Title: CMC Review and Manufacturing (CGMP) in Investigational Products
1CMC 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
2Presentation 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
3Biologics Regulated by CBER
OBRR
OVRR
Blood Derivatives and Recombinant Analogues
Allergenic Extracts
Prophylactic Vaccines
BloodComponents
Therapeutic Vaccines
Whole Blood
SomaticCellular GeneTherapies
Devices
Devices
OCTGT
Tissues
Xenotransplantation Transgenic
4CMC/ 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
5CMC/ 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
6 Control of Investigational Product
CGMP Inspection 21 CFR 210, 211
CMC IND Review 21 CFR 312
Companion
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
7Major 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
8Implications 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
assessment - Difficult to distinguish quality change that can
impact safety
9Chemistry Manufacturing and Controls(CMC)
10General 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,
312.22(a)
11General 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)
12General 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)
13Phase 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,
xenotransplantation)
14 Control of Investigational Product
CMC IND Review
Source Material Components Description of
Manufacturing Process Safety-related Process
Controls/ Data Analytical Methods/
Specifications Stability
15CMC Content Source Material
- Cells, Viruses, Banking Systems
- Origin/ Method of collection
- History (potential exposure)
- Manipulation, establishment of banks,
cryopreservation - 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,
purification - Testing (e.g., sequencing)
16CMC 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
17CMC 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
18TSEs
- 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
19CMC Content - Manufacturing Process Process
Controls
- 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
controls
20CMC 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)
21CMC Content - Analytical Procedures
- Appropriate description- Drug Substance, Drug
Product - 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
22 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
method) - Suitability for Use - Interference from Test
Article - What about short-lived biologics, other
situations (e.g., cell therapies)?
23CMC 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
administration - Patient/physician notification, investigation,
speciation - Rapid Microbial Methods
24Testing - Mycoplasma
- Mycoplasma - test for cultivable and
non-cultivable - Options for non-culture test
- Hoechst stain
- PCR
- Newer methods
25CMC 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
26CMC Content - Stability Studies
- Investigational product should be stable during
planned duration of clinical studies need to
conduct stability in all phases 21 CFR
312.23(a)(7)(ii) - 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
acceptable - 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
protocol
27Phase 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
testing - Product used in preclinical studies different
from that in clinical studies - Combination products (drug, device, biologic)
28IND 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)
29Phase 1- Hold Items
- Absent, inadequate or incomplete information
- Variety of CMC content information described,
including - Incomplete description of the manufacturing
process - Information on animal-derived components not
provided - Sourcing and history information - Source
Material - 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
30General 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)
31CMC 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)
DEVELOPMENT ACTIVITIES DS DP Characterization Fo
rmulation Development Component
Characterization Assay Development/ Validation
Specification Development Stability
Studies Manufacturing Process Control
Validation
32Major Developmental Issues
- Critical Assays - validated, reproducible,
quantitative sensitive, specific and biologically
relevant - 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
Therapy)
33Expectations For Analytical Methods During
Development
- 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
34Analytical 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
35Analytical 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.
36CH, CH, CH, CHANGES
- 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)
37Reporting 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
38CMC 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
biologics - Sponsors with minimal regulatory experience
product/ process understanding generally
experience greater delays in product approval
39Current Good Manufacturing Practices (CGMP)
CGMPs For Clinical Trials, March 1,
2005 http//www.fda.gov/cber/summaries/pda030105cj
.pdf
40What 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
41Regulatory 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
42Investigational 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
products - Types and extent of control may differ due to
stage of development
43CGMP in Clinical Investigation
Component Qualification
Process Validation
Process Controls
Analytical Validation
44Achieving 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
45Achieving 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
document - For example, formal evaluation of production
environment - Apply safeguards before, during and after
manufacture
46Achieving 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
recommendations
47Utilize 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
facilities
48Inspection of Clinical Sites
- Manufacturing (that includes testing sites) are
subject to CGMP inspection - No formal inspection prerequisite requirement for
sites manufacturing clinical investigational
drugs
49 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
50Quality
- 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
51Quality Control
- Written quality control (QC) plan
responsibilities - Review and release components
- Review and approval of production procedures,
testing procedures acceptance criteria - Release or reject each batch upon cumulative
review - Investigate errors and initiate corrective
actions - Responsibilities are performed independently from
production - Appropriately trained individual(s) sufficient
to perform QC function
52Facilities
- 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
mix-ups
53Equipment
- 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
54Multiproduct
- 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,
mix-ups - Effective Cleaning and change over procedures
- Multi-product aspects potential impact on other
product - How to consider unknowns?
55Laboratory
- Production tests
- Specified quality attributes monitored
appropriate acceptance criteria applied (e.g.,
known safety-related and other tests as
appropriate) - 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
56Laboratory
- Retain representative sample for additional
release testing - Initiate stability study to support use in
clinical trials
57Sterile/ 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
product
58Biotechnology 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
intended - 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
59Multiple Batches
- Produces of multiple batches (e.g., therapeutic
vaccines, cell therapies) - Consistency among batches is important
- Accelerated accumulation of data than typical
manufacture - Periodic review and modification to control
procedures and production operations
60CGMP Overall Summary
- cGMP need to be in place for products used in
clinical IND studies - CGMP reflect and are consistent with good product
development - Follow general approaches and principles that are
broadly applicable - Tailor CGMP application to product, process and
facility - Assess risks and take appropriate actions
- Emphasize Product Quality
61 Control of Investigational Clinical Trials
Review and Inspection Activities
CGMP Inspection 21 CFR 210, 211
CMC IND Review 21 CFR 312
Companion
CMC
cGMP
Quality Unit Description Segregation and Tracking
of Autologous cells
62Product Development and Regulation - CBER
Philosophy
- Regulation Goal Balanced, Flexible, Responsive
- Assure the safety and rights of subjects
- Protect the public health
- Not impede technological innovation product
development - Influences
- Available scientific knowledge, pre-clinical,
clinical knowledge experience - Scientific research
- Crises/ tragic events
- Appropriate Risk Management
63Suggestions
- 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
development - Sponsors should proactively address issues that
may arise.
64CBER 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
65FDA 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 www.fda.gov/ohrms/dockets/ac/cder04.html
PharmScience - Cell and Gene Therapy Facilities in development
66Acknowledgements/ 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
(Xenotransplantation) - Stephanie Simek, Ph.D.
- Division of Cell and Gene Therapy, OCTGT, CBER
(Gene Therapy Products)
67Acknowledgements/ 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)
68CBER Available Information
- Internet www.fda.gov/cber/
- Fax Information System
- In US toll-free 1-888-CBER-FAX (1-888-223-7329)
- Outside US 301-827-3844
- Email -Manufacturers assistance
MATT_at_CBER.FDA.GOV - CBER Voice Information System at
- 1-800-835-4709 or 301-827-1800
- Chris Joneckis, Ph.D., Office of the Director,
CBER - Joneckis_at_cber.fda.gov