Transcript Slide 1

Quality Management for 21st Century
S. Srinivasan
CEO & Managing Director
Matrix Laboratories Limited
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Indian Pharmaceutical Companies –
geared up for global market
 Current size of the global Pharma market is around US$ 800 billion –
 Generic market US$ 93 billion &
 the API market US$ 37 billion
(Source: Espicom business intelligence)
 Global demand of APIs is expected to increase at CAGR of over 8% over
the next 5 years (Source: Chemical Pharmaceutical Association (CPA))
 A recent study by E&Y indicates projected growth in Pharma outsourcing
out of India of over 40%.
 India projected as an excellent destination for cost efficiency in
manufacturing, coupled with strong supply of skilled manpower, in
comparison to China, Eastern Europe, Puerto Rico, Singapore & Ireland
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Indian Pharmaceutical Companies –
geared up for global market
 India has maximum number of USFDA approved plants outside the US and
last few years filed the maximum number of DMFs.
 Indian companies play a predominant role in the WHO pre-qualification
programme related to Malaria, TB and HIV/AIDS.
 Indian pharmaceutical and API players are well positioned to take
advantage of this market opportunity.
 Indian companies have created good infrastructure with cGMP compliant
plants over the last decade.
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Quality Management for 21st Century
 An integrated quality system should cross into all areas of operations.
 QMS to be designed to assure quality into the manufacturing and control
processes.
 ICH Q10 is not intended to create any new expectation beyond current
regulatory requirements. This guideline has been formed by integrating
GMP requirements (ICHQ7) and ISO QMS guidelines. It serves as a
bridge between regional requirements, facilitating harmonization of
pharmaceutical quality system.
 Implementation of ICH Q10 should facilitate innovation and continual
improvement and strengthen the link between pharmaceutical
development and manufacturing activities.
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Quality Management for 21st Century
Main objectives of Q10 are :
 To achieve product realization
 Establish and maintain a state of control, and
 Facilitate continual improvement
Pharmaceutical quality system should include the following elements  Process performance and product quality monitoring
 Corrective and preventive actions
 Change management and management review
 Key performance indicators should be identified and used to monitor
effectiveness of processes. These indicators can be derived during the
development process and also from manufacturing experience. They
can be used as enablers for continual improvement.
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Quality Management for 21st Century
The quality management system presents continuous validation -concept to
replace the current three-batch process validation concept, i.e. move from
paradigm of “testing to assure quality” to “designing to assure quality” and
increase process capability to minimize risk.
Implementation of this framework will place tremendous responsibility on the
pharmaceutical manufacturers to have the Operations and Quality teams welltrained in quality management initiatives
In integrated QMS, there is an interplay of several ICH guidelines -
- ICHQ8 on Product Development
- ICHQ9 on Quality Risk Management
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Quality Risk Management
 ICH Q9 should serve as a foundation and complement existing quality
practices, standards and guidelines within the pharmaceutical
industry.
 Appropriate use of quality risk management can facilitate regulatory
compliance to a substantial degree and also improve quality of
communication between industry and regulators.
 A rational approach to risk management has to begin with the
question “What is the impact on the product?”
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Quality Risk Management
This guideline provides a framework that may be applied to all aspects of
pharmaceutical business, including
 development, manufacturing and distribution
 inspection and submission /review processes throughout the lifecycle
of drug substances, biological and biotechnological products and
 use of raw materials, solvents, excipients, packaging and labeling
materials.
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Quality Risk Management
Risk Management is about:
 knowing our processes (manufacturing and business)
 understanding what is truly important
 not spending time on a low risk activity, process, event or system because it
just doesn’t matter!
 focusing our money, time, energy and people on the things that are really
important
 focusing our efforts and resources on the things that provide quality
assurance to our customers
Risk Management is not about:
 making do with insufficient time, money or people
 providing an excuse not to do the right things
 deciding what to do based on what might be observed during an inspection
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Quality Risk Management
It is imperative therefore, that we as API manufacturers are able to and
perform a scientific and practical risk management process as a part of
the quality management and
 document the observations
 the actions and other related details based on current knowledge about
assessing the probability
 the severity and detectability of the risk.
Output of a risk assessment could either be a quantitative estimate of
risk or a qualitative description of a range of risks.
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Quality Risk Management
Based on the risk analysis, one could arrive at appropriate risk control
measures to reduce and /or accept risks.
Training of industry personnel in quality risk management process
provides for greater understanding of decision making processes and
builds confidence in quality risk management outcomes.
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Example 1 : Quality Risk Management
Recent examples of improper evaluation of manufacturing processes
(Source : http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viracept/Viracept-H-164-Z-109-AR.pdf)
Nelfinavir
 Europe wide recall of the HIV drug Nelfinavir
 Patients reported strange smell on the tablets
 Investigation revealed high level of Ethyl Mesylate (EMS) a potential genotoxic
impurity
 Investigation at the manufacturing plant identified ethanol contamination in a
holding tank of Methane Sulphonic Acid (MMS)
 Ethanol was used as a cleaning solvent which was not part of a regular
procedure
 Residual ethanol got converted to EMS in presence of MMS
 Lack of knowledge & understanding of the manufacturing process
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Example 2 : Quality Risk Management
Recent examples of improper evaluation of manufacturing processes
(Source : http://www.ibc-asia.com/GenericsAsia/Day%201/Ron%20Tomer.pdf)
Terbinafine
 A potential impurity was identified in the manufacturing process of the API
 Launch of the Generic version was delayed due to lack of knowledge
 Impurity was expected to be generated due to two starting materials
(Acrolein and PCl5)
 EDQM initially set a limit of 6 ppm and after additional studies fixed the limit
at 500 ppm
 This impurity now appears as a listed impurity in the EP monograph
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Product Development
 Another integral part of the new quality management system is
ICHQ8 on pharmaceutical development.
 The aim of pharmaceutical development is to design a quality
product and its manufacturing process to consistently deliver the
intended performance of the product.
 The information and knowledge gained from pharmaceutical
development and manufacturing experience provide scientific
understanding to support the establishment of specifications and
manufacturing control.
 Information from pharmaceutical development studies can be a
basis for Quality Risk Management
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Product Development
 Changes in formulation and manufacturing processes during
development and lifecycle management are opportunities to gain
additional knowledge.
 Movement out of the “controls window” should be considered a
change and would normally initiate a regulatory post-approval
change process.
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Example 3 : Trend Analysis before CAPA
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Example 3 : Trend Analysis after CAPA
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Process Analytical Technology (PAT)
 Process analytical technology approach should encourage voluntary
development and implementation of innovative approaches to
pharmaceutical manufacturing and quality assurance.
 Many new technologies that provide information on physical, chemical,
biological characteristics of materials will help in improving process
understanding, predict quality and performance.
 Regulatory expectations are so high that manufacturers are expected to
use such technologies to improve efficiency and effectiveness of
process design, manufacturing controls and quality assurance.
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Process Analytical Technology (PAT)
Gains in quality and efficiency from PAT could vary and are likely to come
from:
 reducing production cycle times by using on-line measurements and
controls
 preventing rejects, scrap and re-processing
 real time release
 increased automation to improve operator safety and reduce human errors
 improving energy and material use and increasing capacity
 facilitating continuous processing to improve efficiency and manage
variability
The integrated quality system orientation affords a flexible regulatory
approach for implementation of PAT under the facilities’ own quality system
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Regulatory Review
Regional differences in the regulatory review processes such as filing of
changes are adding complexity to manufacturers during the product life
cycle.
Now considerable emphasis is being placed on :
 Assessment of possible Genotoxic impurities
 Crystal characteristics
 Polymorphism
 Enantiomeric purity besides residual solvents, organic and inorganic
impurities
 Metal catalytic residues
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Regulatory Review
 The regional differences in the regulations and the different requirements
for the same monograph as per different Pharmacopoeias pose its own
challenge to the Industry.
 Compelling necessity to develop a bank of reference standards
 Increasing emphasis by the WHO and its expectation for the APIs for
WHO markets to be compliant with the international pharmacopoeia, has
raised an additional point of complexity.
 One hopes that WHO also joins the initiative of harmonization and
international pharmacopoeia gets harmonized with other standards of
reference.
 It is important for the manufacturers to design and develop their
operations with the aim of avoiding excessive changes to their products
during its lifecycle.
 This would save precious time as well as resources for the organization.
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Indian Pharmaceutical Companies – geared up for global market
Quality Management for 21st Century
Quality Risk Management
Product Development
Process Analytical Technology (PAT)
Regulatory Review
Conclusion
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Conclusion
Quality Guru Deming has the following to say on variability & inspection “Depending on inspection is like treating a symptom while the disease is
killing you. The need for inspection results from excessive variability in the
process. The disease is variability. Ceasing dependence on inspection
means you must understand your processes so well that you can predict
the quality of their output from upstream activities and measurements. To
accomplish this, you must have a thorough understanding of the sources
of variation in your processes and then work toward reducing the variation.
Ceasing dependence on inspection forces you to reduce variability.”
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Conclusion
To conclude, the API industry needs to evolve to a desired quality system:
Present Focus
Desired Focus
Documentation
Trend Data analysis
Have SOPs
Understand parameters that are critical to
quality attributes
Follow SOPs
Measure process capability
Validate process
Perform continuous quality verification
Meet specifications & don’t
change
Undertake continuous improvement
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Thank you
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