1. Pharm (Mrs). Uche Sonny-Afoekelu,
APPLICATION OF QUALITY RISK MANAGEMENT IN PHARMACEUTICAL MANUFACTURING (ICH Q9)
Pharm (Mrs). Uche Sonny-Afoekelu,
M.Sc.(PH), MPCPharm
Assistant Director, Compliance Division
Drug Evaluation and Research Directorate, NAFDAC
US-A

2. OUTLINE Regulatory requirements Definition
Introduction to Quality Risk Management (QRM)
Concept of QRM
Principles of QRM
Proactive and Reactive QRM
QRM Process
Risk Management Methodology
Potential Applications of QRM
US-A

3. Regulatory requirements
Quality Risk Management should be an integral element of the Pharmaceutical Quality System (NAFDAC cGMP guidelines )
ICH Q9

4. Definition:
Quality Risk Management (QRM) is a systematic process for the assessment, control, communication and review of risks to the quality of a drug product across the product lifecycle
It can be applied both proactively and reactively (retrospectively).
US-A

5. Introduction QRM is an enabler-
Together with knowledge management, it enables a company to implement ICH Q10 effectively and successfully.
These enablers will facilitate the achievement of the quality objectives by providing the means for science and risk based decisions related to product quality.
US-A

6. CONCEPT OF QRM IS QRM A NEW REGULATORY REQUIREMENT? YES OR NO?
Companies may use informal risk management approaches eg internal procedures, empirical tools eg from observation, trends etc that are not formal QRM tools.
Appropriate use of QRM can facilitate , but does not obviate industry’s obligation to comply with regulatory requirements. example
US-A

7. NO, QRM is not a new concept
QRM is not a new concept for manufacturers and Regulatory Authorities.
Informal QRM-related activities have been taking place for many years.
Change control, self-inspection, supplier approvals, temperature mapping, ..… are informal QRM-related activities.

8. NO, QRM is not a new concept
GMP requirements are designed to address risks eg: The specific GMP requirements for sterile products are designed to mitigate the risk of sterility failure
In some cases GMP specifies a risk based approach eg “ a risk assessment approach should be used to determine the scope and extent of validation required”(WHO Annex 4, )

9. NO, QRM is not a new concept
Specifications in Pharmacopoeial monographs include tests for known potential contaminants
From a GMP point of view, we are only concerned with risks associated with quality, safety, and efficacy-Quality risk management.
Some organizations use risk approaches in other areas eg to ensure resources are utilized in the most efficient way.
This is also applicable to inspectorates
Risk management is also applied in the medical, telecom, aviation, aerospace and car industries

10. So what is new?
A deliberate effort to formally and systematically apply QRM Principles

11. CONCEPT OF QRM
Effective QRM can facilitate better and more informed decisions
It can provide regulators with greater assurance of the company’s ability to deal with potential risks
It can beneficially affect the level of direct regulatory oversight.
US-A

12. DANGER!
The principles of QRM can be incorrectly applied in pharmaceutical operations example
QRM is not an excuse to violate cGMPs
Release of a contaminated lot because of a low QRM score
Use of QRM to replace root cause analysis
I don’t need an SOP for that because of the QRM score
US-A

13. DANGER…2
QRM is NOT a shortcut for avoiding the hard work of cGMP compliance
Use of QRM to inappropriately reduce process validation studies
Use of QRM to justify minimal on-the-job training
Use of QRM to justify cGMP compliance failures
US-A

14. DANGER..3
There is a desired outcome and risk management is used to justify it
Invalid assumptions- suit the desired outcome
Cost reduction (increased profits) is often the real reason why many risk assessments are done
Cost reduction may be a secondary outcome
Variable tolerance of risk (risk appetite)

15. QRM- From an inspector’s perspective
Be prepared so that the process is understood
Have sufficient knowledge to understand what has been done and challenge assumptions, omissions etc
Be clear about when QRM is not appropriate
Be flexible and accept the outcome of a scientifically sound QRM exercise
If done properly, there should be increased assurance of quality (and possibly cost savings)

16. PRINCIPLES OF QRM Two primary principles of QRM are:
The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.
The level of effort , formality and documentation of the quality risk management process should be commensurate with the level of risk
US-A

17. PRINCIPLES OF QRM…2
QRM is a tool to facilitate cGMP compliance, not replace it.
QRM can be a strong documented ally in demonstrating that we operate in a state of control
US-A

18. PRINCIPLES OF QRM…3
Why is the management of risk important in today’s world of Pharmaceutical manufacturing?
Not all risks can be eliminated- thus we must manage and mitigate those risks that do exist
Not all risks deserve equal attention-by having a process that ranks and prioritizes risks, we can better utilize our resources and efforts
Not all risks are readily apparent- a hidden risk can often pose a greater threat to our business than those we know and can manage
US-A

19. PROACTIVE AND REACTIVE USES OF QRM
REACTIVE- QRM can be used as a reactive tool to assess potential quality issues that have already occurred eg
Assessment of post marketing issues
Complaints
Stability issues
Assessment of manufacturing issues
Potential contamination issue
Incorrect label
US-A

20. PROACTIVE AND REACTIVE USES OF QRM
Assessment of proposed changes
Line speed change
Addition of a third shift
Assessment of new operations
New tablet press
Additional automated inspection system
US-A

21. Proactive uses of QRM -contd
Assessment of adverse trends
Water results
Environmental results
Assess the breadth of an investigation-
Extend to other batches or products

22. Proactive QRM contd;
Assessment of regulatory actions of experience of others on your own operation
Warning letter from another regulatory body
Proposed new regulatory requirements or expectations
Tool for continuous improvement
Lab flow re-design
Batch record review/release processes
US-A

23. Tips- proactive and reactive QRM
In reactive events, containment of the issue becomes a key component of the risk assessment.
The less contained the issue, the higher the risk potential. Thus, there is greater need for mitigation
A comprehensive proactive use of QRM always includes the open-ended question: ‘what can possibly go wrong?’ Each possibility represents a risk that must be listed, assessed, and mitigated if needed.
US-A

24. THE QRM PROCESS RISK ASSESSMENT RISK CONTROL RISK COMMUNICATION
RISK REVIEW
US-A

25. THE QRM PROCESS
THE QRM PROCESS

26. RISK ASSESSMENT Risk assessment consists of: Hazard identification
Risk analysis
Evaluation of risk associated with exposure to those hazards
Three fundamental questions are often helpful…
US-A

27. RISK ASSESSMENT…2 Hazard- Any potential source of harm
Harm- Anything that can cause damage to health including loss of product quality or availability
Risk-The combination of the probability of occurrence of harm and the severity of that harm
US-A

28. RISK ASSESSMENT …3 QUESTIONS:
For Risk (Hazard) Identification – What might go wrong or has gone wrong? (O)
For Risk Analysis- What is the likelihood or probability that it will go wrong and what is the detectability? (D)
For Risk Evaluation- What are the consequences (severity?) (S)
US-A

29. RISK ASSESSMENT…4 Hazard (Risk) Identification:
It is a systematic use of information to identify hazards.
Information can include historical data, theoretical analysis, informed opinion, concerns from stakeholders, expert opinion and brainstorming.-
This underscores the need for a multidisciplinary QRM Team
It answers the “what might go wrong?” question including identifying possible consequences
Provides the basis for further steps in the QRM process
US-A

30. RISK ASSESSMENT…5 Risk Analysis
This is the estimation of the risk associated with the identified hazard.
qualitative or quantitative
links the likelihood of occurrence (probability) with severity
In some risk management tools, it includes detectability
US-A

31. Risk analysis- probability: A simple qualitative tool
P- Probability of occurrence
interpretation
High
Medium
Low
Remote
Likely to occur
May occur
Unlikely to occur
Very unlikely to occur

32. Risk analysis- Severity: A simple qualitative tool
S- Severity level if event occurs
interpretation
Critical
Moderate
Minor
Serious GMP non-compliance. Patient injury possible
Significant GMP non-compliance; impact on patient possible
Minor GMP non-compliance
No patient impact

33. Risk Analysis Detectability:
High- The control is likely to detect the negative event or its effect
Medium- The control may detect the negative event or its effects
Low- the control is not likely to detect the negative event or its effects
Zero- no detection control in place

34. Risk Evaluation
This compares the identified and analyzed risk against given risk criteria.
Risk evaluations consider the strength of evidence for all three of the fundamental questions (probability, severity and detectability)
US-A

35. Output/result of Risk Assessment
Output can be qualitative (high, medium, low)
Output can be quantitative (probability x severity x detectability)
Quantitative provides a relative ranking- prioritizes risk
US-A

36. Simple risk table with risk acceptability criteria
Risk= P X S
SEVERITY
PROBABILITY
Minor
Moderate
Critical
High
Unacceptable risk
Intolerable risk
Medium
Acceptable risk
Low
Remote

37. Risk definitions
Intolerable- action to eliminate the negative event or introduce detection controls is required as a priority
Unacceptable- action to reduce the risk or control the risk to an acceptable level is required
Acceptable-the risk is acceptable and no risk reduction or detection controls are required

38. Quality risk assessment – using FMEA
The identify critical manufacturing steps that will require validation:
Acceptance criteria: RPN= 3X3X3= 27 (JUST AN EXAMPLE!)
Assessment Category 1 2 3 4 5
Probability of occurrence (O)
Low
High
Severity (S)
Minor
Critical
Detectability (D)

39. Quality risk assessment – using FMEA
An RPN value below 27 indicates that this parameter/process step is not critical and does not require validation whereas as one with an RPN value of 27 and above require validation/investigation.
Only a risk with no significant impact on product quality shall be accepted.

40. Caution!
Scale can be from 1 to 5 or from 1 to 10 as long as it remains proportional.
Assessing Risk Some words of caution when using the RPN value to assess risk - RPNs have no value or meaning in themselves.
Although it is true that larger RPN values normally  indicate more critical failure modes, this is not always the case.
For example, below we have three cases where the RPNs are identical, but clearly the second case would warrant the most attention. WHY?
US-A

41. Same RPN
CASE 1:
US-A

42. Points to note
As a general rule, any failure mode that has an effect resulting in a severity value of 4 or 5 (on a scale of 1-5) or 9 or 10 (on a scale of 1-10) would have top priority. Severity is given the most weight when assessing risk. Why? Next the severity and occurrence (SXO) combination would be considered, since this in effect, represents the criticality.
US-A

43. caution
Below is another RPN example reminding us that we need to be careful not to assess risk purely based on the RPN values.
Here, the failure modes with the lowest RPN values are actually the most critical.
Be careful not to just establish “threshold values” for RPNs when assessing risks as this could lead you to making costly mistakes.
Below we see that No 1 is the most critical even though it has the lowest RPN, then no 2, and then no 3. .
US-A

44. Lowest RPN?
Case 2:
US-A

45. CAUTION
In summary, always address high severity failure modes regardless of their overall RPN values.
US-A

46. Risk Control
Risk control includes decision making to either reduce or accept risks.
The purpose of risk control is to reduce the risk to an acceptable level.
The amount of effort used in risk control should be proportional to the significance of the risk
US-A

47. Risk control…2 Questions Is the risk above an acceptable level?
What can be done to reduce risks?
What is the appropriate balance among benefits, risks, and resources?
Are new risks introduced as a result of the identified risk being controlled?
US-A

48. Risk control…3 Risk Reduction (If applicable)
Actions taken to lessen the probability of occurrence of harm and severity of that harm
Typically CAPA and Change control
Processes that improve the detectability of hazards and quality risks might also be used as part of a risk control strategy
US-A

49. Risk control…4 Risk reduction
The implementation of risk reduction measures can introduce new risks into the system or increase the significance of other existing risks.
It might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk after implementing a risk reduction process
US-A

50. Risk control…5 Risk acceptance Is a decision to accept risk.
It can be a formal decision to accept the residual risk.
The best risk management principles may not be able to entirely eliminate risk
The acceptable (specified) level will depend on many parameters and will be decided on a case by case basis
US-A

51. Risk Communication
Is the sharing of information about risk and Risk Management between the decision makers and others.
Parties can communicate at any stage of the Risk Management process
The output/result of a RM process should be appropriately communicated and documented
US-A

52. Risk Communication…2
Communication might include those among interested parties example:
Regulators and industry
Industry and patient
Within a company
Within an industry
Within a regulatory body
US-A

53. Risk communication…3 The communication might have information on
The existence
Nature
Form
Probability
Severity
Acceptability
Control
Treatment
Detectability
Or Other aspects of risk to quality
US-A

54. Risk review
Risk management should be an on-going part of the quality management process.
A mechanism to review or monitor events should be implemented.
The output of the RM process should be reviewed to take into account new knowledge and experience
The frequency of any review should be based on level of risk
Risk review might include reconsideration of risk acceptance decisions
US-A

55. Risk management methodology
QRM supports a scientific and practical approach to decision making
QRM tools include:
Flow charts
Failure Modes and Effects Analysis (FMEA)- RPN
Fault Tree Analysis
HACCP
Hazard Operability analysis (HAZOP)
Pareto diagrams(80/20 Rule)- vital few , trivial many
Cause and effect diagrams (Ishikawa or fishbone diagram)or Fishikawa?
US-A

56. US-A

57. Integration of QRM into industry and Regulatory operations
Example for industry and regulatory operations
Quality Management
Example for industry operations and activities
Development
Facility, equipment, and utilities
Materials management
Production
Laboratory control and stability testing
Packaging and labeling
Example s for regulatory operation
Inspection and assessment activities
US-A

58. Potential applications for QRM
QRM as part of integrated Quality Management
Documentation:
To review current interpretations and application of regulatory expectation
To determine the desirability of and/or develop the content for SOPs, guidelines etc
Training and Education
To determine the appropriateness of initial and/or on-going training sessions based on education, experience, and working habits of staff as well as periodic assessments of previous training (Effectiveness)
To identify training, experience, qualification, and physical abilities that allow personnel to perform an operation reliably without any adverse impact on the quality of the product
US-A

59. Potential applications for QRM
QRM as part of integrated Quality Management
Quality Defects
To provide the basis for identifying, evaluating, and communicating the potential quality impact of a suspected quality defect, complaint, trend, deviation, investigation, OOS result etc
US-A

60. Potential applications for QRM
QRM as part of integrated Quality Management
Auditing/inspection
To define the frequency and scope of audits, both internal and external taking into account factors such as :
Existing legal requirements
Overall compliance status and history of company or facility
Complexity of the site
Complexity of manufacturing process
Results of previous audits/ inspections
Major changes of buildings, equipment, processes, key personnel
Number and significance of quality defects
US-A

61. Potential applications for QRM
QRM as part of integrated Quality Management
Periodic review
To select, evaluate, and interpret trend results of data within the product quality review (PQR)
to interpret monitoring data (eg . To support an assessment of the appropriateness of revalidation or changes in sampling)
US-A

62. Potential applications for QRM
QRM as part of integrated Quality Management
change management/change control
to manage changes based on knowledge and information accumulated in pharmaceutical development and during manufacturing
To evaluate the impact of the change on the availability of the final product
To evaluate the impact on product quality of changes to the facility, equipment, material, manufacturing process, or technology transfers
To determine appropriate actions preceding the implementation of a change eg additional testing, requalification, revalidation, or communication with regulators
US-A

63. Potential applications for QRM
QRM as part of Regulatory Operations
Inspection and assessment activities
To assist with resource allocations eg inspection planning and frequency,
To evaluate the significance of quality defects, inspectional findings (like categorization of deficiencies to critical, major, others)
To determine the appropriateness and type of post inspection regulatory follow up
To evaluate impact of proposed variations or changes
To identify risks that should be communicated between inspectors and assessors to facilitate better understanding of how risks can be or are controlled (eg PAT, Parametric release)
US-A

64. Potential applications for QRM
QRM as part of Development
To design a quality product and its manufacturing process to consistently deliver the intended performance of the product (ICH Q8)
To assess the critical attributes of raw materials, solvents, API starting materials, APIs, excipients or packaging materials
US-A

65. Potential applications for QRM
QRM as part of Development …2
To enhance knowledge of product performance over a wide range of material attributes eg particle size distribution, moisture content, flow properties)
To establish appropriate specifications , identify critical process parameters and establish manufacturing controls
US-A

66. Potential applications for QRM
QRM as part of Development…3
To decrease variability of quality attributes
Reduce product and material defects
Reduce manufacturing defects
To assess the need for additional studies (eg bioequivalence, stability) relating to the scale up and technology transfer
To make use of the design space concept (ICH Q8)
US-A

67. Potential applications for QRM
QRM for Facilities, Equipment and utilities
Design of facility/equipment
To determine appropriate zones when designing buildings and facilities eg
Flow of material and personnel
Minimize contamination/cross contamination
Pest control measures
Prevention of mix ups
Open versus closed equipment
Clean rooms versus isolator technologies
Dedicated or segregated facilities/equipment
US-A

68. Potential applications for QRM
QRM for Facilities, Equipment and utilities
To determine appropriate product contact materials for equipment and containers (eg selection of stainless steel grade, lubricants etc)
To determine appropriate utilities (eg steam, gases, power source, compressed air, HVAC, water
To determine appropriate preventive maintenance for associated equipment (eg inventory of necessary spare parts)
US-A

69. Potential applications for QRM
QRM for Facilities, Equipment and utilities
Hygiene aspects in facilities
To protect the products from environmental hazards, including chemical, microbiological and physical hazards (eg determining appropriate clothing and gowning, hygiene concerns
To protect personnel and environment from hazards related to the product being manufactured
US-A

70. Potential applications for QRM
QRM for Facilities, Equipment and utilities
Qualification of facility/equipment/utilities
To determine the scope and extent of qualification of facilities, buildings, and production equipment and/or laboratory instruments (including proper calibration methods)
US-A

71. Potential applications for QRM
QRM for Facilities, Equipment and utilities
Cleaning of equipment and environmental control
To determine acceptable(specified) cleaning validation limits
Calibration/preventive maintenance
To set appropriate calibration and maintenance schedules
US-A

72. Potential applications for QRM
QRM for Facilities, Equipment and utilities
Computer systems and computer controlled equipment
To select the design of computer hardware and software (eg modular, structured, fault tolerance)
To determine the extent of validation
US-A

73. Potential applications for QRM
QRM as part of materials management
Assessment and evaluation of suppliers and contract manufacturers
To provide a comprehensive evaluation of suppliers and contract manufacturers (eg auditing, supplier quality agreements)
Starting materials
To assess differences and possible quality risks associated with variability in starting materials(eg age, route of synthesis)
Use of material
To determine appropriateness of reprocessing, use of returned goods
US-A

74. Potential applications for QRM
QRM as part of materials management
Storage, logistics and distribution conditions
To assess the adequacy of arrangements to ensure maintenance of appropriate storage and transport conditions (eg temp, humidity, container design)
To determine the effect on product quality of discrepancies in storage or transport (eg cold chain management)
US-A

75. Potential applications for QRM
QRM as part of Production
Validation
To identify the scope and extent of verification, qualification, and validation activities (eg analytical methods, processes, equipment, and cleaning methods)
To distinguish between critical and non critical process steps to facilitate design of a validation study
To determine the extent for follow up activities (eg sampling, monitoring and re-validation)
US-A

76. Potential applications for QRM
QRM as part of Production
In-process sampling and testing
To evaluate the frequency and extent of in-process control testing (eg to justify reduced testing under conditions of proven control)
Production planning
To determine appropriate production planning (eg dedicated, campaign)
US-A

77. Potential applications for QRM
QRM as part of laboratory control and stability studies
Out Of Specification (OOS) Results
To identify potential root causes and corrective actions during the investigation of OOS results
retest period/expiration date
to evaluate adequacy of storage and testing of intermediates, excipients, and starting materials
US-A

78. Potential applications for QRM
QRM as part of packaging and Labeling
Design of packers
To design the secondary package for the protection of primary packaged products (eg to ensure product authenticity, label integrity)
Selection of container closure system
To determine the critical parameters of the container closure system
Label controls
To design label control procedures based on the potential for mix ups involving different product labels, including different versions of the same label
US-A

79. References NAFDAC cGMP for Medicinal Products draft Regulations 2009
NAFDAC cGMP for Medicinal Products Guidelines 2016
ICH Q8, ICH Q9, ICH Q10
ISO/IEC Guide 73:2002- Risk Management
USFDA Guidance for Industry on Quality Risk Management
Tony Gould, WORLD HEALTH ORGANIZATION
US-A

80. Thank you
QUESTIONS ?????????????
US-A

81. Case study… 1
XYZ Pharmaceutical company based in Lagos is authorized to manufacture OSD products.
On November 3rd 2016, the outcome of Laboratory evaluation for Product T tablets. was found to be unsatisfactory.
Reason: Product failed Dissolution Test.
Using the Cause and effect Diagram, what steps would you take to determine the root cause.
US-A

82. Case study ..2
Describe how you will use Quality Risk Management principles to determine the scope and extent of Process validation.