FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. This presentation - Part III in the series- deals with the concepts of critical material attributes, critical process parameters , their linage to the the critical Quality attributes of the Product and Quality Risk Management and its pivotal role in the QbD process.Concepts of control strategy are also discussed briefly. This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.

1. Risk Assessment:
Linking Material Attributes and Process Parameters
to Drug Product CQAs
Presentation prepared by Drug Regulations – a not for profit
organization. Visit www.drugregulations.org for the latest in
Pharmaceuticals.
www.drugregulations.org 1

2. Product Profile  Quality Target Product Profile (QTPP)
CQA’s  Determine “potential” critical quality attributes (CQAs)
Risk Assessments  Link raw material attributes and process parameters to
CQAs and perform risk assessment
Design Space  Develop a design space (optional and not required)
Control Strategy  Design and implement a control strategy
Continual  Manage product lifecycle, including continual
Improvement
improvement
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3.  This presentation Part III of the series “QbD for Beginners”
Product Profile covers basic aspects of
◦ Material attributes & criticality
◦ Process parameters & criticality
CQA’s
◦ Linkage of CMA & CPP to critical quality attributes
◦ Risk , risk assessments
Risk Assessments ◦ General Quality Risk Management process
◦ Risk Management methodology
◦ Overview of Quality Risk Management
Design Space
 FDA IR Tablet example
◦ Risk assessment of Drug Substance
Control Strategy ◦ Excipient selection
◦ Initial Risk assessment of formulation variables
Continual ◦ Process selection & Formulation development overview for the Example IR
Improvement Tab
◦ Updated risk assessment of formulation variables
◦ Manufacturing process development for the example IR Tablets
◦ Initial Risk assessment of the (overall) drug product mfg process variables
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4.  FDA IR Tablet example
Product Profile ◦ Initial RA of Pre roller compaction , blending & lubrication process variables
◦ Updated RA of Pre roller compaction , blending & lubrication process variables
◦ Initial RA of roller compaction & integrated milling process variables
CQA’s
◦ Further manufacturing study based on risk assessment
◦ Updated RA of roller compaction & integrated milling process variables
Risk Assessments ◦ Final blending & lubrication process development
◦ Initial Risk Assessment of final blending & lubrication process variables
◦ Summary of final blending & lubrication process development
Design Space
◦ Updated Risk Assessment of final blending & lubrication process variables
◦ Tablet compression process development
Control Strategy ◦ Initial Risk Assessment of Tablet compression process variables
◦ Tablet compression process development
Continual ◦ Updated Risk Assessment of Tablet compression process variables
Improvement
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5.  Material: raw materials, starting materials, reagents,
solvents, process aids, intermediates, APIs, and packaging
and labelling materials, ICH Q7A
 Attribute: A physical, chemical, biological or
microbiological property or characteristic
 Material Attribute: Can be an excipient CQA, raw material
CQA, starting material CQA, drug substance CQA etc
◦ A Material Attribute can be quantified
◦ Typically fixed
◦ Can sometimes be changed during further processing (e.g. PSD–
milling)
◦ Examples of material attributes: PSD, Impurity profile, porosity,
specific volume, moisture level, sterility
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6.  A process parameter whose variability has an impact
on a critical quality attribute and therefore should be
monitored or controlled to ensure the process
produces the desired quality (Q8R2)
 CPPs have a direct impact on the CQAs
 A process parameter (PP) can be measured and
controlled (adjusted)
◦ Examples of CPPs for small molecule: Temperature,
addition rate, cooling rate, rotation speed
◦ Examples of CPPs for large molecule: Temperature, pH,
Agitation, Dissolved oxygen, Medium constituents, Feed
type and rate
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7. • A Process Parameter is a
Critical Process Parameter
when it has a high impact CPP
High Impact
on a CQA
• CPPs are responsible for
ensuring the right CQA
• CPPs are identified from a PP
list of potential CPPs, (i.e. CQA
PPs) using risk assessment
and experimental work
Low Impact PP
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8.  A material attribute or process parameter is
critical when a realistic change in that
attribute or parameter can significantly
impact the quality of the output material
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9. Material Critical Quality
attributes Critical Process
Attributes
CQA 1 Parameters
MA 1
CQA 2 CPP 1
MA2
CQA 3 CPP 2
Understand & control the variability of
Material attributes and critical process
parameters to meet Product CQA’s.
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10. Two primary principles:
The evaluation of The level of effort,
the risk to quality formality and
should be based on documentation
scientific knowledge of the quality risk
and ultimately link management process
to the protection should be
of the patient commensurate with the
level of risk
ICH Q9
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11. Systematic processes
designed to
coordinate, facilitate and improve
science-based decision making
with respect to risk to quality
ICH Q9
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12. Initiate
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
unacceptable
Risk Management tools
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Team Output / Result of the
approach Quality Risk Management Process
Risk Review
Review Events
ICH Q9
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13.  Risk :The combination of the probability of
occurrence of harm and the severity of that harm
(ISO/IEC Guide 51).
 Risk Acceptance :The decision to accept risk (ISO
Guide 73).
 Risk Analysis :The estimation of the risk
associated with the identified hazards.
 Risk Assessment: 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.
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14.  Risk Communication: The sharing of information
about risk and risk management between the
decision maker and other stakeholders.
 Risk Control: Actions implementing risk
management decisions (ISO Guide 73).
 Risk Evaluation: The comparison of the estimated
risk to given risk criteria using a quantitative or
qualitative scale to determine the significance of
the risk.
 Risk Identification: The systematic use of
information to identify potential sources of harm
(hazards) referring to the risk question or
problem description.
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15.  Risk Management: The systematic application of
quality management policies, procedures, and
practices to the tasks of assessing, controlling,
communicating and reviewing risk.
 Risk Reduction: Actions taken to lessen the
probability of occurrence of harm and the
severity of that harm.
 Risk Review: Review or monitoring of
output/results of the risk management process
considering (if appropriate) new knowledge and
experience about the risk.
 Severity: A measure of the possible consequences
of a hazard.
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16.  Detectability: The ability to discover or
determine the existence, presence, or fact of
a hazard.
 Harm: Damage to health, including the
damage that can occur from loss of product
quality or availability.
 Hazard: The potential source of harm (ISO/IEC
Guide 51).
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17.  Quality attribute criticality is primarily based
upon severity of harm.
 Does not change as a result of risk
management.
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18.  Process parameter criticality is linked to the
parameter’s effect on any critical quality
attribute.
 It is based on the probability of occurrence
and detectability.
 Therefore can change as a result of risk
management.
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19.  Risk includes
◦ severity of harm,
◦ probability of occurrence, and
◦ detectability,
 Therefore the level of risk can change as a
result of risk management.
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20. Use of QRM can improve the decision making
processes from
1. development,
2. technical transfer,
3. manufacturing,
4. post approval changes and
5. throughout the entire product life cycle
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21. Decision makers:
Person(s)
with competence and authority
to make a decision
 Ensuring that
ongoing Quality Risk Management processes operate
Management
responsibility
 Coordinating
quality risk management process
across various functions and departments
 Supporting
the team approach
ICH
Q9
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22. CONSIDERATIONS
Team approach
 Usually, but not always, undertaken by interdisciplinary teams
from areas appropriate to the risk being considered e.g.
◦ Quality unit
◦ Development
◦ Engineering / Statistics
◦ Regulatory affairs
◦ Production operations
◦ Business, Sales and Marketing
◦ Legal
◦ Medical / Clinical
◦ &… Individuals knowledgeable of the QRM processes
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23. When to initiate and plan a QRM Process
 First define the question which should be answered
(e.g. a problem and/or risk question)
◦ including pertinent assumptions identifying
the potential for risk
 Then assemble background information and/ or
data on the potential hazard, harm or human health
impact relevant to the risk
◦ Identify a leader and necessary resources
◦ Specify a timeline, deliverables and
Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
appropriate level of decision making
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
for the QRM process
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
ICH Q9
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24. CONSIDERATIONS
Should risks
be assessed?
1. What might go wrong?
Are there clear rules No or 2. What is the likelihood (probability)
for decision making? justification needed it will go wrong?
e.g. regulations 3. What are the consequences (severity)?
Can you answer
the risk assessment
questions? No
“formal RM“
Yes Yes Agree on a team
“no RM“ “informal RM“ (small project)
Risk assessment not required Initiate Risk assessment Select a Risk Management tool
(No flexibility) (risk identification, analysis & evaluation) (if appropriate e.g. see ICH Q9 Annex I)
Follow procedures Run risk control Carry out the
(e.g. Standard Operating Procedures) (select appropriate measures) quality risk management process
Document results,
decisions and actions Document the steps
Based on K. Connelly, AstraZeneca, 2005
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25. Risk Assessment
3 fundamental
 Risk Identification questions
What might go wrong?
 Risk Analysis
What is the likelihood (probability) it will go
wrong?
 Risk Evaluation
What are the consequences (severity)?
Note: People often use terms Initiate Quality
“Risk analysis”, “Risk assessment” and
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
“Risk management” interchangeably
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
which is incorrect!
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
ICH Q9
www.drugregulations.org 25

26. Risk Assessment: Risk Identification
“What might go wrong?”
 A systematic use of information
to identify hazards
referring to the risk question or problem
◦ historical data
◦ theoretical analysis
Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
◦ informed opinions
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
concerns of stakeholders
Risk Reduction
◦ Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
ICH Q9
www.drugregulations.org 26

27. Risk Assessment: Risk Analysis
“What is the likelihood it will go wrong?”
 The estimation of the risk
associated with the identified hazards.
 A qualitative or quantitative process of
linking the likelihood of occurrence and
severity of harm
Consider detectability if applicable
Initiate Quality
Risk Management Process
 Risk Assessment
Risk Identification
(used in some tools)
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
ICH Q9
www.drugregulations.org 27

28. CONSIDERATIONS
Risk Assessment: Risk Analysis
Often data driven
Keep in mind:
Statistical approach may or may not be used
 Maintain a robust data set!
 Start with the more extensive data set and reduce it
 Trend and use statistics (e.g. extrapolation)
 Comparing between different sets requires
compatible data
 Data must be reliable Initiate Quality
Risk Management Process
Data must be accessible
Risk Assessment
Risk Identification
 Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 28

29. Risk Assessment: Risk Evaluation
“What is the risk?”
 Compare the identified and analysed risk
against given risk criteria
 Consider the strength of evidence
for all three of the fundamental questions
◦ What might go wrong?
◦ What is the likelihood (probability) it will go wrong?
◦ What are the consequences (severity)? Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 29

30. CONSIDERATIONS
Risk Assessment: Risk Evaluation
A picture of the life cycle = Risk Priority Number
Probability x Detectability x Severity
Can you find it?
Data refers to
„ Frequency
of
Impact
“occurences”
driven by
the number
of trials
„ Degree
of belief
past today future time
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31. Risk Control: Decision-making activity
Is the risk above an acceptable level?
What can be done to reduce or eliminate risks?
What is the appropriate balance
between benefits, risks and resources?
Are new risks introduced as Initiate Quality
Risk Management Process
a result of the identified
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
risks being controlled?
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
ICH Q9
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32. CONSIDERATIONS
Risk Control: Residual Risk
 The residual risk consists of e.g.
◦ Hazards that have been assessed and
risks that have been accepted
◦ Hazards which have been identified but
the risks have not been correctly assessed
◦ Hazards that have not yet been identified
◦ Hazards which are not yet linked to the patient risk
 Is the risk reduced to an acceptable level?
◦ Fulfil all legal and internal obligations Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
◦ Consider current scientific knowledge & techniques Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 32

33. Risk Control: Risk Reduction
Mitigation or avoidance of quality risk
Elimination of risks, where appropriate
Focus actions on severity and/or probability
of harm; don’t forget detectability
It might be appropriate to revisit the
risk assessment during the life cycle Initiate Quality
Risk Management Process
for new risks or increased significance
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
of existing risks
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
ICH Q9
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34. Risk Control: Risk Acceptance
Decision to
> Accept the residual risk
> Passively accept non specified residual risks
May require support by (senior) management
> Applies to both industry and competent
authorities
Will always be made on a case-by-case basis
Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 34

35. CONSIDERATIONS
Risk Control: Risk Acceptance
 Discuss the appropriate balance between
benefits, risks, and resources
 Focus on the patients’ interests and
good science/data
 Risk acceptance is not
◦ Inappropriately interpreting
data and information Initiate Quality
Risk Management Process
Risk Assessment
◦ Hiding risks from management /
Risk Identification
Risk Analysis
Risk Evaluation
competent authorities
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 35

36. Risk Control: Risk Acceptance
Who has to accept risk?
 Decision Maker(s)
◦ Person(s) with the competence and authority
to make appropriate and timely
quality risk management decisions
 Stakeholder
◦ Any individual, group or organization
that can …be affected by a risk
◦ Decision makers might also be stakeholders
◦ The primary stakeholders are the patient, healthcare
professional, regulatory authority, and industry
◦ The secondary stakeholders are
patient associations, public opinions, politicians (ICH Q9, definition)
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37. EXAMPLE
A Risk Risk reduction step
Acceptance process finished
1/3
Finish baseline for
risk acceptance decision
risk identification, risk analysis,
risks evaluation, risks reduction
Stakeholders
No
involved as appropiate?
Yes
Revisit All identified Initiate Quality
No
Risk Management Process
risk assessment step risks assessed?
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Yes Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
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38. EXAMPLE
Measures/
actions needed?
Yes
Evaluate measures
on severity, probability, detectability
Check needed resources
e.g. employee, money
A Risk
Acceptance No Measures / Actions
appropriate?
No
Revisit
risk reduction step
process
2/3 Yes
Other hazards
Yes
caused?
Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
No Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Is a risk Risk Acceptance
reducible?
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
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39. EXAMPLE
A Risk Acceptance process 3/3
Is a risk
No
reducible?
Yes
Revisit Accept the Advantage
No Yes
risk assessment step residual risk? outweighs risk?
Yes No
Accept risk Risk not acceptable
Sign off documentation Sign off documentation
Initiate Quality
Ready for communication
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 39

40. Risk Communication
 Bi-directional sharing of information
about risk and risk management
between the decision makers and others
 Communicate at any stage of the QRM process
 Communicate and document
the output/result of the QRM process appropriately
 Communication need not be carried out
for each and every individual risk acceptance
 Use existing channels as specified in Initiate Quality
Risk Management Process
regulations, guidance and SOP’s
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
According to ICH Q9
Risk Review
Review Events
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41. CONSIDERATIONS
Risk Communication
 Exchange or sharing of information, as appropriate
 Sometimes formal sometimes informal
◦ Improve ways of thinking and communicating
 Increase transparency
Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 41

42. CONSIDERATIONS
Communication
facilitates trust
and understanding
Regulators Industry
operation operation
- Reviews - Submissions
- Inspections - Manufacturing
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43. Risk review: Review Events
 Review the output / results of the QRM process
 Take into account new knowledge and experience
 Utilise for planned or unplanned events
 Implement a mechanism to review or monitor
events
 Reconsideration of risk acceptance decisions,
as appropriate Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
ICH Q9
Risk Review
Review Events
www.drugregulations.org 43

44. CONSIDERATIONS
 System Risk (facility & people)
◦ e.g. interfaces, operators risk, environment,
components such as equipment, IT, design elements
 System Risk (organisation)
◦ e.g. Quality systems, controls, measurements,
documentation, regulatory compliance
 Process Risk
◦ e.g. process operations and quality parameters
 Product Risk (safety & efficacy)
◦ e.g. quality attributes:
measured data according to specifications
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45. CONSIDERATIONS
 Supports science-based decisions
 A great variety are listed but other existing or
new ones might also be used
 No single tool is appropriate for all cases
 Specific risks do not always require the same tool
 Using a tool the level of detail of an investigation will
vary according to the risk from case to case
 Different companies, consultancies and competent
authorities may promote use of different tools based
on their culture and experiences
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46.  Supports a scientific and practical approach to
decision-making
 Accomplishing steps of the QRM process
◦ Provides documented, transparent and
reproducible methods
◦ Assessing current knowledge
◦ Assessing probability, severity and
sometimes detectability Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
ICH Q9
Risk Review
Review Events
www.drugregulations.org 46

47.  Adapt the tools for use in specific areas
 Combined use of tools may provide flexibility
 The degree of rigor and formality of QRM
◦ Should be commensurate with the complexity and
/ or criticality of the issue to be addressed and
reflect available knowledge
 Informal ways
◦ empirical methods and / or Initiate Quality
Risk Management Process
internal procedures
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
ICH Q9
Risk Review
Review Events
www.drugregulations.org 47

48.  Might be used in QRM by industry and regulators
 This is not an exhaustive list
 No one tool or set of tools is applicable to every
situation in which a QRM procedure is used
 For each of the tools
◦ Short description & reference
◦ Strength and weaknesses
◦ Purely illustrative examples Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
ICH Q9
Risk Review
Review Events
www.drugregulations.org 48

49. CONSIDERATIONS
 Failure Mode Effects Analysis (FMEA)
◦ Break down large complex processes into manageable steps
 Failure Mode, Effects and Criticality Analysis (FMECA)
◦ FMEA & links severity, probability & detectability to criticality
 Fault Tree Analysis (FTA)
◦ Tree of failure modes combinations with logical operators
 Hazard Analysis and Critical Control Points (HACCP)
◦ Systematic, proactive, and preventive method on criticality
 Hazard Operability Analysis (HAZOP)
◦ Brainstorming technique
 Preliminary Hazard Analysis (PHA)
◦ Possibilities that the risk event happens
 Risk ranking and filtering Initiate Quality
Risk Management Process
◦ Compare and prioritize risks with factors for each risk
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
www.drugregulations.org 49

50.  Supporting statistical tools
◦ Acceptance Control Charts (see ISO 7966)
◦ Control Charts (for example)
 Control Charts with Arithmetic Average and
Warning Limits (see ISO 7873)
 Cumulative Sum Charts; “CuSum” (see ISO 7871)
 Shewhart Control Charts (see ISO 8258)
 Weighted Moving Average
◦ Design of Experiments (DOE)
 Pareto Charts
◦ Process Capability Analysis Initiate Quality
Risk Management Process
Risk Assessment
◦ Histograms
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management tools
unacceptable
Risk Communication
◦ Use others that you are familiar with….
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
ICH Q9
Risk Review
Review Events
www.drugregulations.org 50

51. Opportunities to
impact risk using
Design quality risk
management
Process
Materials Manufacturing
Facilities
Distribution
Patient
G.- Claycamp, FDA, June 2006
www.drugregulations.org 51

52. Opportunities to
impact risk using
Design quality risk Q9
management
Process
Materials Manufacturing
Facilities
Distribution
Patient
Q8 Q10
G.- Claycamp, FDA, June 2006
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53.  Valuable science-based process
 Can identify and rank parameters
◦ Process,
◦ Equipment,
◦ Input materials
 With potential to have an impact on product quality,
based on
◦ Prior knowledge and
◦ Initial experimental data
 Performed early in the development process.
 Repeated as more information becomes available and
greater knowledge is obtained.
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54.  The initial list of potential parameters can be quite extensive
 This can be modified and prioritized by further studies
◦ Combination of design of experiments
◦ Mechanistic models
 The list can be refined further through
◦ Experimentation to determine the significance of individual variables and
◦ Potential interactions
 Once the significant parameters are identified, they can be
further studied through
◦ A combination of design of experiments,
◦ Mathematical models, or
◦ Studies that lead to mechanistic understanding
 Higher level of process understanding
www.drugregulations.org 54

55.  QRM is an iterative process
 Not a one off activity
 Lead to a greater assurance of quality
 Facilitate awareness of risks
 Risk does not go away
 Risk can be predicted, prevented and controlled
 Determine what is important in a process & control
 Should be used over life cycle of the product
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56.  Reduce subjectivity by
◦ Multi disciplinary team
◦ Include all stakeholders
◦ Clear and consistent in wording terms
◦ Use internationally agreed definitions
◦ Transparency on the logic of the methodology and the decision
making
◦ Do not be use to justify failure
◦ Use proactively for increasing the knowledge of product &
processes
www.drugregulations.org 56

57.  “It is neither always appropriate nor always
necessary to use a formal risk management
process (using recognized tools and/or
internal procedures e.g., standard operating
procedures).
 The use of informal risk management
processes (using empirical tools and/or
internal procedures) can also be considered
acceptable.
www.drugregulations.org 57

58.  Appropriate use of quality risk management
can facilitate but does not obviate industry’s
obligation to comply with regulatory
requirements and
 Does not replace appropriate
communications between industry and
regulators.”
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59. www.drugregulations.org 59

60. Component Function Unit Unit
( mg/tablet) ( % W/W)
Acetriptan, USP Active 20 10
Lactose Monohydrate, NF Filler 64-86 32-43
Microcrystalline Cellulose Filler 72-92 36-46
(MCC), NF
Croscarmellose Sodium Disintegrant 2-10 1-5
(CCS), NF
Magnesium Stearate, NF* Lubricant 2-6 1-3
Talc, NF Glidant/Lubricant 1-10 0.5-5
Total tablet weight 200 100
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61. Appearance White to off-white, crystalline powder
Particle Plate-like crystals
morphology
Particle size PSD of drug substance Lot #2 was measured using Malvern Mastersizer. The
distribution results were as follows: d10 – 7.2 µm; d50 – 12 µm; d90 – 20 µm. This is
representative of the drug substance PSD selected for the final drug product
formulation.
Solid state • To date, three different crystalline forms (Form I, II and III) have been
form: identified and reported in the literature.
• The solubility and the melting point are different for each of the three
polymorphs.
• Polymorphic Form III is the most stable form and has the highest melting
point.
• The DMF holder provides acetriptan polymorphic Form III consistently
• Stress testing confirmed that no polymorphic conversion was observed
and Form III is stable under the stress conditions of high temperatures,
high humidity, UV light and mechanical stress.
• Since it is the most stable form, no phase transformation during the
manufacturing process is expected
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62. Aqueous 0.1 N HCL 0.015 mg/ml
solubility as a
pH 4.5 buffer 0.015 mg/ml
function of
pH:
pH 6.8 buffer 0.015 mg/ml
Hyroscopicity Acetriptan Form III is non-hygroscopic and requires no special protection
from humidity during handling, shipping or storage
Density (Bulk, • Bulk density: 0.27 g/cc
Tapped, and • Tapped density: 0.39 g/cc
True) and • True density: 0.55 g/cc
Flowability: • The flow function coefficient (ffc) was 2.95 and the Hausner ratio was
1.44 which both indicate poor flow properties.
Chemical • pKa: Acetriptan is a weak base with a pKa of 9.2.
properties • Overall, acetriptan is susceptible to dry heat, UV light and oxidative
degradation.
Biological • Partition coefficient: Log P 3.55 (25 °C, pH 6.8)
properties • Caco-2 permeability: 34 × 10-6 cm/s. Therefore, acetriptan is highly
permeable.
• BCS Class II compound (low solubility and high permeability)
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63.  The excipients used in acetriptan tablets were
selected based on
◦ The excipients used in the RLD,
◦ Excipient compatibility studies and
◦ Prior use in approved ANDA products that utilize
roller compaction (RC).
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64.  Excipient compatibility is an important part of
understanding the role of inactive ingredients in product
quality.
 The selection of excipients for the compatibility study
should be based on the
◦ Mechanistic understanding of the drug substance and its
impurities,
◦ Excipients and their impurities,
◦ Degradation pathway and
◦ Potential processing conditions for the drug product manufacture.
 A scientifically sound approach should be used in
constructing the compatibility studies.
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65.  To confirm its physical stability, the final drug
product was sampled during lab scale studies
to evaluate whether processing conditions
affected the polymorphic form of the drug
substance.
 The XRPD data showed that the
characteristics 2è peaks of Form III of the
drug substance are retained in the final drug
product.
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66. Low Broadly acceptable risk. No further investigation is needed.
Medium Risk is acceptable. Further investigation may be needed in order to
reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the
risk.
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67. Drug Substance Attributes
Drug Solid PSD Hygrosc Solubil Mois Residual Process Chemi Flow
Product State opicity ity ture Solvent Impurit cal prop
Cont
CQA Form ies stabili
ent
ty
Assay Low Med Low Low Low Low Low High Med
CU Low High Low Low Low Low Low Low High
Dissolution High High Low High Low Low Low Low Low
Degradation Med Low Low Low Low Low Low High Low
products
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68. Drug Substance Drug Product Justification
Attributes CQA’s
Assay Drug substance solid state form does not affect tablet
assay. The risk is low.
Content Drug substance solid state form does not affect tablet
Uniformity CU. The risk is low.
Dissolution Different polymorphic forms of the drug substance
have different solubility and can impact tablet
dissolution. The risk is high.
Solid state form Acetriptan polymorphic Form III is the most stable form
and the DMF holder consistently provides this form. In
addition, pre-formulation studies demonstrated that
Form III does not undergo any polymorphic conversion
under the various stress conditions tested. Thus,
further evaluation of polymorphic form on drug product
attributes was not conducted.
Degradation Drug substance with different polymorphic forms may
Products have different chemical stability and may impact the
degradation products of the tablet. The risk is medium
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69. Drug Substance Drug Product Justification
Attributes CQA’s
Assay A small particle size and a wide PSD may adversely
impact blend flowability. In extreme cases, poor
flowability may cause an assay failure. The risk is
medium.
Content Particle size distribution has a direct impact on drug
Uniformity substance flowability and ultimately on CU. Due to the
Particle Size
fact that the drug substance is milled, the risk is high.
Distribution
Dissolution The drug substance is a BCS class II compound;
therefore, PSD can affect dissolution. The risk is high.
Degradation The effect of particle size reduction on drug substance
Products stability has been evaluated by the DMF holder. The
milled drug substance exhibited similar stability as
unmilled drug substance. The risk is low.
Assay
Content
uniformity
Hygroscopicity Acetriptan is not hygroscopic. The risk is low.
Dissolution
Degradation
Products
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70. Drug Substance Drug Product Justification
Attributes CQA’s
Assay
Content Solubility does not affect tablet assay, CU and
Uniformity degradation products. Thus, the risk is low.
Degradation
Products
Solubility
Dissolution Acetriptan exhibited low (~0.015 mg/mL) and constant
solubility across the physiological pH range. Drug
substance solubility strongly impacts dissolution. The
risk is high. Due to pharmaceutical equivalence
requirements, the free base of the drug substance must
be used in the generic product. The formulation and
manufacturing process will be designed to mitigate this
risk.
Moisture Assay Moisture is controlled in the drug substance
Content specification (NMT 0.3%). Thus, it is unlikely to impact
Content
assay, CU and dissolution. The risk is low.
Uniformity
Dissolution
Degradation The drug substance is not sensitive to moisture based
Products on forced degradation studies. The risk is low.
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71. Drug Substance Drug Product Justification
Attributes CQA’s
Assay Residual solvents are controlled in the drug substance
specification and comply with USP <467>. At ppm
Content level, residual solvents are unlikely to impact assay, CU
Residual Uniformity and dissolution. The risk is low.
Solvents Dissolution
Degradation There are no known incompatibilities between the
Products residual solvents and acetriptan or commonly used
tablet excipients. As a result, the risk is low.
Assay Total impurities are controlled in the drug substance
specification (NMT 1.0%). Impurity limits comply with
Content
Process ICH Q3A recommendations. Within this range, process
Uniformity
Impurities impurities are unlikely to impact assay, CU and
Dissolution dissolution. The risk is low.
Degradation During the excipient compatibility study, no
Products incompatibility between process impurities and
commonly used tablet excipients was observed. The
risk is low.
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72. Drug Substance Drug Product Justification
Attributes CQA’s
Assay The drug substance is susceptible to dry heat, UV light
and oxidative degradation; therefore, acetriptan
chemical stability may affect drug product assay and
degradation products. The risk is high.
Content Tablet CU is mainly impacted by powder flowability and
Chemical
Uniformity blend uniformity. Tablet CU is unrelated to drug
Stability
substance chemical stability. The risk is low
Dissolution Tablet dissolution is mainly impacted by drug
substance solubility and particle size distribution.
Tablet dissolution is unrelated to drug substance
chemical stability. The risk is low.
Degradation The risk is high. See justification for assay.
Products
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73. Drug Substance Drug Product Justification
Attributes CQA’s
Assay Acetriptan has poor flow properties. In extreme cases,
poor flow may impact assay. The risk is medium.
Content Acetriptan has poor flow properties which may lead to
Flow
Uniformity poor tablet CU. The risk is high.
Properties
Dissolution The flowability of the drug substance is not related to
its degradation pathway or solubility. Therefore, the
Degradation risk is low.
Products
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74.  A risk assessment of the drug substance attributes
was performed to evaluate the impact that each
attribute could have on the drug product CQAs.
 The relative risk that each attribute presents was
ranked as high, medium or low.
 The high risk attributes warrant further investigation
 The low risk attributes require no further
investigation.
 The medium risk is considered acceptable based on
current knowledge. Further investigation for medium
risk may be needed in order to reduce the risk.
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75.  In this initial risk assessment for formulation
development, the detailed manufacturing
process has not been established.
 Thus, risks are rated assuming that for each
formulation attribute that changed, an
optimized manufacturing process would be
established.
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76. Formulation Variables
Drug product DS PSD MCC/ CCS Level Talc Level Mag Stearate
CQA Lactose Level
ratios
Assay Medium Medium Low Low Low
Content High High Low Low Low
Uniformity
Dissolution High Medium High Low High
Degradation Low Low Low Low Medium
Products
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77. Formulation Drug Product CQA justification
Variables
Assay A small particle size and a wide PSD may adversely
impact blend flowability. In extreme cases, poor
flowability may cause an assay failure. The risk is
medium.
Content Uniformity Particle size distribution has a direct impact on
drug substance flowability and ultimately on CU.
Due to the fact that the drug substance is milled,
Drug substance
the risk is high.
PSD
Dissolution The drug substance is a BCS class II compound;
therefore, PSD can affect dissolution. The risk is
high.
Degradation Products The effect of particle size reduction on drug
substance stability has been evaluated by the DMF
holder. The milled drug substance exhibited
similar stability as unmilled drug substance. The
risk is low.
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78. Formulation Drug Product CQA justification
Variables
Assay MCC/Lactose ratio can impact the flow properties
of the blend. This, in turn, can impact tablet CU.
Content Uniformity The risk is high. Occasionally, poor CU can also
adversely impact assay. The risk is medium.
Dissolution MCC/lactose ratio can impact dissolution via
MCC/ Lactose
tablet hardness. However, hardness can be
ratio
controlled during compression. The risk is
medium
Degradation Products Since both MCC and lactose are compatible with
the drug substance and will not impact drug
product degradation, the risk is low.
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79. Formulation Drug Product CQA justification
Variables
Assay Since the level of CCS used is low and its impact
on flow is minimal, it is unlikely to impact assay
Content Uniformity and CU. The risk is low.
CCS Level
Dissolution CCS level can impact the disintegration time and,
ultimately, dissolution. Since achieving rapid
disintegration is important for a drug product
containing a BCS class II compound, the risk is
high.
Degradation Products CCS is compatible with the drug substance and
will not impact drug product degradation. Thus,
the risk is low.
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80. Formulation Drug Product CQA justification
Variables
Assay Generally, talc enhances blend flowability. A low
level of talc is not likely to impact assay and CU.
Content Uniformity The risk is low.
Dissolution Compared to magnesium stearate, talc has less
Talc level
impact on disintegration and dissolution. The low
level of talc used in the formulation is not
expected to impact dissolution. The risk is low
Degradation Products Talc is compatible with the drug substance and
will not impact degradation products. The risk is
low.
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81. Formulation Drug Product CQA justification
Variables
Assay Since the level of magnesium stearate used is low
and its impact on flow is minimal, it is unlikely to
Content Uniformity impact assay and CU. The risk is low.
Dissolution Over-lubrication due to excessive lubricant may
retard dissolution. The risk is high.
Magnesium
stearate level Degradation Products Though it formed an adduct with the drug
substance in the binary mixture compatibility
study (magnesium stearate/DS ratio 1:1), the
interaction compatibility study showed that the
adduct formation is negligible when magnesium
stearate is used at a level representative of the
finished drug product composition (magnesium
stearate/DS ratio 1:10). Thus, the risk is medium.
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82.  For DS with plate-like morphology and particle size in the
micrometer range,
◦ a larger drug substance particle size improves manufacturability
because it has better flow.
 However, for a BCS II compound like acetriptan,
◦ larger drug substance particle size may significantly decrease
dissolution and negatively impact the in vivo performance.
 An in silico simulation was conducted to estimate the
impact of the drug substance mean particle size, d50, on
◦ Cmax ratio and
◦ AUC ratio between the test product and the RLD.
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