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CMC Review and Manufacturing (CGMP) in Investigational Products


Manufacturing (CGMP) in Investigational Products NIAID/ NIH April 15, 2005 Chris Joneckis, Ph.D. Senior Advisor For CMC Issues Center For Biologics Evaluation And ... – PowerPoint PPT presentation

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Title: CMC Review and Manufacturing (CGMP) in Investigational Products

CMC Review and Manufacturing (CGMP) in
Investigational Products
NIAID/ NIH April 15, 2005
  • Chris Joneckis, Ph.D.
  • Senior Advisor For CMC Issues
  • Center For Biologics Evaluation And Research

Add FDA Bar and
Presentation Overview
  • Chemistry Manufacturing and Control (CMC)
  • General Principles Approach
  • Information to submit in an IND
  • Good Manufacturing Practices (GMPs)
  • General Principles Approach
  • Specific Considerations
  • Focus mostly on biologics and biotechnology
    products in early phase of clinical study
  • Product class, specific product can influences
    CMC information to submit and approach to CGMP
  • Consult Guidance CBER group responsible for
    review of your product

Biologics Regulated by CBER
Blood Derivatives and Recombinant Analogues
Allergenic Extracts
Prophylactic Vaccines
Therapeutic Vaccines
Whole Blood
SomaticCellular GeneTherapies
Xenotransplantation Transgenic
CMC/ CGMP Goals in Clinical Investigation
  • Assure safe investigational products
  • Assure quality of investigational product
  • Ability to reproduce investigational product, as
    needed assure desired quality of
    investigational product
  • Within a trial
  • Between trials
  • Throughout clinical/ product development to
    commercial manufacture

CMC/ CGMP Goals in Clinical Investigation
  • Establishing the relationship between the
    manufacturing process and resulting product used
    in clinical studies (especially pivotal studies -
    Phase 3) and the process and product to be
    commercially marketed
  • Process controls and product quality
    characteristics/ attributes
  • Ultimately, develop an established manufacturing
    process assuring consistent production of a
    defined quality product for commercial production


Control of Investigational Product
CGMP Inspection 21 CFR 210, 211
CMC IND Review 21 CFR 312
Source Material Components Description of
Manufacturing Process Safety-related Process
Controls/ Data Analytical Methods/
Specs Stability
Personnel Quality Control Facilities Equipment
Laboratory Control Component
Control Production Control Distribution
Records Labeling
Major Considerations For Biological Products
Parameter Considerations Manufacturing L
iving sources Complex process Sensitiv
e to change environmental
influences Large amount of
variability Contaminants/ Impurities Subject
to contamination Viral/bacteria/fungal/TSE
Agent Product and Process Substances
Difficult to define and quantitative Stru
cture Multiple species Active
Ingredient Varying Complexity,
Heterogeneous Characterization Ability to be
Characterized Method Limitations
Implications of Manufacturing a Biologic
  • Requires thorough description, characterization,
    and testing starting with source materials and
    components used throughout manufacturing
  • Greater reliance on manufacturing process control
  • Careful description and evaluation of
    manufacturing changes made during development for
    potential product impact - safety and risk
  • Difficult to distinguish quality change that can
    impact safety

Chemistry Manufacturing and Controls(CMC)
General Principles
  • FDAs primary objectives in reviewing an IND
    are, in all phase of the investigation, to assure
    the safety and rights of subjects, FDAs review
    of Phase 1 submissions will focus on assessing
    the safety of Phase 1 investigations, 21 CFR,

General Principles
  • The amount of information on a particular
    drug that must be submitted in an IND to assure
    the accomplishments of the objectives safety
    quality depends upon such factors as the
    novelty of the drug, the extent to which it has
    been studied previously, the known or suspected
    risks and the developmental phase of the drug.
    21 CFR, 312.22(b)

General Principles
  • Although in each phase of the investigation
    sufficient information is required to be
    submitted to assure the proper identification,
    quality, purity, and strength of the
    investigational drug, the amount of information
    needed to make that assurance will vary with the
    phase of the investigation, the dosage form, and
    the amount of information otherwise available.
    21 CFR 312.23 (a)(7)(i)

Phase 1 Considerations
  • CMC safety issues as they relate to the quality
    aspects of product
  • What is the risk for human subjects? Are there
    any signals from preclinical studies?
  • The product class and the individual product
    affect, to some extent, the type and extent of
    information needed to assess safety
  • Often novel and complex products require
    additional information to address unknowns and
    added complexity (e.g., transgenic,


Control of Investigational Product
CMC IND Review
Source Material Components Description of
Manufacturing Process Safety-related Process
Controls/ Data Analytical Methods/
Specifications Stability
CMC Content Source Material
  • Cells, Viruses, Banking Systems
  • Origin/ Method of collection
  • History (potential exposure)
  • Manipulation, establishment of banks,
  • Testing Source/ source material
  • (e.g., Microbiology, endogenous/ adventitious
    agents, (bovine/ porcine), identity, purity,
    activity, replication competent viruses)
  • Genetic material
  • Origin
  • Gene modification, construction of vector,
  • Testing (e.g., sequencing)

CMC Content Source Material
  • Evaluation
  • Risk assessment of parent cells - history,
    potential exposure to viral agents
  • Screening donors for risk factors, absence of
    disease markers
  • Testing for viruses
  • Endogenous virus testing
  • Donors, animals, host cells, cell banks, EPC
  • General and Species specific tests
  • FDA-approved tests if available
  • Control
  • Establishing maintaining cell banks, viral
    seeds under cGMPs
  • Establishing plasma donor deferral roles for
    unsuitable donors
  • Closed herds flocks, sentinel animals
  • Quarantine until testing and control assures and
    establishes safety

CMC Contents - Components
  • All components (e.g., raw materials, excipients,
    reagents, ancillary products) used in production
  • Safety and quality of material
  • Source, screening, testing
  • Use in process, (evaluated in context of use)
  • Known/ potential toxicities
  • Penicillin, MTX, residual chemicals
  • What is the amount in final product? Consider
    testing, qualification study
  • FDA-approved products (e.g., albumin) preferred
  • Clinical-grade reagents preferred
  • Combination products (biologic, drug, device)
  • Develop qualification program during development

  • Ruminant-derived materials (e.g., bovine origin)
  • Avoidance of animal (human) derived materials, if
    at all possible
  • Assure material from BSE-free country The list
    USDA 9 CFR 94.18
  • Identify country of origin, tissue source,
    supplier, stage of manufacture
  • Maintain traceable records
  • Dont forget to test for viral agents e.g., 9
    CFR provides useful thoughts for assessment
    not a requirement
  • What about the next country to make the list ?
  • Emphasis on avoidance
  • Secondly, risk assessment of material

CMC Content - Manufacturing Process Process
  • Description of the manufacturing process - Drug
    Substance Drug Product
  • Method of preparation, including
  • complete description covering source, expression
    methods, production, materials and components,
    culture, purification, formulation, finishing,
    storage periods and conditions
  • description of differences in manufacturing for
    DS DP in preclinical studies vs. clinical
    studies (if performed)
  • Adequate description of process controls for
    process steps especially those that directly
    affect safety (e.g., virus inactivation, vaccine
    attenuation, cell irradiation)
  • Data demonstrating that safetyrelated processes
    are effective when operated within manufacturing

CMC Content - Analytical Procedures
  • Appropriate testing
  • Description of tests, analytical procedures
    acceptance criteria (Specification)
  • Testing throughout manufacturing - source
    material, components, intermediates, inprocess
    manufacturing, DS DP, stability
  • Appropriate acceptance criteria may not be known
    for all materials and all tests
  • May have report results, broader criteria
  • Establish acceptance criteria for known
    (suspected) safety-related tests (e.g., source
    materials, components, lot release DS/DP)

CMC Content - Analytical Procedures
  • Appropriate description- Drug Substance, Drug
  • Characterization Testing (structural,
    physiochemical, immunological)
  • Release Testing
  • Identity,
  • Purity - process and product
  • Potency bioactivity representative of
    mechanism of action,
  • Strength - concentration
  • Microbiological,
  • Sterility (modified USP method alternate
    microbial methods) methods
  • Mycoplasma -
  • Endotoxin
  • Submission of test results on preliminary/
    available lots (e.g., preclinical studies/ lots
    used in clinical studies) - depends

CMC Content -Testing - Sterility
  • Sterility of the Cell Banks, Product, and Placebo
    must be demonstrated by testing for viable
    organisms (bacteria fungi)
  • Recommend following 21CFR 610.12 (modified USP
  • Suitability for Use - Interference from Test
  • What about short-lived biologics, other
    situations (e.g., cell therapies)?

CMC Content - Testing - Sterility
  • Possible exceptions for cellular therapies,
    (discuss options with CBER)
  • Cell therapies
  • Gram-stain/ Follow-up with culture test
  • Action plan-based upon subsequent positive
    contamination in sterility test after cell
  • Patient/physician notification, investigation,
  • Rapid Microbial Methods

Testing - Mycoplasma
  • Mycoplasma - test for cultivable and
  • Options for non-culture test
  • Hoechst stain
  • PCR
  • Newer methods

CMC Content Testing Endotoxin (pyrogenicity)
  • Options
  • Limulus Amebocyte Lysate (LAL) test or
  • Rabbit-pyrogenicity test (21CFR 610.13(b))
  • Final products - acceptable levels (LAL)
  • 5 Endotoxin units (EU) per kg body weight per
    hour for parenteral administration
  • 0.2 EU per kg body weight per hour for
    intrathecal administration

CMC Content - Stability Studies
  • Investigational product should be stable during
    planned duration of clinical studies need to
    conduct stability in all phases 21 CFR
  • Recommended to submit information to support
    stability - depends
  • Knowledge of product class and stability
  • Unusual situation, labile product, unknown
    product class
  • Preliminary stability test results may be
  • Description of stability testing
  • Typically, a subset of release testing
  • For some products consider accelerated stability
    for major changes in (Phase 2/ 3)
  • Establish a real-time, real-condition stability

Phase 1 Considerations
  • How some information is reported may influence
    the type and extent of other information that
    should be provided
  • Issues associated with specific products
  • Known labile product
  • Substantial time elapsed from manufacture and
  • Product used in preclinical studies different
    from that in clinical studies
  • Combination products (drug, device, biologic)

IND Clinical Hold
  • Human subjects are or would be exposed to an
    unreasonable and significant risk of illness or
    injury. 21 CFR 312.42 (b) (1) (i)
  • The IND does not contain sufficient information
    required under 312.23 to assess the risks to
    subjects of the proposed studies. 21 CFR 312.42
    (b) (1) (iv)

Phase 1- Hold Items
  • Absent, inadequate or incomplete information
  • Variety of CMC content information described,
  • Incomplete description of the manufacturing
  • Information on animal-derived components not
  • Sourcing and history information - Source
  • Description and results of adventitious agent
    safety testing information - components
  • Lack of detailed testing procedure in- process
    and final product
  • Inadequate product release testing
  • Sponsor does not perform test (e.g., endotoxin,
    sterility) at appropriate manufacturing stage -
    after final manipulation, or with appropriate
    test article (e.g, mycoplasma)
  • Inadequate demonstration of viral clearance

General Principles
  • FDAs primary objectives in reviewing an IND
    are and in Phase 2 and 3, to help assure that
    the quality of the scientific evaluation of drugs
    is adequate to permit an evaluation of the drugs
    effectiveness and safety. 21 CFR, 312.22(a)

CMC Development
SAFETY INFORMATION Source characterization Compone
nts info. DS/DP Characterization Testing/Qualifica
tion/ Clearance of impurities,
contaminants Process control esp. for safety
processes (e.g., sterilization, virus clearance)
rmulation Development Component
Characterization Assay Development/ Validation
Specification Development Stability
Studies Manufacturing Process Control

Major Developmental Issues
  • Critical Assays - validated, reproducible,
    quantitative sensitive, specific and biologically
  • Potency (Bioassay) multiple products
  • Identity Cell Therapy
  • Other critical assays
  • Comparability Assessments
  • Need to demonstrate comparability of a vector GT
    product and a cell therapy product
  • Difficulties in establishing comparability (Cell

Expectations For Analytical Methods During
  • Ensure safety of the product
  • Assurance that analytical information gained in
    development can be reliability related to
    commercial manufacturing
  • Provides sufficient foundation for process
    validation, determining acceptance criteria etc.,
    by submission of marketing application

Analytical Methods Validation
  • Methods validation is the process of
    demonstrating that analytical procedures are
    suitable for their intended use. FDA Draft
    Guidance on Analytical Procedures
  • Analytical procedure
  • Does what it is intended to do
  • Yields data to answer a question
  • Provides confidence in results
  • Is reproducible

Analytical Method Validation
  • Methods used in IND studies should be
  • Scientifically sound, yield reproducible results
    and have sufficient sensitivity, specificity, and
    accuracy for the specified purpose.
  • Conducted following established written
    procedures under controlled conditions that may
    include use of reference materials, standards,
    positive, and negative controls or other
    appropriate controls.
  • For pivotal investigational trials validation
    should be strongly considered, may be needed for
    some assays (e.g., potency)
  • Understand risk to product if assays are not
    validated by pivotal trials.

  • FDA recognizes that modifications to the method
    of preparation of the new drug substance and
    dosage formsare likely as the investigation
    progresses 21 CFR 312.23 (a)(7)(i)
  • As drug development proceeds the sponsor
    should submit information amendments to
    supplement the initial information submitted on
    the CMC with information appropriate to the
    expanded scope of the investigation. 21 CFR
    312.23 (a)(7)(iii)

Reporting Changes
  • Intended or Unintended - Change Happens!
  • Evaluate the change(s) for potential to impact
    the DS DP product quality with regard to safety
    and efficacy
  • Comparability Study
  • Report in an information amendment
  • Significant/ most manufacturing changes
  • Changes that are likely to affect safety and
    efficacy prior to use in clinical studies
  • How to determine potential ?
  • Supporting studies and data

CMC Summary
  • CBER - Flexible regulatory approach
  • Different information (type and extent) is
    sometimes necessary for addressing specific IND
    CMC issues for different biologic product classes
    and even individual products within a class
  • Newer therapies/ technologies generally result in
    a greater number and different hold/ product
    development issues than more established
  • Sponsors with minimal regulatory experience
    product/ process understanding generally
    experience greater delays in product approval

Current Good Manufacturing Practices (CGMP)
CGMPs For Clinical Trials, March 1,
2005 http//
What are CGMPs?
  • CGMPs cover a broad range of methods, practices
    and principles that are implemented and
    documented during product development to ensure
    consistent manufacture of quality products

Regulatory Basis
  • Drugs and biologics including investigational
    products are required to be manufactured in
    accordance with CGMPs
  • if not, considered adulterated 501(a)(2)(B)
    Food, Drug and Cosmetic Act
  • Compliance with 21 CFR 210, 211 Current Good
    Manufacturing Practices for Finished
    Pharmaceuticals Regulations 1978
  • No specific regulations for Drug Substance
    (Active Pharmaceutical Ingredient) Production

Investigational Studies cGMP
  • Not always possibly to fully comply with CGMP
    regulations (i.e., 21 CFR 211)
  • Some CGMP regulations designed for repetitive,
    commercial manufacture of an approved product
  • Defined product quality attributes
  • Uses an established manufacturing process
  • However, CGMPs (principles) are clearly
    applicable to manufacture of investigational
  • Types and extent of control may differ due to
    stage of development

CGMP in Clinical Investigation

Component Qualification
Process Validation

Process Controls
Analytical Validation
Achieving CGMP Compliance
  • Effective quality control standards for Phase 1
  • Well defined written procedures
  • Adequately controlled equipment
  • Accurate and consistent recording of data
    (manufacturing and testing)
  • Implement CGMP consistent with good scientific
    methodology, product development and quality
    (control) principles

Achieving CGMP Compliance
  • CGMP are written to allow flexibility, however,
    this has potential for subjective interpretation
    by producer investigator - Alternative ???
  • CGMP are minimum requirements/ expectations
  • Develop control measures specifically tailored to
    the product, manufacturing process and facility
  • How to determine CGMPs that are appropriate for
    my process, product and stage of clinical trial?
  • Risk Assessment - justify your rationale and
  • For example, formal evaluation of production
  • Apply safeguards before, during and after

Achieving CGMP Compliance
  • Implement controls - shown to be both feasible
    and valuable in assuring drug quality
  • Not an excuse for inadequate controls !
  • Specific product and manufacturing process may
    impact ability to comply decide and document
  • Not possible to follow comply with CGMP
  • Include rationale for approaches followed in
    records for investigational product
  • Include reasons not follow obvious

Utilize Technology Resources
  • Facilitate
  • CGMP compliance
  • Product development (streamline)
  • For example, consider utilizing
  • Disposable equipment and process aids
  • Prepackaged WFI sterilized containers
  • Closed process equipment
  • Contract or shared production testing

Inspection of Clinical Sites
  • Manufacturing (that includes testing sites) are
    subject to CGMP inspection
  • No formal inspection prerequisite requirement for
    sites manufacturing clinical investigational


CGMP Inspection
CMC IND Review
Source Material Components Description of
Manufacturing Process Safety-related Process
Controls/ Data Analytical Methods/
Specs Stability
Personnel Quality Control Facilities Equipment
Laboratory Control Component
Control Production Control Distribution
Records Labeling
  • Quality Control - function
  • Quality is the responsibility of all staff
    involved in production
  • Quality should be built into the product, and
    testing alone cannot be relied on to ensure
    product quality

Quality Control
  • Written quality control (QC) plan
  • Review and release components
  • Review and approval of production procedures,
    testing procedures acceptance criteria
  • Release or reject each batch upon cumulative
  • Investigate errors and initiate corrective
  • Responsibilities are performed independently from
  • Appropriately trained individual(s) sufficient
    to perform QC function

  • Adequate and appropriate - HVAC, light, water,
    plumbing, space etc.
  • Maybe dependent upon product and process
  • Adequate work areas for intended tasks
  • Water of appropriate source and quality
  • Adequate air handling to prevent contamination
    and cross-contamination
  • Procedural controls to avoid contamination and

  • Appropriate for intended function
  • Properly maintained, calibrated, cleaned and
    sanitized following written procedures and at
    appropriate intervals
  • Should not contaminate or be reactive additive or
    absorptive with product
  • Identified and documented in production records

  • Multi-product
  • Generally, only one product manufactured in an
    area/ room at a time
  • Same area/ room may be used for multiple
    purposes, if
  • Appropriate design procedural controls allow
    for orderly handling of materials equipment
    prevent contamination/ cross contamination,
  • Effective Cleaning and change over procedures
  • Multi-product aspects potential impact on other
  • How to consider unknowns?

  • Production tests
  • Specified quality attributes monitored
    appropriate acceptance criteria applied (e.g.,
    known safety-related and other tests as
  • Scientifically sound analytical procedures
    (e.g., specificity, sensitivity, accuracy)
  • Tests conducted using written procedures under
    controlled conditions
  • Periodic calibration and maintenance of
    laboratory equipment
  • Consider systems suitability

  • Retain representative sample for additional
    release testing
  • Initiate stability study to support use in
    clinical trials

Sterile/ Aseptic Processing
  • Can be challenging to control and assure in early
    investigational phases
  • Take special precautions
  • Appropriate training
  • Aseptic manipulation conducted under appropriate
    conditions (e.g., Class 100 conditions - laminar
    flow hood) -
  • Document and follow all procedures intended to
    maintain the sterility of the components,
    in-process materials, components and final

Biotechnology and Biological Products
  • Appropriate equipment qualification and controls
    in production needed to assure safety related
    function (e.g., viral clearance, viral toxin
    inactivation, pasteurization) will perform as
  • Accompanying testing for safety-related functions
  • Difficulties to distinguish changes in quality
    attributes or predict impact of observed changes
    on safety
  • Difficulties in assessing Comparability suggest
  • Comprehensive documentation
  • Controls and documentation
  • Sufficient product retains

Multiple Batches
  • Produces of multiple batches (e.g., therapeutic
    vaccines, cell therapies)
  • Consistency among batches is important
  • Accelerated accumulation of data than typical
  • Periodic review and modification to control
    procedures and production operations

CGMP Overall Summary
  • cGMP need to be in place for products used in
    clinical IND studies
  • CGMP reflect and are consistent with good product
  • Follow general approaches and principles that are
    broadly applicable
  • Tailor CGMP application to product, process and
  • Assess risks and take appropriate actions
  • Emphasize Product Quality


Control of Investigational Clinical Trials
Review and Inspection Activities
CGMP Inspection 21 CFR 210, 211
CMC IND Review 21 CFR 312

Quality Unit Description Segregation and Tracking
of Autologous cells
Product Development and Regulation - CBER
  • Regulation Goal Balanced, Flexible, Responsive
  • Assure the safety and rights of subjects
  • Protect the public health
  • Not impede technological innovation product
  • Influences
  • Available scientific knowledge, pre-clinical,
    clinical knowledge experience
  • Scientific research
  • Crises/ tragic events
  • Appropriate Risk Management

  • Know thy process and thy product
  • Reserve sufficient DS DP retain samples
  • Document appropriately (integral part of cGMPs)
  • Consult CBER guidance (not a be all/ end all)
  • Take advantage of the opportunity to interact and
    meet with CBER use time productively
  • Listen and respond to CBERs comments
  • Included non-hold CMC comments for further
  • Sponsors should proactively address issues that
    may arise.

CBER CMC Guidances
  • Draft Guidance for FDA Review Staff and Sponsors
    Content and Review of Chemistry, Manufacturing,
    and Control (CMC) Information for Human Gene
    Therapy Investigational New Drug Applications
    (INDs) November 2004
  • Draft Guidance for Reviewers Instructions and
    Template for Chemistry, Manufacturing, and
    Control (CMC) Reviewers of Human Somatic Cell
    Therapy Investigational New Drug Applications
    (INDs) August 2003
  • Draft Considerations for Plasmid DNA Vaccines For
    Infections Disease Indications February 2005

FDA CGMP Guidance
  • FDA Guidance aimed at fostering compliance with
    CGMP, however few directly address issue related
    to CGMP in clinical investigation
  • Section 19, Q7A GMP Guidance For Active
    Pharmaceutical Ingredients FDA adopted
    September 2001
  • Developing Draft guidance Approaches to
    Complying with CGMP During Phase 1
  • Draft guidance discussed at Office of
    Pharmaceutical Science Advisory Committee July
    21, 2004
  • Cell and Gene Therapy Facilities in development

Acknowledgements/ Contacts
  • Andrew Chang, Ph.D.
  • Division of Hematology, OBRR, CBER (Recombinant
    blood factors
  • Plasma-derivatives)
  • Kimberly Benton, Ph.D.
  • Division of Cell and Gene Therapy, OCTGT, CBER
    (Cellular Products)
  • Eda Bloom, M.D.
  • Division of Cell and Gene Therapy, OCTG, CBER
  • Stephanie Simek, Ph.D.
  • Division of Cell and Gene Therapy, OCTGT, CBER
    (Gene Therapy Products)

Acknowledgements/ Contacts
  • Loris McVittie, Ph.D.
  • Division of Vaccines and Related-Products, OVRR,
    CBER (Viral-vaccines)
  • Paul Richman, Ph.D.
  • Division of Vaccines and Related Products, OVRR,
    CBER (Bacterial vaccines)
  • Laurie Norwood
  • Division of Manufacturing and Product Quality,
    OCBQ, CBER (Facilities)
  • Chiang Syin, Ph.D.
  • Division of Manufacturing and Product Quality,
    OCBQ (Facilities)

CBER Available Information
  • Internet
  • Fax Information System
  • In US toll-free 1-888-CBER-FAX (1-888-223-7329)
  • Outside US 301-827-3844
  • Email -Manufacturers assistance
  • CBER Voice Information System at
  • 1-800-835-4709 or 301-827-1800
  • Chris Joneckis, Ph.D., Office of the Director,
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