CMC 101: Introduction to the Chemistry,

Manufacturing, and Controls Sections of a

Regulatory Dossier
Dr. RS Robin Robinett
Merck & Co., Inc.

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 So…. What is my background?
• Education
– Biochemistry – BS
– Chemical Engineering – BS, MS, PhD

• AMWA Certifications
– Editing & Writing Certification
– Pharmaceutical Certification
– Regulatory & Research Advance Certification

• Areas of Experience
– Medical Devices (i.e., diagnostic testing)
– Pharmaceutical (i.e., assay development, assay validation, & clinical trial sample testing)
– Vaccine (i.e., assay development, assay validation, process development, process validation,
CMC)
– Biologics (i.e., CMC)

• CMC Experience
– Clinical Trial Applications (>300 submission in >15 vaccine/biological products)
– Marketing Applications (9 major market, submissions in >10 MOW in 6 vaccine/biological
products)
– Post-Market Applications (5 major market submissions in 3 vaccine/biological products)
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 So…. What is my background?
• CMC is very exciting and challenging
• Writing • Learning about CMC is not so exciting

– Journal articles (14)

– Abstracts/posters (18)
– Presentations at major meetings (9)
– Book chapters (2)

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 Chocolate is fun!!!!
So we will learn about
CMC by working with
examining how CMC
would be prepared for
a D-ration bar.

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 Assignment: Create Module 3 for D-Ration Bar
• Colonel Logan had four requirements for the D ration Bar.
– Weigh 4 ounces (112 g)
– Be high in food energy value (1800 calories or minimum sustenance recommended
each day)
– Be able to withstand high temperatures (heat-resistant up to 120 F or 49 C)
– Taste "a little better than a boiled potato“
• Ingredients
– Chocolate (API or NCE or active)
– Sugar
– Oat flour
– Cacao fat
– Skim milk powder
– Artificial flavoring
• Packaging
– The 4-ounce (112 g) bars' boxes were covered with an anti-gas coating and were
– packed 12 to a cardboard carton, which was also coated
– cartons were packed 12 to a wooden crate for a total of 144 bars to a crate.
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 What We Will Cover
• CTD Pyramid
– Module 2.3
– Module 3
• Nomenclature
– Drug Substance – active pharmaceutical/biological ingredient
– Drug Product – product that is marketed
– Appendix
• Facilities Information
• Adventitious Agents
• Excipients
– Regional
• Module 3 CMC Sections
– Chemistry
– Manufacturing
– Controls
• Typical Module 3 Submission Timeline
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 CTD Pyramid

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 CTD Triangle

Non-
CMC Clinical Clinical

The Common Technical Document is organized into five modules.

• Module 1 has region-specific information and is intended only for that region.
• Module 2 is a summary of quality (CMC), safety (nonclinical), and efficacy
(clinical) information.
• Modules 3, 4, and 5 have the details for quality, safety, and clinical, respectively.
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 Guidance on CMC Content
• ICH harmonized Table of Content, not content
• ICH guidance document gives general guidelines
but there is no specific good source for exact
content
• Content varies widely due to product type
Vaccines
– Pharmaceutical
For
– Biologics Marketing Biologics
– Vaccine Application
– Biosimilars
Pharms
– Generics
500 pg 2500 pg 10,000 pg
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 Guidance on Content
• Level of detail is dependent upon
– Type of Product
• Well characterized (pharms) – least content
• Somewhat characterized (biologics)
• Not characterized (vaccines) – most content

– Country and Their Specific Requirements

– Stage of the Program

• FIH IND – (least content)
• Phase 2B/Phase 3 IND
• Marketing Application – (most content)
• Post-Marketing – (depends upon topics)

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 CMC Section Reference Sheet
Section Drug Substance (3.2.S) Drug Product (3.2.P)
1 General Information Description/Composition
2 Manufacturing
2.6 DS Development Pharmaceutical Development

3 Characterization/Impurities Manufacturing

4 Control of Drug Substance Control of Excipients

• Specifications • Specifications
• Assay Descriptions • Assay Descriptions
• Assay Validation • Assay Validation
• Batch Analysis • Batch Analysis
• Justification of Specs
• Justification of Specs
5 Control of Drug Product
• Specifications
• Assay Descriptions
Reference Standards or Materials
• Assay Validation
• Batch Analysis
• Justification of Specs

6 Container Closure System Reference Standards or Materials

7 Stability
• Stability Summary
Container Closure System
• Commitments
• Stability Data

8 Stability
• Stability Summary
• Commitments
• Stability Data
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 Nomenclature

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 Nomenclature: API/NCE/Active

• API: active pharmaceutical ingredient

• NCE: new chemical entity
• Active: biological material that elicits a
response in the body
– Peptide – two or more amino acids
– Protein – complex combination of amino acids
– Recombinant Protein – genetically engineered
protein commonly grown in E. coli or S. aureus
– Nucleic Acid – DNA or RNA
– Virus – disease causing agent made up DNA or
RNA surrounded by a protein coat
 Theobroma cacao
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 Drug Substance vs Drug Product
Drug Substance Drug Product
• Active ingredient intended to furnish • Dosage form that contains an active
pharmacologic activity or other direct drug ingredient or placebo.
effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease or
to affect the structure or any function of
the body)
– Liquid

– Powder

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 Drug Substance vs Drug Product
Drug Substance Drug Product
• Active ingredient intended to furnish • Dosage form that contains an active
pharmacologic activity or other direct drug ingredient or placebo.
effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease or – Liquid
to affect the structure or any function of
the body
• Elixir
• Injectable
– Liquid or powder • Drops
containing • Gel caps
• Chemical entity
• Virus particles
– Powder
• Proteins • Tablet
• Nucleic acids • Capsule
• Lyophilized powder
– Ointment
– Suppository
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 Appendix – Facilities Information (A1)
For Biotech
– Diagrams provided illustrating the flow in and out of
manufacturing areas
• Raw materials, personnel, waste, intermediate(s)
– Information on other products manufactured in the area
• List of products, type, manufacturing schedules
– Description of product-contact equipment including
cleaning information (single/multi-use)
• Tanks, lines, fermenters, bottles
– Information on design features
• Area classifications (Class 100/Class A),
features to prevent cross contamination

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 Appendix – Adventitious Agents (A2)

• Non-Viral - Information about the avoidance of

• TSE/BSE (spongiform encephalopathy agents)
• Bacteria
• Mycoplasma
• Fungi

• Viral
– Viral Evaluation Studies
• Materials of Animal Origin (e.g., milk, hair, hooves, bones, BSA)
• Materials of Human Origin (e.g., blood, organs)
– Viral Clearance Studies

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 Appendix – Novel Excipients (A3)

• A common is a novel adjuvant (material not

currently licensed as an adjuvant)

• Or maybe Oatmeal???

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 Regional Section
• US
– Environmental exemptions (IND)
– Executed batch records (BLA)
• EU
– Viral safety dossier, TSE/BSE Declaration, GMP
certificates (CTA)
– Materials of Animal Origin Tables, Table A and Table B
(MAA)
• Canada
– Executed batch records (MAA)

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 Module 3 CMC Sections

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 CMC or Quality Sections

• C: Chemistry – Composition of
product

• M: Manufacturing – How we make it

• C: Controls – How we ensure it is what we

say it is
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 C: Chemistry

• General Information (S1)

• Characterization (S3)
• Composition (P1)

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 General Information (S1)

• S1.1: Nomenclature
– Compendial names, chemical names, laboratory names,
other nonproprietary names
• S1.2: Structure
– NCE: stereochemistry, molecular formula, and molecular
mass
– Biotech: amino acid sequence, protein structure, post-
translational modification, nucleic acid sequence
• S1.3: General Properties of Drug Substance
– NCE: physicochemical and other relevant properties
– Biotech: Biological activity
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 S1.1 Nomenclature
The nomenclature that has been used for D Ration
drug substance is provided in Table 1.
Table 1 Nomenclature for D Ration Drug Substance
Name Classification Designation
Code Name HC-1234
CAS Name 83-67-0
Generic Name Theobromine cacao
Trade Name D Ration Bar
ATC Code C03BD01 R03DA07
Drug Bank DB01412
IUPAC Name 3,7-dimethyl-1H-purine-2,6-dione
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 S1.2 Structure
NCE: stereochemistry, molecular formula, and molecular
mass

Chemical Data
Molecular Formula C7H8N4O2
Molecular Mass 180.164 g/mol

Stereochemistry

Source Wikipedia - Theobromine

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 S1.3 General Properties
• Cocoa Butter
• Brittle fracture below 20 ºC
• A melting point about 35 ºC
• Softening around 30 ̶ 32 ºC

Source: International Cocoa Organization; http://www.icco.org/

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 Characterization (S3)

• S3.1: Elucidation of Structure and other

Characteristics
– NCE: confirmation of structure, stereochemistry,
potential polymorphs
– Biotech: primary, secondary, and higher-order
structure, post-translational forms, purity,
bioactivity, immunochemical properties
• S3.2: Impurities
– Anything that is not intentionally added

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 Elucidation of Structure and other
Characteristics
• Characterization Studies (example methods)
– CD: circular dichroism
– FRET: fluorescence resonance energy transfer
– FTIR: Fourier-transform infrared spectroscopy
– GC-MS: gas chromatography-mass spectrometry
– ICP: inductively coupled plasma
– LC-MS: liquid chromatography-mass spectrometry
– MFI: micro-flow imaging
– NMR: nuclear magnetic resonance
– SEM: scanning electron microscopy
– TEM: transmission electron microscopy
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 Impurities

• Anything that is brought into the process

with a raw material or excipient that was not
intentional

Oat Husks

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 Description and Composition of Drug
Product (P1)
– Description of the Dosage Form
– Composition
– Description of Accompanying
Reconstitution Diluents
– Type of Container and Closure
• Used for the dosage form
• Used for accompanying reconstitution diluent, if
applicable

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 Description and Composition of Drug
Product (P1)
HC-1234 drug product (DP) is a nonsterile heavy paste formed into bars by
pressing into molds. Bars contain 4 oz of chocolate paste. Route of
administration is primarily oral with an alternate route of melting the bar in hot
water prior to drinking. The composition of the DP is presented in Table 1.
Table 1 Composition of HC-1234 Drug Product
Compendial Target Amount
Ingredient Grade (parts) Function
Chocolate Liquor
160 It’s a chocolate bar
(> 54% cocoa fat)
Sugar USP, Ph. Eur. Just enough Make it palatable
Oat Flour 30 Increase melting temperature
Cacao Butter 160 Add calories
Skim Milk Powder USP, Ph. Eur. 20 Make taste better
Vanillin Crystals USP, Ph. Eur. 70 Make taste better
Thiamine Hydrochloride USP, Ph. Eur. 1/6 Prevent beriberi

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 CMC or Quality Sections

• C: Chemistry – Composition of product

• M: Manufacturing – How we make it

• C: Controls – How we ensure it is what we

say it is

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 M: Manufacturing

• Manufacturing: S2 and P3
– Materials (S2.3 and P4)
– Manufacturer (S2.1 and P3.1)
– Manufacturing Process (S2.2 and P3.3)
– Manufacturing Process Validation (S2.5 and
P3.5)
– Manufacturing Process Controls (S2.4 and P3.4)
• Development: S2.6 and P2
• Container Closure: S6 and P7
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 Manufacturing Process
(S2.2 and P3.3)
Excipients

Drug
Substance
(active) DP Process
with Many Steps

DS Process with Drug Product

Many Steps (marketed material)

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 Materials (S2.3 and P4)

• Raw Materials (bought from a vendor or made in-house)

– Cocoa Beans
• Drug Substance
– Chocolate Liquor (> 54% cocoa fat)
Cocoa Beans

• Excipients
Chocolate Liquor
– Sugar (Drug Substance)

– Oat Flour
Sugar
– Skim Milk Powder Oat Flour
Skim Milk Powder
– Vanillin Crystals Vanillin Crystals
Thiamine HCl
– Thiamine Hydrochloride
D Ration Bar
(Drug Product)

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 Raw Materials (S2.3)
• S2.3 Control of Materials
• List of materials used in the manufacture of the
drug substance and where each is used
– Raw Materials (materials bought from a vendor)
– Starting Materials (materials made in house)
• Cell Banks
• Master Seeds
– Solvents (material that substance that dissolves a solute)
– Reagents (a substance or mixture for use in chemical analysis or
other reactions)
– Catalysts (a substance that increases the rate of a chemical reaction
without itself undergoing any permanent chemical change)

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 Excipients (P4)
• P4 Control of Excipients
– Natural or synthetic substance formulated with
the active ingredient
• Bulking up formulations that contain potent active
• Confer a therapeutic enhancement (e.g., facilitating
drug absorption or solubility.
• Aid in the manufacturing process (e.g., make powder
flow-ability, create nonstick properties, allow
lyophilization)
• Improve stability over the expected shelf life

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 Manufacturer (S2.1 and P3.1)

The site responsible for manufacturing,

testing, packaging, and releasing D Ration
bars is:
The Hershey Company
100 Crystal A Drive
P.O. Box 810
Hershey, PA 17033

Note: manufacturing, testing, packaging, and release sites may be different.

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 Manufacturing Process (S2.2 and
P3.3) Drug
Substance
DRUG SUBSTANCE PROCESS

D-ration
bar

Excipients
• Sugar
• Oat flour
Drug DRUG PRODUCT PROCESS • Milk
Product • Vanillin
• Cocoa Butter

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 Cocoa Beans
RAW MATERIAL
Raw Material Processing, not Drug Substance Processing

Not described in submission

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 Manufacturing Process Validation
(S2.5 and P3.5)
• Process validation is defined as “the collection and evaluation of
data, from the process design stage through commercial
production, which establishes scientific evidence that a process
is capable of consistently delivering quality product”.*
• Process performance qualification (PPQ) lots are prepared to
confirm manufacturing process performance expectations and
may include.
– Filter qualifications
– Critical equipment and component qualification
– Process simulations (media challenges)
– Shipping qualification

* FDA’s Guidance for Industry: Process Validation: General Principles and Practices

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 Manufacturing Process Controls
(S2.4 and P3.4)
• CPP (Critical Processing Parameter)
– Physical, chemical, biological, or microbiological property or
characteristic that must be controlled directly or indirectly to ensure
the quality of the product.
• CQA (Critical Quality Attribute)
– Process inputs that have a direct and significant influence on CQAs
when they are varied within regular operation range.
• PAR (Proven Acceptable Range)
– A CPP that has been determined to be achievable and appropriate
for the process or processes with which it is associated.
• NOR (Normal Operating Range)
– The target and range at which a process parameter is controlled.

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 Manufacturing Development
(S2.6 & P2)
Safety PPQ/
Clinical
Assessment Commercial
Lots
Lots Lots
Pilot Scale Scale-up Manufacturing Scale

• S2.6 Manufacturing Process Development

– Changes made to drug substance during scale-
up

• P2 Manufacturing Process Development

– Changes made to drug product during scale-up
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 Development (S2.6 & P2)
• S2.6 Manufacturing Process Development
– Changes made to drug substance during scale-up
• P2 Pharmaceutical Development
– P2.1 Components of the Drug Product
• Drug Substance
• Excipients
– P2.2 Drug Product
• Formulation Development
• Overages
• Physiochemical and Biological Properties
• Manufacturing Process Development
• Container Closure System
• Microbial Attributes
• Compatibility

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 Pharmaceutical Development (P2)
• P2.2 Drug Product
– Formulation Development
• Original 12-ounce bar of equal parts of bitter chocolate, sugar, and peanut
butter was palatable but had poor keeping qualities, was thirst-provoking,
and had poor acceptance
– Manufacturing Process Development
• Heavy paste could not flow at any temperature requiring the development
of special processing methods and machinery where material was pressed
into moulds
• Automated process was required due to imminent war
– Container Closure System
• Three 4-ounce bars sealed in parchment paper
• Possible damage by poison gas required new specifications where bar was
placed in a heavy cellophane bag and individual cardboard carton, 12
waxed cartons in a master carton, and 12 master cartons in a wooden
case.

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 Container Closure
Drug Substance Drug Product
Primary Packaging (paper)
Stainless Steel Tanks

Secondary Packaging (crate)

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 Container Closure – (S6)

• What touches the API/NCE/active

• Considerations
– Liquid? Powder? Crystal?
– Storage conditions – room temp, refrigerated,
frozen?
• Typical Storage Systems
– Stainless steel can
– Bottle
– Bags
– Barrels
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 Container Closure – DP Primary (P7)
• Primary Packaging – what touches the product

– Ampoules
– Blister Packs
– Bottles, Caps
– Syringe, Plungers
– Vials, Caps, Seals

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 Container Closure – DP Secondary
(P7)
• Secondary Packaging – what the product or
primary packaging is stored or shipped in
– Trays
– Cartons
– Boxes

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 Container Closure (S6 & P7)
• Container Closure System Description
– Identity of construction materials for each primary
packaging component (e.g., Type-I borosilicate glass,
DEHP plasticized PVC, polyolefin, HDPE, LDPE,
MDPE, PET, PP, PS, stainless steel, etc.)
– Specifications
• Description (e.g., dimension, characteristics,
compendial compliance (USP, Ph. Eur., JP))
• Identification (e.g., name, manufacturer)
• Critical dimensions with drawings (e.g., od, id
height)
– Noncompendial methods with
validation (e.g., dye ingress, microbial
ingress)

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 CMC or Quality Sections

• C: Chemistry – Composition of product

• M: Manufacturing – How we make it

• C: Controls – How we ensure it is

what we say it is
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 C: Controls

• Specifications
– Actual specification (S4.1 & P5.1)
– Justification of specifications (S4.5 & P5.6)
• Assays
– Description (S4.2 & P5.2)
– Validations (S4.3 & P5.3)
• Reference Standards (S5 & P5)
• Batch Analysis (S4.4 & P5.4)
• Characterization of Impurities (P5.5)
• Stability Testing (S7 & P8)
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 Specifications

• Specification – list of drug substance/drug

product requirements including
– A list of tests
– Reference to analytical procedures
– Acceptance criteria (numerical limits, ranges or
other criteria)

• Actual Specification (S4.1 & P5.1)

• Justification of Specifications (S4.5 & P5.6)
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 Specifications

Table 1: Specifications for Drug Product

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 Justification of Specification – Table
Assay Specification Justification
Appearance Dark brown It’s a chocolate bar!
Light weight for shipping and for soldiers that
Weight 4 oz
needed to carrying them in their packs
Be able to withstand high temperatures due to
Melting
>120 F shipping and storage in tropical conditions and
Temperature deserts
Intended to furnish the individual combat
Calories 1800 soldier with the 1,800 calories (7,500 kJ)
minimum sustenance recommended each day
Better than Expectation that the bar is palatable and will be
Taste
potato consumed by the intended recipients.

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 Justification of Specification - Text
Rationale of the Specification
– Test: Melting temperature is tested using
procedures described in Ph. Eur. 1.2.34, USP
<567>, and JP 8.90.
– Criterion: Melting temperature must be >120 F.
– Justification: Bars must be able to withstand
temperatures found during transportation and
storage in all regions of the world without melting
into a big mess prior to consumption. A minimum
melting temperature of 120 F was found to be
acceptable during shipping and storage studies.

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 Assays

• Assays – how materials are tested and how

we know that the test is accurate
– Description (S4.2 & P5.2) – information about
how the actual testing is performed
– Validations (S4.3 & P5.3) – information on what
parameter were checked to make sure the
information is accurate, repeatable, and reliable

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 Assay Description – Melting Temp
Melting point is determined by the capillary method. The point at which the last solid
particle of a compact column of a substance in a tube passes into the liquid phase is
considered the melting point. A summary of the test method is provided in Table 1. This
method was verified, and the verification summary is provided in Section 3.2.S.4.3.3..

Table 1: Summary of Melting Point Temperature Assay

Attribute Description

Assay Type Capillary method, Class I, Apparatus 1

Test Samples Drug product
• Glass vessel containing a liquid bath
• Means of stirring
Key Equipment • Thermometer
• Alkali-free hard-glass capillary tubes with internal diameter of
0.90.1 mm, a wall of 0.100.15 mm, and sealed at one end
Reference Standard Benzophenone: melting point reference standards
Positive/Negative Controls Regular Hershey bar (positive);
Critical Reagents None
Samples, taken across the lot, are run in triplicate with reference standard panel and
Sampling Plan
controls
Reportable Result Report in F to one decimal point.

Compendial Compliance USP <741>, Ph. Eur. 2.2.14

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 Assay Description - Details
• Sample Preparation
– Test sample is dried in vacuo at 105 C for 5 hours.
– Dried sample is reduced to a fine powder using a mortar and
pestle.
– Powder is packed tightly into a capillary glass tube to form a
column 2.5 to 3.5 mm in height.
• Test Procedure
– Bath temp is raised to ~10 C less than melting temperature.
– Heating rate is adjusted to 1 C/min.
– Capillary tube is immersed with the closed end near center of
thermometer bulb.
– Melting range is determined by observing the temperature at which
the test sample begins to collapse and is completed at the
temperature it becomes liquid throughout.
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 Assay Description – Other Parameters
• System Suitability
– Coefficient of determination (R2) of the standard curve
– Percent spike recovery of spiked samples and spiked control
– % coefficient of variation of spiked samples and spiked control
• Data Processing
– Curve fit used for standard curve
– Equations used to calculate values for both samples and controls

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 Validation vs Compendial vs
Qualification/Verification
• Compendial – assay is performed using testing
described in a pharmacopeia, considered
validated if run as described
• Qualification/Verification
– Compendial to confirm there are no components that
would impact assay performance
– Validated with another product to ensure assay
performs as expected with the new matrix
• Validation – prove the assay performs reliably
between people, labs, and material lots
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 Typical Assay Validation Parameters
• Precision: closeness of individual results when the same sample repeated several times
– Within-run or intra-batch precision: repeatability during a single analytical run
– Between-run or inter-batch precision: repeatability between 2+ analysts, 2+ laboratories, 2+ reagent lots, 2+
sample preparations, etc. (type of assay determines what is tested)
• Intermediate precision – within a laboratory variation
• Reproducibility – between laboratory variation

• Accuracy: closeness between accepted value and actual sample value

• Sensitivity or Limit of detection (LOD): lowest analyte concentration that can reliably
differentiate from background noise
• Specificity: ability to detect a certain material within it’s matrix
• Linearity: ability (within a given range) to obtain test results directly proportional to
analyte concentration (amount) in the sample.
• Range: interval between upper and lower concentration (amounts) where a suitable level
of precision, accuracy, and linearity has been demonstrated
• Robustness: shows that method remains unaffected by small, but deliberate, variations
in any of the method parameters

•
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 Assay Validation/Verification
• Description
Melting point in drug product samples is performed using a compendial capillary-based assay
described in USP <741> and Ph. Eur. 2.2.14 (Section 3.2.P.5.2.3). The method was verified
using two lots of benzophenone reference standard and two lots of drug product. A summary of
the verification results is shown in Table 1.
Table 1: Summary of Verification Parameters for the Melting Point Temperature Assay

Verification Parameter Acceptance Criterion Verification Result

Melting Point Verification
Lot 1123A: 48.7 °C
Benzohenone 4749 °C
Lot 1569D: 47.3 °C
Lot 42-11-43: 49 C
Drug Product 49 C
Lot 43-7-123: 49 C
Intermediate Precision
Lot 1123A: 15.2%
Benzohenone
Lot 1569D: 11.9%
%CV between results is ≤20%
Lot 42-11-43: 13.4%
Drug Product
Lot 43-7-123: 17.2%

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 Assay Validation/Verification
• Data
Tables and figures as appropriate
• Discussion
All analyses were performed using the samples from
drug product Lots 42-11-043 and 43-7-123.
• Conclusion
All method verification acceptance criteria were met for
the melting point method. The method is acceptable
for use for drug product samples.

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 Reference Standards (S5 & P5)

• Reference Standards
– Materials used in assay that have a known
concentration
– Results of known standards are used to calibrate
equipment and predict values for unknown
samples

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 Reference Standards
• Melting-point standard examples:
Standard Melting-Point Range
Benzophenone +47 to +49°C
p - Nitrotoluene +52 to + 54°C
Vanillin +81 to +83°C
Benzoic Acid +121 to +123°C
Phenacetin +133 to +135°C
Salicylic Acid +158 to +160°C
Sulphanilamide +164 to +166°C
Caffeine +235 to +237°C
Carbazole +244 to 248°C
Anthraquinone +283 to +286°C

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 Stability (S7 & P8)

• Stability information includes

– Stability Summary and Conclusions (S7.1 &
P8.1)
– Post-Approval Stability Protocol and Stability
Commitment (S7.2 & P8.2)
– Stability Data (S7.3 & P8.3)

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 Stability Summary and Conclusions (S7.1 & P8.1)

• Stability Summary and Conclusions

– Types of studies conducted
– Protocols used
– Results of studies summarized with respect to
storage conditions and retest or shelf-life (e.g.,
ICH studies including forced degradation and
stress conditions)

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 Stability Summary and Conclusions
This section provides a summary of the stability studies performed to support the
shelf life of the HC-1234. An initial shelf-life of 12 months at 120 °F is proposed
based on real-time stability data from the formal stability study (FSS) lots. The
shelf-life of the DP at 120 °F will be extended to a maximum of 24 months. Lots
used for stability studies are summarized in Table 1.

.Table 1: HC-1234 Lots Used in Stability Studies

Lot Date of Lot Size Available Data at

Number Manufacture (bars) Lot Purpose 120 F
42-11-043 17-Nov-1942 11,792 FSS 12 months
43-7-123 29-Jul-1943 567,987 PPQ 6 months
FSS: formal stability studies
PPQ: process performance qualification

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 Stability Data (S7.3 & P8.3)

• Results of the stability studies

– List of testing
– Acceptance criteria
– Initial testing results (i.e., batch release)
– Testing times and data where available
• Batches typically include
– Pivotal batches
• Clinical trials – clinical lots, important safety assessment lots
• Formal stability studies – lots to support shelf life
• Marketing – process and clinical consistency lots; critical lots
• Accelerated stability testing
– All batches that are included in the batch analysis
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 Stability Data
Table 1: Stability Results for Lot 42-11-043 at Room Temperature,
Ambient Humidity
Acceptance Stability Test Intervals
Test Criteria Initial 6 month 1 year 2 years
Dark Dark Dark
Appearance Dark brown TBT
brown brown brown
Weight 4 oz 4.1 oz 4.0 oz 4.0 oz TBT
Melting
>120 F 127 F 128 F 123 F TBT
Temperature
Calories 1800 1820 1837 1818 TBT
Better than
Taste yes yes yes TBT
potato
TBT: to be tested

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 Post-Approval Stability Protocol and Stability
Commitment (S7.2 & P8.2)

• Post-approval stability protocol and commitment

• A commitment to continue the ongoing stability
studies to support the shelf-life
• Ongoing long-term stability studies
– Information about test methods and specifications
• Post-approval stability studies
– Intentions of lots to be put on stability
– Protocol for studies

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 Stability Protocol and Commitment
• This section provides the post-approval stability protocol, stability commitment, and
ongoing stability studies (Section 3.2.S.7.1) for drug product manufactured at the
commercial manufacturing site. These studies will support the shelf life of the K-rations
stored in paper packaging stored at room temperature/ambient humidity. The data used
to support the proposed expiry at the long-term storage condition were evaluated against
the proposed commercial specifications (Section 3.2.S.4.1).
Table 1: Protocol for Annual Stability Studies on Commercial Batches
Stored at Room Temperature/Ambient Humidity

Stability Test Intervals

Test Protocol
Initial 1 month 6 months 1 year

Appearance X X X X

Weight Scale X X - X
Melting Class 1a melting
X - - X
Temperature point
Calories Calorimeter X X X X
Better than X X X
Taste X
potato
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 Typical Module 3 Submission
Timeline

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 Typical Timeline
Duration
Step (weeks) Purpose
Draft Content 4-12 Create content
Team Review 2-4 Get content alignment within section
Update Sections/
Comment Resolution 4-8 Update sections based upon review
Management Review
2-4 Get content alignment between sections
Update Sections/
Comment Resolution 4-8 Update sections based upon review
End-to-End Review
2-4 High level consistency check & approval
Comment Resolution 1-2 Resolve E2E comments
Quality Check 4-6 Ensure accuracy of content
Publishing 4-6 Create submission document
Total 2754 weeks
 Realistically, 6 months maybe for a pharm product, 1.5 – 2 years for a
vaccine or biological product
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 Factors Effecting Timing

• Team members
– Number of dedicated people working on the
submission
– Experience of the team members
• In-house or CMO/CRO organizations
– Manufacturing site
– Packaging site
– Analytical data
– Stability data

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 Factors Driving ( or delaying) Timeline

• Data availability from

– Stability Studies
– Process Performance Qualification Lots
– Validation Studies (e.g., shipping, cleaning, etc.)
– Adventitious Agent Testing
– Characterization Work (e.g., leachables)
– On and on and on

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 References

• Good references to explore more about CMC

– ICH Harmonised Tripartite Guideline, The Common
Technical Document for the Registration of
Pharmaceuticals for Human Use: QUALITY –
M4Q(R1), QUALITY OVERALL SUMMARY OF
MODULE 2 MODULE 3 : QUALITY , 12-Sep-2002
– International Conference on Harmonization of
Technical Requirements for Registration of
Pharmaceuticals for Human Use, M4Q
Implementation Working Group Questions &
Answers (R1), 17-Jul-2003

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 Questions?

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 Contact Information

Robin Robinett
Merck
770 Sumneytown Pike, PO Box 4
Bldg WP2A-20
West Point, PA 19486
215-652-7331

[email protected]

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