# Presentation: 036332

## CMC Review and Manufacturing (CGMP)  in Investigational Products 

**Chris Joneckis, Ph.D.**
**Senior Advisor For CMC Issues**
**Center For Biologics Evaluation And Research **

**Add FDA Bar and **

**NIAID/ NIH**
**April 15, 2005**

## 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

- Whole Blood

- BloodComponents

- Blood Derivatives and Recombinant Analogues

- SomaticCellular & GeneTherapies

- Tissues

- Therapeutic Vaccines

- Allergenic Extracts

- Prophylactic Vaccines

- Xenotransplantation
-        Transgenic

- Devices

_**OBRR**_

_**OVRR**_

_**OCTGT**_

- Devices

## 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**

- 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

**CGMP**
**Inspection**
**[21 CFR 210, 211]**

**CMC IND**
**Review**
**[21 CFR 312]**

- Control of Investigational Product

- Companion

## 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

## 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

## Chemistry Manufacturing and Controls(CMC)

## 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)]

## 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, xenotransplantation)

- Source Material
- Components
- Description of
-  Manufacturing Process
- Safety-related
-  Process Controls/ Data
- Analytical Methods/
-  Specifications
- Stability

**CMC IND**
**Review**

- Control of Investigational Product

## 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)

## 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

## 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 *

## 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

## 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

## 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)

## 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

##  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)?

## 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

## Testing - Mycoplasma

- Mycoplasma - test for cultivable and non-cultivable
- 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 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

## 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)

## 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)]

## 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 

- 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

- Phase 1- Hold Items

## 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)]

## 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

## 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)

## 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

## 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.

## 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 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 biologics
- Sponsors with minimal regulatory experience &  product/ process understanding generally experience greater delays in product approval

## Current Good Manufacturing Practices

- http://www.fda.gov/cber/summaries/pda030105cj.pdf

- (CGMP)

## 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 products
- Types and extent of control may differ due to stage of development

## CGMP in Clinical Investigation

- Analytical Validation

- Process
-  Validation

- Process Controls

- Component Qualification

## 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 document
- For example, formal evaluation of production environment
- Apply safeguards before, during and after manufacture

## 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

## 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

## 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

- 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

**CGMP**
**Inspection**

**CMC IND**
**Review**

## 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

## 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

## 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

## 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

## 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?

## 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

## Laboratory

- 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 product

## 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

## 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

## 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

**CGMP**
**Inspection**
**[21 CFR 210, 211]**

**CMC IND**
**Review**
**[21 CFR 312]**

*Review and Inspection Activities*

**cGMP**

**CMC**

- Control of Investigational Clinical Trials

- Companion

- Quality Unit Description
- Segregation and Tracking
- of Autologous cells

## 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

## 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.

## 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 _[www.fda.gov/ohrms/dockets/ac/cder04.html#PharmScience](http://www.fda.gov/ohrms/dockets/ac/cder04.html#PharmScience)_
- 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 (Xenotransplantation)
- 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  _[www.fda.gov/cber/](http://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@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@cber.fda.gov_