Quality and Compliance Challenges for Biopharmaceutical Products

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Quality and Compliance Challenges for
Biopharmaceutical Products

• Ramon Rivera Gonzalez, Ph.D.
• Director Quality Assurance
• Amgen Manufacturing, Limited

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Outline

• Background Information
• Regulatory and Process Challenges
• Quality by Design
• Risk Management
• Process Analytical Technology
• Key Quality Systems
• Deviations/Nonconformities
• Corrective and Preventive Actions
• Biological Product Deviations
• FDA and EMEA Observations

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Biotechnology

• Biotechnology is a set of scientific techniques
• used to derive valuable products from living
  organisms
• Applications
• biopharmaceutical drugs
• agriculture
• waste management

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Background information

• FDA- sterile drugs should be manufactured by
  aseptic processing only when terminal
  sterilization is not feasible.
• Parenterals -Drug administration other than by
  the mouth or rectum- ex. Injection, infusion or
  implantation.
• Biological products (vials or syringes)
• solubility, stability, maintain activity

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Biotechnology

CHEMISTRY
ENGINEERING
BIOLOGY
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Biological Products Manufacturing
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Biological Products Manufacturing
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Bacterial Systems

• ()
• Grow fast
• Easy to maintain
• High yield
• (-)
• Endotoxins
• Low expression or extracellular secretion
• No post-translational modifications machinery

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Mammalian Cells

• ()
• Adequate conformation
• Post-translational modifications
• Preferred for complex proteins
• (-)
• Grow slower than bacteria
• Maintenance is expensive
• Usually lower yield
• Limited manufacturing applications

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Quality and the Product Life Cycle

• Adherence to regulations
• Control and maintenance of documentation
• Quality of suppliers, components and raw
  materials
• Reliability and consistency
• Monitor/audit of the manufacturing process
• Deviations, unexpected situations - product
  impact
• Correction and prevention - CAPA
• Lot release/rejection decision
• Customer complaints
• Continuous improvement

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Quality Systems Emphasis

• Quality Management
• Quality Assurance
• Risk Management
• Evaluation analysis and quality risk management
  tools
• Preventive Action
• Promote product and process improvement (i.e.,
  continuous improvement)
• Continuous Improvement of the Quality System

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Regulatory Environment Challenges

• Transfer of CBER products to CDER
• GMPs for the 21st. Century
• Aseptic Processing Guideline
• Risk management
• Increased scrutiny of product insert claims
• Focus on patient safety
• Process Analytical Technology (PAT)

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Regulatory Environment Challenges

• Quality by Design
• Bioterrorism
• Animal-derived materials
• Country-specific regulatory requirements
• Mexico, Brazil, Saudi Arabia, Japan
• Biogenerics in EU
• State of the art technology
• Isolators

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Major Process Challenges

• Sterile vs. Aseptic
• Requires the application of microbiological
  contamination control to prevent infectious
  organisms to be present in the sterile product
• Demonstrate CONTROL of the process, while
  technical complexity increases
• Characterization to identify variability
  components
• Application of science and new technologies
• Maintenance of the cell lines
• Contamination risks
• Personnel as incubators
• Source of microbial load

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Quality by Design

• Quality can not be tested into products it has
  to
• be built in by design
• Product quality and performance requires
  efficient design of manufacturing processes
• Product specifications based on deep
  understanding of how formulation and process
  factors impact product performance
• It provides a framework for continuous "real
  time" assurance of quality and continuous
  Improvement

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The importance of Design

• Multidimensional combination and interaction of
  input variables and process parameters that have
  been demonstrated to provide an assurance of
  quality
• Operating within design parameters will produce a
  product meeting designed quality attributes
• Working within the design parameters is not
  considered a reportable change
• Movement outside of design space is considered a
  change subject to regulatory approval

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Risk Management

• What are the potential hazards to process and
  product ?
• Identify potential hazards both prospectively and
  in a reactive mode
• Applies to components, container closure, raw
  materials, dosing devices, manufacturing process,
  drug substance, intermediates
• How these factors influence variability of
  process, product performance, product safety and
  efficacy?

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Risk Management

• Risk management is a regulatory expectation for a
  modern quality system
• Risk assessment, risk control, risk communication
  and risk review throughout product lifecycle
• Decisions should be based upon process and
  product understanding
• Balance between the use of risk management and
  compliance with GMPs
• Always include intended use, patient safety and
  availability

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Process Analytical Technology

• any system for continuous analysis and/or
  control of manufacturing processes based on
  real-time measurements, or rapid measurements
  during processing.
• Source FDA Human Drug cGMP Notes, Q1 2002

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Process Analytical Technology

• At line - the sample is removed, isolated from,
  and analyzed in close proximity to the process
  stream
• On-line - the sample is diverted from the
  manufacturing process, and may be returned to the
  process stream
• In-line the sample is not removed from the
  process stream and can be invasive or
  non-invasive
• Source FDA PAT Guidance

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PAT - Benefits

• Enhancement of process understanding
• Sources of variability identified and explained
• Meet requirements for validating and controlling
  process
• Quality attributes can be accurately and reliably
  predicated
• Continuous improvement
• Integration of development, manufacturing, QA and
  knowledge management
• Acceptability of in-process materials and final
  product based on process data

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Management Controls

• Written quality policy and objectives
• Management reviews
• regulations and quality objectives
• attendance documented
• results, action plans/corrective actions
  documented
• Internal audits
• auditors no direct responsibility for matters
  being audited

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Deviations/Nonconformities

• Classification based on impact/risk
• Investigations need to be thorough, stand-alone
• Root cause analysis
• Product impact
• Stability data, intrinsic vs. extrinsic,
  historical data
• Toxicological/health hazard evaluations based on
  route of administration to patient
• Corrective and Preventive actions

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Corrective and Preventive Actions(CAPA)

• Corrective correct existing nonconformity
• Prevention potential recurrence of
  nonconformity
• Regulatory expectations
• Identify sources of problems/nonconformities
• Unfavorable trends
• Prioritize based on risk
• Defined action plans
• Timely implementation
• Measure and document effectiveness
• Reviewed by Management

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If a deviation/nonconformity involves distributed
product

• Evaluate per 21CFR600.14 Biological Product
  Deviation (BPD)
• must report any event and any information
  relevant to the event associated with the
  manufacturing, to include testing, processing,
  packing, labeling or storage, or with the holding
  or distribution, of a licensed biological product
  if the event meets the following criteria
• Either
• Represents a deviation from cGMP, applicable
  regulations, applicable standards, or established
  specifications that may affect the safety, purity
  or potency of that product or
• Represents an unexpected or unforeseeable event
  that may affect the safety, purity, or potency of
  that product and
• Occurs in your facility or a facility under
  contract with you and
• Involves a distributed biological product

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Some points regarding BPDs

• Distributed biological product has left the
  control of the licensed manufacturer
• Contract manufacturing
• The decision to report should be based on whether
  the event had the potential to affect safety,
  purity, or potency of the product
• The license holder is required to file at a date
  not to exceed 45 calendar days from the date that
  you, your agent, or another person, acquire
  information reasonably suggesting that a
  reportable event has occurred
• Must report even if the investigation determined
  that there was no impact

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BPD- Reportable Examples

• Raw materials that failed specifications used in
  manufacturing
• Aseptic processing not performed according to
  procedures
• Stability testing not performed at required
  interval
• Missing information in label (product type, lot
  number, storage temperature, concentration)
• Distributed product prior to completion of
  required testing
• Product release prior to validation of
  manufacturing process
• Biological Drug Substance stored at the incorrect
  temperature

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BPD Non-reportable Examples

• Raw material did not meet specification and was
  rejected prior to its use
• Testing performed incorrectly, invalidated and
  repeated and found acceptable prior to
  distribution
• Product labeled with a shortened expiration date
  (not due to failure to meet specification)
• Product shipped to the incorrect facility
• Customer order filled incorrectly (wrong product,
  wrong amount), but labeled correctly

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EMEA Observations

• Critical give rise to product that could be
  harmful to patient
• Major result in product not meeting marketing
  authorization, major deviation from EU GMP
• Other usually lack information to be classified

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EMEA 1995 - 2005

• Critical
• Design and maintenance of premises
• Potential for microbiological or
  chemical/physical contamination
• Major/Other
• Potential for microbial contamination
• Documentation- Quality system elements/procedures
  
• Unauthorized activities requiring regulatory
  filing
• Design and maintenance of equipment and premises

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FDA Observations (1996-2006)

• Failure Investigations (Nonconformities)
• Failure to conduct investigations
• Failure to extend investigations to related
  batches and products
• Averaging OOS results with in-specification
  results to support release
• Delays in starting the investigation
• Incomplete investigation into root cause
• Failure to take immediate corrective action
• Failure to address product impact

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FDA Observations (1996-2006)

• Record keeping
• Batch Production and Control records do not
  include complete information
• post-it notes with hand-written original data
• Lack of procedures
• No revision history for procedures
• Validations
• Discrepancies against Master Validation Plan
• Inadequate cleaning validation
• Inadequate process validation
• Inadequate validation of analytical methods

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In Summary

• The successful application of quality systems for
  the manufacturing of biological products requires
  the comprehensive synergy between regulations,
  science/new technologies, process knowledge,
  Management accountability and efficient risk
  management

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Questions?