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Using Risk Assessment Tools to Lead Development into the Right Direction A Case Study
Petra Brožič, PhD, Senior Scientist, Pharmaceutical
Development, Lek Pharmaceuticals d.d., a Sandoz company
Arlington, Virginia (Washington DC) USA, 27 January 2015
The views expressed herein are not necessarily the views of Novartis, Sandoz International, GmbH or any of its affiliated companies.
Focusing the development in the right
direction from the very beginning
Transparent technological transfers,
efficient scale ups*, mitigate risks to
launch
Maintain right focus throughout lifecycle of
product, enhance root cause analysis
Sound Science and
Quality Risk
Management
Product & Process
Understanding &
Control
Key message – QbD mindset needs to be maintained throughout the lifecycle of the product
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
* Lab scale → pilot scale → commercial scale
2
Risk Assessment Link material attributes and process
parameters to CQAs and define CMAs, CPPs
Quality Target Product Profile (QTPP)
Critical Quality Attributes (CQAs)
Developing a product Setting the right focus in order to obtain thorough product & process understanding
Set the
right focus
Risk
• Identification
• Analysis
• Evaluation
3 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
Risk reduction/
communication Control Strategy
Development Production
Risk reduction
Product and Process
Understanding
Process Capabilities
Continous Improvement
Focusing the development in the right
direction from the early beginning
Transparent technological transfers,
efficient scale ups, mitigate risks to
launch
Maintain right focus throughout lifecycle of
product, enhance root cause analysis
Sound Science and
Quality Risk
Management
Product & Process
Understanding &
Control
Key message – QbD mindset needs to be maintained throughout the lifecycle of the product
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
* Lab scale → pilot scale → commercial scale
4
Risk Assessment Link material attributes and process
parameters to CQAs and define CMAs, CPPs
Quality Target Product Profile (QTPP)
Critical Quality Attributes (CQAs)
Developing a product Setting the right focus in order to obtain thorough product & process understanding
Set the
right focus
5 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
Control Strategy
Development Production
Product and Process
Understanding
Process Capabilities
Continous Improvement
Formulation and process information Case study
- extended release (ER) matrix tablet for oral
administration – film coated tablet
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
ER tablet core
Film coating
6
Quality Target Product Profile (QTPP) Case study
QTPP ELEMENT TARGET JUSTIFICATION
Dosage Form Tablet Pharmaceutical equivalence requirement:
same dosage form.
Dosage Design Film coated prolonged release tablet Needed to match label claims
Route Of Administration Oral Pharmaceutical equivalence requirement:
same route of administration.
Dosage Strength 10 mg
Pharmaceutical equivalence requirement:
same strength.
Pharmacokinetics Fasting and fed study 90% confidence
interval of the AUCi, AUC0-t and Cmax to
fall within bioequivalence limits.
Bioequivalnece requirement.
Stability Shelf life 24 months Market requirements. Equivalent to RLD.
Container Closure system Suitable container closure system to
achieve the target shelf-life and to ensure
tablet integrity during shipping.
Similar to RLD. Protection from moisture
(drug substance unstable in presence of
water)
Administration/concurrence with labeling Taken without regard to food. Information is provided in the RLD labeling
Alternative methods of administration None. None are listed in the RLD labeling.
Drug Product Quality Attributes Identity Pharmaceutical equivalence requirement:
Meeting the same compendial or other
applicable (quality) standards (i.e., identity,
assay, purity, and quality).
Assay
Content Uniformity
Drug Release
Physical attributes
Microbiology
Residual Solvents
Impurities
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 7
Critical quality attribute(s) – CQA(s) Case study
Drug Product
quality attributes
Target Is this
critical?
Justification
Assay 100% w/w of label claim
Yes Variability can influence safety and efficacy.
Process and formulation variables can influence the assay.
(low dose preparation, unstable substance)
Impurities Any unknown impurity:
ICH identification
threshold
Total impurities:
RLD analysis
Yes Amount of impurities can influence safety and efficacy.
Process and formulation variables can influence the
amount of impurities.
(Active is unstable in humid conditions, needs to be
produced and stored under lowered
humidity/stabilized/protected. Influence of formulation,
process and packaging on impurities should be evaluated.)
Drug Release
Comparable to RLD Yes Drug release is important for bioavailability. Safety and
efficacy are influenced. Process and formulation variables
can influence drug release (controlled release product).
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
*Note: This represents an example of some of the CQAs, not all are listed on this slide
8
Risk Assessment Link material attributes and process
parameters to CQAs and define CMAs, CPPs
Quality Target Product Profile (QTPP)
Critical Quality Attributes (CQAs)
Developing a product Setting the right focus in order to obtain thorough product & process understanding
Risk
• Identification
• Analysis
• Evaluation
9 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
Control Strategy
Development Production
Product and Process
Understanding
Process Capabilities
Continous Improvement
Quality Risk Assessment At the begining of the development
Purpose
Preliminary identification of risks from formulation, process, excipients, API
Rough outline of risks to be tackled during development
General and prior knowledge available
Substance info available
Factors
CQAs
API Excipients Process Packaging
Assay High High High Low
Impurities High High High High
Drug Release Med High High Low
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 10
Quality Risk Assessment
Factors
CQAs
API Excipients Process Packaging
Assay High High High Low
Impurities High High High High
Drug Release Med High High Low
Low
Broadly acceptable risk.
Follow-up action not mandatory.
Med
Acceptable risk.
Follow-up action may be needed to reduce the risk.
High
Unacceptable risk.
Follow-up action mandatory to reduce the risk.
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
At the begining of the development
11
Focusing the development in the right
direction from the early beginning
Transparent technological transfers,
efficient scale ups, mitigate risks to
launch
Maintain right focus throughout lifecycle of
product, enhance root cause analysis
Sound Science and
Quality Risk
Management
Product & Process
Understanding &
Control
Key message – QbD mindset needs to be maintained throughout the lifecycle of the product
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
* Lab scale → pilot scale → commercial scale
12
Process Design
Development TechTransfer to TechOps
Process validation
Commercial production
Site transfers / major
changes
Commercial production
Process Qualification
Continued process Verification Process Design
Definition of CQA, CPP,
CMA, Control strategy
Challenges • Process design must lead to a robust and reproducible
manufacturing process (benefit from prior knowledge)
• Transition from lab scale over pilot scale to full scale
• Verification of product/process criticalities during scale up
• Understand opportunities and limitations of full scale equipment
• Successful technology transfer by early interaction between
Development and TechOps
13 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
QRM QRM QRM
Quality Risk Assessment Initial
Purpose Knowledge
To link CQAs with possible CPPs and CMAs
Set the focus for further experimentation
General and prior knowledge available
Substance info available
Experimentation results
Factors
CQAs
API Excipients core Excipients
coating
Process
step1
Process
step2
Process
step3
Process
step4
Assay High Low Low High Low Low Low
Impurities High High High Med High High High
Drug release Med Med High Low Low Med Low
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 14
Define scale/equipment dependent/independent parameters
{CQAs}
= function (CMAs, CPPs)
Experimentation/DoE Building product and process understanding
( e.g. determine dependent vs. independent parameters – coating layer mass, pan diameter, number of spray nozzles, inlet air flow/temeperature,
relative humidity at product, pan fill fraction, etc...)
Chose experimental design (DoE)
Conduct randomized experimental trials
Analyze data
1
2
4
3
Select relevant output variables
( e.g.: water content, impurities)
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 15
CQA - Impurities
Process parameters Active/excipients attributes
Enviromental parameters
relative humidity
Packaging material attributes
material permeability
{CQAs} = function (CMAs, CPPs) Building product and process understanding in a transparent way
inlet air humidity,
inlet air temperature,
dispersion spray rate
active substance crystalline form
excipients water content
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 16
Factors
CQAs
API
Assay High
Factors
CQAs
API
Assay Low
No CMA
Factors
CQAs
API
Impurities High
Factors
CQAs
API
Impurities Med
Risk response changes from High to Low
Risk response changes from High to Med (ALARP) CMA1
Factors
CQAs
Process step3
Impurities High
Risk response changes from High to Med (ALARP)
Factors
CQAs
Process step3
Impurities Med
CPP1-3
Factors
CQAs
Process step3
Drug release Med
Risk response changes from Med to Low
Factors
CQAs
Process step3
Drug release Low
No CPP
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
{CQAs} = function (CMAs, CPPs) Mitigation of risks
17
Quality Risk Assessment Final
Purpose Knowledge
Clear relationship CMAs, CPPs, CQAs
Basis for defining the Control Strategy
Basis for further RA
General and prior knowledge available
Substance info available
Experimentation results – development and scale – up activities
Factors
CQAs
API Excipients
core
Excipients
coating
Process
step1
Process
step2
Process
step3
Process
step4
Assay Low Low Low Low Low Low Low
Impurities Med Low Low Low Med Low Med
Drug release Low Low Low Low Low Low Low
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 18
Risk Assessment Link material attributes and process
parameters to CQAs and define CMAs, CPPs
Quality Target Product Profile (QTPP)
Critical Quality Attributes (CQAs)
Developing a product Setting the right focus in order to obtain thorough product & process understanding
19 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
Risk reduction/
communication Control Strategy
Development Production
Product and Process
Understanding
Process Capabilities
Continous Improvement
Control Strategy Final
Purpose
Focus on critical aspects of the formulation and process
To set controls for all identified CMAs, CPPs, CQAs
To set In-process testing and controls
Basis for further RA
Basis for PPQ protocol and CPV plan
Product and process understanding gathered through development and scale-up activities
Factor
Attributes or
Parameters
Affected
CQA
Ranged Studied
(Indicate Scale)
Proposed Range
for Commercial
Scale Purpose of Control Control Strategy
Active Crystalline
form Impurities
crystalline form I
amorphous API form I
To ensure impurities inside acceptance criteria
throughout the shelf life.
API
specification
Process step 3
inlet air
humidity,
inlet air
temperature,
dispersion
spray rate
Impurities
inlet air humidity
1–5 g/kg,
inlet air
temperature: 35–
90ºC,
dispersion spray
rate: 60–
110 g/min
inlet air humidity
2–4 g/kg,
inlet air
temperature: 55–
90ºC,
dispersion spray
rate: 50–
100 g/min,
To ensure impurities inside acceptance criteria
throughout the shelf life.
Fixed in BR
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 *Note: This represents only a portion of the
control strategy
20
Focusing the development in the right
direction from the early beginning
Transparent technological transfers,
efficient scale ups, mitigate risks to
launch
Maintain right focus throughout lifecycle of
product, enhance root cause analysis
Sound Science and
Quality Risk
Management
Product & Process
Understanding &
Control
Key message – QbD mindset needs to be maintained throughout the lifecycle of the product
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
* Lab scale → pilot scale → commercial scale
21
Process Qualification (PPQ)
Development TechTransfer to TechOps
PPQ Commercial production
Site transfers / major
changes
Commercial production
Definition of CQA, CPP,
CMA, Control strategy PPQ report
Update risk assessment
PPQ protocol
PPQ execution
Process Design Process
Qualification Continued process Verification
QRM QRM QRM QRM
QRM
22 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
Continued process verification
Development TechTransfer to TechOps
PPQ Commercial production
Site transfers / major
changes
Commercial production
Definition of CQA, CPP,
CMA, Control strategy PPQ report
Update risk assessment,
redefine CPPs/CMAs
PPQ protocol
PPQ execution
Process Design Process
Qualification Continued process Verification
Continuous Process
Verification (CPV) plan
CPV execution
CPV report/ PQR/APR
Update risk assessment
QRM QRM QRM QRM
QRM
23 | IFPAC Annual meeting | Petra Brozic | 27 January 2015
Each challenge leads to a benefit
Improved product and process understanding
• Consistent product quality, reduced failures and recalls
• Increased robustness of processes leverages process transfers
• Potential quality issues are identified and avoided from early stage development on to commercial production
• Helps to evaluate impact of process deviations
Improved knowledge management
• Subjectivity reduced, science and data driven
• Knowledge transfer at interfaces leveraged, e.g. at Tech Transfer due to aligned wording / definitions
• Improved communication with the regulators
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 24
Conclusion
The systematic, science and risk-based QbD approach
helps setting the right focus at the right time, leading to
improved product and process understanding, and high
quality products.
| IFPAC Annual meeting | Petra Brozic | 27 January 2015 25
References
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1. Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms
(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandA
pproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf)
2. Quality by Design for ANDAs: An Example for Modified Release Dosage Forms
(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandA
pproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf)
3. ICH quality guidelines: ICHQ8 Pharmaceutical Development, ICHQ9 Quality Risk
Management, ICHQ10 Pharmaceutical Quality System
4. Markus Kiefer (Head Manufacturing Science & Technology), Sandoz, 9/10-October-2013:
„Challenges in Implementing the Lifecycle Approach to PV for Generic Manufacturing“, ISPE
Process Validation Conference
Acknowledgements
| IFPAC Annual meeting | Petra Brozic | 27 January 2015
Apiromraj (Pito) Roslansky
Gregor Schuetz
Matej Horvat
Karin Klokkers
Sandoz Global QbD Team
Petra Perhavec
Veronika Debevec
Vicky Pirzas
Sara Cesar
Tatjana Joksimovic
27