Quality Management for 21st Century

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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 EY 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. Implementati
on of this framework will place tremendous
responsibility on the pharmaceutical
manufacturers to have the Operations and Quality
teams well-trained 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 doesnt
  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/Ron20Tomer.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 dont change Undertake continuous improvement
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Thank you