Quality by Design : Critical Material attributes ,Process parameters and its linkage to Critical Quality Attributes.

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.

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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


 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


 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


 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


 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


• 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


 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


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.


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

Systematic processes
designed to
coordinate, facilitate and improve
science-based decision making
with respect to risk to quality

ICH Q9

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

 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.


 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.


 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.


 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).


 Quality attribute criticality is primarily based
upon severity of harm.
 Does not change as a result of risk
management.


 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.


 Risk includes
◦ severity of harm,
◦ probability of occurrence, and
◦ detectability,
 Therefore the level of risk can change as a
result of risk management.


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


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

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


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

unacceptable

Risk Communication
Risk Control

for the QRM process
Risk Reduction

Risk Acceptance

Output / Result of the Quality

Risk Review
Review Events

ICH Q9

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

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 Assessment
Risk Identification

Risk Analysis

“Risk management” interchangeably
Risk Evaluation

unacceptable

Risk Communication
Risk Control

which is incorrect!
Risk Reduction

Risk Acceptance


Risk Review
Review Events

ICH Q9

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 Assessment
Risk Identification

◦ informed opinions
Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control

concerns of stakeholders
Risk Reduction

◦ Risk Acceptance


Risk Review
Review Events

ICH Q9

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 Assessment
Risk Identification

(used in some tools)
Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events

ICH Q9

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

Data must be accessible
Risk Assessment
Risk Identification

 Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


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

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

a result of the identified
Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

risks being controlled?

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events

ICH Q9

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 Assessment
Risk Identification

◦ Consider current scientific knowledge & techniques Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


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

for new risks or increased significance
Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation

of existing risks

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events

ICH Q9

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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


CONSIDERATIONS


 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 Assessment

◦ Hiding risks from management /
Risk Identification

Risk Analysis

Risk Evaluation

competent authorities

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


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)


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 assessment step risks assessed?
Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Yes Risk Acceptance


Risk Review
Review Events


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 Assessment
Risk Identification

No Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Is a risk Risk Acceptance

reducible?

Risk Review
Review Events


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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


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

regulations, guidance and SOP’s
Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


According to ICH Q9
Risk Review
Review Events


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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


CONSIDERATIONS

Communication
facilitates trust
and understanding

Regulators Industry
operation operation
- Reviews - Submissions
- Inspections - Manufacturing


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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


ICH Q9
Risk Review
Review Events


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


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


 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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


ICH Q9
Risk Review
Review Events


 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

internal procedures
Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


ICH Q9
Risk Review
Review Events


 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 Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


ICH Q9
Risk Review
Review Events


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

◦ Compare and prioritize risks with factors for each risk
Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
Risk Control
Risk Reduction

Risk Acceptance


Risk Review
Review Events


 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 Assessment

◦ Histograms
Risk Identification

Risk Analysis

Risk Evaluation

unacceptable

Risk Communication
◦ Use others that you are familiar with….
Risk Control
Risk Reduction

Risk Acceptance


ICH Q9
Risk Review
Review Events


Opportunities to
impact risk using
Design quality risk
management
Process

Materials Manufacturing

Facilities
Distribution

Patient

G.- Claycamp, FDA, June 2006

Opportunities to
impact risk using
Design quality risk Q9
management
Process

Materials Manufacturing

Facilities
Distribution

Patient

Q8 Q10
G.- Claycamp, FDA, June 2006

 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.


 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


 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


 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


 “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.


 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.”


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


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


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)


 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).


 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.


 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.


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.


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


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


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

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.

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.


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


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


 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.


 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.


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


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.


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.


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.


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.


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.


 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.


 The predefined selection criterion was
◦ a mean particle size that yielded both a Cmax ratio
and an AUC ratio between 0.9 and 1.11.
 The data indicate that a d50 of 30 µm or less
met the predefined criterion and
 Exhibited a limited effect on the
pharmacokinetic profile when compared to
the RLD.


 Acetriptan is cohesive and displays poor flowability as evidenced by
the
◦ compressibility index,
◦ Hausner ratio,
◦ flow function coefficient and
◦ specific energy.
 Poor material flow may produce tablets with high weight and content
variability due to
◦ an uneven distribution of the drug substance in the blend,
◦ uneven bulk density and,
◦ eventually, uneven filling of die cavities on the tablet press.
 Poor acetriptan flow rules out the use of a high drug load
formulation and
 Supports the use of a similar drug load to the RLD which is 10%.


 Initially, direct compression of the blend was
performed.
 The blend uniformity (BU) percent relative
standard deviation (% RSD) was higher than 6%.
 The tablet content uniformity % RSD was even
higher.
 Therefore, direct compression was considered an
unacceptable process for this formulation


 Wet granulation was excluded due to
potential thermal degradation of the drug
substance during drying based on the forced
degradation study results.
 The use of wet granulation with an organic
solvent was also excluded because of the
desire to avoid the environmental
considerations involved.


 For dry granulation by roller compaction, the powder
particles of drug substance and fillers are aggregated
under high pressure to form a ribbon and
 Then broken down to produce granules by milling before
compression (tableting).
 The risk of drug particle segregation can be minimized.
 By controlling the size distribution and flow properties of
the granules, the risk of poor tablet content uniformity can
be reduced.
 Thus, dry granulation by roller compaction was selected as
the process for further drug product development efforts.


 A univariate method (i.e., one-factor-at-a time (OFAT)) is
acceptable in cases where there is no potential interaction
between factors.
 Since this is often not known, a multivariate statistical design
(i.e., Design of Experiments (DOE)) is often used.
 A sequential strategy is commonly employed when planning a
DOE.
 Initially, a screening DOE can be used to narrow down the
extensive list of factors identified during initial risk
assessment to a few vital factors.
 Then, a characterization DOE can be used to understand the
main effects and potential interaction(s) between these vital
factors.
 When center points are included in a 2-level factorial DOE, it
is possible to test if the curvature effect is significant.


 Data analysis is done by separating the curvature term
from the regression model in an adjusted model.
 If the curvature is significant, the design should be
augmented to a response surface DOE to estimate the
quadratic terms.
 On the other hand, if the curvature is not significant,
the adjusted model and unadjusted model will be
similar.
 Finally, a verification DOE can be employed to study the
robustness of the system by varying the identified
critical factors over ranges that are expected to be
encountered during routine manufacturing.


 Randomization, blocking and replication are the three
basic principles of statistical experimental design.
 By properly randomizing the experiment, the effects of
uncontrollable factors that may be present can be
“averaged out”.
 Blocking is the arrangement of experimental units into
groups (blocks) that are similar to one another.
 Blocking reduces known but irrelevant sources of variation
between groups and thus allows greater precision in the
estimation of the source of variation under study.
 Replication allows the estimation of the pure experimental
error for determining whether observed differences in the
data are really statistically different


 ANOVA results should accompany all DOE data analysis,
especially if conclusions concerning the significance of the model
terms are discussed.
 For all DOE data analysis, the commonly used alpha of 0.05 is
chosen to differentiate between significant and non significant
factors.
 It is important that any experimental design has sufficient power
to ensure that the conclusions drawn are meaningful.
 Power can be estimated by calculating the signal to noise ratio.
 If the power is lower than the desired level, some remedies can
be employed to increase the power.
 For example, by adding more runs, increasing the signal or
decreasing the system noise.
 ICH Points to Consider document for guidance on the level of
DOE documentation recommended for regulatory submissions.


 Formulation development focused on evaluation of
the high risk formulation variables as identified in the
initial risk assessment shown earlier.
 The development was conducted in two stages.
 The first formulation study evaluated the impact of
the drug substance particle size distribution, the
MCC/Lactose ratio and the disintegrant level on the
drug product CQAs.
 The second formulation study was conducted to
understand the impact of extragranular magnesium
stearate and talc level in the formulation on product
quality and manufacturability.
 Formulation development studies were conducted at
laboratory scale (1.0 kg, 5,000 units).

 Goal of Formulation Development Study #1
 Select the MCC/Lactose ratio and
 Disintegrant level and
 To understand if there was any interaction of
these variables with drug substance particle size
distribution.
 This study also sought to establish the
robustness of the proposed formulation.
 A 2³ full factorial Design of Experiments (DOE)
with three center points was used to study the
impact of these three formulation factors on the
response variables.


 Formulation development study # 2
 Based on the results of Formulation Development
Study #1, the intragranular excipients levels were
tentatively finalized.
 However, magnesium stearate was linked to adduct
formation with acetriptan during the binary excipient
compatibility study .
 The goal of this study was to find
◦ the minimum level of extragranular magnesium stearate
needed for tabletting and
◦ to evaluate if an increase in talc could compensate for a
reduction in magnesium stearate.


 The level of extragranular magnesium stearate
used in Formulation Development Study #1 was
1.0%.
 The minimum level recommended in the
Handbook of Pharmaceuticals is 0.25%.
 Thus, the extragranular magnesium stearate level
was studied between 0.3% and 0.9%.
 The talc level was adjusted accordingly to
maintain a total of 3.5% extragranular glidant and
lubricant using a two component mixture DOE.


 The formulation composition was finalized based on
Formulation Development Studies #1 and #2.
 The MCC/Lactose ratio and the disintegrant level
were finalized in the first study.
 In the second study, it was concluded that a
minimum level of magnesium stearate is required in
the formulation to prevent picking and sticking.
 The level of magnesium stearate in the formulation
was reduced by using it in combination with talc.


 Acceptable ranges for the high risk
formulation variables have been established
and should be included in the control
strategy.
 Based on the results of the formulation
development studies, the risk assessment of
the formulation variables is updated


Formulation Variables
Drug product DS PSD MCC/ CCS Level Mag Stearate
CQA Lactose Level
ratios
Assay Low Low Low Low
Content Low Low Low Low
Uniformity
Dissolution Low Low Low Low

Degradation Low Low Low Low
Products


Variables
Assay All tablets showed acceptable assay. The risk is
reduced from medium to low.
Content Uniformity The poor flow of the drug substance is mitigated
by using a roller compaction process, low drug
Drug substance
load and fillers that have good flowability. The risk
PSD
is reduced from high to low.
Dissolution The risk is reduced from high to low by controlling
drug substance PSD and optimizing intragranular
superdisintegrant.


Variables
The risk is reduced from high to low by optimizing
Content Uniformity the MCC/Lactose ratio and using a roller
MCC/ Lactose compaction process
ratio
Dissolution The risk is reduced from medium to low because
the selected filler ratio yielded tablets with
acceptable friability within a wide range of tablet
hardness (5.0-12.0 kP). Tablets with hardness
within this range demonstrated acceptable
dissolution (> 85% in 30 min).
CCS Level Dissolution All tablets showed rapid disintegration. The risk is
reduced from high to low.
Magnesium Dissolution The risk is reduced from high to low by optimizing
Stearate extragranular magnesium stearate
Level
Degradation Products The risk is reduced from medium to low by only
using magnesium stearate extragranularly and by
using talc to minimize the level of magnesium
stearate needed. The stability data further
demonstrated that the product was stable


 There are various approaches to process
development used in the generic pharmaceutical
industry.
 This is one of many possible examples.
 All QbD approaches to process development should
identify the
◦ Critical material attributes (CMAs) and
◦ Critical process parameters (CPPs) for each process step.
 A firm may choose to do this through
◦ Reference to documented prior knowledge or
◦ Through empirical experiments on a range of process
scales building toward the exhibit scale and proposed
commercial scale.


 The process development of
◦ Pre-roller compaction blending and
◦ Lubrication is an example of experimentally determining
CPPs when there is variation in an input material
attribute.
 QbD emphasizes building understanding to avert
failures during scale-up.
 The multivariate experiments described here are
a step toward defining acceptable ranges for
CPPs and CMAs.


 List each process step in the manufacturing
process in the sequence of occurrence.
 List material attributes and process parameters
that can potentially impact intermediate and
finished product quality attributes.
 The material attributes of the input materials and
the process parameters used at the very first
process step determine the quality attributes of
the output material (intermediate) produced at
this step.


 Material attributes of the intermediate from this
step and process parameters of the subsequent
process step in the manufacturing process will
determine quality attributes of the next
intermediate and, eventually, those of the
finished drug product.
 This cycle repeats until the final process step
where finished drug product is manufactured and
the product quality attributes are evaluated.
 This map is used to guide the risk assessments
performed during process development.


Identify drug
product CQAs

For each process step,
identify intermediate
CQAs that impact
drug product CQA

Identify material
attributes and process
parameters that may
impact the intermediate
CQAs of the process step


Process parameters Material attributes
• Blender type
• Acetriptan PSD
• Order of addition
• Blender fill level • Acetriptan cohesiveness
• Rotation speed (if variable) • Acetriptan flowability
• Number of revolutions • Excipient PSD
• intensifier bar (on / off) • Excipient flowability
• Holding time • Excipient bulk density
• Discharge method
• Drum-to-hopper transfer • Excipient moisture content
• Environment (temperature and RH) • Excipient lot-to-lot variability

Pre-Roller
Compaction
Blending and
Lubrication
Manufacturing
CQA of output
process step
• Blend uniformity
• Blend assay
• Blend bulk density
• Blend flowability
• Blend compressibility /
compactability
• Appearance
• Dimensions


• Blend holding time prior to RC • Blend assay
• Roller compactor type
• Feed screw speed • Blend uniformity
• Deaeration • Blend bulk density
• Roller surface design • Blend flowability
• Roller pressure • Blend compressibility /
• Roller speed
• Roller gap compactability
• Environment (temperature and RH) • Compression

Roller
Compaction

Manufacturing
CQA of output
process step

• Ribbon thickness
• Ribbon density



• Mill type
• Blade configuration / type /
orientation
• Oscillation degree / speed • Ribbon thickness
• Screen type • Ribbon density
• Screen size
• Number of recycles
• Environment (temperature and RH)

Milling

Manufacturing
CQA of output
process step

• Granule uniformity
• Granule size distribution
• Granule flowability
• Granule bulk density
• Assay of granule sieve cut



• Blender type • Granule uniformity
• Order of addition • Granule size distribution
• Blender fill level • Granule flowability
• Rotation speed (if variable)
• Number of revolutions • Granule bulk density
• Intensifier bar (on / off)Holding time • Assay of granule sieve cut
• Discharge method • Magnesium stearate
• Drum-to-hopper transfer
• specific surface area
• Environment (temperature and RH

Final blending &
lubrication

Manufacturing
CQA of output
process step
• Blend assay
compactability


Process parameters
Material attributes
• Press type and number of stations
• Tooling design • Blend assay
• Feed frame paddle speed • Blend uniformity
• Feeder fill depth • Granule size distribution
• Pre-compression force
• Main compression force
• Press speed (dwell time) • Blend flowability
• Hopper design • Blend compressibility /
• Hopper fill level compactability
• Drop height of finished tablets
• Run time

Compression
(Tableting)

Manufacturing
CQA of output
process step • Appearance
• Dimensions (length, width,
thickness)
• Weight (individual and composite)
• Hardness
• Friability
• Content uniformity
• Assay
• Disintegration
www.drugregulations.org • Dissolution 110

 A risk assessment of the overall drug product
manufacturing process is performed to
identify the high risk steps that may affect
the CQAs of the final drug product.
 Subsequently, the intermediate CQAs of the
output material from each process step that
impact the final drug product CQAs are
identified.


 For each process step, a risk assessment is
conducted to identify potentially high risk
process variables which could impact the
identified intermediate CQAs and, ultimately, the
drug product CQAs.
 These variables are then further investigated in
order to better understand the manufacturing
process and to develop a control strategy to
reduce the risk of a failed batch


 Previous experience with these process steps
is used to determine the degree of risk
associated with each process step and
 Its potential to impact the CQAs of the
finished drug product.


Drug Pre –RC Roller Milling Final Compression
blending & Compaction Blending &
product lubrication Lubrication
CQA’s
Assay Medium Low Medium Low Medium

Content High High High Low High
Uniformity
Dissolution Medium High Medium High High

Degradation Low Low Low Low Low
Products


Process Step Drug Product Justification
CQA
Assay Suboptimal pre-roller compaction blending and
lubrication may cause variable flowability of the blend.
The risk is medium.
Pre-Roller Content The PSD and cohesiveness of the drug substance
Compaction uniformity adversely impact its flowability which, in turn, affects
Blending and CU. The risk is high.
Lubrication
Dissolution Blending process variables may impact the distribution
of CCS in the blend which could impact disintegration of
the granules and, ultimately, dissolution of the tablets.
The risk is medium.
Degradation Blending process variables are unrelated to the
products degradation products of Generic Acetriptan Tablets, 20
mg. The risk is low.


CQA
Assay Roller compaction is performed to improve flow,
minimize segregation and enhance CU. The risk is low.
Content Variability in ribbon density during processing can
uniformity potentially impact the PSD of the milled granules, thus
impacting flowability and, ultimately, CU. The risk is
Roller
Compaction high.
Dissolution Density of the ribbon can impact density and plasticity
of the granules, thus impacting compressibility of the
granules, hardness of the tablet and, ultimately,
Degradation Based on experience gained from other approved ANDAs
products using roller compaction, the roller temperature does not
exceed 45 °C and the dwell time during roller
compaction is very short. Thus, roller compaction
should not impact degradation products. The risk is low.


CQA
Assay The milling step controls the final granule size
distribution. A suboptimal distribution may affect flow,
causing variable tablet weight and assay during
compression. The risk is medium.
Content If milling generates excessive fines, both bulk density
Milling
uniformity and flowability of the blend may be impacted. This, in
turn, may impact CU. The risk is high.
Dissolution A large amount of fines may impact tablet hardness and
dissolution. The risk is medium.
Degradation Although the screen may heat up during the milling
products process, the dwell time is brief. Milling is unlikely to
impact degradation products. The risk is low.


CQA
Assay The granule uniformity which affects assay and CU is
controlled by earlier steps (pre-RC blending and
lubrication as well as roller compaction and integrated
Content milling). This step is to blend the granules with small
uniformity quantities of extragranular glidant and lubricant and is
Final unlikely to impact assay and CU. The risk is low.
Blending &
Dissolution Over-lubrication due to an excessive number of
Lubrication
revolutions may impact disintegration and, ultimately,
dissolution of the tablets. The risk is high.

Degradation Acetriptan is only susceptible to degradation at a high
products temperature (. 105 ‹C). Blending is unlikely to impact
degradation products; therefore, the risk is low.


CQA
Assay In extreme cases, tablet weight variability can lead to
out of-specification assay results. The risk is medium.
Content Compression process variables such as feed frame
uniformity paddle speed and press speed can cause tablet weight
variability which could cause tablets to fall out-of-
specification for CU. The risk is high.
Compression
Dissolution Tablet hardness may be impacted if compression force
is not adjusted to accommodate batch-to-batch
variability in ribbon density. Over-lubrication of the
blend by the feed frame paddle may also slow
Degradation Acetriptan is only susceptible to degradation at a high
products temperature (. 105 ‹C). Compression is unlikely to
impact degradation products; therefore, the risk is low.


 Further risk assessment is performed on each
high risk process step to identify which process
variables may potentially impact the intermediate
CQAs.
 Evaluation of all possible process variables that
could potentially impact the quality attributes of
the output material of any given process step is
not feasible;
 Therefore, some of the variables were set
constant based on current understanding


 The initial risk assessment of the overall
manufacturing process presented earlier
identified the risk of the pre-roller compaction
blending and lubrication step to impact tablet
content uniformity as high.
 Subsequently, blend uniformity was identified as
an intermediate CQA of the powder blend from
the pre-roller compaction blending and
lubrication step.
 Process variables that could potentially impact
blend uniformity were identified and their
associated risk is evaluated

• Blender type
• Acetriptan PSD
• Order of addition
• Blender fill level • Acetriptan cohesiveness
• Rotation speed (if variable) • Acetriptan flowability
• Number of revolutions • Excipient PSD
• intensifier bar (on / off) • Excipient flowability
• Holding time • Excipient bulk density
• Discharge method
• Drum-to-hopper transfer • Excipient moisture content
• Environment (temperature and RH) • Excipient lot-to-lot variability

Pre-Roller
Compaction
Blending and
Lubrication
Manufacturing
CQA of output
process step
• Blend assay
compactability
• Appearance
• Dimensions

 Following table presents the initial risk
assessment for the pre-roller compaction
blending and lubrication step


Process Step: Pre-Roller Compaction Blending and Lubrication
Output Material CQA: Blend Uniformity
Input material attributes
Variables Risk Justification & initial strategy
assessment
Acetriptan PSD High The pilot BE study indicated that a d90 . 30 ƒÊm is
needed for bioequivalence. Based on several lots of
acetriptan analyzed during preformulation, the drug
substance meeting this d90 criterion has poor flowability
(ffc < 3.50) which may impact BU. The risk is high.
Acetriptan Medium The specific energy of acetriptan Lot #1-4 indicated that
cohesiveness acetriptan is moderately to highly cohesive which will
make achieving BU more challenging. The risk is medium.
Acetriptan Medium The ffc value of acetriptan Lot #1-4 suggested poor flow
flowability which could impact BU. The risk is medium.
Excipient Low Filler comprises the majority (~ 80%) of the formulation.
flowability MCC grade B02 and lactose monohydrate grade A01 are
used in a 1:1 ratio because this ratio demonstrated good
flowability (ffc . 7). Glidant and lubricant are used in
small quantities and are unlikely to impact BU. The risk is
low.




Input materials attributes

assessment
Excipient PSD Low Experience with previously approved ANDA 123456 and ANDA
456123 demonstrated that when the selected grades of MCC and
lactose monohydrate are used in a 1:1 ratio, the flowability is
good. This suggests that the PSD of the fillers will not impact BU.
Because the quantities of glidant and lubricant used are small,
their PSD are unlikely to impact BU. The risk is low.

Excipient bulk density Low The 1:1 ratio of MCC to lactose monohydrate has a comparable
bulk density to acetriptan. Glidant and lubricant are used in small
quantities and their bulk densities are unlikely to impact BU. The
risk is low.
Excipient moisture Low The moisture content of the excipients is controlled per
content compendial/in-house specifications. Based on previous experience
with approved ANDA 123456, excipient moisture content did not
exhibit any significant impact on BU. The risk is low
Excipient lot-to-lot Large variations in the PSD of the excipients could impact BU;
variability however, previous experience with the chosen excipient grades has
shown that the lot-to-lot variability within grade is minimal. The
risk is low.




Blending Variables

assessment
Blender Type Low Different blender types have different mixing dynamics.
V-blender is selected based on equipment availability.
The risk is low.
However, if the blender type is changed during scale-up
or commercialization, the risk should be re-evaluated.

Order of addition Low Order of addition may impact the ease of evenly
dispersing ingredients charged in lower quantities.
Materials are added in the following order: lactose
monohydrate, CCS, acetriptan, talc, and MCC. The risk is
low.
Rotation speed Medium Rotation speed is often fixed by equipment constraint.
( rpm) Different size blenders have different rotation speeds.
The rotation speed for the 16 qt blender is fixed at 20
rpm. The risk is medium.




Blending Variables

assessment
Number of High Under- or over-blending will result in suboptimal BU. The
revolutions risk is high

Intensifier bar Low The intensifier bar is often not needed to improve BU. In
(on/off) addition, the intensifier bar may interfere with BU
measurements if an NIR probe is used. The intensifier bar
is fixed in the off position. The risk is low.
Blender fill level High The blender fill level depends on equipment capacity,
blend bulk density (0.43-0.48 g/cc) and batch size. Since
the blender fill level may affect mixing dynamics, the risk
is high.




Blending Variables

assessment
Holding time Medium Even if adequate BU is achieved, the drug substance may
segregate prior to granulation during holding, discharge
Blender discharge Medium or transfer. The risk is medium.
Drum-to-hopper Medium
transfer
Environment Low If not controlled, fluctuations in the facility temperature
(temperature and and RH could impact BU. Routine environment
RH) temperature and RH set point in the cGMP manufacturing
facility is fixed at 25 ºC ± 5% and 40%-60% RH,
respectively, and will be monitored during
manufacturing. The risk is low.


 A two-factor, three-level full factorial DOE,
was used to investigate the impact of
acetriptan PSD (d90) and number of
revolutions (Nrev) on blend uniformity.
 Blender fill level is also likely to impact blend
uniformity based on the initial risk
assessment.
 Blender fill level was evaluated subsequent to
the DOE.


 In order to ensure a homogeneous blend for
any input acetriptan drug substance d90
within the range of 10-30 µm, an in-line NIR
spectrophotometric method was developed
and validated.
 This technology allows a real-time response
and can be used at the laboratory, pilot and
commercial scale.

13

 Following table presents the risk reduction
for the pre-roller compaction blending and
lubrication process as a result of the
development studies.
 Only the process variables that were initially
identified as high risk to the blend uniformity
are shown.

13



assessment
Acetriptan PSD Low In order for the blending process to be robust enough to
accommodate different acetriptan PSD, an in-line NIR
Number of Low method was developed for blending endpoint
revolutions determination. Blender fill levels from 35-75% had no
Blender fill level Low impact on blending endpoint. The risk was reduced from
high to low.


 Based on the initial risk assessment of the
overall manufacturing process:
 The risk of the roller compaction step to
impact tablet content uniformity and
dissolution was identified as high and
 The risk of the milling step to impact tablet
content uniformity was identified as high.

13


• Blend holding time prior to RC • Blend assay
• Roller compactor type
• Feed screw speed • Blend uniformity
• Deaeration • Blend bulk density
• Roller surface design • Blend flowability
• Roller pressure • Blend compressibility /
• Roller speed
• Roller gap compactability
• Environment (temperature and RH) • Compression

Roller
Compaction

Manufacturing
CQA of output
process step

• Ribbon thickness
• Ribbon density



• Mill type
• Blade configuration / type /
orientation
• Oscillation degree / speed • Ribbon thickness
• Screen type • Ribbon density
• Screen size
• Number of recycles

Milling

Manufacturing
CQA of output
process step

• Granule uniformity
• Granule size distribution
• Granule flowability
• Granule bulk density
• Assay of granule sieve cut


 Intermediate CQAs of the output material
from the roller compaction and integrated
milling step identified were:
◦ Ribbon density,
◦ Granule size distribution,
◦ Granule uniformity and
◦ Granule flowability


 Ribbon density is an intermediate CQA because it has
a direct impact on granule particle size distribution,
granule bulk and tapped density, granule flowability,
and, ultimately, tablet hardness and dissolution.
 Granule size distribution, granule uniformity and
granule flowability are intermediate CQAs because
they are intimately related to tablet weight variability
and content uniformity.
 The input material attributes and process parameters
for this step that could potentially impact the four
intermediate CQAs of the output material were
identified and their associated risk was evaluated.


Process Step: Roller compaction and integrated milling process
Output Material CQA: Ribbon Density, Granule Size Distribution, Granule Uniformity and
Granule Flowability
Variables Output Material Risk Justification & initial strategy
CQAs assessment
Input Material Attributes
Ribbon Density Low The formulation has been optimized
Granule Size Low (Section P.2.2). Consistent blend bulk
Distribution density between 0.43-0.48 g/cc was
Blend bulk observed. This low variability of blend
Granule Uniformity Low
density bulk density has a negligible impact on
the four CQAs. The risk is low.
Granule Flowability Low

Ribbon Density Low The assay of the final blend was
Granule Size Low consistently within 95.0-105.0% w/w
Distribution (ranging from 98.7-101.2%). The risk is
Blend assay low.



Granule Flowability
CQAs assessment
Ribbon Density Low In-line NIR monitoring is used to
Granule Size Low achieve adequate blend uniformity (RSD
Blend Distribution < 5%). The risk is low.
uniformity


Ribbon Density Low Compressibility and compactability
Granule Size Low were optimized during formulation
Blend Distribution development. The tablet demonstrated
compressibility/ good friability (< 0.2% weight loss) at
compactability low hardness (5.0 kP) and achieved the
desired dissolution at high hardness
(12.0 kP). The risk is low.


Granule Flowability
CQAs assessment
Ribbon Density Low The blend demonstrated acceptable
Granule Size Low flowability (ffc > 6). The risk is low.
Distribution
Blend
flowability



Granule Flowability
CQAs assessment
Roller Compaction and Milling Process Variables
Ribbon Density Low Due to the cohesiveness of acetriptan, no
demixing was observed with extended
Granule Size Low
blending up to 500 revolutions. The risk of the
Pre-RC blend Distribution
pre-RC blend to segregate during holding is
holding time low.

Ribbon Density Low Due to operating principle differences between
roller compactors, the ribbon attributes and
Granule Size Low
PSD of milled granules can vary significantly.
Roller Distribution
Based on availability, Alexanderwerk WP 120 is
compactor type selected and fixed for development work. The
risk is low.
However, if the roller compactor type is
Granule Flowability Low changed during scale-up or
commercialization, the risk should be re-
evaluated.


Granule Flowability
CQAs assessment
Ribbon Density Low Deaeration is used to enhance the flow of the
blend feeding into the roller compactor. It will
Granule Size Low
always be used and is considered a fixed
Deaeration Distribution
factor. The risk is low

Ribbon Density Low Feed screw speed is a floating parameter
dependent on roller pressure and roller gap.
Granule Size Medium
The risk is medium.
Feed screw Distribution
speed
Granule Uniformity Medium



Granule Flowability
CQAs assessment
Roller surface Ribbon Density Low Roller surface design may impact the power
design feeding from the slip region into the nip
Granule Size Low
region. For this product, a roller with a
Distribution
knurled surface was selected to enhance
Granule Uniformity Low material feeding by providing more friction
than a smooth surface roller and is considered
Granule Flowability Low a fixed factor. The risk is low

Roller pressure Ribbon Density High Ribbon density is directly related to roller
pressure and, in turn, may impact the PSD,
Granule Size High
flowability, uniformity, compressibility and
Distribution
compactability of the milled granules. The risk
Granule Uniformity High is high.
Granule Flowability High


Granule Flowability
CQAs assessment
Ribbon Density Medium The roller speed determines the throughput of
the process and is adjusted according to the
Granule Size Medium
selected feed screw speed to avoid material
Distribution
build-up. In addition, roller speed is inversely
Roller speed related to the dwell time for particle
Granule Uniformity Medium
compaction which may impact the ribbon
Granule Flowability Medium density. Based on previous experience with
approved ANDA 123456 using roller
compaction, roller speed is fixed to 8 rpm.
Adjustment may be needed. The risk is
medium.
Ribbon Density High According to the Johanson model¹¹, ribbon
density is inversely related to the roller gap
Granule Size High
and, in turn, it may impact PSD, flowability,
Roller gap Distribution
uniformity, compressibility and compactability
Granule Uniformity High of the milled granules. The risk is high.


Granule Flowability
CQAs assessment
Ribbon Density NA The type of mill governs the type of attrition
and impacts the PSD of the milled granules.
Granule Size Low
An integrated mill was selected and is
Mill type Distribution
considered a fixed factor. The risk is low.
Granule Uniformity Low However, if the mill type is changed during
scale-up or commercialization, the risk should
Granule Flowability Low be re-evaluated.

Ribbon Density NA The mill screen type may impact the granule
size distribution, granule uniformity and
Granule Size Low
granule flowability obtained from the milling
Mill screen type Distribution
step. A mesh screen is selected based on
Granule Uniformity Low availability. The risk is low.
If the mill screen type is changed, risk will
need to be reassessed

Johanson, J. R. A rolling theory for granular solids. ASME, Journal of Applied
Mechanics Series E, 1965, 32(4): 842–848


Granule Flowability
CQAs assessment
Ribbon Density NA The ribbon is formed during the roller
compaction step
Granule Size High The mill speed may impact the PSD of the
Mill speed Distribution milled granules which can potentially impact
granule uniformity and flowability. The risk is
Granule Uniformity High
high.

compaction step.
Blade Granule Size Low The milling blade can apply variable shear to
configuration Distribution the material based on design. Low shear can
result in a coarser but more uniform PSD,
whereas high shear can result in a non-
Granule Flowability Low uniform, multi-modal PSD. The resulting PSD
affects flowability and uniformity. The risk is
low because the blade is fixed by equipment
design.


Granule Flowability
CQAs assessment
compaction step.
Mill screen Granule Size High The mill screen orifice size directly
orifice size Distribution impacts PSD which can potentially
Granule Uniformity High impact granule uniformity and
Granule Flowability High flowability. The risk is high.

Ribbon Density Medium If excessive powder leakage occurs
Granule Size Medium during roller compaction or excessive
Number of Distribution fines are generated during milling,
recycles Granule Uniformity Medium recycles of the fine particles may be
considered. However, the number of
Granule Flowability Medium
recycles may impact the homogeneity
of the granule quality attributes. The
goal is to not recycle material. The risk
is medium.


Granule Flowability
CQAs assessment
Ribbon Density NA If not controlled, fluctuations in the
Granule Size High facility temperature and RH could
Environment Distribution impact the CQAs. Routine environment
(temperature Granule Uniformity High temperature and RH set point in the
and RH) cGMP manufacturing facility is fixed at
Granule Flowability High 25 ºC ± 5% and 40%-60% RH,
respectively, and will be monitored
during manufacturing. The risk is low.


 The main objective of the study was to evaluate the
effect of the roller compaction and integrated milling
process parameters on the quality attributes of the
◦ ribbon,
◦ milled granules and
◦ finished drug product using DOE.
 The process parameters investigated were
◦ roller pressure,
◦ roller gap,
◦ milling speed and
◦ mill screen orifice size.


 A preliminary feasibility experiment was conducted.
 The effect of roller pressure on the quantity of by-pass material (un-compacted
material) was studied.
 The study showed that within the roller pressure range of 20-80 bar, the quantity
of by-pass material was less than 5% and the potency matched that of the blend
fed into the roller compactor.
 Therefore, the roller pressure range of 20-80 bar was suitable for further studies.
 During the feasibility study, product temperature was monitored by a non-invasive
measuring device.
 No significant increase (> 5°C) was observed.
 The ranges for roller gap, mill speed and mill screen orifice size were selected
based on previous experience with approved ANDA 123456 and ANDA 456123.
 For this study, a 24-1 fractional factorial DOE was used and three center points
were included to evaluate if any curvature effects exist

www.drugregulations.org
150

 Roller pressure had a significant impact on ribbon
density, mean granule size (d50), granule flowability,
tablet hardness and tablet content uniformity.
 Roller gap exhibited a significant impact on ribbon
density, granule flowability, tablet hardness and
tablet content uniformity.
 Mill screen orifice size had a significant impact on
mean granule size (d50), granule flowability and
tablet content uniformity.
 Mill speed did not show a significant impact on any of
the responses studied. In addition, no curvature
effects were observed for any of the responses.

15

 Based on the results of the DOE study,
◦ roller pressure,
◦ roller gap and
◦ mill screen orifice size
 were identified as the CPPs while mill speed
was determined to be not critical.
 Results of process development done by DOE
were used to identify an appropriate range
for each CPP that would ensure that the
targets for all quality attributes are met
concurrently.

15

Granule Flowability
Variables Output Material Risk Justification for the risks
CQAs assessment
Roller pressure Ribbon Density Low An acceptable range for roller pressure was
identified during the DOE. Within the range
Granule Size Low
(20-77 bar), all CQAs met the predefined
Distribution
acceptance criteria by using an appropriate
Granule Uniformity Low roller gap. Thus, the risk is reduced from high

Granule Flowability Low to low.

Roller gap Ribbon Density Low An acceptable range for roller gap was
identified during the DOE. Within the range
Granule Size Low
(1.2-2.4 mm), all CQAs met the predefined
Distribution
acceptance criteria by using an appropriate
Granule Uniformity Low roller pressure. Thus, the risk is reduced from
high to low.


Granule Flowability
Variables Output Material Risk Justification for the risks
CQAs assessment
Mill screen Ribbon Density Low The mill screen orifice size (1.0 mm) was
orifice size selected because it allows a wider acceptable
Granule Size Low
operating range for both roller pressure and
Distribution
roller gap compared to the other studied sizes
Granule Uniformity Low (0.6 mm and 1.4 mm). When using the
selected mill screen orifice size (1.0 mm), all
Granule Flowability Low CQAs met the predefined acceptance criteria.
Thus, the risk is reduced from high to low.


 The initial risk assessment of the overall
manufacturing process identified the risk of the
final blending and lubrication step to impact tablet
dissolution as high.
 The lubrication process variables that could
potentially impact tablet dissolution were identified
and their associated risk was evaluated.



• Blender type • Granule uniformity
• Order of addition • Granule size distribution
• Blender fill level • Granule flowability
• Rotation speed (if variable)
• Number of revolutions • Granule bulk density
• Intensifier bar (on / off)Holding time • Assay of granule sieve cut
• Discharge method • Magnesium stearate
• Drum-to-hopper transfer
• specific surface area
• Environment (temperature and RH

Final blending &
lubrication

Manufacturing
CQA of output
process step
• Blend assay
compactability


 Following table presents the initial risk assessment
of the final blending and lubrication step.


Process Step: Final Blending and Lubrication
Output Material CQA: Tablet Dissolution
assessment
Granule uniformity Low The granules produced during roller compaction
development demonstrated uniformity with % RSD < 3%.
Therefore, granule uniformity should have little impact
on tablet dissolution. The risk is low.
Assay of granule Low Sieve cuts studied during roller compaction development
sieve cut ranged in assay from 98.2% to 101.2%. This low
variability will have little impact on tablet dissolution. The
risk is low.
Granule flowability Low For a ribbon relative density of 0.68 to 0.81, the
flowability was good (ffc > 6) and should not impact
tablet dissolution. The risk is low.
Granule size Low The rapid disintegration of the tablets is achieved by
distribution using 5% CCS in the formulation. The variability in
granule size distribution observed during roller
compaction development showed no impact on
dissolution. Therefore, the risk is low.


assessment
Granule bulk Low The granule bulk density is consistently between 0.62-
density 0.69 g/cc. The low variability has little impact on tablet
dissolution. The risk is low.
Magnesium High The lubricating effect of magnesium stearate improves as
Stearate specific specific surface area increases. The risk of over-
surface area lubrication leading to retarded disintegration and
dissolution is high.


Lubrication process variables
assessment
Blender type Low Due to differences in the operating principle, different
types of blenders may impact blending efficiency. Based
on availability, V-blender is selected. The risk is low.
However, if the blender type is changed during scale-up
or commercialization, the risk should be re-evaluated.
Order of addition Low Granules and talc are blended together first, followed by
magnesium stearate. Magnesium stearate is traditionally
charged last to lubricate the other particles. Order of
addition is fixed and has a minimal impact on
Rotation speed Medium Rotation speed is often fixed by equipment constraint.
(rpm) Different size blenders have different rotation speeds.
The rotation speed for the 16 qt blender is fixed at 20
rpm. The risk to impact tablet dissolution is medium.
Number of High Over-lubricating may result in retarded disintegration
revolutions and dissolution. For a BCS class II compound like
acetriptan, the risk is high.


assessment
Intensifier bar Low If the intensifier bar is on, then it may cause granule
(on/off) attrition. To avoid generating fines, the intensifier bar is
fixed in the off position during the final blending and
lubrication. The risk is low
Blender fill level Medium Blender fill level may affect mixing dynamics. It is fixed
for these development studies but could change upon
scale-up. The risk is medium.
Holding time Low These three process variables are not related to
Blender discharge Low
Drum-to-hopper Low
transfer
Environment Low If not controlled, fluctuations in the facility temperature
(temperature and and RH could impact the CQAs. Routine environment
RH) temperature and RH set point in the cGMP manufacturing
facility is fixed at 25 ºC ± 5% and 40%-60% RH,
respectively, and will be monitored during
manufacturing. The risk is low.

 A study was performed to investigate the
effect of magnesium stearate specific surface
area and number of revolutions during
lubrication on tablet hardness, disintegration,
and dissolution.
 Within the ranges studied, magnesium
stearate specific surface area (5.8-10.4
m2/g) and number of revolutions (60-100)
did not have a significant impact on the drug
product quality attributes studied

16

assessment
Magnesium Low Within the range 5.8-10.4 m2/g, magnesium stearate
stearate specific specific surface area does not adversely impact tablet
surface area dissolution. The risk is reduced from high to low and this
material attribute will be controlled in the control
strategy
Number of Low A proven acceptable range for number of revolutions
revolutions (60-100) was established for this scale based on elegant
tablet appearance and rapid dissolution. The risk is
reduced from high to low and number of revolutions is
controlled in the control strategy


 Based on the initial risk assessment of the overall
manufacturing process shown earlier, the risk of the
compression step to impact
◦ content uniformity and
◦ dissolution of the tablets was identified as high.
 Process variables that could potentially impact these two drug
product CQAs were identified and their associated risk was
evaluated.
 The results of the initial risk assessment of the compression
process variables are summarized in following tables.


Process parameters
Material attributes
• Press type and number of stations
• Tooling design • Blend assay
• Feed frame paddle speed • Blend uniformity
• Feeder fill depth • Granule size distribution
• Pre-compression force
• Main compression force
• Press speed (dwell time) • Blend flowability
• Hopper design • Blend compressibility /
• Hopper fill level compactability
• Drop height of finished tablets
• Run time

Compression
(Tableting)

Manufacturing
CQA of output
process step • Appearance
• Dimensions (length, width,
thickness)
• Weight (individual and composite)
• Hardness
• Friability
• Content uniformity
• Assay
• Disintegration
www.drugregulations.org • Dissolution 165

Process Step: Tablet Compression
Output Material CQA: Content Uniformity, Dissolution
Variables Drug Risk Justification & initial strategy
Product assessment
CQA’s
Blend Content Low The blend assay varied between 98.3% and 101.7%
Assay Uniformity during the lubrication process development. This
low variability is unlikely to impact CU and
Dissolution Low
Blend Content Low The lubricated blend demonstrated acceptable BU
uniformity Uniformity (% RSD < 3%) during the lubrication process
development. Therefore, the risk is low
Dissolution Low

Granule Content Low The granule size distribution is controlled by
size Uniformity milling after the roller compaction process step.
distribution The granules demonstrated good flowability (ffc >
6) and should not impact CU. The risk is low.
Dissolution Low The formulation contains 5% CCS and the
variability in granule size distribution observed
during roller compaction development showed no
impact on dissolution. The risk is low.


Variables Drug Product Risk Justification & initial strategy
CQA’s assessment

Blend Content Low Blend flowability could impact powder flow from the
flowability Uniformity hopper to the feed frame and, ultimately, to the die cavity.
However, adequate flow was demonstrated during roller
Dissolution Low
compaction development. Small amounts of extragranular
glidant and lubricant will not impact blend flowability. The
risk is low.
Blend Content Low CU is unaffected by the blend compressibility and
compressibi Uniformity compactability. The risk is low.
lity and
Dissolution Low Suboptimal blend compressibility and compactability can
compactabil
affect tablet hardness. The compressibility and
ity
compactability of the blend are directly related to the
ribbon relative density achieved during roller compaction.
Ribbon relative density may vary from batch-to-batch and
may cause tablet hardness variation if the compression
force is not adjusted. This may, in turn, impact dissolution.
The risk is high
Blend bulk Content Low The blend bulk density is consistently between 0.62-0.69
density Uniformity g/cc. The low variability has little impact on CU and
Dissolution Low

Compression Process Variables
Variables Drug Product Risk Justification & initial strategy
CQA’s assessment

Press type Content Low The press type was selected based on equipment
and number Uniformity availability and 3 stations will be used during
of stations development. The same press model but all 51 stations
Dissolution Low
used will be used for both exhibit and commercial scale. Thus,
the risk is low.
Tooling Content Low Tooling design was selected to compress a tablet with a
design Uniformity similar size and shape as the RLD. No picking was
observed during the final blending and lubrication studies.
Dissolution Low
The risk is low

Feed frame Content High A greater than optimal feed frame paddle speed may cause
paddle Uniformity over-lubrication. A lower than optimal feed frame paddle
speed speed may cause inconsistent die filling. The risk is high.
Dissolution High


Product assessment
CQA’s
Feeder fill Content Low The feeder fill depth is set to 80% full and is monitored
depth Uniformity and controlled by an automatic feedback control loop on
the tablet press. The risk is low.
Dissolution Low

Pre- Content Low CU is dominated by BU and flowability and is unrelated to
compression Uniformity pre-compression force. The risk is low
force
Dissolution Medium A greater than optimal pre-compression force may cause
lamination. A lower than optimal pre-compression force
may trap air in the tablets, leading to capping. Either
scenario could impact dissolution. The pre-compression
force is set to 1.0 kN based on experience with similar
formulations compressed on the same equipment.
Adjustment may be needed. The risk is medium.
Main Content Low CU is dominated by BU and flowability and is unrelated to
compression Uniformity main compression force. The risk is low.
force
Dissolution High Suboptimal compression force may affect tablet hardness
and friability and, ultimately, dissolution. The risk is high.


Product assessment
CQA’s
Press speed Content High A faster than optimal press speed may cause inconsistent
(dwell time) Uniformity die filling and weight variability which may then impact CU
and dissolution. For efficiency, the press speed will be set
Dissolution High
as fast as practically possible without adversely impacting
tablet quality. The risk is high.

Hopper Content Low Since acetriptan is roller compacted with excipients, the
design and Uniformity risk of drug substance segregation is minimized. Tablet
vibration press vibrations and the hopper angle design are unlikely
Dissolution Low
to have an impact on CU and dissolution. The risk is low.

Hopper fill Content Low The blend has acceptable flowability and the hopper fill
level Uniformity level is maintained at 50%. Maintaining the hopper fill level
makes it improbable that this parameter will impact CU
Dissolution Low and dissolution. The risk is low.


Product assessment
CQA’s
Drop height Content Medium Finished tablets may chip, crack, cleave or break if the
of finished Uniformity drop height is great. The risk is medium.
tablets Dissolution Medium

Compression Content Medium It is possible during long compression run times that the
run time Uniformity CU may drift. The risk is medium.
Dissolution Low It is unlikely for compression run time to cause a drift that
leads to a dissolution failure. The risk is low.
Environment Content Low If not controlled, fluctuations in the facility temperature
(temperature Uniformity and RH could impact the CQAs. Routine environment
and RH) temperature and RH set point in the cGMP manufacturing
Dissolution Low facility is fixed at 25 ºC ± 5% and 40%-60% RH,
respectively, and will be monitored during manufacturing.
The risk is low.


 A screening study was conducted to investigate the impact of
the feeder frame paddle speed (8-20 rpm) on tablet quality.
 Since the final blend flows well, changes in feeder frame
paddle speed within the specified range had no impact on
tablet weight variability or content uniformity.
 Tablet dissolution was also unaffected by changes in feeder
speed, suggesting that over-lubrication due to the additional
mixing is not a concern.
 This process variable was eliminated from further study..


 Compression force and press speed (which is related to dwell
time) can affect numerous quality attributes including
◦ hardness,
◦ disintegration,
◦ dissolution,
◦ assay,
◦ content uniformity,
◦ friability,
◦ weight variability and
◦ appearance.


 The density of the ribbon following roller compaction may also
impact the compressibility and compactability of the granules which
would then impact tablet hardness and dissolution.
 Therefore, a 2³ full factorial DOE with three center points was
performed to understand the effects of these parameters on tablet
quality attributes.
 Pre-compression force is important to reduce entrapped air that can
impact the tablet integrity.
 However, based on previous experience with similar formulations
compressed with similar tooling (ANDA 123456), the pre-
compression force was fixed to 1 kN for this DOE.


 Summary of Tablet Compression Process
Development
 Within the range studied (8-20 rpm), feeder frame
paddle speed did not impact the tablet dissolution.
 A press speed in the range of 20-60 rpm did not
show any significant impact on the responses
investigated.
 An acceptable range for compression force was
identified.
 Force adjustments can be made to accommodate the
acceptable variation in ribbon relative density (0.68-
0.81) between batches.
17

Product assessment
CQA’s
Blend Dissolution Low Compression force can be adjusted to accommodate the
compressibility acceptable ribbon relative density (0.68-0.81) in order to
and achieve the target tablet hardness. The risk is reduced
compactability from high to low.
Feeder frame Content Low Feeder frame paddle speed in the range of 8-20 rpm had
paddle speed Uniformity no impact on CU or dissolution. The same tablet press
model will be used for pilot scale and commercial scale
Dissolution Low
manufacture. If necessary, slight adjustments in the feeder
frame paddle speed may be made when all stations are
utilized. The risk is reduced from high to low.
Main Dissolution Low Tablet hardness increases with compression force. Within
compression the compression force range studied, the resulting tablet
force hardness did not adversely affect dissolution and > 90%
dissolution at 30 min was achieved. The risk is reduced
from high to low.
Press speed Content Low A press speed of 20-60 rpm had no impact on CU or
(dwell time) Uniformity dissolution. Thus, the risk is reduced from high to low.
Dissolution Low


Role of Quality Risk Management
in
Development & Manufacturing
Product Process Process Scale-up
Manufacturing
Development Development & Tech Transfer

Product/prior Process Process
Knowledge Understanding History

Risk Risk Risk Risk
Assessment Assessment Control Review

Excipient &
Process Product quality Continual
drug
substance design space control strategy improvement
design space

Quality Risk Management

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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Quality by Design : Critical Material attributes ,Process parameters and its linkage to Critical Quality Attributes.

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