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Quality and Compliance Challenges for Biopharmaceutical Products


Quality and Compliance Challenges for Biopharmaceutical Products Ramon Rivera Gonzalez, Ph.D. Director Quality Assurance Amgen Manufacturing, Limited – PowerPoint PPT presentation

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Title: Quality and Compliance Challenges for Biopharmaceutical Products

Quality and Compliance Challenges for
Biopharmaceutical Products
  • Ramon Rivera Gonzalez, Ph.D.
  • Director Quality Assurance
  • Amgen Manufacturing, Limited

  • 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

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

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
  • Biological products (vials or syringes)
  • solubility, stability, maintain activity


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

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

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

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

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)

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

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
  • Application of science and new technologies
  • Maintenance of the cell lines
  • Contamination risks
  • Personnel as incubators
  • Source of microbial load

Quality by Design
  • Quality can not be tested into products it has
  • 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

The importance of Design
  • Multidimensional combination and interaction of
    input variables and process parameters that have
    been demonstrated to provide an assurance of
  • 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

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

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

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

Process Analytical Technology
  • At line - the sample is removed, isolated from,
    and analyzed in close proximity to the process
  • 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
  • Source FDA PAT Guidance

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

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

  • 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

Corrective and Preventive Actions(CAPA)
  • Corrective correct existing nonconformity
  • Prevention potential recurrence of
  • 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

If a deviation/nonconformity involves distributed
  • 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

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

BPD- Reportable Examples
  • Raw materials that failed specifications used in
  • Aseptic processing not performed according to
  • Stability testing not performed at required
  • 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

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
  • 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

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

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
  • Design and maintenance of equipment and premises

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

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

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

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