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CMC Review and Manufacturing (CGMP) in Investigational Products . Chris Joneckis, Ph.D. Senior Advisor For CMC Issues Center For Biologics Evaluation And Research . NIAID/ NIH April 15, 2005. Add FDA Bar and . Presentation Overview. Chemistry Manufacturing and Control (CMC)

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CMC Review and Manufacturing (CGMP) in Investigational Products

Chris Joneckis, Ph.D.

Senior Advisor For CMC Issues

Center For Biologics Evaluation And Research


April 15, 2005

Add FDA Bar and

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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

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Biologics Regulated by CBER



Blood Derivatives and Recombinant Analogues

Allergenic Extracts

Prophylactic Vaccines


Therapeutic Vaccines

Whole Blood

SomaticCellular & GeneTherapies







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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

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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

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Control of Investigational Product



[21 CFR 312]



[21 CFR 210, 211]


Source Material


Description of

Manufacturing Process


Process Controls/ Data

Analytical Methods/ Specs



Quality Control



Laboratory Control

Component Control

Production Control




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Major Considerations For Biological Products


Manufacturing Living sources

Complex process

Sensitive 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

Structure Multiple species

Active Ingredient Varying Complexity, Heterogeneous

Characterization Ability to be Characterized

Method Limitations

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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 assessment

    • Difficult to distinguish quality change that can impact safety

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General Principles

“FDA’s primary objectives in reviewing an IND are, in all phase of the investigation, to assure the safety and rights of subjects, … FDA’s review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations…, [21 CFR, 312.22(a)]

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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)]

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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)]

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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, xenotransplantation)

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Control of Investigational Product



Source Material


Description of

Manufacturing Process


Process Controls/ Data

Analytical Methods/



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CMC 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)

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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 cGMP’s

    • Establishing plasma donor deferral roles for unsuitable donors

    • Closed herds & flocks, sentinel animals

    • Quarantine until testing and control assures and establishes safety

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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

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  • 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

    • Don’t 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

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CMC 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 safety–related processes are effective when operated within manufacturing controls

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Appropriate testing

Description of tests, analytical procedures & acceptance criteria (Specification)

Testing throughout manufacturing - source material, components, intermediates, in–process 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

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CMC 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

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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)?

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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 administration

      • Patient/physician notification, investigation, speciation

  • Rapid Microbial Methods

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Testing - Mycoplasma

  • Mycoplasma - test for cultivable and non-cultivable

  • Options for non-culture test:

    • Hoechst stain

    • PCR

    • Newer methods

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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

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CMC 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

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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 testing

    • Product used in preclinical studies different from that in clinical studies

    • Combination products (drug, device, biologic)

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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)]

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Phase 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

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General Principles

  • “ {FDA’s 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 drug’s effectiveness and safety….” [21 CFR, 312.22(a)]

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CMC Development


Incremental Approach - CMC

Phase 3


Phase 2

Phase 1



Source characterization

Components info.

DS/DP Characterization

Testing/Qualification/ Clearance of impurities, contaminants

Process control esp. for safety processes (e.g., sterilization, virus clearance)


DS & DP Characterization

Formulation Development

Component Characterization

Assay Development/ Validation

Specification Development

Stability Studies

Manufacturing Process

Control & Validation

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Major 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)

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Expectations 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

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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

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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.

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“ FDA recognizes that modifications to the method of preparation of the new drug substance and dosage forms…are 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)]

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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

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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 biologics

  • Sponsors with minimal regulatory experience & product/ process understanding generally experience greater delays in product approval

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Current Good Manufacturing Practices


CGMP’s For Clinical Trials, March 1, 2005

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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

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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

Regulatory Basis

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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 products

  • Types and extent of control may differ due to stage of development

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CGMP in Clinical Investigation


Incremental CMC

Phase 3


Phase III

Phase 2

Phase 1

Incremental CGMP


Component Qualification



Process Controls

Analytical Validation

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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

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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 document

    • For example, formal evaluation of production environment

    • Apply safeguards before, during and after manufacture

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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 recommendations

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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 facilities

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Inspection of Clinical Sites

  • Manufacturing (that includes testing sites) are subject to CGMP inspection

  • No formal inspection prerequisite requirement for sites manufacturing clinical investigational drugs

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Source Material


Description of

Manufacturing Process


Process Controls/ Data

Analytical Methods/ Specs



Quality Control



Laboratory Control

Component Control

Production Control




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  • 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

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Quality 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

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  • 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

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  • 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

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  • 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?

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  • 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

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  • Retain representative sample for additional release testing

  • Initiate stability study to support use in clinical trials

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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 product

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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 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

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Multiple 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

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CGMP 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

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Control of Investigational Clinical Trials

Review and Inspection Activities



[21 CFR 210, 211]



[21 CFR 312]




Quality Unit Description

Segregation and Tracking

of Autologous cells

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Product 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

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  • “Know thy process and thy product”

  • Reserve sufficient DS & DP retain samples

  • Document appropriately (integral part of cGMP’s)

  • 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 CBER’s comments

    • Included non-hold CMC comments for further development

  • Sponsors should proactively address issues that may arise.

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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]

CBER CMC Guidances

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FDA CGMP Guidance and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

  • 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]

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Acknowledgements/ Contacts and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

Andrew Chang, Ph.D.

Division of Hematology, OBRR, CBER (Recombinant blood factors;


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)

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Acknowledgements/ Contacts and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

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)

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CBER Available Information and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

  • Internet

  • Fax Information System

    • In US toll-free: 1-888-CBER-FAX (1-888-223-7329)

    • Outside US: 301-827-3844

  • Email -Manufacturers assistance: [email protected]

  • CBER Voice Information System at:

    • 1-800-835-4709 or 301-827-1800

      Chris Joneckis, Ph.D., Office of the Director, CBER

      [email protected]