Chemistry, Manufacturing and

Controls (CMC)
Regulation of Pharmaceuticals
Riggs School of Applied Life Sciences ALS 419

Dr. Michael S. Koeris

Spring 2020 – Week 2

ALS 419 - CMC 1

Syllabus overview
Session Topic

Syllabus Review
26-Mar Product Types & Business Impact in Biosciences
Intro to FDA org & CMC Regulatory

Deep-dive Module 3
2-Apr
Pick a Product Proposals

Post-approval change (PACs)

9-Apr
Pick a PAC for your project

16-Apr Case Study Projects: Preliminary Presentations

23-Apr Global Agencies / WHO / ICH

30-Apr Applications: Novel, Biosimilar, CGT, Vaccines, Device/Diagnostic, FMT

7-May Case Study Projects: Final Presentations

14-May Final Exam / Course Evaluations

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Course tools
Sakai
• Doc storage and assignment

Teams

Piazza
• Discussion board

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Course norms
Keep the video on

We will have breaks

Ask – interrupt – raise hand functionality – when the question arises

Glossary

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Lecture outline
Discussion of readings

Section 08: CTD deep dive

Section 09: CMC Considerations

Section 10: Class project

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Assignment

Discussion of readings

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Glossary 2

IPC Components
CoA Drug Substance
CQA Drug product
CPP Batch
KOP

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CFR Review cGMP (general)
• Part C
• 211

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Breakout rooms reporting
It’s not stupid
It’s got to set the standard for safety WHILE giving you room for the
future (new products)
Guidelines / paths to your OWN standard
Looks at systems, people,
Documentation !!!!!! Not just what you do when you do it but also
how you “recover” from it
Labeling (v. important)
What happens if you have recalled product

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cGMP in a nutshell

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cGMP
Write down what you’re going to do

Do what you wrote you will do

Write down what you did

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Golden rules of cGMP

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Key CMC / cGMP tenets
Process & Product Control
Goal is a robust, scaleable process
“Process is the Product”
Process Validation demonstrates reproducibility
Quality by Design
CQA’s (Critical Quality Attribute)
CPPs (Critical Process Parameters)
KOP’s (Key Operating Parameters)

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Key CMC / cGMP tenets
Testing required, but not sufficient
Expect to consistently meet specifications
“Quality cannot be tested in” - Quality BY DESIGN
Documentation
SOPs – Standard Operating Procedures
“Anything not documented is a rumor”
Continual improvement
Current standards
Cleanliness
Orderly, clean, neat, tidy
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CFR Review small molecules vs. biologics
• Part C
• 211
• Part F
• 600
• 610

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Small molecules vs. biologics
Discuss differences 211 vs. 610

What shall we focus on?

What does it matter?

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Breakout rooms reporting

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NCE Product Characterization per CFR

Safety Constituent Materials

Identity, strength,
21 CFR 211.82-86, 21 211.82-86
quality, and purity
211.113,
Microbiological Components rejections /
211.103, 211 Subpart I,
contamination approval

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Biologics Product Characterization per CFR
Identity Purity
Safety
21 CFR 610.14 21 CFR 610.13
21 CFR 610.12,
610.30, 610.40 Free of extraneous
Specific test to
Sterility, Endotoxin, distinguish it from others materials
Mycoplasma,
opportunistic viruses

Potency (600.3 and

Constituent Materials
610.10)
21 610.15
Assay for Biological
Ingredients,
function
Preservatives, diluents,
Adjuvants, excipients

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Section 08

The Common Technical Document

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The CTD – What it is and what it is not

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CTD – What it is
A common harmonized format for applications for preparing
marketing authorizations in ICH regions.

It is a TEMPLATE for presenting data in the dossier

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CTD – What it isn’t
A statement of data requirements for applications.

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CMC
Chemistry – Product description at molecular level

Manufacturing – Process to make product reproducibly

Controls – Specifications to ensure consistent product

Therefore, CMC defines Quality of product

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CMC CTD
CTD == Common Technical
Document
Bottom up build with regards
to data density and work
We focus on Module 3:
Quality

International Conference on Harmonization, M4: The Common Technical Document. n.d. Accessed on March 20, 2017
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CMC CTD
Quality Section
Chemistry, Manufacturing and Controls
(CMC)
Submitted with Non-Clinical, Clinical Data
Includes all process development,
validation and stability data
Demonstrate at full scale for clinical studies

Common Technical Document (eCTD)

Defined framework
Electronic file through agency gateways

Alignment with regulatory files

Change control includes proper updates

ALS 419 - CMC International Conference on Harmonization, M4: The Common Technical Document. n.d. Accessed on March 20, 201726
CMC CTD – where’s the meat?

International Conference on Harmonization, M4: The Common Technical Document. n.d. Accessed on March 20, 2017
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Module 1: Regional Requirements
Forms, Labeling, DMF Letters, Environmental Assessment
3.2.R Regional Information
Executed Batch Record (U.S., in English)
Method Validation Package (U.S., EDQM)
Comparability Protocols (U.S.)
Process Validation Scheme (EU)
Medical Device (EU)
Reviewer-Specified Information
Market-Specific Information (e.g. specs)
ONLY SECTION NOT SPECIFIED BY ICH

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Module 2: Quality Overall Summary (QOS)
Section 2.3 Example Quality Overall Summery
• Summary is 40 pages text
• Present key product parameters and data
• Format same as Module 3
• Content consistent with Module 3
• Content integrated with other summaries
• Explain any deviations from the guidelines
• “Expert report” critical assessments.
• Canadians require table formats.

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 Module 3 Quality Detailed Overview
3.2.S. DRUG SUBSTANCE 3.2.P.1 DRUG PRODUCT 3.2.A APPENDICES
3.2.S.1.1 GENERAL INFORMATION (Nomenclature) 3.2.P.2.1 COMPONENTS OF THE DRUG PRODUCT (Drug Substance, Excipients) 3.2.A.1 FACILITIES AND EQUIPMENT
3.2.S.1.2 GENERAL INFORMATION (Structure) 3.2.P.2.2 DRUG PRODUCT (Formulation Development, Overages, Physiochemical and 3.2.A.2 ADVENTITIOUS AGENTS SAFETY EVALUATION
3.2.S.1.3 GENERAL INFORMATION (General Properties) Biological Properties) 3.2.A.3 NOVEL EXCIPIENTS
3.2.S.2.1 MANUFACTURE (Manufacturers) 3.2.P.2.3 MANUFACTURING PROCESS DEVELOPMENT 3.2.R Regional
3.2.S.2.2 MANUFACTURE (Description of Manufacturing and Manufacturing 3.2.P.2.4 CONTAINER CLOSURE SYSTEM 3.2.R.1 REGIONAL INFORMATION
Controls) 3.2.P.2.5 MICROBIOLOGICAL ATTRIBUTES
3.2.R.2 METHODS VALIDATION PACKAGE
3.2.S.2.3 MANUFACTURE (Control of Materials) 3.2.P.2.6 COMPATIBILITY
3.2.S.2.4 MANUFACTURE (Control of Critical Steps and Intermediates) 3.2.P.3.1 MANUFACTURERS
3.2.S.2.5 MANUFACTURE (Process Validation and-or Evaluation) 3.2.P.3.2 BATCH FORMULA
3.2.S.3.1 CHARACTERIZATION (Elucidation of Structure and other Characteristics) 3.2.P.3.3 DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS
3.2.S.3.2 CHARACTERIZATION (Impurities) 3.2.P.3.4 CONTROLS OF CRITICAL STEPS AND INTERMEDIATES
3.2.S.4.1 CONTROL OF DRUG SUBSTANCE (Specifications) 3.2.P.3.5 PROCESS VALIDATION AND-OR EVALUATION
3.2.S.4.2 CONTROL OF DRUG SUBSTANCE (Analytical Procedures) 3.2.P.4.1 CONTROL OF EXCIPIENTS (Specifications)
3.2.S.4.3 CONTROL OF DRUG SUBSTANCE (Validation of Analytical Procedures) 3.2.P.4.2 CONTROL OF EXCIPIENTS (Analytical Procedures)
3.2.S.4.4 CONTROL OF DRUG SUBSTANCE (Batch Analyses) 3.2.P.4.3 CONTROL OF EXCIPIENTS (Validation of Analytical Procedures)
3.2.S.4.5 CONTROL OF DRUG SUBSTANCE (Justification of Specification) 3.2.P.4.4 CONTROL OF EXCIPIENTS (Justification of Specifications)
3.2.S.5 REFERENCE STANDARDS 3.2.P.4.5 CONTROL OF EXCIPIENTS (Excipients of Human or Animal Origin)
3.2.S.6 CONTAINER CLOSURE 3.2.P.4.6 CONTROL OF EXCIPIENTS (Novel Excipients)
3.2.S.7.1 STABILITY (Summary and Conclusions) 3.2.P.5.1 SPECIFICATIONS
3.2.S.7.2 STABILITY (Post Approval Stability Protocol and Stability Commitment) 3.2.P.5.2 ANALYTICAL PROCEDURES
3.2.S.7.3 STABILITY (Stability Data) 3.2.P. Drug Product 3.2.P.5.3 VALIDATION OF ANALYTICAL PROCEDURES
3.2.P.5.4 BATCH ANALYSES
3.2.P.5.5 CHARACTERIZATION OF IMPURITIES
3.2.P.5.6 JUSTIFICATION OF SPECIFICATIONS
3.2.P.6 REFERENCE STANDARDS OR MATERIALS
3.2.P.7 CONTAINER CLOSURE
3.2.P.8.1 STABILITY SUMMARY AND CONCLUSIONS
3.2.P.8.2 POSTAPPROVAL STABILITY PROTOCOL AND STABILITY COMMITMENT
3.2.P.8.3 STABILITY DATA

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DHS, FDA, CDER. (2001, August) Guidance for Industry. M4Q: CTD-Quality. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073280.pdf
Module 3.2.S Drug Substance (DS)
Section Title Functional Area
3.2.S.1 General Information DS Characterization
3.2.S.2 Manufacture DS Manufacture
3.2.S.3 Characterization DS Characterization
3.2.S.4 Control of Drug Substance Analytical
3.2.S.5 Reference Standard Analytical
3.2.S.6 Container Closure System DS Manufacture
3.2.S.7 Stability Stability

Slide
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Example: 3.2.S.1. & 3.2.S.2.
3.2.S.1. GENERAL INFORMATION [{DRUG SUBSTANCE NAME}, {MANUFACTURER}]
3.2.S.2. STRUCTURE [{DRUG SUBSTANCE NAME}, {MANUFACTURER}]
• For NCE
• The structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass
should be provided.
• For Biotech
• The schematic amino acid sequence indicating glycosylation sites or other posttranslational modifications and relative molecular
mass should be provided, as appropriate.
• Structural Formula
• {Structural Formula}
• Stereochemistry
• {Stereochemistry Information}
• Molecular Formula
• {Molecular Formula}
• Relative Molecular Mass
• {Relative Molecular Mass}

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3.2.S.7. STABILITY SUMMARY AND CONCLUSIONS [{DRUG
SUBSTANCE NAME}, {MANUFACTURER}]
The types of studies conducted, protocols used, and the results of the studies
should be summarized. The summary should include results, for example, from
forced degradation studies and stress conditions, as well as conclusions regarding
storage conditions and retest date or shelf life, as appropriate.
Number of batches should be confirmed with the FDA at the pre-NDA meeting but
typically three batches manufactured at the pilot scale is the minimum. These
should be from the same synthetic route as the proposed production process and
of the same quality starting materials and container closure systems.
Protocol discussion should include discussion about parameters that are
susceptible to change, any physicochemical, biological, and microbiological tests.
Also note that stability studies may have additional testing that is not in the final
drug substance release specifications.
Reference ICH guidances Q1A, Q1B, and Q5C.

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DS Manufacture Special Considerations
Detailed flow charts: materials, parameters, testing
Critical steps: Define and justify testing
Biotech: Batch numbering, pooling, cell line development, elution profiles,
column/membrane lifetimes
Intermediates: QC and stability data
MFG Development: Batch history (all scales from pre-clinical to file), process
changes
Comparability: Side-by-side flowcharts and data

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DS Characterization Special Considerations
Origin of impurities: synthetic, degradation pathways
• Isomerism, stereochemistry, polymorphism
Intermediates
Biotech/proteins: Post-translational, heterogeneity, bioactivity,
immunogenicity
• Full scale manufacture required for Biologics (stability/clinical)
Process impurities: residual solvents and extractables/leachables

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Module 3.2.P Drug Product (DP)
Section Title Functional Area
3.2.P.1 Description & Composition DP Manufacture
3.2.P.2 Pharmaceutical Development DP Manufacture
3.2.P.3 Manufacture DP Manufacture
3.2.P.4 Control of Excipients Analytical
3.2.P.5 Control of Drug Product Analytical
3.2.P.6 Reference Standard Analytical
3.2.P.7 Container Closure System DP Manufacture
3.2.P.8 Stability Stability

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3.2.P.2 Pharmaceutical Development [{Drug Product Name},
{Dosage Form}]
5. MICROBIOLOGICAL ATTRIBUTES [{DRUG PRODUCT NAME}, {DOSAGE FORM}]
Where appropriate, the microbiological attributes of the dosage form should be
discussed including, for example, the rationale for not performing microbial limits
testing for nonsterile products and the selection and effectiveness of preservative
systems in products containing antimicrobial preservatives. If the product has
inherent anti-microbial properties, these should be described here as well.
For sterile products, the integrity of the container closure system to prevent
microbial contamination should be addressed. Preservative selection, level, and
effectiveness should also be discussed.
If product is non-sterile, see Q6A Decision Tree #8.

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ICH Q6A: Decision Tree #8

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DP Manufacture Special Considerations
• PharmDev: Development of formulation/process, container-closure,
compatibility, comparability
• Excipients (serve quality function): Source, characterization, control
• Sterile processes: hold times, transfers, storage
• Sterile Process Validation (FDA guideline)
• Container-closure (FDA guideline)
• Sub-modules for diluents and placebo

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Analytical Special Considerations
• Compendial excipients
• USP, EP, JP
• Non-compendial
• Provide specs
• DS and DP Specs
• Release, shelf-life
• Methods
• Describe development and proposed/alternate methods
• Provide bridging data for revised procedures
• Provide representative chromatograms
• Batch analyses
• Clinical and commercial lots
• Justification of specs
• Provide data and rationales

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Stability Special Considerations
• Data support the label for storage/shipping
• Justification of stability-indicating methods (SIM)
• Stress (forced degradation) studies
• Pilot studies: justify lots are “representative”
• Full scale manufacture required for Biologics
• Representative scans, chromatograms
• Stability data tables (FDA guideline)

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Module 3 Appendices
Section Title
3.2.A Appendices
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents
3.2.A.3 Novel Excipients
3.2.R Regional Information
3.3 Literature References

Slide
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Facilities & Equipment Special Considerations
• Precautions taken to prevent contamination
• Environmental monitoring
• Flow diagrams: product, personnel, waste
• Other Products: Campaign, changeover
• Cleaning validation summary
• Equipment: Product-contact, sterilization

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Adventitious Agents Special Considerations
• Required when process includes live cells
• TSE/BSE Certificates of Suitability (EU)
• Testing
• Cell banks
• In-process
• Release
• Viral clearance and inactivation studies
• History of facility contamination
• BSE-free statement
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Section 09

CMC Considerations
Case study light on mAB

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CMC Requirements
Module 3 “Quality” describes the characterization, control, validation, and
stability requirements consistent with ICH

This information is required for the approval of a new drug

Specific, relevant information is updated for post approval changes

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Manufacturing – CMC Considerations
• Process
• Facility
• Utilities
• Equipment

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CMC Considerations for a recombinant protein (mAB)
More Detail - Process Related
Upstream (cell culture process steps)
Downstream (purification process steps)
Formulation
Fill and Finish steps

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CMC Considerations for a recombinant protein (mAB)

• Product Characterization
• Comprehensive analytical studies that demonstrate to products structure
and variants, functionality, degradation mechanisms
• In process controls
• Release specifications
• Stability
• Fill and Finish steps

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Introduction to Specifications
• Chemical molecular entity specifications utilize a specific method to
define correct structure and infer potency
• For example chromatography
• Biopharmaceuticals do not have definitive structure/function methods
• Biopharmaceutical specifications utilize a specific method to test for a
specific “critical quality attribute”
• For example Size Exclusion chromatography to test for aggregate amount

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Quality Cannot be Tested into Product

Recombinant Human
Aspirin IgG MW approx.
MW 136 165,000
Slide
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Specifications
• Specifications are both:

• Tests and acceptance criteria for specific product attributes (potency, purity)

• Tests and acceptance criteria for general drug product quality attributes (sterility,
endotoxin, pH)

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Specifications
The acceptance criteria and the method used together define the
specification:

• The tests and references to analytical procedures and…

• Appropriate acceptance criteria that are numerical limits, ranges or other

criteria for the tests described

ICH Q6A

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Certificate of Analysis (CoA)
Quality Control testing is performed to a Certificate of
Analysis with defined tests and specifications

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Quality Control Testing Program
DP

Environmental
Container In-Process
DS monitoring Excipients
Closures Controls (IPC)
(EM)

Process Purification
IPC Resins EM Raw mat
materials interm

Process Fermentation
Media EM IPC Raw mats
materials interm.

Process Production
EM Media IPC
materials cells

EM Media Cell bank IPC

Light Blue Color Indicates CoA is Necessary

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FDA Required Specifications for Drug Product
Identity
21 CFR 211.84 (d) at least one test shall be conducted to verify the identity of each component of a drug product.
Safety
21 CFR 600.3 (p) safety as the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in relationship to the condition of the recipient at the time.
Strength (or Quantity)
21 CFR 211.65 The amount (or mass) of product
Potency
21 CFR 600.3 (s) specific ability or capacity of the product, as indicated by its appropriate laboratory tests or by adequately controlled
clinical data obtained through the administration of the product in the manner indicated to effect the given result.
Purity
21 CFR 600.3 (r) relative freedom from extraneous matters in the finished product, whether or not harmful to the recipient or deleterious
to the product.
(Stability – Must meet spec’s at end of shelf life!)
21 CFR 211.137 (a) to assure that a drug product meets applicable standards of identity, quality, and purity at the time of use; it shall bear
an expiration date determined by stability testing.

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Establishing Specifications
• Specifications are developed and justified based on the following:
• Materials used in clinical trials and clinical experience
• Manufacturing history at commercial scale
• Relevant development data such as scale down and product characterization
studies
• Stability studies
• Method validation studies

• Sophisticated statistical analysis used to establish control limits

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Reference Materials
• Most Biopharmaceutical potency and purity specifications are defined
relative to a reference material.
• The reference material can be an international standard or developed in
house if none exists.
• Reference materials must be extensively characterized and inventory
controlled carefully.
• QC should have a Reference Material and Critical Reagents Control
Program that ensures inventory and reproducibility.

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Section 10

Class Project

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 Class stats

College background # Applicable technical work experience Year #

Microbiology 1 RA 2 1 10
Chemistry 1 QA/QC 5 2 6
Process development 1
Bioengineering 2
N/A 3
Geology 1
CMC 1
Biology 7 Product development 1
Psychology 2 Biology 3
Nursing 1
Biochemistry 1

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Teams setup guiding principles
Distribute as even as possible
First and second year students
Technical background
Work experience

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Teams setup
Student Teams
Acosta, Alex (aacosta18@kgi) 1
Pham, Cathy (cpham19@kgi) 1
Shah, Diti Ajay (dshah19@kgi) 1
Anyaduba, Uchechukwu (uanyaduba19@kgi) 1
Mohindroo, Neha (nmohindroo18@kgi) 2
Gulati, Divij (dgulati19@kgi) 2
Vizcaya, Joselin (jvizcaya18@kgi) 2
Del Cid, Gissel (gdelcid19@kgi) 2
Mustafa, Ana (amustafa15@kgi) 3
Joshi, Alanna (ajoshi19@kgi) 3
Pecoraro, Joseph (jpecoraro19@kgi) 3
Mataki, Ralston (rmataki17@kgi) 3
Evans, Ronise (revans18@kgi) 4
Nittayo, Benjamin (bnittayo19@kgi) 4
Dang, Jessica (jdang19@kgi) 4
Zimmerman,
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Project scope
Team 1
Elelyso – Goucher’s disease (enzyme replacement)
Truvada – HIV (Gilead)
Team 2
Avastin – CRC
Levonorgestrel – birth control
Team 3
Gardasil – HPV vaccine
Yondelis – targeted chemotherapy
Team 4
Sovaldi – HepC cure
Repatha – hypercholersteremia / atherosclerosis

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Project topics
Propose one small molecule & one Biologic

Status needs to be marketed (US/EU)

Marketing approval no earlier than 2000 no later than 2015

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Section 3 example

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Recommendations
Planning ahead is key to success
• Strategy: Plan ahead, first prepare Summary

• Mapping: Prepare outline with key Messages

• Authoring: The right authors and Accountability

• Reviewing: The right reviewers and Resolution

• Training: Sharing knowledge and Teamwork

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