quality by design...pharmaceutical development ich q8 quality by design (qbd) a systematic approach...
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Slide 2
Guidelines
• Please contribute and ask questions
• Please relax and enjoy yourself
• Phone on silent / mute?
• Native presentation can be emailed.
Slide 3
Agenda
What is QbD? 1
2
Why are we talking about QbD? 3
Where will QbD be applicable? 4
Who is driving QbD?
The what, who, why, where, when but not the how of QbD
When will we need to adopt QbD? 5
How do we do QbD? 6
Slide 4
What is QbD?
The quality by design (QbD) principle can be simply stated as follows:
Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space.
Slide 5
Who is driving QbD?
“As we’ve said many, many times, FDA Office of Generic Drugs expects QbD applications starting January 2013. You heard right, full implementation of QbD in January 2013.” FDA’s Lawrence Yu, deputy director for science and chemistry in the Office of Generic Drugs Joint EU / US QbD program.
Slide 6
Why are we talking about QbD?
QbD
ICH Q8, Q9 Q10 and Q11
Other documents
•Case studies
•PDA & FDA
GMP’s
•EU
•US FDA
•PIC/S
Design space
Risk
Quality Targeted Product Profiles QTPP
Control strategy
Design of experiments
DOE
Critical Process
Parameters CPP
Critical Quality
Attributes (CQA)
Product Lifecycle
Slide 7
Where will QbD be applicable?
Lifecycle concept, but QbD is at the start of the product lifecycle, i.e. product design, R&D
FDA Process Validation - 3 stages
1. Process Design = Quality by Design
2. Process Qualification (National Validation Forum)
3. Continued Process Verification
National Validation Forum 1 http://www.pharmout.com.au/events/validation-forum.shtml
National Validation Forum 2 http://pharmout.com.au/events/validation-forum2.shtml
Slide 8
When will we need to adopt QbD?
1987 | 2000 |2002 | 2004 | 2006 | 2008 2010 | 2011 | 2013
FDA Guide to Process Validation
EU Annex
15
FDA: Pharmaceutical cGMPs For The
21st Century
ICH Q9
FDA: Quality System
Approach to Pharmaceutical
cGMP
PICS VMP
ICH Q10
ICH Q11
ISPE C&Q Baseline 5
Guide
ISPE 21st Century
Qualification White Paper
ICH Q8
FDA Process
Val. Guidance
US Law
as from
1st Jan
2013?
ASTM E2500-
07
Slide 9
Australian GMPs - Risk
Year GMP reference x times risk mentioned
1971 First TGA code of GMP 3
1990 TGA GMP code (Blue Book) 20
2002 First PIC/S code adopted in Australia 57
2008 Current – 2009 version of the PIC/S GMP code 390
ICH ICH Title x times risk mentioned
Q8 Pharmaceutical Development (2006) 10
Q9 Quality Risk Management (June 2006) 279
Q10 Pharmaceutical Quality System (April 2009) 34
Q11 Development & Manufacture of Drug Substances (May 2012) 51
Slide 10
What is QbD?
Quality by Design (QbD) is a concept first outlined by Juran
ICH - concepts
1. Quality by Design
2. Design Space
3. Design of Experiments
4. Critical Quality Attributes (CQA)
5. Critical Process Parameters (CPP)
6. Control Strategy
Slide 11
“Dosage form Design”
“A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug substance.”
DOSAGE FORM DESIGN: A PHYSICOCHEMICAL APPROACH. Michael B. Maurin (DuPont Pharmaceuticals Company, Wilmington, Delaware, U.S.A.), Anwar A. Hussain and Lewis W. Dittert (University of Kentucky, Lexington, Kentucky, U.S.A.)
FDA Publication - Quality by Design: Next Steps to Realize Opportunities? Ajaz S. Hussain, Ph.D.
Office of Pharmaceutical Sciences, CDER, FDA, 17 September 2003
Slide 12
FDA Process Validation
PharmOut White Paper on FDA http://www.pharmout.com.au/downloads/white_pape
r_fda_process_validation_guidance_final.pdf
ICH Q11 discusses the
Enhanced vs Traditional
approach
Slide 13
FDA PV Stages
Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
[FDA Guidance for Industry Process Validation: General Principles and Practices, Jan 2011]
Slide 14
FDA Stage 1
Stage Intent Typical activities
Process design
To define the commercial process on knowledge gained through development and scale up activities The outcome is the design of a process suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes
A combination of product and process design (Quality by Design) Product development activities Experiments to determine process parameters, variability and necessary controls Risk assessments Other activities required to define the commercial process Design of Experiment testing
Slide 15
FDA Stage 2
Stage Intent Typical activities
Process Qualification
To confirm the process design as capable of reproducible commercial manufacturing
Facility design Equipment & utilities qualification Process Performance qualification (PPQ)* Strong emphasis on the use of statistical analysis of process data to understand process consistency and performance
* Note: The term “Process Performance Qualification” or PPQ has been carried over from the 1987
guidance. This term is analogous with the traditional concept of ‘process validation’, as multiple batches of
product made at commercial scale under commercial manufacturing conditions. It is not the same as the
concept of ‘equipment performance qualification’.
Slide 16
FDA Stage 3
Stage Intent Typical activities
Continued Process Verification
To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives.
Product review SOP data collection from every batch Data trending and statistical analysis Equipment and facility maintenance Calibration Management review and production staff feedback Improvement initiatives through process experience
Slide 17
FDA and Industry publications
• Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms April 2012 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf
• Quality by Design for ANDAs: An example for Modified Release Dosage Forms Dec 2011 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf
• Applying Quality by Design to Vaccines CMC-Vaccines Working Group May 2012 http://www.pda.org/Home-Page-Content/CMC-VWG-A-VAX.asp
Slide 18
ICH
• ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle
• ICH Q8 Pharmaceutical Development
• ICH Q9 Quality Risk Management
• ICH Q10 Pharmaceutical Quality System
• ICH Q11 - Development and Manufacture of Drug Substances
Slide 19
ICH Q8 Concepts
Design Space
CQA
Variable 1
CQA Variable 2
CDQ
Variable 3
CQA Variable 4
Critical Process Parameter (CPP) Control strategy
Design Space
Acceptable Range
Most profitable
Slide 21
Pharmaceutical Development ICH Q8
Quality by Design (QbD)
A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
Slide 22
Pharmaceutical Development ICH Q8
Critical Quality Attribute (CQA)
– Quality attributes that must be controlled within pre defined limits
– Assurance that product meets its intended safety, efficacy, stability and performance
Slide 23
Pharmaceutical Development ICH Q8
Critical Process Parameter (CPP)
a process parameter that must be controlled within pre defined limits
– Assurance the product meets its pre defined quality attributes
Slide 25
Pharmaceutical Quality Systems Q10
• Knowledge Management
• Describes systems that facilitate establishment and maintenance of a state of control for process performance and product quality.
• Facilitates innovation and continual improvement
• Applies to drug substance and drug product throughout product lifecycle
• Control strategy
Slide 26
Pharmaceutical Quality System (PQS) ICH Q10
Good Manufacturing Practice
Pharmaceutical Development
Technology Transfer
Commercial Manufacturing
Product Discontinuation
Investigational
products
Management Responsibilities
Process Performance & Product Quality Monitoring System
Corrective Action / Preventative Action System
Change Managements System
Management review
Knowledge Management
Quality Risk Management Enablers
PQS
elements
Slide 27
Development and Manufacture of Drug Substances - ICH Q11
Provides further clarification on the principles and concepts described in ICH guidelines on -
• Pharmaceutical Development (Q8),
• Quality Risk Management (Q9)
• Pharmaceutical Quality Systems (Q10)
as they pertain to the development and manufacture of drug substance.
Slide 28
Development and Manufacture of Drug Substances - ICH Q11
Traditional approach
– Set points & operating ranges
– Process reproducibility and testing to meet acceptance criteria
Enhanced approach
– Risk management & science.
– process parameters and unit operations that impact on CQA
– Further studies, design space & control strategies over the lifecycle.
Slide 29
Development and Manufacture of Drug Substances - ICH Q11
A company can choose to follow different approaches in developing a drug substance.
For the purpose of this guideline, the terms “traditional” and “enhanced” are used to differentiate two possible approaches.
Slide 30
ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA
At Step F – Temp reflux
Only 1 impurity is formed –
hydrolysis_impurity
t = c, Conc. = c, H2O = c
hydrolysis_impurity = <0.30% hydrolysis_impurity
Slide 32
ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA
Traditional Approach:
Set a proven acceptable
range for % water and time
that achieves the
acceptance criteria for the
hydrolysis impurity of
0.30% in intermediate F.
Dry Intermediate E to a
water content < 1.0%.
Target reflux time of 1.5
hours and a maximum
reflux time of 4 hours
Slide 33
ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA
Enhanced Approach:
Where:
[F]o refers to the initial concentration of intermediate F,
[H20] o refers to the initial concentration of water,
M=[F]o/ [H20] o refers to the ratio of the initial concentration of intermediate F
to the initial concentration of water, and
XF refers to the time-dependent concentration of the hydrolysis
degradant of intermediate F.
Slide 34
ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA
Summary:
While both the traditional
and enhanced approach
provide ranges of water
content and time to control
the formation of the
hydrolysis impurity, the
enhanced approach allows
more manufacturing
flexibility.
Slide 35
Control Strategy
Planned set of controls, derived from current product and process understanding that assures process performance and product quality
A control strategy can include, but is not limited to, the following:
• Material attributes (raw materials, starting materials, intermediates, reagents, primary packaging materials)
• Controls are implicit in the design of the manufacturing process
• In-process controls
• Controls on drug substance
Slide 36
Control strategy table Drug Substance CQA (3.2.S.2.6) / Limit In Drug Substance
In process Controls (Including In-process testing and process parameters)
Controls on material attributes (raw materials / starting materials / intermediates)
Impact of Manufacturing Process Design
Is CQA tested on drug substance / Included in Drug Substance specification (3.2.S.4.1)
Organic Purity
Impurity X NMT 0.15%
Impurity Y
NMT 0.20%
Any individual unspecified impurity
NMT 0.10%
Design space of the reflux unit operation composed of a combination of % water in Intermediate E and the reflux time in step 5 that delivers Intermediate F with Hydrolysis Impurity ≤0.30% (3.2.S.2.2)
Process parameters step 4 (3.2.S.2.2)
P(H2) ≥2 barg
T <50°C
In-process test step 4 (3.2.S.2.4)
Impurity Y ≤0.50%
Specs for starting material D (3.2.S.2.3)
Yes/Yes
Yes/Yes
Yes/Yes
Total impurities
NMT 0.50%
Enantiomeric purity
S-enantiomer
NMT 0.50%
Specs for starting material D (3.2.S.2.3)
S-enantiomer ≤0.50%
Stereocentre is shown not to racemize; (3.2.S.2.6)
Yes/Yes
No/No
Residual Solvent
Ethanol
NMT 5000 ppm
In-process test during drying after final purification step (3.2.S.2.4)
LOD ≤0.40%
In-process results correlated to test results on drug substance
No/Yes
Slide 37
Extracted from the FDA IM release worked example
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Abbreviat
edNewDrugApplicationANDAGenerics/UCM304305.pdf
Slide 38
Submission of Control Strategy Information
The information provided on the control strategy should include detailed descriptions of the individual elements of the control strategy plus, when appropriate, a summary of the overall drug substance control strategy.
ICH M4Q recommends ….
• Description of Manufacturing Process and Process Controls (3.2.S.2.2)
• Control of Materials (3.2.S.2.3)
• Controls of Critical Steps and Intermediates (3.2.S.2.4)
• Container Closure System (3.2.S.6)
• Control of Drug Substance (3.2.S.4)
Slide 39
Common Technical Document (CTD) - Quality (ICH M4Q) guideline
Regional Admin
Information
Module 1
Nonclinical Overview
Nonclinical Summary
Clinical Overview
Clinical Summary
Quality Overall
Summary
Quality Nonclinical
Study Reports Clinical
Study Reports
Module 3 Module 4 Module 5
Module 2
Not Part of the CTD
The CTD
Slide 40
Thanks
http://au.linkedin.com/in/schoerie
1. What is QbD?
2. Who is driving QbD?
3. Why are we talking about QbD?
4. Where will QbD be applicable?
5. When will we need to adopt QbD?
6. How do we do QbD?
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