By:
Muhammad Naeem
Quality Assurance and Regulatory Manager
CCL Pharmaceuticals (Pvt.) Ltd.
Quality Assurance
Quality assurance is a wide ranging concept covering all
matters that individually or collectively influence the
quality of a product.
It is the totality of the arrangements made with the object
of ensuring that pharmaceutical products are of the quality
required for their intended use.
QA is the heart and soul of quality control
QA = QC + GMP
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QA
GMP
QC
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GMP
Is that part of Quality Assurance
aimed at ensuring that products are
consistently manufactured to a
quality appropriate to their intended
use
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QC
Is that part of GMP concerned with
sampling, specification & testing,
documentation & release procedures
which ensure that the necessary &
relevant tests are performed & the
product is released for use only after
ascertaining it’s quality
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Public Health Expectations
Every unit, Every Batch, Every Day..
 “We rely upon the manufacturing controls and standards
to ensure that time and time again, lot after lot, year after
year the same clinical profile will be delivered because the
product will be the same in its quality…
 We have to think of the primary customers as people
consuming that medicine and we have to think of the
statute and what we are guaranteeing in there, that the
drug will continue to be safe and effective and perform as
described in the label.”
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Pharmaceutical Manufacturing
Current State
 Conventionally Pharmaceutical mfg is a batch process operation with
laboratory testing conducted on collected samples to evaluate quality
 Quality assurance is ensured by end-product testing, i.e., quality by testing
and inspection and not by design
 Regulatory uncertainty-often cited reason for industry’s hesitancy to
introduce innovative systems
 Significant opportunities exist for improving
o pharmaceutical development, manufacturing, and quality assurance
through innovation in
o
product and process development, process analysis, process control, and
automation
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Current State of Pharmaceutical Manufacturing: A snapshot…
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Quality Issues: Examples
 Microbial contamination
 Potency questioned
 Visible growth
 Oversize tablet
 Container/closure defects
 Capsule fill caries
 Syringe malfunction
 Volume/quantity questioned
 Aerosol non-function
 Dosage unit missing
 Pump malfunction
 Empty capsule units
 Excessive spray
 Discoloration
 Adhesion lacking
 Precipitation
 Patient reaction
 Cloudy
 Death
 Clumping
 Foreign particulates
 Odor/taste abnormal
 Chipped, cracked
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Pharmaceutical Manufacturing
Desired State
 Product quality and performance
 ensured through the design of effective and efficient manufacturing processes
 Product and process specifications
 based on a mechanistic understanding o f how formulation and process factors affect product
performance
 Continuous real time quality control and assurance
 Regulatory policies and procedures tailored to
 accommodate the most current level of scientific knowledge
 Risk-based regulatory approaches recognize
 the level of scientific understanding of how formulation and manufacturing process factors affect product
quality and performance
 the capability of process control strategies to prevent or mitigate the risk of producing a poor quality
product
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Desired State: Systematic Approaches
 Innovation in manufacturing

Incorporation of Quality by Design approaches based on sound science, engineering and risk management principles

Drug Development, Manufacture and Quality Assurance

Engineering Quality

Continuous processing (Manufacturing)
 Implementing effective Pharmaceutical Quality System

Process performance and Product Quality Monitoring System

CAPA System

Change Management System

Knowledge & Quality Risk management Systems

Management review of Process performance and Product
 Applying integrated systems approach to quality assessment both by industry and regulators

R&D, Production, and QA

CMC review and GMP compliance
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Quality By Design
 A systematic approach to development that begins with predefined
objectives and emphasizes process and product understanding and
process control, based on sound science and quality risk
management.
 It is a Scientific, risk-based and proactive approach to
pharmaceutical development.
 It is a Full understanding of how product attributes and process
relate to product performance.
 It is a Quality Risk Management in Development & Manufacturing
of drug product.
 It is a building in Quality and Flexibility from day one.
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Significance of QbD
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Elements of QbD Approach
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QbD Approaches
 Creating a design space during product
development.
 Process Analytical Technology (PAT)
implementation.
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Design Space
 Definition
The multidimensional combination and interaction of input variables (e.g.,
material attributes) and process parameters that have been demonstrated to
provide assurance of quality
 Design Space Determination
 First-principles approach
 combination of experimental data and mechanistic knowledge of chemistry, physics, and
engineering to model and predict performance
 Non-mechanistic/empirical approach
 statistically designed experiments
 linear and multiple-linear regression
 Scale-up correlations
 translate operating conditions between different scales or pieces of equipment
 Risk Analysis
 determine significance of effects
 Any combination of the above
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Application of QbD
 Applications of QbD by establishing a Design Space
during Product Development:




Lactose monohydrate is used in place of (defined) Lactose
anhydrous.
Experiment with different mesh sizes of API.
Experiment with different container/closure system.
Experiment with different equipment as defined in proposed
formulation.
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Approaches to Pharmaceutical Development
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Benefit of QbD
 Increased understanding of formula and process.
 Greater understanding of excepients.
 Meaningful specifications.
 Excepients come from variety of sources is acknowledged.
 Excepients’ compatibility testing allows to determine the
level of interaction between a given active pharmaceutical
ingredient (API) and a selection of excepients.
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ICH Guidance
 Q8–Pharmaceutical Development
 Describes good practices for pharmaceutical product development
 Introduces concepts of design space and flexible regulatory approaches
 Q8(R)
 Addendum to original Q8
 Includes concepts of Quality by Design and examples of design space
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ICH Guidance (Cont.)
 Q9: Quality Risk Management
 Describes a systematic process for the assessment, control, communication and
review of quality risks
 Applies over product lifecycle: development, manufacturing and distribution
 Includes principles and examples of tools for quality risk management
 Q10: Pharmaceutical Quality Systems
 Describes systems that facilitate establishment and maintenance of a state of
control for process performance and product quality
 Facilitates continual improvement
 Applies to drug substance and drug product throughout product lifecycle
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Process Analytical Technology (PAT)-1
 “A system for designing and controlling manufacturing
through timely measurements/testing/analyzing (i.e.
during processing) of critical quality and performance
attributes for raw and in-process materials and also
processes with the goal of ensuring final product quality”.
 PAT facilitates the implementation of QbD
 QbD and PAT = Tremendous benefits to industry,
regulatory and the public!
 So the goal is ‘product quality’ and NOT just meeting
specifications
Quality Attributes: Identity, purity, strength and efficacy
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Process Analytical Technology (PAT)-2
Need of PAT
“The goal of PAT is to understand and control the critical
manufacturing processes (critical quality attributes and
performance attributes)”.
“Quality cannot be tested into final products; it should be
built-in by design”.
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Process Analytical Technology (PAT)-3
 Types of Testing




In-line (Real-time)Testing (actual PAT)
On-line Testing (Container sensor installed at equipment,
Unit counter, Automatic removal of broken tablets on
blister)
At line (In-process control)
Off-line (Lab Testing on final stage or final product)
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Application of PAT
 Inline analysis of uniform distribution of materials during
mixing in cone blender or mixer through FTNIR / Raman
Spectroscopy.
 Inline drying process monitoring in FBD.
 Inline cleaning status of equipment during cleaning
through TOC or UPLC.
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PAT and QbD
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Closing Remarks
 Successful implementation of QbD & PAT relies on industry’s adoption of
innovative approaches to
 Development that are based on sound (material) science, engineering, and quality
risk management principles
 Manufacturing Process through

process understanding and timely process monitoring

implementing risk-commensurate process control strategy

to prevent/mitigate risk to product quality and performance
 Quality Assurance through

validated processes (state of control)

Continuous Process/Quality Verification

Real Time Release
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Acknowledgements
Thanks
Questions??
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References

Guidance for Industry: PAT —A Framework for Innovative Pharmaceutical Development, Manufacturing, and
Quality Assurance, September 2004
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf

Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice
Regulations, September 2006
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070337.pdf

Guidance for Industry: Q9 Quality Risk Management, June 2006
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdf

Guidance for Industry: Q8(R2) Pharmaceutical Development Revision 2, November 2009
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073507.pdf

Guidance for Industry: Q10 Pharmaceutical Quality System, April 2009
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073517.pdf

Guidance for Industry: Process Validation: General Principles and Practices, January 2011
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf
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