CGMP Compliance in the 21st Century

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CGMP Compliance in the 21st Century
Arden HouseJanuary 25 -30, 2004

• Joseph C. Famulare
• Director,
• Division of Manufacturing and Product Quality
• Office of Compliance, CDER

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Current Good Manufacturing Practices

• Current
• indicates the GMPs change with time and evolving
  technology
  
• Good
• feasible and valuable standard
• not necessarily best or state-of-the-art
• GMP regulations are a minimum standard 21 CFR
  210.1(a) and 211.1(a)

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Current Good Manufacturing Practices

• Practice
• Relates to drug industry capabilities, and what
  is being done
  
• Does not have to be prevailing, majority or
  average practice
  
• Relates to those processes or procedures which
  assure integrity and quality, even if only done
  by a few
  
• Although industry practice is at issue, FDA has
  expertise in determining what cGMPS are

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Current Good Manufacturing Practices

• Does the pharmaceutical industry meet current
  GMP requirements for quality systems?
  
• Pharmaceutical cGMPs for the 21st Century
  A Risk Based Approach
  
• In the future, pharmaceutical manufacturing will
  need to employthe best principles of quality
  management to respond to the challenges of new
  discoveries and ways of doing business such as
  individualized therapies or genetically tailored
  treatments.

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CGMP Requirement

• 211.180(e) so that for evaluating the quality
  standards of each drug product to determine the
  need for changes in drug product specifications,
  or manufacturing or control procedures

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Current Good Manufacturing Practices

• CGMP requires no regulatory submission?
• CGMP record requirements
• Master/Batch Production and Control Record
• Protocol/Report of Process Validation
• Periodic Product Review
• Protocol/Record of Reprocessing

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Current Good Manufacturing Practices

• CGMP conformance assessment
• includes review of these records
• includes acquisition of copies of these records
• Application supplements/annual reports refer to
  this information
  
• Need for synergy between these processes

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What are the Risk Management Goals of the CGMP
Initiative?

• Implement systematic risk management approaches
  to all aspects of drug quality regulation,
  including
  
• Standard-setting
• Review
• Inspection and
• Regulatory action decision making

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Defining Risk

• Risk is intuitive and familiar to everyone, yet
  it is rarely defined with sufficient rigor for
  complex risk analysis
  

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Defining Quality

• Fitness for use is a start
• Depends on customer expectations
• Patients
• Health care professionals
• FDA
• September 17, 2003, Janet Woodcock
• Clinical performance is the key
• Could be defined as the delivery of efficacy and
  safety as described in the label, derived from
  the clinical trials
  
• Not aesthetics, price, other consumer-defined
  attributes
  

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Applying Risk Management to Drug Quality
Regulation

• Industry can demonstrate to FDA that reduced
  regulatory scrutiny is justified by the
  science/data
  
• Cannot individually examine GMP requirements in
  isolation from the system of which they are a
  part
  
• The whole is greater than the sum of its parts
• Indirect risks to drug quality cannot be ignored

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Risk Management and Resource Allocation

• Work-planning and risk management group
• Risk-based approaches to targeting Field
  inspectional resources based upon the risk of
  manufacturing deficiencies that would reduce drug
  quality
• Prioritize sites for inspections, focusing first
  on
  
• Post-approval inspections
• Not including biologics (covered by Team Bio)

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A RISK-BASED FRAMEWORK FOR PRIORITIZING SITES FOR
CGMP INSPECTION
PRODUCT
PROCESS
FACILITY
SITE RISK
3 Decision Modules 1) Product, 2) Process, 3) F
acility
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Risk Management and Resource Allocation (contd)

• Phase 1 Starting in FY 03, shifted emphasis to
  facilities making drugs perceived to be of higher
  risk if subject to manufacturing deficiencies
  
• Sterile drugs
• Rx drugs (non-medical gas)
• New registrants
• Far exceeded performance target to inspect at
  least 55 of facilities in these categories

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Risk Management and Resource Allocation (contd)

• Product-type factors
• What are the intrinsic properties of products
  such that their deficiencies in quality would
  have more adverse public health impact than
  others?
• Narrow therapeutic range
• sterile
• Rx vs. OTC
• Route of administration
• Mining recall data can help weight product
  factors (e.g., product or dosage form associated
  with prevalence of serious recalls?)

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Risk Management and Resource Allocation (contd)

• Facility-type factors
• Are some manufacturers or particular
  manufacturing facilities more likely to produce a
  product with quality problems?
  
• Effectiveness of quality systems and process
  capability
  
• Inspectional record and compliance history
• Exposure volume produced at facility
• Product sales volume
• Special/sensitive populations
• Other characteristics?
• New Registrants?
• Macher and Nickerson study will help identify

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A RISK-BASED FRAMEWORK FOR PRIORITIZING SITES FOR
cGMP INSPECTION
SITE RISK POTENTIAL
PRODUCT
PROCESS
FACILITY
Site potential risk score wp Product weight x
wPr Process weight x wfx Facility weight
w is the relative weight assign to the
individual module Semi-quantitative weights
high, medium, low yes/no ordinal scales
1- 5
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Risk Management and Resource Allocation (contd)

• Risk ranking and filtering technique should be a
  useful tool for other aspects of drug quality
  regulation
  
• Focus compliance programs?
• Guidance development?
• Regulatory action decisions?

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Risk Management and Resource Allocation (contd)

• Process-type factors
• Are some manufacturing processes more likely to
  go wrong than others?
  
• Are some process problems of greater public
  health significance? What are the consequences
  of process problems?
  
• Risk of contamination or mix-ups
• Maintaining state of control of the process
• Use expert elicitation to identify additional
  risk factors and weightings
  
• At the unit operation level
• By product classes

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Risk Management and Resource Allocation (contd)

• The model can only be as good as the
  scientific/technical input/assumptions that are
  used to develop the risk scores
  
• Implementing systematic risk-based approaches to
  focus regulatory oversight of drug quality
  regulation is a long term endeavor that will go
  well beyond the stated 2-year time frame of the
  initiative

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Quality and Continuous Improvement

• How do we get there?
• In a quality system environment
• modern principle of quality management
• design controls Formulation design,
  development of the manufacturing process, and
  process control designed by research and
  development scientists, engineers and other
  manufacturing specialists preamble to the
  1978 CGMP regulations
  

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Quality and Continuous Improvement (contd)

• Process Validation
• what is it?
• how do you get there?
• lifecycle approach
• application of knowledge for continuous
  improvement

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Quality and Continuous Improvement (contd)

• idea of three batches for product launch has to
  depart for intended ideas of experimental
  design, evaluation of data and process
  development through commercial production
• Setting specifications and the handling of out of
  specification results
  
• opportunity for improvement called for by the
  CGMP regulations

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Quality and Continuous Improvement (contd)

• Corrective and preventive actions stemming from
  examination of out of specification results,
  lifecycle approach to validation, and annual
  review
• Continuous improvement is embodied in the CGMP
  program
  
• Modern manufacturing technology and control
  provides greater opportunity for continuous
  improvement

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The Near Future

• Regulatory oversight based on
• science
• risk management principles
• manufacturing processes designed with process
  understanding
  
• the goal of reaching the desired state promoting
  and not preventing continuous improvement
  

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The Near Future (contd)

• Greater ability for firms to innovate based on
  scientific understanding of manufacturing
  processes
  
• More readily available guidance
• Modern quality systems thinking
• More convergence internationally on approaches

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The Near Future (contd)

• Better communication with and between regulators
• Better focus and training of the investigator,
  and integration with the activities of the
  reviewer