisture content, flow properties), processing options and process
725
parameters;
726
To assess the critical attributes of raw materials, solvents, Active Pharmaceutical Ingredient
727
(API) starting materials, APIs, excipients, or packaging materials;
728
To establish appropriate specifications, identify critical process parameters and establish
729
manufacturing controls (e.g., using information from pharmaceutical development studies
730
regarding the clinical significance of quality attributes and the ability to control them during
731
processing);
732
To decrease variability of quality attributes:
733
• reduce product and material defects;
734
• reduce manufacturing defects.
735
To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up
736
and technology transfer;
737
To make use of the “design space” concept (see ICH Q8).
738
II.4 Quality Risk Management for Facilities, Equipment and Utilities 739
Design of facility / equipment
740
To determine appropriate zones when designing buildings and facilities, e.g.,
741
• flow of material and personnel;
742
• minimize contamination;
743
• pest control measures;
744
• prevention of mix-ups;
745
• open versus closed equipment;
746
• clean rooms versus isolator technologies;
747
• dedicated or segregated facilities / equipment.
748
To determine appropriate product contact materials for equipment and containers (e.g.,
749
selection of stainless steel grade, gaskets, lubricants);
750
To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating,
751
ventilation and air conditioning (HVAC), water);
752
To determine appropriate preventive maintenance for associated equipment (e.g., inventory of
753
necessary spare parts).
754
Hygiene aspects in facilities
755
To protect the product from environmental hazards, including chemical, microbiological, and
756
physical hazards (e.g., determining appropriate clothing and gowning, hygiene concerns);
757
To protect the environment (e.g., personnel, potential for cross-contamination) from hazards
758
related to the product being manufactured.
759
Qualification of facility/equipment/utilities
760
To determine the scope and extent of qualification of facilities, buildings, and production
761
equipment and/or laboratory instruments (including proper calibration methods).
762
Cleaning of equipment and environmental control
763
To differentiate efforts and decisions based on the intended use (e.g., multi- versus
single-764
purpose, batch versus continuous production);
765
To determine acceptable (specified) cleaning validation limits.
766
Calibration/preventive maintenance
767
To set appropriate calibration and maintenance schedules.
768
Computer systems and computer controlled equipment
769
To select the design of computer hardware and software (e.g., modular, structured, fault
770
tolerance);
771
To determine the extent of validation, e.g.,
772
• selection of the requirements and design;
774
• code review;
775
• the extent of testing and test methods;
776
• reliability of electronic records and signatures.
777
II.5 Quality Risk Management as Part of Materials Management 778
Assessment and evaluation of suppliers and contract manufacturers
779
To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing,
780
supplier quality agreements).
781
Starting material
782
To assess differences and possible quality risks associated with variability in starting materials
783
(e.g., age, route of synthesis).
784
Use of materials
785
To determine whether it is appropriate to use material under quarantine (e.g., for further internal
786
processing);
787
To determine appropriateness of reprocessing, reworking, use of returned goods.
788
Storage, logistics and distribution conditions
789
To assess the adequacy of arrangements to ensure maintenance of appropriate storage and
790
transport conditions (e.g., temperature, humidity, container design);
791
To determine the effect on product quality of discrepancies in storage or transport conditions
792
(e.g., cold chain management) in conjunction with other ICH guidelines;
793
To maintain infrastructure (e.g., capacity to ensure proper shipping conditions, interim storage,
794
handling of hazardous materials and controlled substances, customs clearance);
795
To provide information for ensuring the availability of pharmaceuticals (e.g., ranking risks to
796
the supply chain).
797
II.6 Quality Risk Management as Part of Production 798
Validation
799
To identify the scope and extent of verification, qualification and validation activities (e.g.,
800
analytical methods, processes, equipment and cleaning methods;
801
To determine the extent for follow-up activities (e.g., sampling, monitoring and re-validation);
802
To distinguish between critical and non-critical process steps to facilitate design of a validation
803
study.
804
In-process sampling & testing
805
To evaluate the frequency and extent of in-process control testing (e.g., to justify reduced
806
testing under conditions of proven control);
807
To evaluate and justify the use of process analytical technologies (PAT) in conjunction with
808
parametric and real time release.
809
Production planning
810
To determine appropriate production planning (e.g., dedicated, campaign and concurrent
811
production process sequences).
812
II.7 Quality Risk Management as Part of Laboratory Control and Stability Studies 813
Out of specification results
814
To identify potential root causes and corrective actions during the investigation of out of
815
specification results.
816
Retest period / expiration date
817
To evaluate adequacy of storage and testing of intermediates, excipients and starting materials.
818
II.8 Quality Risk Management as Part of Packaging and Labelling 819
Design of packages
820
To design the secondary package for the protection of primary packaged product (e.g., to ensure
821
Selection of container closure system
823
To determine the critical parameters of the container closure system.
824
Label controls
825
To design label control procedures based on the potential for mix-ups involving different
826
product labels, including different versions of the same label.
827
II.9 Quality Risk Management as Part of Supply Chain Control 828
With regard to product availability risks related to quality/manufacturing issues, lifecycle
829
oversight of the supply chain includes maintaining current knowledge of quality/manufacturing
830
hazards and prioritizing efforts to manage such risks. Understanding hazards
831
to quality/manufacturing is critical to maintaining supply predictability. When risks are well
832
understood and minimized, a higher confidence in product availability can be attained.
833
Manufacturing Process Variation and State of Control
834
To decrease variability in the manufacturing process (e.g., process drift, non-uniformity) and
835
associated capability gaps that can result in unpredictable outputs, adversely impact quality and
836
consequently timeliness, yield and product availability;
837
To design monitoring systems that are capable of detecting departures from a state of control
838
and deficiencies in manufacturing processes, so they can be appropriately investigated to
839
determine root causes and any required risk mitigations.
840
Manufacturing Facilities
841
To ensure that facility infrastructure and equipment are suitable and well-designed for
842
manufacturing and packaging;
843
To establish equipment and facility maintenance programmes that assure reliable facility and
844
equipment performance;
845
To ensure that the operational design of equipment is not vulnerable to human error;
846
To obtain efficiency gains (e.g. speed, throughput, supply timeliness, etc.) from investing in
847
quality through the utilization of digitalization, automation, isolation technology, and other
848
innovations.
849
Supplier Oversight and Relationships
850
To enhance review and monitoring activities (see Section 2.7 of ICH Q10) when substantial
851
variability is identified in the quality and safety of supplied materials or in the services
852
provided.
853
To manage external product availability risks relating to quality/manufacturing, (e.g. from raw
854
material suppliers, contracted organizations, service providers, etc.)
855