Quality Assurance in
Pharmaceuticals
OBJECTIVES
Define the term quality as it relates to the pharmaceutical
manufacturing industry.
Define and distinguish between the terms Quality
Assurance and Quality Control and explain
Analyse how they both fit within a Quality System in
the industry
Relate GMP and cGMP and their place in a QA system
Describe the specific functions of the QA, QC and
regulatory affairs.
Analyze a situation where a QA failure in the
pharmaceutical industry resulted in significant public
impact
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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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QUALITY
The totality of features and characteristics of a
medicinal product and its ability to satisfy stated
and/or implied needs
QUALITY ASSURANCE
The sum total of the organized arrangements
made with the object of ensuring that medicinal
products are of the quality required for their
intended use.
4
GOOD MANUFACTURING PRACTICE (GMP)
That part of QA which ensures that products are
consistently produced and controlled to the
quality standards appropriate to their intended
use.
QUALITY CONTROL
That part of GMP which is concerned with
sampling, specifications and testing.
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Quality relationships
Quality Management
Quality Assurance
GMP
Quality Control
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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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Quality Assurance Operation
Reviewing the daily lab and production
reports is a part of the QA
responsibilities. This is to determine
that the procedures are being followed
and the tests are being made. QA can
spot trends by conducting consistent
record reviews. If record reviews don’t
stay current, no one will get timely
feedback before a real problem crops
up.
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Primary Functions
Primary Functions
Quality Control
Analytical testing of products
Active and Non active material control
Sampling, inspecting and testing of incoming raw materials
Packaging and labeling components
Bottles, caps, foils, labels, measures, cartons
Physical inspection of product and operations at
critical intermediate stages
In-process controls, HACCP
Control of product through its distribution
GSP, GDP
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Elements of the Quality Assurance Cycle in
Pharmaceutical Manufacturing
Research
Development
Prototyping
Documentation
Raw Materials
Facilities
Equipment
Personnel and Supervision
Monitoring, Feedback, Follow-up 12
Analytical Control Laboratory
Heart of Quality Management in
Pharmaceuticals
Academically trained and certified staff
Experienced supervision/management
Capable of performing complex analyses
Able to report honestly and in a timely manner
Equipment and instrumentation must be suitable
for performing testing
Access to reliable power, water and other stable
infrastructure
13
FACTORS IN DRUG QUALITY ASSURANCE
LEGISLATIVE IMPORT
FRAMEWORK & EXPORT
-REGULATIONS CONTROL PACKAGING
HUMAN LABELLING &
RESOURCES- PRODUCT
PROFESSIONALS INFROMATION
DRUG
RAW PRODUCT
MATERIALS- QUALITY QC &
ACTIVE & ANALYSIS
INACTIVE
TRANSPORT
MANUFACURING DISTRIBUTION
PROCESSES DISPENSING
STORAGE & USE
& PROCEDURES
14 14
Quality Control & Analysis
Qualification
Design, Installation, Process and Operational
Calibration
Daily and periodic
Validation
Equipment, Method and process
SOPs
Authorized, used and updated
Documentation
Systematic and well kept
Quality Manual
Quality manager, staff trained and motivated to comply.
Safety measures
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Quality Assurance Throughout
the Manufacturing Process
Monitoring environmental conditions
under which products are
manufactured/stored
Monitoring of air and water systems to
prevent contamination– Air Handling
Units
Monitoring of humidity
Monitoring of personnel
Feedback and follow-up 16
Manufacturing Process and Procedures
Dispensing / Weighing
Mixing / Granulation / Preparation
Compression / Encapsulation / Filling
Equipment, Operational & Process
Qualification
Validation & calibration
Documentation and record keeping
Yield Reconciliation
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Support
Top management must be into what QA is
doing
QA manager must report to CEO or direct
link
Corporate support does not always make one
popular with local managers but is critical for
maintaining high quality standards
Safety
Conflicts may exist between optimum quality
and safety
Manufacturers must recognize that many
processes that ensure product safety do not
enhance product quality
Any time a process change occurs to improve
quality, product safety requires reverification
Responsibility may fall to QA
Installation of QA plan
Organization of department
Make use of supervisors
Amount and quality of training affects finished
product quality
Every line employee should be trained
Verify job is being done correctly
Automation of process changes types and
quantities of analyses needed
Speed of testing
What level of accuracy is necessary
Maintenance and calibration of lab equipment
Training of technicians
Verification of accuracy and variation of technicians
CONSEQUENCES OF QA BREACHES
Poor Treatment outcomes
High Health Bills
Treatment Failures & Deaths
Loss of Confidence in the Health Services
Enormous Economic Losses
National Security Issue
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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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Major Risks in Pharmaceutical
Production
Contamination of products (microbial,
particulate or other)
Incorrect labels on containers
Insufficient active ingredient
Excess active ingredient
Poor quality raw materials
Poor formulation practices 23
Quality Issues: Examples
Microbial contamination Potency questioned
Visible growth Oversize tablet
Container/closure Capsule fill caries
defects Volume/quantity
Syringe malfunction questioned
Dosage unit missing
Aerosol non-function
Empty capsule units
Pump malfunction
Discoloration
Excessive spray
Precipitation
Adhesion lacking
Cloudy
Patient reaction
Clumping
Death
Odor/taste abnormal
Foreign particulates
Chipped, cracked
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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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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
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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
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GMP compliance
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. 28
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 32
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.
35
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
36
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
37
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
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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)
40
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.
41
PAT and QbD
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Summary
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
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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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