1. 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

2. Presentation Overview
Chemistry Manufacturing and Control (CMC)
General Principles & Approach
Information to submit in an IND
Good Manufacturing Practices (GMPs)
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

3. Biologics Regulated by CBER
OBRR
OVRR
Blood Derivatives and Recombinant Analogues
Allergenic Extracts
Prophylactic Vaccines
Blood Components
Therapeutic Vaccines
Whole Blood
Somatic Cellular & Gene Therapies
Devices
Devices
OCTGT
Tissues
Xenotransplantation
Transgenic

4. 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

5. 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

6. Control of Investigational Product
CMC IND
Review
[21 CFR 312]
CGMP
Inspection
[21 CFR 210, 211]
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

7. Major Considerations For Biological Products
Parameter Considerations
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

8. 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

9. Chemistry Manufacturing and Controls (CMC)

10. 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, (a)]

11. 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, (b)]

12. 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 (a)(7)(i)]

13. 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)

14. Control of Investigational Product
CMC IND
Review
Source Material
Components
Description of
Manufacturing Process
Safety-related
Process Controls/ Data
Analytical Methods/
Specifications
Stability

15. 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)

16. 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

17. 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

18. TSE’s 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

19. 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

20. CMC Content - Analytical Procedures
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)

21. 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

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 (modified USP method)
Suitability for Use - Interference from Test Article
What about short-lived biologics, other situations (e.g., cell therapies)?

23. 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

24. Testing - Mycoplasma
Mycoplasma - test for cultivable and non-cultivable
Options for non-culture test:
Hoechst stain
PCR
Newer methods

25. CMC – Content Testing Endotoxin (pyrogenicity)
Options
Limulus Amebocyte Lysate (LAL) test or
Rabbit-pyrogenicity test (21CFR (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

26. CMC Content - Stability Studies
Investigational product should be stable during planned duration of clinical studies – need to conduct stability in all phases [21 CFR (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

27. 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)

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

29. 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

30. 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, (a)]

31. DEVELOPMENT ACTIVITIES
CMC Development
SAFETY INFORMATION
Source characterization
Components info.
DS/DP Characterization
Testing/Qualification/ Clearance of impurities, contaminants
Process control esp. for safety processes (e.g., sterilization, virus clearance)
DEVELOPMENT ACTIVITIES
DS & DP Characterization
Formulation Development
Component Characterization
Assay Development/ Validation
Specification Development
Stability Studies
Manufacturing Process
Control & Validation
Pre-clinical
Discovery
BLA
Incremental Approach - CMC
Phase 1
Phase 3
Phase 2

32. 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)

33. 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

34. 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

35. 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.

36. CH, CH, CH, CHANGES
“ 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 (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 (a)(7)(iii)]

37. 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

38. 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

39. Current Good Manufacturing Practices
(CGMP)
CGMP’s For Clinical Trials, March 1, 2005

40. 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

41. 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

42. 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

43. CGMP in Clinical Investigation
Component Qualification
Process
Validation
Process Controls
Analytical Validation
Phase III
Pre-clinical
Discovery
BLA
Phase 2
Phase 3
Incremental CGMP
Incremental CMC
Phase 1

44. 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

45. 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

46. 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

47. 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

48. 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

49. CMC IND CGMP Review Inspection Personnel 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

50. Quality 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

51. 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

52. Facilities
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

53. Equipment 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 We

54. Multiproduct 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?

55. Laboratory 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

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

57. 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

58. 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

59. 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

60. 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

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

62. 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

63. Suggestions “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.

64. 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]

65. 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,
Cell and Gene Therapy Facilities [in development]

66. 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 (Xenotransplantation)
Stephanie Simek, Ph.D.
Division of Cell and Gene Therapy, OCTGT, CBER (Gene Therapy Products)

67. 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)

68. CBER Available Information
Internet
Fax Information System
In US toll-free: CBER-FAX ( )
Outside US:
-Manufacturers assistance:
CBER Voice Information System at: or
Chris Joneckis, Ph.D., Office of the Director, CBER