Specification of Drug Substances and

Products: Development and Validation

of Analytical Methods 2nd Edition
Christopher M. Riley
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SPECIFICATION OF
DRUG SUBSTANCES
AND PRODUCTS
Development and Validation of Analytical Methods

SECOND EDITION

Edited by

Christopher M. Riley
Riley and Rabel Consulting Services, Inc., Maryville, MO, United States

Thomas W. Rosanske
T. W. Rosanske Consulting, Overland Park, KS, United States

George L. Reid
Cardinal Health Regulatory Sciences, Kansas City, MO, United States
Elsevier
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 Contributors
Kent L. Amsberry Cardinal Health Regulatory Sci-
ences, Overland Park, KS, United States
Daniel W. Armstrong Department of Chemistry
and Biochemistry, University of Texas at Arlington,
Arlington, TX, United States
S. Baertschi Baertschi Consulting LLC, Carmel, IN,
United States
James Bergum BergumSTATS, LLC, Howell, NJ,
United States
Ping Chen Albany Molecular Research, Inc., West
Lafayette, IN, United States
A.M. Clarke Novartis, GDD/TRD/Chemical &
Analytical Development (CHAD), Novartis
Campus, Basel, Switzerland
Ian Clegg Bruker BioSpin
Jennifer E. Dally GlaxoSmithKline, King of Prussia,
PA, United States
Vivian A. Gray V. A. Gray Consulting, Inc., Hockes-
sin, DE, United States
Brian L. He Chemical and Synthetic Development,
Bristol-Myers Squibb, New Brunswick, NJ, United
States
Qin C. Ji Bristol-Myers Squibb, Princeton, NJ,
United States
E. Kikovska-Stojanovska Research and Develop-
ment, Alkaloid AD-Skopje, Skopje, Republic of
North Macedonia (former); Merck Healthcare
KGaA, Global Regulatory Affairs CMC, Darmstadt,
Germany (present)
Ryan Klein Tergus Pharma, Durham, NC, United
States
Yin Hwa Lai Cardinal Health Regulatory Sciences,
Overland Park, KS, United States
David K. Lloyd Analytical and Bioanalytical Devel-
opment, Bristol-Myers Squibb, New Brunswick, NJ,
United States
xi
Myrna A. Monck GlaxoSmithKline, King of Prussia,
PA, United States
Kurt L. Moyer Pine Lake Laboratories, Bristol, CT,
United States
B. Olsen Olsen Pharmaceutical Consulting, Wake
Forest, NC, United States
John D. Orr Associated Analytics LLC, Amesbury,
MA, United States
Li Pan PTC Therapeutics, South Plainfield, NJ,
United States
Ernest Parente Cardinal Health Regulatory Sci-
ences, Overland Park, KS, United States
R.L. Phelps PharmAdvance Consulting, Inc.,
Sequim, WA, United States
George L. Reid Cardinal Health Regulatory Sci-
ences, Kansas City, MO, United States
Christopher M. Riley Riley and Rabel Consulting
Services, Inc., Maryville, MO, United States
Thomas W. Rosanske T.W. Rosanske Consulting,
Overland Park, KS, United States
Michael Ruberto Material Needs Consulting, Mon-
tvale, NJ, United States
James R. Scull Element Materials Technology, Santa
Fe Springs, CA, United States
Eric B. Sheinin Sheinin & Associates LLC, North
Potomac, MD, United States
Pamela A. Smith Improved Pharma, West Lafay-
ette, IN, United States
Mohsen Talebi Department of Chemistry and
Biochemistry, University of Texas at Arlington,
Arlington, TX, United States
Kailas Thakker Tergus Pharma, Durham, NC,
United States
Patrick A. Tishmack Albany Molecular Research,
Inc., West Lafayette, IN, United States
xii Contributors

Linna Wang Bristol-Myers Squibb, Princeton, NJ,
United States
Qinggang Wang Chemical and Synthetic Develop-
ment, Bristol-Myers Squibb, New Brunswick, NJ,
United States
Harry Yang Non-Clinical Biostatistics, Translational
Sciences, MedImmune, LLC, Gaithersburg, MD,
United States
Long Yuan Bristol-Myers Squibb, Princeton, NJ,
United States
 C H A P T E R

1
Introduction
Christopher M. Riley1, Thomas W. Rosanske2, George L. Reid3
1
Riley and Rabel Consulting Services, Inc., Maryville, MO, United States; 2T.W. Rosanske Consulting,
Overland Park, KS, United States; 3Cardinal Health Regulatory Sciences, Kansas City, MO,
United States

O U T L I N E

References 6

The previous edition of this book was pub-
lished in 2014.1 The general framework of that
book was based on key quality guidelines
(Q1eQ11)2e26 published by the International
Council on Harmonisation (ICH) (then referred
to as International Conference on Harmoniza-
tion), along with regional regulatory guidelines
and compendial requirements. Since then, revi-
sions to some published ICH guidelines have
occurred, and new guidelines related more to
the drug development process and life cycle
management have been added (e.g., ICH
Q12eQ14)27e29 either in the form of drafts or
concept papers.
This book edition references the new and
updated ICH guidelines, regulatory guidance
documents, and compendial requirements as
the basic framework for the text. The primary ob-
jectives of this book are (1) to capture the many
regulatory and technical advances that have
occurred in the field since publication of the pre-
vious edition, (2) to provide an updated critical
and comprehensive assessment of the ap-
proaches used to identify the key quality attri-
butes of a drug substance or drug product that
impact the safety, efficacy, and manufacturabil-
ity, (3) to select appropriate analytical techniques
based on the sensitivity, accuracy, and precision
needed to adequately measure and control the
identified quality attributes, and (4) to determine
how the analytical methods are developed and
validated for their intended use. New chapters,
not included in the first edition,1 cover analytical
methods in the clinical phase of development

Specification of Drug Substances and Products

https://doi.org/10.1016/B978-0-08-102824-7.00001-4 3 Copyright © 2020 Elsevier Ltd. All rights reserved.
4 1. Introduction
(Chapter 5), method transfer (Chapter 6), process
analytical technology (Chapter 7), mutagenic im-
purities (Chapter 12), drug release for topical
products (Chapter 19), and biotechnology prod-
ucts (Chapters 20 and 21). The previous edition1
chapters have been updated.
The ICH Quality Guidelines form the general
framework for the application of worldwide
marketing submissions and reviews of new
drug products. Where the quality
(Q1eQ14)2e29 and relevant key multidisci-
plinary (M4, M7eM10)30e34 ICH Guidelines fit
into the general drug development, framework
is shown in Fig. 1.1. The Common Technical
Document (CTD, ICH M4)30 or its electronic
version (eCTD, ICH M8) is the generally harmo-
nized document most widely used by the ICH
and many non-ICH countries for clinical trial
and marketing authorization applications. The
ICH Quality Guidelines Q1eQ6 describe most
of the general requirements for the analytical
content of the CTD and are then followed by a
series of guidelines (Q7eQ14) addressing some
Discovery Preclinical Phase I
• QUALITY (ANALYTICAL CONTENT)
• Stability (Q1)
• Validation (Q2)
• Impurities (Q3)
• Pharmacopeias (Q4)
• Biotechnology Products (Q5)
• Specifications (Q6)
• MULTIDISCIPLINARY
• Common Technical Document (CTD) (M4)
• Mutagenic Impurities (M7)
• Electronic Common Technical Document (eCTD) (M8)
FIGURE 1.1 Illustration of how the ICH quality guidelines fit into the drug-development process.
I. Introduction
of the key approaches to drug development
and life cycle management that may also be
included in the CTD.
According to the ICH definition, the specifica-
tion of a new drug substance or a drug product
(Q6A and Q6B) contains three elements: (1) the
quality attributes (or tests), (2) references to the
associated methods, and (3) the acceptance
criteria. While ICH guidelines on specifications
(Q6) and method validation (Q2) describe what
information regulators expect to see in a new
drug application, they provide very little detail
on how the guidelines are to be implemented
at the technical level. The absence of specific di-
rection on the implementation of the ICH Qual-
ity Guidelines also allows for sponsor-to-
sponsor differences, including the application
of new and improved analytical technologies
(such as process analytical technology) targeted
to measuring the critical quality attributes which
impact product performance. In keeping with
the spirit of the previous edition of this book,
this version is not intended as just a review of
NDA
MAA
Product
Phase II Phase III Launch Life-Cycle
Management
• QUALITY (DRUG DEVELOPMENT/LIFE-CYCLE
MANAGEMENT)
• GMPs for Active Pharmaceutical Ingredient (Q7)
• Pharmaceutical Development (Q8)
• Quality Risk Management (Q9)
• Pharmaceutical Quality System (Q10)
• Development/Manufacture of DS (Q11)
• Life Cycle Management (Q12)
• Continuous Manufacturing (Q13)
• Analytical Development (Q14)
 1. Introduction
existing regulatory guidance and industry prac-
tices. Rather, in addition to discussing conven-
tional approaches, each chapter will address
current and critical issues and novel approaches.
The authors have again been carefully selected as
being former members of the ICH Expert Work-
ing Groups charged with developing the ICH
guidelines and/or subject-matter experts from
industry, academia, and government labora-
tories. This book provides the reader not only
with an understanding of industry best practices
but also with future directions.
The general principles of the specification
setting and method validations processes are
reviewed in Chapter 2 and Chapter 3, respec-
tively, and explored in greater detail in subse-
quent chapters. The ICH Guideline on Method
Validation (Q2(R1)) was primarily developed
with chromatographic techniques in mind and
the following tests in particular:
• Identification tests
• Quantitative tests for impurities content
• Limit tests for the control of impurities
• Quantitative tests of the active moiety in
samples of drug substance and drug product
or other selected components in the drug
product (e.g., preservatives, antioxidants).
Recently, ICH constituted a new Expert
Working Group, which will develop a new topic
Q14 Analytical Method Development as well as
expand Q2(R1) to include the validation of non-
chromatographic methods.29 This Q14 guideline,
when drafted, is expected to apply the concept of
Quality by Design (QbD) and analytical life-cy-
cle management to pharmaceutical analysis
(Analytical QbD [AQbD]). The concept QbD
was introduced into the drug development pro-
cess through the more recent ICH Guidelines
(Q8eQ12),23e27 with the primary aim of
increasing the understanding and the knowl-
edge base of the processes for the manufacturing
of drug substances and products. Contemporary
thoughts and tactics for AQbD are described in
Chapter 4 and analytical life-cycle management
I. Introduction
5
in Chapter 10. General process considerations
related to analytical methods (clinical phase
methods and specifications, analytical method
transfer, and process analytical technology) are
discussed in Chapters 5e7. Chapters 8e23
discuss specific applications (e.g., elemental im-
purities, solid state characterization) and how
the principles of method validation set forth in
Q2(R1) have been adapted to these nonchroma-
tographic techniques. Chapter 24 pertains to
the development and validation of bioanalytical
methods and Chapter 25 discusses microbial and
endotoxin testing methods.
In addition to providing the “what” but not
the “how” to set specifications and validate
analytical methods, the ICH Quality Guidelines
(Q1eQ6) only define what is to be provided for
product registration in a new drug application.
They expressly exclude what is expected in the
clinical stages of drug development such as an
Investigational New Drug Application (IND in
the United States). Therefore, a common theme
throughout the book is how the methods,
method validations, and specifications evolve
over the drug life cycle (see Fig. 1.2).
The “how” of the earlier Q1eQ6 Guidelines
are to be applied is described in large part in sub-
sequent guidelines (Q7eQ14). For example, 16
attributes were identified for a polymeric excip-
ient, derived from a natural product, and used
in sustained release product to control the poten-
tially variable performance of the excipient in the
product.35 The only way to manage the 16 attri-
butes and achieve acceptable product perfor-
mance was to understand the contributions of
the various attributes and the interactions be-
tween them (i.e., each physical and chemical
characteristic). By analytically measuring each
of the attributes and then using statistical/che-
mometric approaches, it was possible to define
a “design space” of all parameters which could
deliver the overall desired effect of drug release.
These same statistical/chemometric approaches
can also be used to better connect method perfor-
mance requirements with respect to control
6 1. Introduction

Life-cycle

Define
CTQs
Perform-
Continuous
ance
Monitoring
Needs

Evaluate
Risk
Transfer Method Develop
Assessment
Method Performance Method
Analytical
Target
Profile

Modeling Design
Validation
Space

Validation System Development

Control
Suitability
Space
Needs

FIGURE 1.2 The life-cycle of a pharmaceutical test method.

limits for critical quality attributes as well as to
monitor long-term analytical method perfor-
mance over the method’s life cycle. This is an
area critical to the development and mainte-
nance of analytical methods.
Thus, this edition is intended to be not only a
review of the ICH Guidelines relating to the
specification and method validation of new
drugs but also to provide a critical analysis of
the regulatory guidelines and a comprehensive
treatment of how those guidelines are applied
to the development of new drugs. It is intended
to be an updated educational tool and a refer-
ence source for those involved in the develop-
ment and regulation of new drug products.
References
1. Riley, C. M.; Rosanske, T. W.; Riley, S. R.; Eds.
Specification of Drug Substances and Products, Development
and Validation of Analytical Methods; Elsevier, 2014.
2. Stability Testing of New Substances and Products
(Q1A(R2)). The International Council on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals
for Human Use, Second Revision, 2003.

I. Introduction
 References
3. Stability Testing: Photostability Testing of New Drug
Substances and Products (Q1B). The International Council
on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, 1996.
4. Stability Testing: New Dosage Forms (Q1C). The Interna-
tional Council on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use, 1997.
5. Bracketing and Matrixing Design for Stability Testing:
New Drug Substances and Products (Q1D). The Interna-
tional Council on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use, 2002.
6. Evaluation of Stability Data (Q1E). The International
Council on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use, 2003.
7. Stability Data Package for Registration Applications in
Climatic Zones III and IV (Q1F). The International Council
on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, 2006.
8. Validation of Analytical Procedures: Text and Meth-
odology (Q2(R1)). The International Council on Harmo-
nisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use, First Revision, 1996.
9. Impurities in New Drugs Substances (Q3A(R2)). The In-
ternational Council on Harmonisation of Technical Require-
ments for Registration of Pharmaceuticals for Human Use,
Second Revision, 2006.
10. Impurities in New Drugs Products (Q3B(R2)). The Inter-
national Council on Harmonisation of Technical Require-
ments for Registration of Pharmaceuticals for Human Use,
Second Revision, 2006.
11. Impurities: Guideline for Residual Solvents (Q3C(R7)).
The International Council on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use, Seventh Revision, 2018.
12. Impurities: Guideline for Elemental Impurities
(Q3D(R1)). The International Council on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals
for Human Use, Second Revision, 2019.
13. Pharmacopeial Harmonisation (Q4A). The International
Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use, in
Development. Unpublished.
14. Evaluation and Recommendation of Pharmacopeial
Texts for Use in the ICH Regions (Q4B) [and associated
Annexes]. The International Council on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals
for Human Use, 2007 and 2010e2013.
15. Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin
(Q5A(R1)). The International Council on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals
for Human Use, First Revision, 1999.
I. Introduction
7
16. Analysis of the Expression Construct in Cells Used for
Production of r-DNA Derived Protein Products (Q5B).
The International Council on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use, 1995.
17. Stability Testing of Biotechnological/Biological Prod-
ucts (Q5C). The International Council on Harmonisation
of Technical Requirements for Registration of Pharmaceuti-
cals for Human Use, 1995.
18. Derivation and Characterisation of Cell Substrates Used
for Production of Biotechnological/Biological Products
(Q5D). The International Council on Harmonisation of Tech-
nical Requirements for Registration of Pharmaceuticals for
Human Use, 1997.
19. Comparability of Biotechnological/Biological Products
Subject to Changes in their Manufacturing Process
(Q5E). The International Council on Harmonisation of Tech-
nical Requirements for Registration of Pharmaceuticals for
Human Use, 2004.
20. Specifications: Test Procedures and Acceptance Criteria
for New Drug Substances and New Drug Products:
Chemical Substances (Q6A). The International Council
on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, 1999.
21. Specifications: Test Procedures and Acceptance Criteria
for Biotechnological/Biological Products (Q6B). The Inter-
national Council on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use, 1999.
22. Good Manufacturing actice Guide for Active Pharma-
ceutical Ingredients (Q7). The International Council on
Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, 2000.
23. Pharmaceutical Development (Q8(R2)). The International
Council on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use, Second
Revision, 2009.
24. Quality Risk Management (Q9). The International Council
on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, Second Revision, 2005.
25. Pharmaceutical Quality System (Q10(R4)). The Interna-
tional Council on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use, Fourth
Revision, 2010.
26. Development and Manufacture of Drug Substances
(Q11). The International Council on Harmonisation of Tech-
nical Requirements for Registration of Pharmaceuticals for
Human Use, 2012.
27. Technical and Regulatory Considerations for Pharma-
ceutical Product Lifecycle Management (Q12). The Inter-
national Council on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use. Draft Guidance, 2017.
8 1. Introduction
28. Continuous Manufacturing of Drug Substances
and Drug Products (Q13). The International Council
on Harmonization of Technical Requirements for Registra-
tion of Pharmaceuticals for Human Use. Concept Paper,
2018.
29. Analytical Procedure Development (Q14). The Interna-
tional Council on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use.
Concept Paper, 2018.
30. The Common Technical Document for the Registration
of Pharmaceuticals for Human Use: Quality e
M4Q(R1). The International Council on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals
for Human Use, First Revision, 2002.
31. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential
Carcinogenic Risk (M7). The International Council on
Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use, 2017.
I. Introduction
32. Electronic Common Technical Document (eCTD) (M8).
The International Council on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use, 2016.
33. Biopharmaceutics Classification System-based Bio-
wavers (M9). The International Council on Harmonisation
of Technical Requirements for Registration of Pharmaceuti-
cals for Hunan Use. Draft Guidance, 2018.
34. Bioanalytical Method Validation (M10). The International
Council of Harmonisation on Technical Requirements for
Registration of Pharmaceuticals for Human Use. Draft
Guidance, 2019.
35. Brown, B.; Caster, D.; Clarke, B.; Hopkins, S.;
Llewelyn, J.; Martin, L.; Meehan, E.; Timko, R.;
Yang, H. Extended Release Formulations Comprising Que-
tiapine and Methods for Their Manufacture, 2011. United
States Patent Application, US 2011/0319383.
 C H A P T E R

2
General principles and regulatory
considerations: specifications and shelf life
setting
Christopher M. Riley1, Harry Yang2
1
Riley and Rabel Consulting Services, Inc., Maryville, MO, United States; 2Non-Clinical Biostatistics,
Translational Sciences, MedImmune, LLC, Gaithersburg, MD, United States

O U T L I N E

2.1 Introduction 10 2.3.2.1 Data sources 29

2.3.2.2 Frame of reference 29
2.2 Regulatory requirements 11
2.3.2.3 Sources of variation 29
2.2.1 International council on harmonization
2.3.2.4 Clinical relevance 30
of the technical requirements for
2.3.2.5 Multivariate specifications 30
pharmaceuticals for human use 11
2.3.2.6 Specifications in early
2.2.1.1 Universal tests 14
development 30
2.2.1.2 Specific tests 17
2.3.3 Statistical tools for setting acceptable
2.2.2 Compendial requirements 19
limits 32
2.2.2.1 Testing requirements 20
2.2.2.2 USP general chapters <1> 2.4 Shelf life and retest date 33
to <5> 21
2.5 Release and stability specification 35
2.2.3 Biotechnology products
(macromolecules) and biological 2.6 Reference standards 36
products 24 2.6.1 Qualitative tests 37
2.2.4 Regional differences 25 2.6.2 Quantitative tests 37
2.6.2.1 Drug substance 37
2.3 Specification setting process 27
2.6.2.2 Impurities 38
2.3.1 Identification of critical quality attributes 27
2.6.3 Pharmacopeial reference standards 38
2.3.2 Considerations in setting acceptance
criteria 29 2.7 Documentation 39

Specification of Drug Substances and Products

https://doi.org/10.1016/B978-0-08-102824-7.00002-6 9 Copyright © 2020 Elsevier Ltd. All rights reserved.
10 2. General principles and regulatory considerations: specifications and shelf life setting

2.8 Conclusions 39 References 40

2.1 Introduction on those characteristics found to be useful in

The specificationa of a drug substance (DS)
(APIb) or drug product (DP) contains the attri-
butes, analytical methods, and acceptance
criteria which are designed to ensure that a
product is acceptable for its intended applica-
tion. However, conformance to the set of
criteria described in the specification alone
does not assure the quality, safety, and efficacy
of a pharmaceutical product because the
specification is only part of the overall control
strategy of the DS and the DP contained the
current Good Manufacturing Practices (cGMPs)
for human products and Good Laboratory
Practices (GLP) for animal studies. The Interna-
tional Council for Harmonisation (ICH) of the
Technical Requirements for Pharmaceuticals
for Human Use Guidelines on Specifications
(Q6A and Q6B) states1,2: “Specifications are one
part of a total control strategy for the drug substance
and drug product designed to ensure product qual-
ity and consistency. Other parts of this strategy
include thorough product characterization during
development, upon which specifications are based,
and adherence to Good Manufacturing Practices;
e.g., suitable facilities, a validated manufacturing
process, validated test procedure, raw material
testing, in-process testing, stability testing, etc.
Specifications are chosen to confirm the quality of
the drug substance and drug product rather than
to establish full characterization and should focus
ensuring the safety and efficacy of the drug sub-
stance and drug product.”
A distinction can be made between the
“release specification” (the tests and acceptance
criteria) that apply at the point of release of the
product into the marketplace (or distribution to
the clinical site for investigational drugs) and
the “stability specification” (the tests and accep-
tance criteria that apply after release of the prod-
uct up to the expiration date of the product).
Certain tests apply only at release, and the
remaining tests apply at release and throughout
the shelf life of the product. More restrictive
acceptance criteria may be appropriate for
certain tests at release than during the shelf life
to allow for changes in the product during stor-
age (such as assay, impurities, and dissolution).
Attributes that have been shown during devel-
opment not to change with time are only tested
at batch release.
There is no regulatory requirement to estab-
lish the shelf life of the DS; instead development
studies on the stability of the DS are conducted
to establish a retest date after which a batch of
DS must be reanalyzed, and the acceptance
criteria met before the batch can be used to
manufacture DP. While there is no regulatory
requirement to establish a regulatory shelf life
of the DS, an internal shelf life may be estab-
lished, beyond which the DS may not be used
for the manufacture of clinical supplies or

a
The word “specification” in NDAs or drugs registered with regulatory authorities is synonymous with the word
“monograph” in a pharmacopeia.
b
The International Council on the Harmonization (ICH) of the Technical Requirements for Pharmaceuticals for
Human Use uses the terms drug substance and active pharmaceutical ingredient (API) interchangeably to describe
the pharmacologically active component in a pharmaceutical product.

I. Introduction
 2.2 Regulatory requirements
commercial products. While a maximum shelf
life of 5 years for a DS is not uncommon, there
is no reason that expired DS or DP cannot be
used in method development studies, method
validation, and method transfer, provided the
exception is appropriately documenteddthis
avoids the possibility out-of-specification (OOS)
results being generated on product in the clinical
or in commercial distribution. In fact, the use of
aged samples of DS or DP in development
studies can provide useful information to study
the stability of the DS and DP and to establish
the retest date or shelf life.
2.2 Regulatory requirements
The establishment of specifications for all
components of a pharmaceutical product for hu-
man or animal use is a legal requirement, in all
parts of the world, as part of the overall control
strategy contained within the cGMPs. The re-
quirements for the testing of an article for use
in animal studies (nonclinical studies) are
covered by the GLPs. In the United States, the
legal requirements for cGMPs are defined in 21
CFR Part 210 and 211.3 21 CFR211.160(a) states
“The establishment of any specifications, standards,
sampling plans, test procedures, or other laboratory
control mechanisms required by this subpart,
including any change in such specifications, stan-
dards, sampling plans, test procedures, or other labo-
ratory control mechanisms, shall be drafted by the
appropriate organizational unit and reviewed and
approved by the quality control unit. The require-
ments in this subpart shall be followed and shall be
documented at the time of performance. Any devia-
tion from the written specifications, standards, sam-
pling plans, test procedures, or other laboratory
control mechanisms shall be recorded and justified.”
In the United States, the legal requirements for
GLPs are defined in 21 CFR Part 58.4 Testing of
articles for nonclinical studies is described in
CFR 21 58.105(a): “The identity, strength, purity,
and composition or other characteristics which will
I. Introduction
11
appropriately define the test or control article shall
be determined for each batch and shall be docu-
mented.” While the GLPs do not explicitly state
that specifications are required for nonclinical
test articles, specifications are usually estab-
lished as part of the overall control strategy in
a similar fashion to specifications for cGMPs.
Similar legal requirements for cGMPs and
GLPs exist in other regions of the world.
2.2.1 International council on
harmonization of the technical
requirements for pharmaceuticals for
human use
The technical requirements for the world
registration of new pharmaceutical products in
the ICH regions (European Union [EU], Japan,
and United States) are defined in the ICH Guide-
lines, which are divided into three sections, each
covering principle areas of drug development,
efficacy (E), quality (Q), and safety (S), plus a
fourth section that deals with multidisciplinary
topics (M) (see Section 2.2.1). The technical re-
quirements for the inclusion of a new mono-
graph of an approved drug in a regional
pharmacopeia are described in the general chap-
ters of the applicable pharmacopeia (see also
Section 2.2.2 and Chapter 23).
The Chemistry, Manufacturing, and Controls
(CMC) requirements for the registration of new
DSs and new DPs are covered primarily in the
ICH Quality Guidelines (Q1eQ14). The main
ICH guideline covering the specification of new
chemical entities (NCEs or “small molecules”)
is Q6A: “Specifications: Test Procedures and Accep-
tance Criteria for New Drug Substances and New
Drug Products: Chemical Substances.”1 The corre-
sponding ICH Guideline covering biotechnology
products and biologicals (“macromolecules”) is
Q6B2: “Specifications: Test Procedures and Accep-
tance Criteria for Biotechnological/Biological Prod-
ucts.” Additional information on specification
setting can be found in other ICH Guidelines
12 2. General principles and regulatory considerations: specifications and shelf life setting
including Q1A-F (stability),5e10 Q3
11e14
(impurities), and Q4 (pharmacopeias).15e17
The later ICH Guidelines, Q8,18 Q9,19 Q10,20
Q11,21 Q12,22 and Q13,23 also have important im-
plications for specification setting, especially
within the context of the application of Quality
by Design (QbD) to process optimization/vali-
dation and formulation development, as well
as to analytical method development and valida-
tion. The QbD concepts (in Q8, Q9, Q10, and
Q11) and their application to pharmaceutical
analysis, Analytical Quality by Design (AQbD),
risk assessment, and method life cycle manage-
ment are discussed in detail in Chapter 4 as
well as in other places throughout this book. In
2018, the ICH Steering Committee convened a
new Expert Working Group (EWG), Q14,24
with two objectives: to define the requirements
for analytical procedure development (ideally
focusing on AQbD principles) and to expand
the ICH method validation guideline, Q2(R2),25
to include nonchromatographic techniques.
The ICH specification guidelines do not cover
the requirements for certain more specialized
products such as transdermal or inhalation prod-
ucts leaving a void, which is filled by regional
guidelines and pharmacopeial requirements. It
should also be noted that not all the ICH quality
guidelines apply to test articles in nonclinical
studies or clinical supplies because they only cover
the technical requirements for a new drug applica-
tion (NDA) (see Chapter 5, Section 5.6 for more de-
tails). Nevertheless, the ICH guidelines do provide
a useful framework for the development of
nonclinical and clinical specifications.
One of the critical quality attributes (CQAs)
that plays prominently in the development of a
specification is impurities because of the possible
negative effect they can have on safety. There-
fore, the establishment of appropriate acceptance
criteria requires the close collaboration of several
disciplines, not just analytical development,
c
Formerly known as heavy metals.
I. Introduction
quality control, and quality assurance but also
nonclinical development, clinical development,
formulation development, process chemistry,
commercial manufacturing, and regulatory af-
fairs. Impurities are discussed in more detail in
Chapter 11 (Assay and Impurities), Chapter 12
(Genotoxic Impurities), Chapter 13 (Residual
Solvents), and Chapter 14 (Elemental Impuri-
tiesc). The control of DS impurities is also dis-
cussed in ICH Q11 Development and
Manufacture of Drug Substances (Chemical En-
tities and Biotechnological/Biological Entities).21
A full listing of all the ICH quality guidelines
and relevant multidisciplinary ICH guidelines
is given in Table 2.1.
According to ICH Q6A1 and Q6B,2 a specifica-
tion (singular) contains three components: a list
of tests (or attributes), references to test methods,
and acceptance criteria. The ICH specification
guideline Q6A distinguishes between universal
tests, which are required in any specification
for a new DS or DP, and specific tests, which
should be included, on a case-by-case basis,
depending on the nature of the DS or the DP
and the route of administration. The universal
and specific tests for NCEs in ICH Q6A1 are
summarized in Figs. 2.1 and 2.2 for DS and DP,
respectively.
In addition to harmonizing the technical re-
quirements for the registration of new drugs in
the EU, the United States, and Japan, the ICH
Guidelines attempted to standardize the termi-
nology, which resulted in the replacement of
some of the terms in common usage at the
time. The terminology and definitions in the
United States Pharmacopeia (USP)/National
Formulary (NF), European Pharmacopoeia (Ph.
Eur.), and Japanese Pharmacopoeia (JP),
together with many regional pharmacopeias,
have also been standardized through the ICH
Q4A16 and Q4B17 guidelines. For example, the
term “appearance” has been replaced by
 2.2 Regulatory requirements 13
TABLE 2.1 Summary of the ICH Quality (Q) Guidelines and those Multidisciplinary Guidelines (M) Relevant to
Specification Setting.

Numbera Titleb

Q1A Stability testing of new substances and products

Q1B Photostability of new substances and products
Q1C Stability testing: new dosage forms
Q1D Bracketing and matrixing design for stability testing: new substances and products
Q1E Evaluation of stability data

Q1F Stability data package for registration applications in climatic zones III and IV
Q2(R1) Validation of analytical procedures: text and methodology
Q3A(R1) Impurities in new DSs
Q3B(R1) Impurities in new drug products
Q3C(R5) Impurities: guideline for residual solvents

Q3D Impurities: elemental impurities

Q4A Pharmacopeial harmonization
Q4B Evaluation and recommendation of pharmacopeial texts for use in ICH regions
Q5A Viral Safety evaluation of biotechnological products from cell lines of human or animal origin
Q5B Analysis of the expression construct in cells used for production of r-DNA derived protein products
Q5C Stability testing of biotechnological/biological products

Q5D Derivation and characterization of cell substrates used for production of biotechnological/biological products
Q5E Comparability of biotechnological/biological products subject to changes in their manufacturing process
Q6A Specifications: test procedures and acceptance criteria for new substances and new drug products: chemical
substances
Q6B Specifications: test procedures and acceptance criteria for biotechnological/biological products
Q7 Good manufacturing practice guide for active pharmaceutical ingredients
Q8(R2) Pharmaceutical development
Q9 Quality risk management
Q10(R4) Pharmaceutical quality system

Q11 Development and manufacture of DSs (Chemical entities and biotechnological/biological entities)
Q14 Analytical procedure development
M4 Common technical document
M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit carcinogenic risk)
M8 Electronic common technical document
a
The designation in parentheses refers to the most recent revision.
b
See http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html for copies of the Guidelines and other details.

I. Introduction
14 2. General principles and regulatory considerations: specifications and shelf life setting

Drug Substance

Universal Tests Specific Tests

Physicochemical
Description Particle Size
Properties

Polymorphic Melting
Identification
Form Point/Range

Elemental
Assay pH
Impurities (Q3D)

Impurities Water Content Refractive Index

Organic Microbial Limits

Chirality
Impurities (Q3A) or Sterility

Residual
Solvents (Q3C)

FIGURE 2.1 Universal and specific tests for a new drug substance in ICH Q6A.

“description” and “heavy metals” has been
replaced by “elemental impurities.” The term
“related substances” has largely disappeared
from regulatory documents and the major phar-
macopeias and replaced by “impurities” in the
DS and DP but still persists in many internal
company documents. However, the use of the
term-related substances may have some utility
in distinguishing impurities structurally related
to the DS from other structurally unrelated im-
purities, such as residual solvents and catalysts.
2.2.1.1 Universal tests
Figs. 2.1 and 2.2 show the universal tests for
both new DSs and DPs, respectively.
2.2.1.1.1 Description
Description (formerly appearance) is defined
in ICH Q6A1 as “. a qualitative statement about
the state (e.g., solid, liquid) and color of the new
drug substance.” It is important to note that the
description relates to the DS or the DP itself,
not to the primary packaging container. The
description of the DS should include color and
any other distinguishing features. The descrip-
tion of the DP should include color, shape, size,
physical form (solid, semisolid, or liquid), and
any other distinguishing features such as print-
ing, debossing, or embossing. The guideline
goes on to state “If any of these characteristics
change during storage, this change should be investi-
gated and appropriate action taken.”
2.2.1.1.2 Identification
Identification is a qualitative test to ensure the
DS or the DP is what it is claimed to be on the label
and the package insert. The identification test

I. Introduction
 2.2 Regulatory requirements 15

Drug Product

Universal Tests Specific Tests

Description Oral Parenteral

Identification Tablets/Capsules Liquid Uniformity of Preservative

Dosage Units Content

Assay Uniformity of
Dissolution Dissolution Antioxidant
Dosage Units pH
Content
Impurities Particle Size
Disintegration pH
Distribution Microbial Limits Extractables

Organic Hardness/
Impurities (Q3B) Microbial Limits Resdispersibility Functionality
Friability Sterility
Testing
Uniformity of Preservative Rheological
Dosage Units Properties Endotoxins/
Content Osmolality
Pyrogens

Water Content Antioxidant Reconstitution

Time Particulate
Content Resdispersibility
Matter

Microbial Limits Extractables Water Content Reconstitution

Water Content
Time

Alcohol Content

FIGURE 2.2 Universal and specific tests for a new drug product in ICH Q6A.

should be specific for the DS and capable of unam-
biguously distinguishing between DS and closely
related compounds (such impurities) that could
reasonably be expected to be present in the sample
(see Chapter 8 for a more detailed discussion of
description and identification). Organoleptic
properties, such as odor and taste, are inappro-
priate and no longer used. The specificity of the
identification of the DS in the DP should be
demonstrated by the absence of interference
from excipients. Consequently, spectroscopic
methods with high degree of specificity (such as
FT-IR, NIR, or solid-state NMR) are preferred for
the identification of NCEs because of their ability
to distinguish differences in functional groups
and geometric isomers. When the DS is predomi-
nantly a single enantiomer, a chiral identity
test (such as chiral chromatography or optical
rotation) should be included in the specification
to distinguish the labeled enantiomeric form
from the unwanted enantiomer and the racemic
mixture. A separate chiral assay may be needed
to determine the level of the unwanted enan-
tiomer. Alternatively, the chiral identification
test and the chiral assay may be combined into a
single method. The chiral identification test may
not be needed in the specification of the DP pro-
vided it has been shown during development
that the drug does not convert to the unwanted
enantiomer during manufacturing or storage. A
more detailed discussion on the development
and validation of chiral identification tests is pro-
vided in Chapter 16. With appropriate validation,
a single spectroscopic technique may be suitable
for the identification of the chemical structure
and the physical form.

I. Introduction
16 2. General principles and regulatory considerations: specifications and shelf life setting
While chiral chromatography may be appro-
priate for the identification of the desired enan-
tiomer of NCEs, a single chromatographic
technique is not considered sufficiently specific
for the identification of the drug itself. Two chro-
matographic (orthogonal) procedures, which
rely on different separation mechanisms (e.g.,
reversed-phase high-performance liquid chro-
matography [HPLC] and capillary electropho-
resis), different nonspecific spectroscopic tests
techniques or hyphenated techniques involving
the combination of chromatography and
nonspecific detection (e.g., HPLC with diode
array detection) may be appropriate if suitably
validated.
When the labeled drug is a salt, a specific test
to distinguish the individual ions should be
included in the specification for the DS. A single
identification test may be appropriate if the tech-
nique is capable of distinguishing the neutral
form of the drug from the salt (e.g., FT-IR).
Although a DS mix-up should be avoided by
compliance with the cGMPs, some regulatory
authorities may require an identification test
for the counterion in the DP. A counterion assay
may also be needed in the DP if disproportion-
ation of the salts, followed by loss of a volatile
acid (or base), has not been ruled out during
development.
2.2.1.1.3 Assay
Assay is a quantitative test method used to
determine the content, concentration, or the pu-
rity of the drug in the DS or the DP. Ideally,
the assay method should be stability-indicating
and specific for the DS. Under certain circum-
stances, the use of a nonspecific assay method
or a method that is not stability-indicating (e.g.,
titration or UV-visible spectrophotometry) may
be justifieddICH Q6A1 3.2.1.c states “[i]n cases
d
The ICH process expanded the concept of testing for trace levels of impurities to include all potentially toxic ele-
ments, not just “heavy metals”dthe term which has been replaced by the term “elemental impurities” in most in-
ternational guidelines, regional guidelines, and pharmacopeias.
I. Introduction
where use of a non-specific assay is justified, other
supporting analytical procedures should be used to
achieve overall specificity. For example, where titra-
tion is adopted to assay the drug substance, the com-
bination of the assay and a suitable test for impurities
should be used.” The specification, development,
and validation of methods for assay and impu-
rities are discussed in more detail in Chapters
9e11, respectively. If the drug is a salt, an assay
for the counterion is usually used in develop-
ment and may be necessary for the commercial
product if the salt is susceptible to disproportion-
ation and the counterion is volatile. Replacement
of the counterion assay with an identification test
for the counterion may be justified if the drug
does not disproportionate, the counterion is not
volatile, or both.
2.2.1.1.4 Impurities
Impurities are compounds or elements that
are known to be present or likely to be present
in the DS or DP in trace quantities. The risk of
other contaminants being present in NCEs or
products is minimized by the use of other control
strategies in the cGMPs and GLPs. However,
certain contaminants in biotechnology products,
such as fermentation by-products, may be un-
avoidable and are controlled during
manufacturing and quality control of the final
product. The impurities guidelines are contained
in four separate documents: ICH Q3A(R2) “Im-
purities in New Drug Substances,”11 ICH
Q3B(R2) “Impurities in New Drug Products,”12
ICH Q3C(R8) “Impurities: Residual Solvents,”13
and ICH Q3D “Guideline for Elemental
Impurities.”d14 ICH Q3A and Q3B, originally
released in March 1994, were developed by the
same Expert Working Group (EWG) in an
attempt to develop consistency between the re-
quirements for DS and DP. Combining the two
 2.2 Regulatory requirements
guidelines under one EWG achieved one of its
stated objectives of defining the identification,
qualification, and reporting requirements of im-
purities arising from the manufacture, process-
ing, and storage of the DS (Q3A(R2))11 and DP
(Q3B(R2)).12 Both ICH Q3A and Q3B have been
updated twice, in October 1999 and February
2002, to provide clarification and address incon-
sistencies between the two guidelines. Although
ICH Q3A(R2)11 and Q3B(R2)12 cover impurities
structurally related to the DS itself, the term
“related substances” is disappearing from com-
mon usage because it is not used in the ICH
guidelines and has been replaced in the pharma-
copeias by the term “impurities.” Other terms,
such as “organic impurities” or “ordinary impu-
rities,” are also in occasional usage.
Impurities arising during the manufacture,
processing, and storage of the DS are defined
in ICH Q3A(R2)11 and include starting materials,
by-products, intermediates, degradation prod-
ucts, reagents, ligands, and catalysts. The ICH
Q3B(R2)12 defines impurities in the DP as degra-
dation products of the DS in the DP. Accord-
ingly, impurities carried over into the DP do
not have to be monitored in the DP, unless
they are also degradation products. This does
not mean that DS impurities carried over into
the DP can be ignoreddthe specificity of the
DP impurity method should be validated to
show that DS impurities, as well as excipients,
do not interfere with the determination of degra-
dants or with the drug itself. The principle of not
requiring the control of the DS impurities in the
DP extends to residual solvents (ICH
Q3C(R8))13 and elemental impurities (ICH
Q3D),14 provided a risk assessment (see ICH
Q9, ref. 19) is conducted to confirm they are
not introduced during processing of the DP or
from other sources such as excipients, equip-
ment, and processing solvents. The ICH Guide-
lines Q3A(R2)11 and Q3B(R2)12 recognize
“unusually toxic” impurities, such as mutagens
and neurotoxins may require special attention
but provide no specific recommendations, first
I. Introduction
17
leading to the development of a European
Guideline, an industry white paper, and then a
multidisciplinary ICH Guideline M7(R1)26
“Assessment and Control of DNA Reactive (Muta-
genic) Impurities in Pharmaceuticals to Limit Poten-
tial Carcinogenic Risk” (discussed in more detail
in Chapter 12). The ICH guidelines Q3A(R2)11
and Q3B(R2)12 are discussed in detail in Chapter
11. Residual solvents (Q3C(R8))13 and elemental
impurities (Q3D)14 in the DS and the DP are
covered in detail in Chapters 13 and 14, respec-
tively. Decision trees #1 and #2 in ICH Q6A1 pro-
vide guidance on the setting of acceptance
criteria for impurities in the DS and DP,
respectively.
2.2.1.2 Specific tests
The specific tests and universal tests (Section
2.2.1.1) are part of the overall control strategy
to ensure the drug is safe, is effective, and per-
forms as expected, delivering the prescribed
dose of the drug either directly to site of action
(e.g., topical or pulmonary products) or to the
site of absorption (e.g., oral products and inject-
ables) in a consistent and predictable fashion.
The ICH guidelines on specifications (Q6A)1
divide the specific tests into those required for
DS (Fig. 2.1) and DP (Fig. 2.2).
2.2.1.2.1 Drug substance
The specific tests for NCEs (Fig. 2.1) are deter-
mined by the chemical structure (including
chirality), physical form (particle size, polymor-
phic forms), and hygroscopicity (water content)
of the DS. Other distinguishing physicochemical
properties, such as melting point or melting
range, pH (of an aqueous solution), and refrac-
tive index, may also be useful. A test for
elemental impurities (ICH Q3D)14 may also be
necessary, particularly if metal catalysts are
used in the manufacture of the DS. Decision trees
#3, #4, and #5 in ICH Q6A1 provide guidance on
the setting of acceptance criteria for particle size,
polymorphism, and chirality, respectively. The
type of microbial testing required depends on
18 2. General principles and regulatory considerations: specifications and shelf life setting
the intended application of the DSdthe methods
are described in the applicable pharmacopeia
(harmonized through ICH Q4A16 and Q4B17).
Microbiological attributes (Microbial Enumera-
tion (USP <61>)27 and Tests for Specified Micro-
organisms (USP <62>))28 are required for any
DS intended for nonsterile products. Decision
tree #6 provides further guidance on setting the
microbial quality attributes of the DS. Testing
for Sterility (USP <71>)29 and Bacterial
Endotoxins (USP <85>)30 or Pyrogens
(USP <151>)31 are required for DS intended
for sterile products (injectables and ophthalmic
products). The requirements for sterile products
are discussed in detail in Chapter 25.
2.2.1.2.2 Drug product
As discussed previously, the purposes of the
product-specific tests are to ensure that the prod-
uct performs as expected and the patient receives
a reproducible dose of the prescribed drug that is
delivered either to the site of action or to the site
of absorption. The DP-specific tests are divided
into oral products and parenteral products, and
the section on oral products is further divided
in solid and liquid dosage forms (Fig. 2.2). One
of the primary objectives of the control of all
dosage forms is to ensure that the drug is
released from the formulation in a consistent
fashion, maintaining the dose-to-dose and
batch-to-batch variability within appropriate
specified limits. The dose of the active ingredient
should be within specified limits of the label
claim and is measured by the assay, which is
an average value of the concentration of the
drug across the batch. For unit dosage forms,
such as tablets and capsules, the within-batch
variability is assessed by determining the unifor-
mity of dosage units, typically using the same
analytical method used for the assay. Uniformity
of dosage units is only tested at release for solid
dosage forms because it is unlikely that the
active ingredient can migrate from one dosage
unit to the next.
I. Introduction
For liquid or semisolid dosage forms, unifor-
mity of the active ingredient across the batch is
assessed in process and at release by testing a
predetermined number of individual containers.
Testing the distribution of the active ingredient
within single container at release and on stability
may be appropriate if the potential exists for
segregation of the formulation, or migration of
the drug, during packaging or upon storage. So-
lution formulations, by definition, are consid-
ered to be homogeneous and the assessment of
redistribution of the active ingredient during
storage is usually unnecessary (inadequate mix-
ing should be detected by appropriate in-process
testing). To ensure that the product remains
within specification throughout its shelf life,
antimicrobial preservatives, antioxidants, and
other excipients (such as buffers) may be added
to control the stability of the product. In these
cases, specific tests such as pH, antioxidant
content, and preservative content may be
appropriate.
In general, more tests are required for liquid
products than for solid dosage forms. Mea-
surement of rheological properties of semi-
solids and liquids may be required if the
delivery of the dug to the intended site of
action is affected by the viscosity of the
product. Redispersibility testing is required
for suspensions and emulsions, and reconstitu-
tion time is required for products that are
manufactured in concentrated form (either a
solid or a liquid) and mixed with a diluent
before dosing.
As with DS, microbiological attributes (Micro-
bial Enumeration (USP <61>)27 and Tests for
Specified Microorganisms (USP <62>))28 (Staph-
ylococcus aureus, Pseudomonas aeruginosa, Escheri-
chia coli, Salmonella enterica subspecies, and
Candida albicans) are required for nonsterile
products, and testing for Sterility (USP <71>)29
and Bacterial Endotoxins (USP <85>)30 or Pyro-
gens (USP <151>)31 is required for sterile prod-
ucts (parenteral and ophthalmic products) (see
also Chapter 25). Osmolality testing is required
 2.2 Regulatory requirements
for isotonic products such as parenteral products
and ophthalmic preparations.
One of the most challenging tests for solid
dosage forms (both oral products and implants)
is dissolution, which is designed to ensure that
the active ingredient is released from the dosage
form and subsequently dissolved in the extracel-
lular fluids or close to the site of absorption.
(Note: for water-soluble, high-permeability
drugs, a disintegration test may be justified
instead of a dissolution test.) While it is desir-
able that the rate and extent of drug absorption
is predictable from the dissolution (in vitro/
in vivo correlation, IVIVC), this is often difficult
to achieve, particularly when drug absorption is
controlled by biological membrane permeability
rather than the rate of dissolution of the drug in
gastrointestinal tract. Even in the absence of an
IVIVC, the inclusion of a discriminating dissolu-
tion test, which is capable of detecting batch-to-
batch variability and changes during storage
in the specification, is essential to ensure the
reproducibility of a solid dosage. Disintegration
of a solid dosage form (or erosion of matrix tab-
lets) is a prerequisite to the dissolution of the
active ingredient in a solid dosage form and
changes in disintegration rate may be predictive
of changes in the rate of dissolution. Therefore,
disintegration of solid dosage forms, together
with friability and hardness, is usually
measured as in-process controls to allow any
adjustment of process parameters during a
manufacturing run.
The specific tests required for more
complex dosage forms, such as transdermal
delivery systems (TDS), topicals, and inhala-
tion products, are not covered by ICH Q6A.
Complex TDS often require specialized
equipment to assess the quality and perfor-
mance of the product, which are discussed
in detail in the various pharmacopeia and in
FDA Guidances. The tests and regulatory
requirements for topical products are also
summarized in Section 2.2.2 and discussed in
detail in Chapter 19.
I. Introduction
19
2.2.2 Compendial requirements
While there is no regulatory requirement for
the registration of a new pharmaceutical to
follow the test procedures described in the gen-
eral chapters of a pharmacopeia, there are signif-
icant advantages to using compendial methods
when possible. In particular, the compendial
methods have stood the test time, and most of
the key methods have been harmonized in the
major pharmacopeias, including USP, Ph. Eur.,
and JP. Therefore, reviewing chemists and field
inspectors are familiar with the details of most
compendial procedures. Consequently, the com-
pendial tests do not have to be described in detail
in the marketing application and they do not
have to be updated when the procedures or
acceptance criteria are changed, provided the
application states that the product is tested ac-
cording to current compendial methods, meets
the acceptance criteria in the pharmacopeia,
and is not significantly modified. Therefore, it
may be inadvisable to reproduce a general chap-
ter or the acceptance criteria in the pharmacopeia
in an NDA because changes in the general chap-
ter may result in use of a wrong method or the
wrong acceptance criteria. However, any signif-
icant modifications of a compendial test or dif-
ference between listed acceptance criteria and
those being used should be justified in the appli-
cation. The requirements for the validation, or
verification of compendial methods, described
in the pharmacopeial general chapters are dis-
cussed in detail in Chapter 23 and are usually
less than those required for the validation of a
new nonpharmacopeial method, which are sub-
ject to the full requirements of ICH Q2(R2).25
General Chapter <1225> of the USP states “[t]
est procedures for assessment of the quality levels of
pharmaceutical articles are subject to various require-
ments. According to Section 501 of the Federal Food,
Drug, and Cosmetic Act, assays and specifications in
monographs of the USPeNF constitute legal stan-
dards. The Current Good Manufacturing Practice
regulations [21 CFR 211.194(a)] require that test
20 2. General principles and regulatory considerations: specifications and shelf life setting
methods, which are used for assessing compliance of
pharmaceutical articles with established specifica-
tions, must meet proper standards of accuracy and
reliability. Also, according to these regulations [21
CFR 211.194(a)2], users of analytical methods
described in USPeNF are not required to validate
the accuracy and reliability of these methods, but
merely verify their suitability under actual conditions
of use. Recognizing the legal status of USP and NF
standards, it is essential, therefore, that proposals
for adoption of new or revised compendial analytical
procedures be supported by sufficient laboratory
data to document their validity. The text of this infor-
mation chapter harmonizes, to the extent possible,
with the International Council for Harmonisation
(ICH) tripartite guideline Validation of Analytical
Procedures and the Methodology extension text,
which are concerned with analytical procedures
included as part of registration applications submit-
ted within the EC, Japan, and the USA.”23
These statements in the USP imply that new
methods to be included in a USP monograph
that are not covered by a general chapter must
be validated according to the General
Chapter <1225>,32 which covers essentially the
same requirements as ICH Q2(R2).25 Methods
already listed in a compendial monograph do
not have to be validated but simply verified
when used for the first time in a particular labo-
ratory according to General Chapter <1226>,25
provided they are used for the particular listed
product. It is important to note that General
Chapters <1225>32 and <1226>33 relate to
USP methods for new or existing drugs specified
by a USP monograph. Additional verification or
validation of a method described in the USP may
be required to demonstrate that the method is
suitable for the analysis of new DS or DP.
Furthermore, it may be unreasonable to expect
that a method (especially HPLC methods) for
the testing of a particular DP or DS listed in a
pharmacopeial monograph will be suitable for
the analysis of a new drug delivery system con-
taining a listed DS (an “old drug in a new prod-
uct”). Therefore, an analytical method described
I. Introduction
in a pharmacopeial monograph may be a useful
starting point for the development of a method
for the analysis of a new dosage form and the
establishment of acceptance criteria. The require-
ments for the development, verification, and
validation of methods in a pharmacopeia or pro-
posed methods for inclusion in a pharmacopeia
are discussed in more detail in Chapters 3 and
23, as well as in various other places throughout
this book.
2.2.2.1 Testing requirements
Although the attributes listed in the various
general chapters of the pharmacopeias apply
only to the requirements for the inclusion of a
new monograph, these attributes can provide
very useful references for the development of
specifications of new DSs and new DPs, particu-
larly where national or international guidelines
are inadequate or absent. Furthermore, some dif-
ferences between compendial, national, and in-
ternational guidelines exist for certain types of
products and sponsors of NDAs are always rec-
ommended to seek advice from regulatory au-
thorities to confirm the suitability of a
proposed specification before filing. The USP
builds on the taxonomy introduced in ICH
Q6A,1 which divides the specifications of DS
and DP into universal tests and specific tests.
The universal DS tests in the USP are the same
as those in ICH Q6A1: description, assay, identi-
fication, and impurities. The USP also separates
the attributes required for inclusion of a new
DP monograph into universal tests (required
for all DPs) and specific tests, which depend on
the type of product, the route of administration,
or both. The USP also distinguishes between
quality tests and performance tests, also accord-
ing to the type of dosage form, the route of
administration, or both. The USP classification
of dosage forms is summarized in Fig. 2.3. The
universal quality tests, the specific quality tests,
and the specific performance tests are described
in detail in the first five general chapters of the
USP and are summarized in Fig. 2.4e2.10.
 2.2 Regulatory requirements 21

Dosage Forms

Injections/Implants Oral Topical/Transdermal Mucosal Nasal/Inhalation

<1> <2> <3> <4> <5>2

Solutions Solids Creams Otic Aerosols

Powders for Tablets Gels Ophthalmic Powders

Solutions

Suspensions Capsules Nasal Sprays

Ointments

Granules
Liposomes Pastes Oropharyngeal Solutions

Powders for Powders Urethral

Suspensions Suspensions
Solutions
Liquids
Emulsions Lotions Vaginal

Solutions
Implants Foams Rectal

Emulsions
1
In Situ Gels Sprays Parenterals
2
Suspensions Nasal Gels and Ointments are covered by Chapter <3>

Microparticles Solutions/Powders Aerosols

/Granules for Solutions

Drug Eluting Solutions/Powders/ Solutions

Stents Suspensions /Granules for
Suspensions

Transdermal
Delivery Systems

FIGURE 2.3 Dosage forms defined in the first five general chapters of the USP.

2.2.2.2 USP general chapters <1> to <5>
The first five USP general chapters classify
DPs according to their route of administration
as Injections and Implants (<1>),34 Oral Prod-
ucts (<2>),35 Topical and Transdermal Products
(<3>),36 Mucosal Products (<4>),37 or Inhala-
tion Products (<5>)38 and are summarized in
Fig. 2.3. General Chapter <1> Injections and Im-
plants34 does not list description (which may be
an oversight) but lists seven universal tests, in
addition to identification, assay, and impurities,
as well as a number of tests that are specific to
the type of product or route of administration
(Fig. 2.4). The specific tests for oral products
(<2>)35 are divided into solids and liquids
(Fig. 2.5). General Chapter <3>36 divides the
specific tests into those that apply to all topical
and TDS and those that apply additionally to
TDS (Fig. 2.6). The testing requirements for
topical products are discussed in more detail
in Chapter 19. General Chapter <4>37 divides

I. Introduction
22 2. General principles and regulatory considerations: specifications and shelf life setting

Injections/Implants
<1>

Universal Tests Specific Tests

Identification
All Product Other Products14

Assay
Uniformity of
Dosage Units8

Impurities
Vehicles and Added
Substances9
Foreign and
Particulate Matter1 Antimicrobial
Effectiveness10

Sterility2
Water Content11

Bacterial
Endotoxins3 Aluminum
Content12
Container
Content4 Completeness and
Clarity of Solution13

Packaging5

Container-Closure
Integrity6

Labeling7

FIGURE 2.4 Universal and specific tests for injectable products and implants in USP <1>.

DPs for application to mucous membranes
into seven categories according to the site of
administration: optic, ophthalmic, nasal,
oropharyngeal, urethral, vaginal, and rectal
(Fig. 2.7). General Chapter <5>38 divides the
specific tests for inhalation products into six
categories according to the type of dosage
form: inhalation aerosols, inhalation solutions,
inhalation suspensions, solutions or drug
for inhalation solution (nebulization products),
inhalation sprays, and inhalation powder (see
Fig. 2.8). The specific tests for nasal products

I. Introduction
 2.2 Regulatory requirements 23

Oral Products
<2>

Universal Tests Specific Tests

Description Solids Liquids

Deliverable
Identification Volatile Content1
Volume7

Alcohol
Assay Disintegration2
Determination8

Impurities pH9
Friability4

Microbial
Breaking Force5 Content10

Uniformity of Antioxidant11
6
Dosage Units

Extractables12

FIGURE 2.5 Universal and specific tests for oral products in USP <2>.

are divided into three categories: sprays, solu-
tions, and powders (Fig. 2.9).
One of the several complications, and potential
areas of confusion, in the classification and testing
requirements of nasal products and inhalation
products, arises from the fact that the USP re-
quirements for nasal sprays are described in Gen-
eral Chapter USP <4>30 and the requirements for
inhalation products are described in USP <5>,
but the FDA guidelines for these types of prod-
ucts are contained in the same document: “Guid-
ance for Industry: Nasal Sprays and Inhalation
Solution, Suspension and Spray Products e Chemis-
try, Manufacturing and Controls Documentation.”39
As discussed previously, the performance
tests are intended to demonstrate that the pre-
scribed dose of the active ingredient in the DP
is delivered at a consistent predictable rate either
directly to the site of action or to the site of ab-
sorption. The performance tests in the USP for
oral, topical, transdermal, nasal, and inhalation
products are summarized in Fig. 2.10. Although
the USP recognizes that systemic drug delivery
may occur intentionally or unintentionally from
drugs delivered to the mucosal membranes,
there are no specific performance tests described
in General Chapter <4>.37 Similarly, there are
no performance tests for parental products listed

I. Introduction
24 2. General principles and regulatory considerations: specifications and shelf life setting

Topical and Transdermal

Products
<3>

Universal Tests Specific Tests

Additional TDS
All Products
Specific Tests

Description Uniformity of
Particle Size Peel Adhesion Test Cold Flow Test
Dosage Units

Identification Release Liner Peel

Crystal Formation Shear Test
Water Content Test

Assay
Microbial
Minimum Fill9 Tack Test Static Shear Test
Content

Impurities Apparent Probe Tack

Antimicrobial Leak Test
Preservative Content Viscosity Method

Antioxidant Uniformity in Rolling Ball

Content5 Containers Method

pH6

FIGURE 2.6 Universal and specific tests for topical and transdermal products in USP <3>.

in General Chapter <1>,34 despite the fact that entities”), the pharmacological activity is deter-
many injectable products, such as implants and mined by the chemical structure (including any
subcutaneous or intramuscular injections, are specific stereochemical arrangements). For large
intended for controlled or sustained delivery. molecules, produced by biotechnology or bio-
(One exception to this is parenteral emulsions, logical processes, pharmacologic activity de-
which are tested for globule size (USP <729>), pends not only on the chemical structure but
which may affect release rate of the drug from also on the conformational structure and post-
the emulsion.) In these cases, appropriate translational modifications. Therefore, the spe-
in vitro release rate tests should be included in cific tests described in ICH Q6B2 may be
the specification. required in addition to, or instead of, those
described in Q6A1 to provide a complete speci-
fication of a biotechnological product. As a
consequence of the need to specify the confor-
2.2.3 Biotechnology products mational and posttranslational characteristics,
(macromolecules) and biological products the number and complexity of the tests in the
A basic principle of molecular pharmacology specification of biotechnology products may
is that a drug must be present in solution at the be greater than what is required for a NCE.
site of action to exert its biological activity. For For example, more than one test is usually
small molecules (also known as “chemical required for the identification of a biotech-

I. Introduction
 2.2 Regulatory requirements 25

Mucosal
<4>

Microbial Particulate and Aerosols – see Buccal Patches – Microbial Microbial Foams – see
Enumeration Foreign Matter Fig. 2.6 see Fig. 2.4 Enumeration Enumeration Vaginal Foams

Specified Gels – see Fig. 2.4 Gels – see Fig. 2.4 Specified Specified Suppositories
Organisms Minimum Fill Minimum Fill Organisms Organisms Softening Time

Antimicrobial Particulate Size Ointments – Ointments – Gels – see Fig. 2.4 Ointments –
Effectiveness and Distribution see Fig. 2.4 see Fig. 2.4 Minimum Fill see Fig. 2.4

Antimicrobial Antimicrobial Sprays – Sprays – Creams – see Fig 2.4

Agents-Content Preservative see Fig. 2.6 see Fig. 2.6 Minimum Fill

Solutions and Solutions – Tablets –

Suspension see Fig. 2.6 see Fig. 2.3

Physical
Appearance

FIGURE 2.7 Universal and specific tests for mucosal products in USP <4>.

nology product and several tests may be 2.2.4 Regional differences

required for the determination of biological ac-
tivity (potency and purity).
The ICH guideline on the specification of
biotechnology products (Q6B)2 divides the
attributes into DS and DP. In contrast to the
specification of chemical entities (Q6A),1 Q6B2
makes no distinction between universal tests
and specific tests for biotechnology products or
biological products. However, the ICH specifica-
tion guidelines for both DS and DP contain
requirements for appearance and description,
identity, purity and impurities, potency and
quantity. The ICH guideline on the specification
of biotechnology products also contains general
tests applicable to all DPs and additional tests
applicable to specific dosage forms. Additional
information on the specification of biotech-
nology products is provided in Chapters 21
and 22.
Despite the efforts of the ICH, there are some
regional differences in the expectations of the
various regulatory authorities. For example,
the EU, in contrast to the United States, typically
requires more stringent (“tighter”) acceptance
criteria at release for those attributes that are ex-
pected to change during the shelf life, to ensure
that the product stays within specification
throughout the shelf life. The difference between
the requirements in the EU and United States
can be attributed to the fact the USP requires
that the DS and DP meet the requirements in
the applicable USP monograph throughout the
shelf life. Although the US Food and Drug
Administration (FDA) strives to meet both the
USP requirements (see Section 2.1.2) and the re-
quirements of the ICH, the USP represents the
highest legal standard in the United States as
defined in the 1906 Pure Food and Drug Act.

I. Introduction
26 2. General principles and regulatory considerations: specifications and shelf life setting

Inhalation Products
<5>

Universal Tests Specific Tests

Inhalation Inhalation Inhalation Solution or Drug

Inhalation Spray Inhalation Powder
Aerosols Solutions Suspension for Inhalation

Description Content Particle Size Color/Clarity upon

Water Content Plume Geometry Water Content
Uniformity Distribution Dissolution

Identification Foreign Particulate Preservatives and See Inhalation Solutions See Inhalation Solutions Foreign Particulate
for Other Tests
Water Content
Matter Stabilizers for Other Tests Matter

Assay See Inhalation Solutions

Leachables Sterility for Other Tests Microbial limit

Impurities Foreign Particulate Content Uniformity

Spray Pattern
Mater (premetered)

Microbial Limit pH Leachables

Alcohol Content Osmolality Net Content

(device metered)

Net Fill Weight Leachables Residual

Solvents

Leak Rate Net Fill Weight

Weight Loss

FIGURE 2.8 Universal and specific tests for inhalation products in USP <5>.

Therefore, when there is a conflict between the opportunity for different release and stability
USP and ICH, the FDA will defer to the USP, specifications for marketing applications of
although the requirements in the pharmacopeia NCEs in the EU, but not in the United States.
only define what is expected for the inclusion of That being said, it is becoming more common
a new monograph and do not apply directly to for firms to file release and stability specification
an NDA. Through the efforts of the ICH Expert worldwide because this simplifies the applica-
Working Group Pharmacopoeial Harmonisa- tion process. Separate release and stability spec-
tion, ICH Q4,15 ICH Q4A,16 and ICH Q4B,17 ifications are always required for biotechnology
many of the general chapters in the major phar- products and biologicals as described in ICH
macopeias (USP, Ph. Eur., JP) have been harmo- Q6B. One area of particular interest is the
nized, which means the test procedures rapidly growing markets in the emerging na-
described in the general chapters are either the tions, particularly Brazil (ANVISAe), which is
same or have been determined to be equivalent. developing its own regional standardsdthis
However, one significant area that remains topic is discussed in a recent review by
unharmonized in the ICH regions is the Huynh-Ba and Beumer-Sassi.40 Many countries

e
Ag^encia Nacional de Vigil^
ancia Sanit
aria.

I. Introduction
 2.3 Specification setting process 27

Nasal Products
<5>

Universal Tests Specific Tests

Nasal
Nasal Sprays Solutions Nasal Powder

Description Preservative/ Preservative/ See Inhalation

Leachables Leachables
Stabiizer Assay Stabiizer Assay Powder (Fig. 2.6)

Identification Content Uniformity Foreign Particulate

(premetered) Net Fill Weight Matter
Net Fill Weight

Assay Particle Size

pH Microbial Limit pH
(suspension)

Impurities Foreign Particulate

Osmolality Viscosity Test Osmolality
Matter

Spray Pattern Viscosity Test

Sterility
Microbial Limit
(Premetered)

FIGURE 2.9 Universal and specific tests for nasal products in USP <5>.

outside the original ICH regions have adopted
the ICH Guidelines; however, other require-
ments may also apply in the Association of
Southeast Nations (ASEAN) regions, South
and Central America, Africa, Australia, and
Canada.
2.3 Specification setting process
Setting specifications is a complex and
involved process, requiring the synthesis of in-
formation from various sources, including data
from preclinical and clinical trials, analytical
method development, stability studies, process
validation, and regulatory guidelines. Tradition-
ally, setting specifications was compliance-
driven and largely relying on a small number
of commercial-scale batches used for marketing
approval. In recent years, there has been a shift
from the traditional “test to compliance” to a
risk-based and life cycle approaches for setting
specifications. Thus, the ICH requirements allow
acceptance criteria to be based on qualified levels
or maximum allowable daily exposures; howev-
er, some regulatory authorities may require
tighter limits based on historical batch data.
The process of setting specification starts with
the identification of CQAs that are indicative of
the safety, efficacy, and quality of the product.
The next step is to couple the CQAs with global
regulatory requirements to establish specifica-
tions from a holistic and overall control strategy
perspective. Finally, the acceptance criteria or
numerical limits of the specifications are deter-
mined using appropriate statistical methods.
2.3.1 Identification of critical quality
attributes
A risk assessment process is used to
determine CQAs, which begins with a criticality
analysis of potential impact of all quality attri-
butes on activity, the pharmacokinetic/phar-

I. Introduction
28 2. General principles and regulatory considerations: specifications and shelf life setting

Performance
Tests

Oral Topical/Transdermal Nasal/Inhalaon

<2> <3> <5>

Drug Release Nasal/Inhalaon

Dissoluon
<724> <601>
<711>

Apparatus 1 Apparatus 5 Delivered-dose

(Basket) (Paddle Over Disk) Uniformity

Apparatus 2 Apparatus 6 Droplet/Parcle

(Paddle) (Cyclinder) Size

Apparatus 3
(Reciprocang
Apparatus 7 Aerodynamic Size
Cyclinder) (Reciprocang Holder) Distribuon

Apparatus 4
(Flow-Through Cell)

FIGURE 2.10 Performance tests for oral (USP <2>), topical and transdermal (USP <3>), and nasal and inhalation
(USP <5>) products.

macodynamic (PK/PD) relationship, safety, criticality is quantified as a total risk score,

and immunogenicity. There are many tools which is the function of severity and probability
such as failure effect mode analysis that can of occurrence. Overall risk is assigned a score
also be used to determine the CQAs (FDA, ranging from 0 to 9, depending on the severity
2006). In the example shown in Table 2.241 the and occurrence (Table 2.2). For example, a
severity score of 3 and an occurrence score of
3 are assigned a risk score of 5, and a severity
TABLE 2.2 Risk ranking based on severity and score of 5 and an occurrence score of 5 is
occurrence. The total risk score is
defined as the product of severity and assigned a risk score of 9 and so one. The low-
probability of occurrence. risk, moderate-risk, and high-risk scores corre-
spond to risk scores
3, 4
scores
6, and
5 5 6 7 8 9 scores 7, respectively. An attribute with “low
4 4 5 6 7 8 risk” designation is considered noncritical and
Severity

3 3 4 5 6 7 routine monitoring is not required. Depending

2 2 3 4 5 6 on the extent of prior product knowledge, an
1 1 2 3 4 5
attribute of moderate risk may be tested
0 1 2 3 4 5
Occurrence
through routine monitoring or characterization
only. Finally, an attribute having a high-risk
score is deemed to be a CQA and specification
of that CQA is required.

I. Introduction
 2.3 Specification setting process
Once identified, the appropriate ranges of
CQAs are determined through design of experi-
ments as part of the QbD development program
(see also Chapter 4). The CQAs can also form
the basis of a comparability protocol included
in the Common technical document (CTD) to
define the filing requirements for any postap-
proval changes to the API, formulation, or
manufacturing processes.
As previously discussed, various regulatory
guidelines regarding specifications exist. Of
particular note are ICH Q6A and ICH Q6B for
chemicals and biologicals, respectively.
Although the two guidelines attempted to
harmonize specification requirements across
different regions, the final list of tests should be
determined on a case-by-case basis because the
specific requirements are not totally harmo-
nized. It is also important to note that it is incum-
bent on the sponsor to propose and justify
specifications. This entails the identification of
CQAs followed by establishment of appropriate
acceptance criteria.
2.3.2 Considerations in setting
acceptance criteria
2.3.2.1 Data sources
Establishment of acceptance criteria relies on
data from various sources, including nonclinical
and clinical experiences, historical knowledge
of the product or similar products in the
same class, analytical method variability,
manufacturing process capability, and regulato-
ry and pharmacopeial requirements. Although
experience with nonclinical and clinical batches
is most relevant, data are often limited as there
are typically only a few batches of the product
available and manufactured at noncommercial
scale. As a result, setting acceptance criteria is
an iterative process, starting with provisional
limits for product release for nonclinical and
clinical batches, which evolve over time and
ending with establishing a set of limits for
I. Introduction
29
marketing approval. These approved specifica-
tion limits may require updating as commercial
manufacturing experience is gained and data
from batches become available. This is in keep-
ing with the recent regulatory requirement of
continued process validation and verification.
2.3.2.2 Frame of reference
As pointed out by Burdick et al.,42 one com-
mon mistake in setting acceptance limits is the
lack of clarity of the frame of reference for
intended use of the specification. Here the
“frame of reference” refers to the sampling pop-
ulation and parameter(s) of interest for statistical
inference. For example, it is important to under-
stand if the acceptance limits are intended for in-
dividual units from a batch as in a sterility test or
the average of the batch as the case of assessing
the potency of the batch. As the variability
in the individual measurements is larger than
that in the average, acceptance limits can be
either too wide or too narrow, thus inflating a
consumer’s or producer’s risk. Yang et al.41
consider an influenza vaccine for which a po-
tency assay is performed as part of batch release
test. As the purpose of the test is to ensure that
the potency of the batch is within the specifica-
tion limits, 6.5e7.5 log10 titer, the intent of the
assay is to estimate the batch potency. For this
assay, 12 samples from the batch are tested, giv-
ing rise to 12 readouts. The assay result is re-
ported as the average of the 12 measurements
and evaluated against the above acceptable
limits. However, if an assay is intended to assess
residual host cell DNA in the product which may
have unintended safety concerns, specification
limits should be set for individual vials. The sub-
ject of averaging and uniformity of dosage units
for chemical entities is discussed in more detail
in Chapter 11.
2.3.2.3 Sources of variation
A manufacturing process is influenced by
various sources of variation such as raw mate-
rials and environment factors. When using
30 2. General principles and regulatory considerations: specifications and shelf life setting
statistical process capability to set acceptable
limits, it is important to account for the full range
of variability.41 This necessitates the use of data
obtained during the development of the process
up to the process for commercial production. It is
common that results from 20 to 30 batches of
biotechnology products are needed to encom-
pass all sources of variation. A smaller number
of batches may be required for NCEs. Equally
important is appropriate applications of experi-
mental design and statistical analysis to estimate
the variability and set specifications. An example
by Yang et al.44 shows that failing to correctly es-
timate the variability in the mean of 3 determina-
tions results in a narrow acceptance range.
Knowing that there are usually a limited number
of batches available before marketing approval,
statistical methods such as tolerance intervals
(see Section 2.3.4) may be used to compensate
for the lack of knowledge about the sources of
variation.42
2.3.2.4 Clinical relevance
Although acceptable limits based on statisti-
cal process capabilities are sometimes used as
the acceptable limits, clinically relevant limits
are most appropriate as they directly link the
CQA with the product safety and efficacy. In
the literature, some efforts have been made to-
ward this purpose. For example, Capen et al.43
used results from a clinical dose-ranging study
to verify statistically based acceptable limits.
Yang et al.44 provided an example, demon-
strating how acceptable limits of a potency assay
for influenza vaccine of live virus can be estab-
lished based on statistical modeling that con-
nects the assay titer with clinical performance.
Another example by Yang44 describes a method
that provides a functional relationship between
three correlated CQAs of a monoclonal antibody
and a surrogate efficacy marker, namely, area
under the drug concentration curve. Such a link-
age allows for an assessment of the impact of
changes in these CQAs on the product efficacy
and also allows for the establishment of clinically
I. Introduction
relevant joint acceptance ranges for the CQAs.
Schenerman et al.45 consider a case where an im-
purity safety factor (ISF) is used to link to the
toxicity of an impurity to the maximum accept-
able level in the product through the following
function:
ISF ¼ LD50 =r (2.1)
where LD50 is the amount of an impurity that re-
sults in lethality in 50% of animals tested, and r is
the maximum amount of an impurity in the final
product dose. The higher the ISF, the lower is the
safety risk caused by the impurity. If a lower
limit on the ISF is available (for example, from
regulatory guidelines), it can be translated into
a bound on the maximum amount of impurity
in a final product dose.
2.3.2.5 Multivariate specifications
Because a specification consists of a list of
tests, some of which may be correlated, failure
to account for such correlations may result in
an inflated risk to the consumer or the
producer.44,46 For example, Yang et al.47,48 noted
that for certain biotechnology products, DS im-
purities can promote aggregation exacerbating
immunogenicity. It is critical to understand the
relationship in setting specification limits for
both quality attributes. In addition, because
correlated tests may result in redundant infor-
mation and incur unnecessary costs, it is of great
benefit to identify a smaller set of “orthogonal”
tests.50 In this case, identification of CQAs
should not be done in isolation; correlations
among potential CQAs should be considered.
2.3.2.6 Specifications in early development
The previous discussions have focused pri-
marily on late development specifications and
specifications to be included in the marketing
dossier. A working group of an industry group,
the IQ Consortium, has published an article on
“Early Development GMPs for Small-Molecule
Specifications. An Industry Perspective.”51 This
article emphasizes the fact that very little
 2.3 Specification setting process
information may be available to support firm
specifications for the DS and the DP in early
development. Therefore, “early development
specifications should focus on those tests and
acceptance criteria determined to be critical for
the control of product quality and supported
by preclinical (safety) and early clinical safety
studies.” In that paper, the authors propose stan-
dardized early phase tests and acceptance
criteria for both the DS and the DP. They also
differentiate between test results that are to be
reported to the agency at release and on stability
from internal tests and acceptance criteria that
are not part of the formal specifications. The pa-
per differentiates between the early nonclinical
batches where there are no formal (regulatory)
specifications and first-in-human (FIH) batches,
where the aims of the former are to
31
• Ensure that the correct dosage is administered
in the nonclinical studies
• Determine the correct potency value of the DS
to ensure proper dosing of the animals
• Quantify impurities for nonclinical
qualification (establish the initial impurity
profile).
The paper goes on to emphasize that the initial
acceptance criteria for early clinical batches are
targets based on the results of the initial nonclin-
ical studies. They further emphasize the value of
using the same batch of DS in both the early
nonclinical studies and the FIH studies, in which
case the impurities are inherently qualified (given
the appropriate safety margins). Table 2.3 pro-
vides the standard specification for a DS in early
development as an illustration of the approach.

TABLE 2.3 Example of a specification for a drug substance in early development.

Testing

Attribute Proposed acceptance criteria Release Internala Stability

Description Range of color description þ  þ

Identification Spectrum conforms to reference þ  
Counterion assay Report result þ  
Assay 97.0%e103.0% on anhydrous solvent free basis þ  þ
Impurities Individual NMT 1.0% total NMT 3.0% þ þ þ

Chiral impurity NMT 1.0% þ þ þ

Residual solvents ICH Q3C or other justified limits for solvents þ þ þ
in final synthetic step

Mutagenic impurities ICH M7 limits þ þ þ

Elemental impurities ICH Q3D limits e þ þ
Water content Report results  þ þ
Solid form Report results  þ þ
Particle size Report results  þ þ

Residue on ignition Report results  þ þ

a
Internal testing can be performed in addition to or in replacement of release testing in the final drug substance. Internal testing may have target acceptance
criteria that are tighter than the release testing criteria.
Adapted from Zhang, S., Coutant, M., O’Connor, D., Szulc, M., Trone, M. D., Swanek, F., Wong-Moon, K., Yazdanian, M., Yehl, P., Ge, Z., McElvain, J. S.,
Miller, S. A. Early Development GMPs for Small-Molecule Specifications. An Industry Perspective (Part IV). Pharm. Technol. 2012, 36 (10). http://www.
pharmtech.com/early-development-gmps-small-molecule-specifications-industry-perspective-part-v.

I. Introduction
32 2. General principles and regulatory considerations: specifications and shelf life setting
See Chapter 5 for more details on specification
setting in clinical development.
2.3.3 Statistical tools for setting
acceptable limits
There are three types of statistical intervals,
which are often used in setting specifications.
They are confidence, prediction, and tolerance
intervals. Which interval is used to set the spec-
ification depends on the intended purpose of
the specification. For example, a specification
aimed at ensuring product potency is usually
aimed at the average performance of the
manufacturing process. In this situation, confi-
dence interval is appropriate to use in calculating
the specification limits. On the other hand, a test
concerning the product safety is more focused on
individual outcome. Therefore, prediction inter-
val is more suited for establishing the acceptance
criteria. In addition, a prediction interval is also
useful for setting the acceptable range for an
OOS investigation. If one is interested in the
long-term performance of a large proportion of
samples (say, tablets) of batches from a
manufacturing process, a tolerance interval
should be used to set the specification. Assuming
that the data are normally distributed, the (1-a)
100% confidence interval, (1-a)100% prediction
interval, and (1-a)100% tolerance interval with
p100% coverage are given, respectively, by

pffiffiffi pffiffiffi
X  t1a=2 ðn  1Þs = n; X þ t1a=2 ðn  1Þs = n

pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
X  t1a=2 ðn  1Þs = 1 þ 1=n ;
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 
X þ t1a=2 ðn  1Þs = 1 þ 1=n
 
X  kn;a;p s; X þ kn;a;p s
where X ¼ X1 þ.þX n
n
is the sample mean and s2 ¼
Pn
ðXi XÞ
2
i¼1
the sample variance. t1a=2 ðn 1Þ is the
n1
upper ð1 a =2Þ100th percentile of the t-
distribution with n1 degree of freedom. The
factor kn;a;p can be approximated by52
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u
uvð1 þ 1=nÞz2ð1pÞ=2
kn;a;p ¼t (2.5)
c21a;v
with kn;a;p ¼ c21a;v being the (1-a)100th percen-
tile of the chi-square distribution with degrees
of freedom n and the sample variance s2 : Values
of kn;a;p can be found in published tables.
The intervals in Eqs. (2.2)e(2.4) are two-sided.
One-sided intervals can be similarly constructed
in keeping with the intent of the specifications.
For example, for an impurity test, only an upper,
one-sided acceptable limit is of interest. In
addition, in many analytical methodologies, a
skewed or nonnormal distribution is seen when
calculating the reportable values. This is a com-
mon occurrence for methods for bio-
pharmaceuticals, which are calculated using a
log scale for the underlying doseeresponse
curves. It is a common practice to perform a
transformation to normalize the data. Such data-
sets are often said to be “log-normally distrib-
uted.” Typical transformations include log, ln,
and BoxeCox transformations. Biological po-
tency assays, titer-based assays, and many
enzyme-linked immunosorbent assay (ELISA)
require transformation before performing any
of the following calculations. Therefore, the
previous statistics discussed above should be
calculated utilizing a transformed dataset.
When using the tolerance interval to set the
(2.2) acceptable criteria, the limits have an intuitive
interpretation. For simplicity, we assume the
quality attribute is impurity. Let X be the test
value, and mT be the population mean. The upper
(2.3)
specification limit is l þ mT , which is set to be
equal to the one-sided tolerance limit which
(2.4)
covers p100% of the population with (1-a)
100% confidence, which is denoted as TL(a, p).
Let qX ðpÞ be the p100% percentile of the distri-
bution of X. Theoretically, it can be shown that
I. Introduction
 2.4 Shelf life and retest date 33

FIGURE 2.11 Illustration of when the one-sided upper specification limit is set to be the one-sided upper tolerance limit
which covers p100% of population with (1-a)100% confidence, there is (1-a)100% confidence that the probability for X
to be within the specification limit exceeds p100%.

TL(a, p) is the (1-a)100% confidence interval
of.qX ðpÞ45 The fact that TL(a, p) ¼ lþ mT implies
that with (1-a)100%, confidence lþ mT  qX ðpÞ
because l þ mT  qX ðpÞ is equivalent to Pr(X -
mT < l) > p. Therefore, it can be concluded
that with (1-a)100% confidence Pr(X - mT < l)
> p) holds. In other words, with (1-a)100%,
the probability for X to be within the specifica-
tion limit exceeds p100%. The above example
is illustrated in Fig. 2.11.
2.4 Shelf life and retest date
Because both the DS and the DP can degrade
over time, it is important that stability studies
are carried out to estimate the shelf life such
that the product remains safe and efficacious
and performs as expected within the expiry
dating. In practice, a shelf life of at least 18
months with storage at room temperature is
preferred to ensure manageable inventories
and supply chains for chemical entities. Many
biopharmaceuticals have refrigerated or frozen
storage requirements. Many of the newer bio-
pharmaceuticals, such as cell therapies, have
extremely short shelf lives, often shorter than
2 weeks. In general, shorter shelf lives at
refrigeration temperature are reserved for special
cases or where the stability of the product does
not allow room temperature storage for
18e24 months.
Irrespective of the stability profile of the prod-
uct, an accurate estimate of shelf life is critical.
This is usually accomplished through a formal
stability study, in which at least three batches
of the product are tested, and a regression anal-
ysis is performed to determine the shelf life as
is outlined in ICH Q1E.9 Specifically, the stability
study consists of
1. selection of the time points at which stability
samples are collected and tested;
2. fitting statistical models to the measured
results;

I. Introduction
34 2. General principles and regulatory considerations: specifications and shelf life setting

3. estimating the shelf life, which is defined as
the time point at which the lower 95%
confidence limit intersects either the lower
specification limit (LSL) or the upper
specification limit (USL).
For some attributes, there may be a one-sided
specification limit if the change can only be in
one direction, for example, impurities, in which
case there is only a USL. Some attributes may
have one or two limits depending on the type
of dosage form; for example, for the dissolution
of an immediate-release tablet, an LSL limit is
required. For a controlled-release tablet, both
an LSL and a USL for dissolution are required
because the drug must be released at a defined
rate. As estimation of the stability characteris-
tics, such as rate of degradation and shelf
life, depends on when the sampling points are
120
110
100
Assay (%)
taken, the design of the stability study based
on optimal statistical criteria would render
more a robust estimate of the product stability
profile.
Fig. 2.12 shows simulated data designed to
demonstrate the calculation of shelf life (in this
example: assay) for a product with a degradation
rate of 0.5% per month at 25 C/60%RH. Note:
This illustration uses one batch for the estimation
of shelf life. In practice, several batches will be
used. It is tempting to set the shelf life at
25 months (Fig. 2.12) based on the intersection
of the extrapolated data and the LSL of 90%.
However, based on the previous discussion,
there will be determinate (random) errors in
the estimation of the estimated value of the assay
at the LSL. Therefore, a more statistically valid
approach to the estimation of the shelf is to

90
80
70

0 5 10 15 20 25 30

Month

FIGURE 2.12 Calculation of shelf life (based on assay) for a product with a degradation rate of 0.5% per month. The solid
line is the predicted mean value while the curve and horizontal dashed lines are the lower 95% confidence limit of the predicted
mean value and lower specification limit, respectively. The shelf life is determined to be the time point at which the lower 95%
confidence interval of the mean predicted value intersects the lower specification limit.

I. Introduction
 2.5 Release and stability specification
calculate the value of the assay at the point
where the lower 95% confidence interval limit
for the predicted assay value at a given time
point intersects the LSL (e.g., Fig. 2.12) (see
ICH Q1E: Evaluation of Stability Data). Using
the latter approach, the shelf life is estimated to
be 20 months.
In contrast to small molecules, biopharma-
ceutical shelf life calculations are not usually
calculated based upon accelerated tempera-
tures. It has been shown that the complexity of
the active ingredient and the requirement for a
specific three-dimensional structure is not
conducive to using various models, such as the
Arrhenius equation, to estimate real-time stor-
age stability. Therefore, only real-time storage
data at the proposed storage temperature are
typically accepted by the regulatory authorities
for establishing the shelf life of biotechnology
products. It has been proposed to the World
Health Organization (WHO) and other govern-
ment regulatory authorities that additional
real-time data points for biopharmaceutical
products be collected rather than those
recommended by the ICH Guidelines for the
calculation of shelf life.
2.5 Release and stability specification
As a DP often degrades over time, width of
the target values is set, either by in-house limits
or in the regulatory specification, at product
release to ensure that the product does not go
out of specification before expiration. By conven-
tion, the acceptance criteria for assay (potency) in
the release specification are typically 95.0%
e105.0% of label and the typical acceptance
criteria in the shelf life specifications are 90.0%
e110.0% of label. (The use of release and shelf
life specifications for assay (potency) is discussed
in more detail in Chapter 9.) Thus, tightening the
release specification decreases the likelihood that
the product will fail the stability specification
during storage. However, too tight a release
I. Introduction
35
specification will result in more batches failing
at release. Conversely, too loose a release specifi-
cation can result in a greater number of batches
failing the stability specification during storage.
Several considerations need to be given to set
appropriate release limits. They include vari-
ability in the estimated attribute value at release
and uncertainty with degradation rate estimate.
Consider a situation where the quality attribute
is potency, which decreases over time. The lower
release limit (LRL) and upper release limit (URL)
may be set at52
rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
S2
LRL ¼ LSL þ bT þ t1a;df S2L þ (2.6)
n
rffiffiffiffiffi
S2
URL ¼ USL  t1a;df (2.7)
n
where T is the shelf life, b is the average degrada-
tion rate, which is obtained from a stability study,
and bT represents the total loss due to degrada-
tion over the shelf life; SL ¼ SEðbÞ  T is the stan-
dard error associated with the total degradation
loss bT; Sis variability in the estimate attribute
at release, which is estimated by the mean square
error; n is the number of samples tested at release;
and t1a;df is the 100ð1  aÞth percentile of the cen-
tral t-distribution with degrees of freedom (df)
that can be estimated using the Satterthwaite
approximation54:
 2
S2
S2L þ
n
df ¼  2 2 (2.8)
 2 2 S
SL =ðnb  1Þ þ =ðn  1Þ
n
Fig. 2.13 shows graphically how the afore-
mentioned factors are considered to ensure the
product to remain above the LSL at the end of
the product shelf life.
The use of release and stability specifications
is one area in ICH Q6A that is not harmonized.
In the United States, a product must meet a sin-
gle specification at release and throughout the
36 2. General principles and regulatory considerations: specifications and shelf life setting

FIGURE 2.13 Release limits taking into account the lower specification limit (LSL), the total loss of potency over the expiry
period of 24 months, and uncertainties associated with the estimated potency at time zero and degradation slope estimate.
Adapted Ref. Yang, H. Novick, S., Roskos, L. Interpretation and Treatment of Data. In Statistics for Biotechnology Process Development;
Coffey, T.; Yang, H., Eds Vols. 1e37; CRC Press, 2018.

shelf life (this is also generally true for a pharma-
copeial monograph). By contrast, in the EU,
separate specifications are required at release
and on stability. However, in the absence of a
regulatory release specification, tighter “in-
house” release specifications are generally used
to ensure that the product will meet the regulato-
ry specification throughout its shelf life. If this is
done, it should be noted that the US regulators
may treat the “in-house” release specification
just like any label specification when deter-
mining if a reported value is an OOS and require
a thorough formal OOS investigation.
2.6 Reference standards
Most qualitative and quantitative analytical
methods in pharmaceutical analysis require the
use of an external reference standard, which is
typically taken from a batch of the DS that is
considered to be representative of the DS in the
analytical sample. In certain situations, a batch
of reference standard that has a higher degree
of purity than the samples of DS or DP to be
tested may be preferred to minimize interference
from impurities or other contaminants during
calibration. When a highly pure sample of the
DS is required and difficult to obtain, the refer-
ence standard sample may be recrystallized or
otherwise purified from a batch of the API.
When the DS is a salt, it is acceptable to use the
neutral form of the drug or a different salt form
as the reference standard, provided the appro-
priate correction factors are included in the
calculation of its puritydthis may be necessary
if the DS is unusually unstable or difficult to
obtain. The storage conditions, sampling instruc-
tions, and requalification dates should be care-
fully controlled and documented to minimize
the risk of contamination or degradation.
The tests used to characterize a reference stan-
dard are usually based on those used to charac-
terize the DS. However, full characterization of
the reference standard also involves additional
procedures not used during routine testing to
confirm its identity and determine its purity.

I. Introduction
 2.6 Reference standards
When a reference standard is difficult to obtain
in sufficient quantities, a “working standard”
traceable to the reference standard may be
qualified for use in routine analysis.
2.6.1 Qualitative tests
Identification and description of the DS
either in the API or in DP are the main qualita-
tive tests in the specification. As discussed
earlier in Section 2.2.1.1.2, identification is con-
ducted using one specific spectroscopic test
(such as FT-IR) or two nonspecific tests such
as HPLC combined with an offline spectro-
scopic test or online diode array detection. The
identity of the drug is confirmed by comparison
of the sample spectrum with an archived spec-
trum of the reference standard or with the spec-
trum of the reference standard obtained at the
time of analysis. As discussed in Section
2.2.1.1.2, a single chromatographic technique
is not considered sufficiently specific for the
identification of the DS and a second nonspe-
cific technique such as UV-visible spectropho-
tometry, or an orthogonal chromatographic
procedure is required. Description and identifi-
cation testing are discussed in more detail in
Chapter 8.
Unusual observations, such as additional or
shifts in spectral bands or unexpected chro-
matographic peaks, may suggest the presence
of impurities or other conformational forms of
the drug, requiring further investigation. How-
ever, it is important to note that a qualitative
test may not be used for quantitation without
further validation of the method. Reference
spectra or chromatographic retention times
may be used in routine analysis in lieu of refer-
ence data obtained at the time of analysis for
qualitative tests such as identification, provided
the acceptance criteria have to be justified dur-
ing method development and validation. With
suitable validation, identification of impurities,
including chiral impurities, based on chromato-
graphic retention time (RT), relative retention
I. Introduction
37
time (RRT), or relative retention factor (Rf) is
acceptable (this topic is discussed in more detail
in Chapter 9).
2.6.2 Quantitative tests
2.6.2.1 Drug substance
Quantitative procedures require knowledge
of the purity (P) of the reference standard for
the DS, which is defined as the difference be-
tween the sum of all the components in the refer-
ence standard sample (qtotal) and the sum of the
components in the sample other than the drug it-
self (qother), expressed as a percentage, according
the following equation:
 
qtotal  qother
P¼  100 (2.9)
qtotal
or
 
qother
P ¼ 100   100 (2.10)
qtotal
The other components in the reference stan-
dard sample include impurities (qi) (see ICH
Q3A(R2) and Chapters 9e11), residual solvents
(qrs) (see ICH Q3C(R7) and Chapter 13),
elemental impurities (qei), water (qw), and any
additional extraneous material, including any
solid material (qsolid), salts (qsalts), counterion
(qci) and processing aids (qpa), follows
 
qi þ qrs þ qei þ qw þ qci þ qsolid þ qsalts þ qpa þ .
qother ¼
qtotal
 100
(2.11)
To avoid “double counting,” the concentration
of any metals should be subtracted from the con-
centration of any solid material, which is typically
determined by loss on ignition (USP <733>). The
concentration of water and any residual solvents
may be determined using loss on drying
(USP <731>); however, separate determinations
of water (see Chapter 17) and residual solvents
(see Chapter 13) using more accurate and precise
38 2. General principles and regulatory considerations: specifications and shelf life setting
methods are preferred. The approach described
above should be used to qualify development
batches and the initial batches of reference
standards used in commercial quality control.
Under certain circumstances, for example, when
a substantial body of historical data is available,
it may be acceptable to qualify or requalify refer-
ence standards by comparison with an existing
qualified reference standard.
2.6.2.2 Impurities
Ideally, qualification of reference standards
for impurities should be conducted in the
manner described in Section 2.6.2.1. However,
this approach can present a significant challenge
if only small quantities are available and the reli-
able determination of the other components in
the impurity reference standard (Eq. 2.11) can
be very difficult and sometimes impossible.
The limited supply of reference standard of
impurities also results in the need to determine
impurity concentrations in routine testing by
comparison with the DS itself and the use of rela-
tive response factors (RRF) in the calculations.
The application of RRF values in the calculation
assumes that the relationships between the
measured responses of the DS (Rs) and impu-
rities (Ri) and the concentration (Cs or Ci) in the
sample are linear with zero intercepts (i.e., no
interferences from the matrix):
Rs ¼ RFs þ intercept ð ¼ 0Þ
Ri ¼ RFi þ intercept ð ¼ 0Þ
Determination of the relative response factor
of each impurity (RRFi) would appear to be
a simple matter of combining Eqs. (2.12) and
(2.13):
Ri RFi
RRFi ¼ ¼ (2.14)
Rs RFs
However, Bhattachatyya et al.55 have com-
mented in the Pharmacopeial Forum on the
absence of a standardized approach to the
calculation of RRF values and inconsistencies in
the calculations of impurity concentrations in
DS and DP in the USP. These and other issues
surrounding the quantitative determination of
impurities are discussed in Chapters 9e11.
2.6.3 Pharmacopeial reference standards
Certified reference standards for the DS and
impurities are available from the pharmaco-
peias. However, it is important to note that a
pharmacopeial reference standard applies only
to the calibration of instruments and methods
described in the applicable monograph. It
should also be noted that the reference standard
is provided by a commercial manufacturer of
the drug, and the pharmacopeias usually rely
on important information, such as purity, from
the supplier and the pharmacopeias do
not necessarily retest the sample received.
Furthermore, reliance on the labeled purity of
pharmacopeial standards should be treated
with caution when used for the development
of new dosage forms containing a drug listed
in a pharmacopeia and requalification of the
compendial standard is recommended to
ensure that it is suitable for its intended use.
Finally, development of an “old drug in a new
product” can result in the discovery of new im-
purities not listed in a pharmacopeia (such as
(2.12) drugs covered in the United States by section
505(b)2 of the Federal Food, Drug, and Cosmetic
(2.13) Act). Different pharmacopeias do not always
list the same impurities, even when the analyt-
ical methods are the same. Therefore, review
of the pharmacopeias as well as the scientific
literature is an important first step in the devel-
opment of a new DP containing a DS that is
already listed in one or more pharmacopeias
(“old drug in a new product”). When new
impurities are discovered, identification and
qualification are required as described in ICH
Q3A(R2) and Q3B(R2).
I. Introduction
 2.8 Conclusions
2.7 Documentation
Good documentation practices (GDPs)56 are
the foundation of all scientific undertakings. No-
where is the truism “if you didn’t write it down,
you didn’t do it” more relevant than in the phar-
maceutical industry where the safety and the ef-
ficacy of its products depend on the truthfulness
of its scientists and the integrity of their data.
Virtually all data and reports are subject to inter-
nal and external scrutiny, and a robust system
for the recording, storage, archiving, retention,
and retrieval of records and documents is the
critical component of the overall control strate-
gies underlying cGMPs. A detailed discussion
of GDPs is outside the scope of this book and
the reader is referred to other publications on
this subject including General Chapter <1029>
Good Documentation Practices in the USP.
Compliance with the requirements of FDA 21
CFR Part 11 “Electronic Records” is understood
and is not discussed in this publication. Howev-
er, certain aspects related to the recording of data
and reporting of results are critical to an in-depth
treatment of data and the development and vali-
dation of pharmaceutical methods. Although
these aspects are discussed in more detail in
Chapters 9e11, within the specific context of
methods for assay and impurities, the discussion
contained in that chapter is generally applicable
to the treatment of all analytical data.
2.8 Conclusions
Specifications form the cornerstone of the
control strategy of the DS and the DP contained
within the regulatory requirement and the
framework provided by the cGMP and GLP
for animal studies. The International Council
on the Harmonisation (ICH) of the technical re-
quirements for new drugs and new products
provides the most appropriate starting point
for the development of specifications for new
products. According to ICH, DS and DP
specifications contain three components: a list
I. Introduction
39
of attributes, references to test methods, and
the acceptance criteria. These specifications
together with the other systems within the
cGMP and GLP are designed to ensure the
drug is safe, is efficacious, and performs as ex-
pected. The ICH guidelines are divided into
two types of tests: universal tests, which apply
to all types of a products (description, identity,
assay, and impurities), and specific tests, which
depend on the type of dosage form and the route
of administration. Not all types of dosage forms
or routes of administration are described in the
ICH Quality Guidelines; absent are products
that include transdermal products, inhalation
products, nasal sprays, and other types of
specialized drug delivery system. These gaps
in the ICH guidelines have been mostly filled
by regional guidelines from the three ICH re-
gions published by the United Food and Drug
Administration (FDA), the European Medicines
Agency, and the Japanese Ministry of Health.
Although many non-ICH countries follow the
ICH Guidelines, additional information can
also be found in guidelines from the countries
such as Brazil, Canada, and the ASEAN Region,
as well as the World Health Organization. These
national and international guidelines are com-
plimented by general chapters in the various
pharmacopeias. For example, the first five gen-
eral chapters of the USP define the testing re-
quirements for drug products according to
their route of administration and then classify
the tests as quality tests or performance tests.
Although not a regulatory requirement in all re-
gions or for all types of products, a distinction is
often made between release specifications and
stability specifications, with the former being
more restrictive that the latter to ensure that a
product does not go out of specification during
storage. The list of tests in a specification should
consider not only the regulatory requirements
but also the CQAs that can potentially affect
the quality, safety, and efficacy of the productd
this is achieved through a thorough risk assess-
ment and criticality analysis. Sound statistical
approaches are essential to the establishment
40 2. General principles and regulatory considerations: specifications and shelf life setting
of the meaningful acceptance criteria and shelf
life, which can be challenging because of the
small number of relevant batches and the
limited amount of data available at the time of
filing a marketing application for a new drug.
References
1. ICH Q6A. Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug Products:
Chemical Substances In: The International Council on Har-
monisation of Technical Requirements for Pharmaceuticals
for Human Use, 1999. Geneva.
2. ICH Q6B. Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug Products:
Biotechnological/Biological Products In: The International
Council on Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use, 1999. Geneva.
3. Code of Federal Regulations. 210 and 211: Food and
Drug Administration e Current Good Manufacturing
Practice in Manufacturing, Processing, or Holding of
Drugs; General and Current Good Manufacturing Prac-
tice for Finished Pharmaceuticals.
4. Code of Federal Regulations. Title 21, Part 58: Food and
Drug Administration eGood Laboratory Practice for
Nonclinical Laboratory Studies, Vol. 1.
5. ICH Q1A(R2). Stability Testing of New Drug Substances
and New Drug Products, 2nd Revision; In: The Interna-
tional Council on Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use , 2003. Geneva.
6. ICH Q1B. Photostability Testing of New Drug Substances
and New Drug Products In: The International Council on
Harmonisation of Technical Requirements for Pharmaceuti-
cals for Human Use, 1997. Geneva.
7. ICH Q1C. Stability Testing of New Dosage Forms In: The In-
ternational Council on Harmonisation of Technical Require-
ments for Pharmaceuticals for Human Use, 1999. Geneva.
8. ICH Q1D. Bracketing and Matrixing Designs Stability Testing
of New Drug Substances and New Drug Products In: The Inter-
national Council on Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use, 2003. Geneva.
9. ICH Q1E. Evaluation of Stability Data In: The International
Council on Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use, 2003. Geneva.
10. ICH Q1F. Stability Data Package for Registration Applica-
tions in Climatic Zones III and IV In: The International
Council on Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use, 2006. Geneva.
11. ICH Q3A(R2). Impurities in New Drug Substances, 2nd
Revision; In: The International Council on Harmonisation
of Technical Requirements for Pharmaceuticals for Human
Use , 2006. Geneva.
I. Introduction
12. ICH Q3B(R2). Impurities in New Drug Products, 2nd
Revision; In: The International Council on Harmonisation
of Technical Requirements for Pharmaceuticals for Human
Use , 2006. Geneva.
13. ICH Q3C(R8). Impurities: Guideline for Residual Solvents
In: The International Council on Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use, 2003.
14. ICH Q3D(R1). Guideline for Elemental Impurities, 7th
Revision; In: The International Council on Harmonisation
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Use , 2018. Geneva.
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17. ICH Q4B. Evaluation and Recommendation of Pharmaco-
poeial Texts for Use in ICH Regions Harmonisation In: The
International Council on Harmonisation of Technical Require-
ments for Pharmaceuticals for Human Use, 2010. Geneva.
18. ICH Q8. Pharmaceutical Development, 2nd Revision; In: The
International Council on Harmonisation of Technical Require-
ments for Pharmaceuticals for Human Use , 2016. Geneva.
19. ICH Q9. Quality Risk Management In: The International
Council on Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use, 2009. Geneva.
20. ICH Q10. Pharmaceutical Quality System In: The Interna-
tional Council on Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use, 2009. Geneva.
21. ICH Q11. Development and Manufacture of Drug Sub-
stances (Chemical Entities and Biotechnological/Biological
Entities) In: The International Council on Harmonisation
for Human Use, 2016. Geneva.
22. ICH Q12. Technical and Regulatory Considerations for
Pharmaceutical Product Lifecycle Management In: The Inter-
national Council on Harmonisation of Technical Require-
ments for Pharmaceuticals for Human Use, 2018. Geneva.
23. ICH Q13. Continuous Manufacturing of Drug Substances
and Drug Products In: The International Council on Harmo-
nisation for Human Use, 2018. Geneva.
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national Council on Harmonisation for Human Use, 2018.
Geneva.
25. ICH Q2(R2). Validation of Analytical Procedures: Text and
Methodology In: The International Council on Harmonisa-
tion for Human Use, 2005. Geneva.
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(Mutagenic) Impurities in Pharmaceuticals to Limit Poten-
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31. Pyrogen Test, USP General Chapter <151>, United
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 C H A P T E R

3
General principles and regulatory
considerations: method validation
Thomas W. Rosanske
T.W. Rosanske Consulting, Overland Park, KS, United States

O U T L I N E

3.1 Introduction 44 3.2.6 Detection limit 47

3.1.1 Design, proof of concept, and life cycle 3.2.7 Quantitation limit 48
management of analytical methods 44 3.2.8 Robustness 48
3.1.1.1 Design 44 3.2.9 System suitability 48
3.1.1.2 Proof of concept 44
3.3 Guidelines 48
3.1.1.3 Method life cycle
management 46 3.4 Phase appropriate method validation 49
3.2 Definitions 46 3.5 Verification of compendial methods 52
3.2.1 Bias and accuracy 46
3.6 Revalidation of methods 53
3.2.2 Linearity 47
3.2.3 Range 47 3.7 Method remediation 54
3.2.4 Specificity 47
3.8 Conclusions 56
3.2.5 Precision 47
3.2.5.1 Repeatability 47 References 56
3.2.5.2 Intermediate precision 47
3.2.5.3 Reproducibility 47

Specification of Drug Substances and Products

https://doi.org/10.1016/B978-0-08-102824-7.00003-8 43 Copyright © 2020 Elsevier Ltd. All rights reserved.
44 3. General principles and regulatory considerations: method validation
3.1 Introduction
3.1.1 Design, proof of concept, and life
cycle management of analytical methods
If one views an analytical method as a “prod-
uct,” the process by which it is developed, vali-
dated, and maintained can be put into terms
familiar to development teams charged with
bringing a new product to the market. As such,
the evolution of analytical methods can be seen
as progressing through three stages: design,
proof of concept, and life cycle management.
3.1.1.1 Design
Once the quality parameters and acceptance
criteria that must be met to achieve the desired
product or process performance have been
defined (i.e., the analytical target profile [ATP],
discussed in Chapter 10), the analytical chemist
will identify approaches to measure the quality
parameters with appropriate accuracy, preci-
sion, specificity, and sensitivity to achieve what
is required for control. By establishing the
analytical method “product” characteristics and
assessing “design” options, the analyst can
then develop a strategy and approach to select-
ing the appropriate analytical methodology to
achieve what is required to measure the quality
parameter.
Chapter 4 of this book describes how the prin-
ciples of Quality by Design and design of exper-
iments can be used in the design stage of method
development. Chapters 4 and 10 contain discus-
sions of the concepts of ATP and analytical life
cycle management. The data and knowledge
gained at the initial stages of an analytical
method development will provide a high level
of assurance that the analytical procedure has
the desired characteristics to meet its intended
performance. This chapter discusses core tech-
nical attributes (validation parameters), which
should be evaluated to support the applicability
of the analytical method “product.” One aspect
that is often overlooked when designing an
I. Introduction
analytical method is the needs of the customers
(e.g., the lab(s) receiving the method and the
project team using the results). The analytical
method should be customer-friendly with
respect to efficiency and ease of use, cost-
effectiveness, and resources (personnel and
equipment) required to implement and main-
tain. Therefore, an understanding of the
customer needs and capabilities is essential dur-
ing the design phase; this is achieved by
including the customer(s) in the design of the
product whenever possible. Some companies
will manage this through co-development
teams, comprised of members from both the
development and receiving sites.
Changing needs of the customer(s) during the
life cycle of a product often serves as the basis for
establishing analytical method requirements and
the level of method validation required. This
chapter discusses how a phased approach to
method validation can be implemented to ensure
that the key customer analytical data needs and
regulatory requirements are met at various
stages of product development.
3.1.1.2 Proof of concept
The next step of the process is verifying that
the method is able to achieve its design goals
(as described in the ATP). This is the “proof of
concept,” verifying that the method is capable
of achieving predetermined performance
criteria. In conventional thinking, this constitutes
traditional method validation. The validation
parameters normally employed to demonstrate
the proof of concept are described in the Interna-
tional Council for Harmonisation (ICH) Quality
Guidance Q2 (R1), Validation of Analytical Pro-
cedures: Text and Methodology.1 While this
guidance document defines the typical method
quality parameters and assessment approaches
for an analytical method at the product registra-
tion and postapproval product life cycle phases,
it is often augmented by learning in the design
phase of the method development and even pre-
vious life cycle iterations of the method (as
Another random document with
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If the certain chivalric romanticism of Weber’s music is hard to
analyze, the special charm of Schubert’s is wholly elusive. We have
to do with an utterly different nature. Weber was an aristocrat, a
rover among wild companions, a hanger-on at the theatre for a while,
if you will, but none the less of distinguished birth, of polished
manners and of fine wit. Schubert was more than any other of the
composers, even more than Haydn, a man of the people. He was
happy to mingle with the peasants, happy to play hours at a time for
their dancing. Beethoven is said to have modelled the music of the
country people’s dance in the ‘Pastoral Symphony’ upon the music
he heard played in a certain country tavern to which at one time he
delighted to go. Brahms in his impoverished boyhood used to earn a
few pence by playing for the sailors’ dancing in the taverns along the
waterfront of Hamburg. But Beethoven regarded himself, as we have
said, as the high priest of an exalted art; and Brahms was hardly less
imperious. Yet Schubert, for all his ideals which rose ever and ever
higher, for all the fact that he numbered acquaintances in the same
aristocratic families which had seen Haydn, Mozart, and Beethoven
come and go, remained a man of the people, a singer in the sway of
his art, a loveable, reckless, sentimental and affectionate boy.

All his music is lyrical. The song is never absent from his pianoforte
works, no matter how instrumental parts of them may be. He is
essentially a melodist. His rhythms have the lilt of a dance. These
two elements are not disguised. They undergo no intellectual
transformations. They are as obvious as in the folk-songs and
dances of the country people with whom he loved to associate.
Hence the almost complete lack of sophistication in his music, the
naturalness which distinguishes it from all other music.

His harmonies are strange and warm. They lack the subtlety of
Mozart on the one hand, the frankness of Weber on the other. They
have not the expressive significance of Beethoven. They seem
rather to go beside his music than to go under it. One listens through
them, so to speak, as one might look upon a procession through a
colored mist that now conceals, now discloses, that always plays
magic tricks with the sight. Two harmonic procedures appear more
or less regularly in his music. One is the interchange of major and
minor, the other the bodily shifting of the harmonic fabric up and
down the scale. The latter are changes rather than modulations. By
reason of these unexpected, unaccountable harmonies, his music
sounds now near, now far. One moment it is with us and familiar, the
next it is aloof and strange.

Schubert’s hands were thick, his fingers short and fat. Though he
was not an elegant or a polished player, he had great beauty of
touch and a natural, easy fluency, especially in the rapid passages of
his own works. Richard Heuberger, in his excellent book on
Schubert, points to the fact that most of Schubert’s pianoforte music
is written in keys that require the use of many black notes on the
keyboard; and suggests, as one reason for this, that Schubert found
it easier to play in such keys. It is generally admitted that the key of
G major is the most difficult for the pianist.

Schubert’s pianoforte music comprises many long sonatas, two sets

of impromptus, a set of short pieces called ‘Musical Moments’ and a
number of waltzes and other dances. The sonatas are for the most
part unsatisfactory as such. In such extended forms there is need of
an intellectual command of the science of music, and a sense of
great proportions, both of which Schubert lacked. Hence the
separate movements, the first and even more often the last, are
loose and rambling in structure, and too long for the work as a
whole. There is so little cohesion in the group that one may in most
cases take the individual movements quite out of it and play them
with perfect satisfaction.

Not all the movements are over-long, and some of the sonatas can
be enjoyed in their entirety. Perhaps the most satisfactory from the
point of view of structure is that in A minor, opus 42. In this the first
movement is admirably constructed, firmly knit, full of distinct
contrast, and in the middle section well developed. The andante and
variations is undeniably long, but the formal preciseness of the
following movement and of the rondo succeeds in giving to the group
a definiteness and balance which will pass muster.
A sonata in D major, opus 120, is considerably shorter, but is even
from the point of view of form less satisfactory. The first movement
reveals one of Schubert’s great weaknesses. It happens here to be
almost inconsiderable, but it is none the less evident. This is the lack
of ideas in the treatment of the development section. There are nine
measures which give the impression that Schubert was content to
keep his music going with makeshifts. We have nothing of any
significance, a series of octaves in the left hand answered by a
series in the right, and a full chord at the beginning of each measure,
whereby a desired modulation from the key of C-sharp minor to that
of A major is accomplished.

This is bare music. The passage is so short that it hardly mars the
movement seriously, but unhappily other movements are nearly
destroyed by the weakness at which this one hints. For example, the
first movement of a sonata in A minor, opus 143, which contains
themes that are truly inspired, breaks hopelessly adrift in the
development section. The section is fatally long, too. And what does
it offer to hold our interest? Only measure after measure of an
unvaried dotted rhythm, for the most part in the right hand over
chords which may be beautiful but are seemingly without any aim.
Schubert either does not know what to do or he is utterly lost in
dreaming.

This is real tragedy in music, the ruin of most beautiful ideas by a

fatal weakness. The opening theme promises even more than that of
the earlier sonata in the same key. It is most mysterious, most
suggestive, the very best of Schubert. And the second theme is of
unearthly beauty. But in this weak movement both are lost, both
thrown away. The whole sonata suffers in consequence. The
andante is not especially noteworthy, but the scherzo is a
masterpiece, not only of expression, but of workmanship; and so is
the final rondo.

Similarly, the sonata in B-flat major, written not long before he died,
falls into a heap of ruins. The first theme of the first movement is
matchless in beauty. Schubert is loth to leave it, we are loth to have
it go. A strange melody in F-sharp minor does for a second theme,
and this simply rambles on through sudden changes of harmony until
it reaches the key of F major, only to give way to measure after
measure of equally aimless wandering, with only figures to save the
music from amorphousness. Note then a closing theme of perfect
beauty! Play it with all tenderness, with all the delicate suggestion
you can put into it, and still even this first section of the music is long
and overbalanced. There is a wealth of poetry in it, even a great
depth of feeling and a heart-moving sadness. It seems a sacrilege to
decry it; yet there it stands, frustrate.

The development section is what one would expect, weak in

structure. Yet the second part of it is strangely moving, from the
establishment of the key of D minor to the return of the first theme.
The life of the music seems held in suspense. There is only a steady
hushed tapping of triads, measure after measure, swaying from D
minor to F major and ever back again, with reminiscences of the
rambling measures in F major of the first section, floating here and
there like mist in a dull rain. Strains of the first theme drift by, there
are low muffled trills on D. Finally, the tapping ceases, as rain might
cease; a quiet scale, like drops from the branches of some wet tree,
falls to a low trill, and, after a silence, the first theme comes back into
the music.

One can hardly find sadder or more beautiful music than these
measures, or than the lovely first theme; and yet the movement is
strangely without form and void. The andante which follows it is
overdrawn. The repetitions of the sections in A major might have
been omitted to better effect; but there is no looseness of structure.
The music is unspeakably sad, with the sadness of the songs of the
Winterreise. The scherzo is flawless, the final rondo long but well
sustained. Yet, by reason of the aimlessness of long measures in the
first movement, the sonata as a whole is like a condemned building.
And in this sonata, too, there is an intensity of mood that, except for
the last movement, should succeed in welding the whole group
together. Even the last movement is not entirely independent.
What is most lamentable in all this is that Schubert poured much of
his most inspired music into the sonatas. Little of his music presents
more intrinsically beautiful material. In no other of his pianoforte
pieces did he show such a wide and varied control of the technical
possibilities of the instrument. Yet all would seem to be of little or no
avail. Many of the most precious of his poetic fancies lie buried in
these imperfect works.

Though Schubert was not a virtuoso, he displayed instinct for and

ingenuity in devising pianoforte effects. In the huge ‘Wanderer
Fantasy,’ opus 15, he seems to have set himself the task of
awakening the greatest possible resonance of the instrument. The
big chords and arpeggios in the first movement are not, however,
overpoweringly effective. The variations in the second are more
successful. They certainly look impressive on the printed page, and
the sound of the climax is gigantic. But the stupendous is not natural
to Schubert on the whole. He is more of a poet than a virtuoso. The
first movement and the scherzo of the sonata in D major, opus 53,
are big in effect. The spacing and rhythm in the piu lento section of
the first movement has been pointed out by Heuberger as significant.
The vigorous first subject of the scherzo can make the piano ring.
But in general Schubert shows at his best as regards pianoforte
writing in more delicate measures, and in brilliant rather than
massive and sonorous effects. The last movement of the sonata in A
major, opus 120, is a good example of a piquant style of which he
was master. Here the long scales terminating in chords high up on
the keyboard are quite dazzling.

He was not especially original in accompaniment figures. One finds a

great deal of mediocre Alberti-bass stuff. On the other hand, he is a
master in weaving a more subtle sort of arabesque about his
melodies, or over or below them. One sees this not far from the
beginning of the adagio movement of the big fantasy opus 15, in the
ornamentation of the Fantasia, opus 27, and in the Trio of the
Scherzo in opus 147. The closing measures of the first section of the
first movement of this sonata are very like Chopin. There are many
passages of excellent free writing for the instrument, such as the C
major section of the allegretto in opus 164. This, and, in another way,
the second section of the minuet in opus 122, are very like passages
in the Schumann Carnaval. On the whole his treatment of the
pianoforte is more delicate and more distinguished than Weber’s.

Dr. Oskar Bie has remarked wisely in his history of pianoforte music
that to one who has not a soft touch the beauties of Schubert’s
music will not be revealed. It is particularly in lovely, veiled passages
that he excels. Except for the final rondo almost all of the sonata in
B-flat major to which we have referred is to be played very nearly
pianissimo. The poetic and generous Schumann felt that in certain
parts of the andante of the great C major symphony, a spirit from
heaven might be walking through the orchestra, to which the
instruments would seem to be listening. There are many passages in
the pianoforte music which suggest such ghostly visitations, which
whisper far more than speak. And in such places Schubert’s scoring
will be found to be matchless, as delicate as Chopin’s, though less
complicated.

In spite of the many inspired themes in the sonatas, and of the

variety and richness of pianoforte effects with which they are often
presented, the works are, as we have already said, too faulty or too
weak in structure to hold a secure and honored place in pianoforte
literature. It is vain to speculate on what Schubert might have done
with the form had he lived longer. The last sonata is discouraging.

But in shorter forms there is no doubt that he was a supreme and

perfect artist. The two sets of impromptus and the set of shorter
pieces called the Moments Musicals are masterpieces. It is hardly an
exaggeration to say that in them lie concealed the root and flower of
the finest pianoforte literature produced during the next half century
or more in Germany. Mendelssohn, Schumann, and Brahms owe
immensely to them.

Each set of Impromptus consists of four pieces. The title was not
given to them by Schubert, but was added by the publishers of the
first editions, the Haslingers of Vienna. Schumann suggested that
the first, second, and fourth of the second set might be taken as
three movements of a sonata in F minor. The first of these is very
much after the manner of the first movements of Schubert’s sonatas;
but the first section is not repeated, and the section which at first
might suggest a real development section is repeated entirely at the
end of the piece.

The first impromptu of the first set is built on a single phrase. The
quality of the music is legendary. A sharp preliminary G claims our
attention, and then the story begins, pianissimo, a single voice,
answered, as it were, by a chorus; and what this voice sings, or
rather chants, is the burden of the rest. One might fancy the piece a
series of variations but that there seems to be some story
progressing with it. At times the theme is smooth and serene, as in
the A-flat major section near the beginning, where it floats along over
a rolling accompaniment. Later on it is passing through dark, wild
forests. The agitated triplet octaves, inexorably on G, suggest the
‘Erl King.’ And so ever on, the same phrase, as if it were a lone
soldier on his way through a land now wild and dreary, now sunny.
During the last two pages the restless triplet figures are never still,
and always they come back to beat on G. Just before the end the
agitation stops, but still the G persists, in long octaves, and still the
tramp of the soldier keeps on. What it may mean no one can tell.
The impression is that the strange music continues on, long after our
ears have heard it die away.

The second impromptu is for the most part in a light and happy vein.
There is a constant flow of triplet figures, wonderfully graceful and
sinuous, over the simplest of accompaniments. A sudden change of
mood, an abrupt modulation, usher in a section in the nature of a
trio. There is a bold melody, greatly impassioned, very much after
the manner of Schumann; a breadth of style and a power wholly
different from the light figure-work which has preceded it. But back to
the lighter mood the music comes again, back to the flow of
exquisite, light sound, only to be brought once more to a sudden
check. There is a short coda of greatest vehemence and brilliance.
Here is salon music of a wholly new variety. It has nothing in
common with the showy polonaises and rondos of Weber, nor yet
with the sentimental nocturnes of Field. In fact, one would find it
difficult to find its parallel elsewhere in the literature of pianoforte
music, its strange combination of ingenuousness and grace and wild
passion.

The third is in G-flat major, though it is perhaps better known in the

key of G, to which Haslinger took the liberty of transposing it, much
to the harm of its effect. It is in the nature of a reverie, akin to the
nocturnes of Field in spirit, but far broader in plan and more healthy
in sentiment.

Something of the airiness of the second impromptu is to be found in

the fourth; but here the runs have an harmonic significance rather
than a melodic. They are flowing chords, successive light showers of
harmonies. The very sameness of the figuration adds to the charm,
and does not, it may be added, take away from the difficulty. Only
twice is the gentle vibration so produced interrupted for long; once to
give way to a short melody, once during the long, impassioned
middle-section in C-sharp minor.

What stands out in this group of pieces as a whole is the restraint in

form, so lacking in the sonatas, and the fineness of pianoforte style.
There is a great economy of writing. The piano is left to speak for
itself; it is not often taxed to make music grand enough for the
orchestra. In the second and fourth of the series an accompaniment
is hardly more than suggested, except in the impassioned middle
sections; yet the passage work is in no way of the virtuoso type. It
has a refinement that is, apart from Bach, Mozart, and Chopin,
unusual in pianoforte music. And what is ever worthy of notice in all
the work of Schubert is the prevalent pianissimo. The spiritual visitor
is ever present. One feels that Schubert was wholly lost in his music,
that he surrendered himself utterly to the delight of sound, of softest
sound. The four works are equally inspired. They are full of ecstasy,
full of rapture.
The impromptus of the second set are not so invariably fine, yet as a
whole they are a momentous contribution. The first and the fourth
are longer and more elaborate than any in the first set, and
consequently one feels in them the lack of proportion and control
which weakened the sonatas. The third is, as a matter of fact, a
series of variations; and they can hardly be said to suffer from any
weakness. Rather they are exceedingly well done. However, better
variations have been written—not, it may be remarked, by Weber—
and the form is dangerously likely to prove stupid except in the
hands of a man who has a special skill in it. There is necessarily
lacking a chance for that spontaneity and freedom which one
associates more with Schubert than with any other composer.

The last impromptu is conspicuous for a gay brilliance, perhaps a

better brilliance than Weber revealed, but a less effective one. It
suggests Liszt. Passages remind one of the Gnomenreigen. There
can be no mistaking the Hungarian quality of the melodies, the mad,
rhapsodical, Gypsy style.

The first impromptu contains more of the quality of the extraordinary

Schubert; is perhaps too long, but is full of fine inspiration and
romantic fancy. The opening theme is in ballade style, with a rather
incongruous touch of conventionality here and there. The second
theme is purely lyrical, though the persistent eighth-note rhythm in
which it is presented gives it a spirit of restlessness. It is thrice
repeated, and the figure-work in the high registers which adorns the
third statement of it is effective and beautiful. The theme itself is
silenced unexpectedly and the figure-work leads down again into the
deep registers, where it flows in a hushed arpeggio figure. Over this
a third theme is suggested, which, with its answer woven in the
accompaniment, constitutes a distinct second section of the piece,
releases a different mood. It is for the most part soft, yet it is
strangely impassioned. It leads back again to the first theme and the
whole is repeated, with a change only of key. At the end, the first
theme once more adds a touch of the ballade. The two measures
before the final chords have all the strange power of suggestion
which one associates with Schubert, leaving one with the impression
that the music has rather passed on than ended, as if the song, like
that of the ‘Solitary Reaper,’ could have no ending.

There is no contemporary music with which one may compare these

impromptus. They are not sentimental idylls like the nocturnes of
Field, nor show pieces like the shorter works of Weber. They have
nothing in common with the music of the contemporary virtuosi, nor
with that of any virtuosi. They are extraordinarily rich in genuine
musical worth, and, like all of Schubert’s music, in form or out of
form, inspired. Even more remarkable are the six short pieces called
‘Musical Moments.’ Three of these are but two pages long; only one
more than four. Each is wholly different from the others in mood. In
all of them the pianissimo prevails. Schubert is whispering, not
speaking. They are essentially pianoforte music, too. Though there is
nothing elaborate in the style of them, not the slightest trace of a
striving for new effects, yet it may be questioned if any German
pianoforte music shows greater understanding of what one might call
the secret and intimate qualities of the instrument.

There is practically no thickness of scoring. Only the trio sections of

the first and last are open to even suspicion in this regard. There is
no commonplaceness or makeshift in the accompaniments. The
monotonous tum-tum of the third is necessary in the expression of
the mood of dance and song which the piece embodies, of wild
dancing and intensely emotional song, more than half sad. The
workmanship of all is delicate, whether it be deliberate or instinctive.
There is in all a great appreciation of effects of contrast, of loud and
soft, which are the very first of the peculiarities of the instrument; an
appreciation of the sonority, rich but not noisy, which the pedal
allows; of the charm of soft and distinct passage notes, of vigorous,
percussive rhythm. All is perhaps in miniature; but the six pieces are
the essence of German pianoforte music, both in quality and style;
the very root and stock of the short pieces of Schumann and Brahms
by which they are distinguished.

As to the nature of the separate pieces, little need be said. They are
pure music, perfect art. In the sound of them are their completeness
and their justification. The first may suggest dreams. The figure out
of which it is made is of the woodland. It suggests the horns of elf-
land faintly blowing. It is now near, now far. As the notes of the bugle
will blend in echoes till the air is full of a soft chord, so does this
phrase weave a harmony out of its own echo that, like the sounds of
a harp blown by the wind, is more of spirit than of flesh. Even in the
trio something of this echo persists.

The remaining five keep us closer to earth, are of more substantial

and more human stuff. Yet note in the second, in the second
statement of the first theme after the first episode, how a persistent
E-flat suggests again the ghostly visitor to which the music itself
seems to listen. The third is, as has been suggested, a dance, soft
yet half barbaric. Is the melody sad or gay? It is blended of both, like
the folk-songs of the Slavs and the Celts, the character of which it
breathes. One is tempted to ask if there ever was softer music than
Schubert’s. The music enters its coda here thrice piano, and twice
on its way to the end it grows still softer.

The fourth suggests a prelude of Bach, except for the trio, which
again has the character of a folk-song and again is softer than soft.
The fifth is a study in grotesque. Even here there are fine effects,
such as the echo of the first phrases; but the general impression is of
almost savage accents and harsh dissonances. The last has a touch
of Beethoven, though the melodies are of the kind that Schubert
alone has ever heard, and the harmonies here and there rise, as it
were, like shifting, colored mist across the line of the music.

It cannot be said that the melodies and harmonies of either the

Impromptus or the ‘Musical Moments’ are more inspired than those
of the sonatas. Indeed, there are passages in the latter of more
profound and more intense emotion than finds expression in the
shorter pieces. But most of the sonatas are in ruins. Their beauties
are fragmentary and isolated; whereas nearly all the Impromptus and
all the ‘Musical Moments’ have a beauty and firmness of line and
design as well as of content. For this reason they stand as the best
of his pianoforte works; and of their kind they are unexcelled in
music. They are genuinely beautiful music; they are perfectly suited
to the piano, drawing upon its various qualities without showing them
off; they are finished in detail, balanced and well-knit in structure. A
new epoch in the art begins with them.

It should be mentioned that Schubert’s waltzes and other dances

bear very clearly the stamp of his great genius. They are not
elaborate. Much of their beauty is in their naïve simplicity. They gain
nothing by being dressed up in the gaudy raiment which Liszt chose
to hang upon many of them. They should be known and played as
Schubert wrote them, not as profound or as brilliant music, but as
spontaneous melodies in undisguised dance rhythms. They are, in
fact, dance music, full of the spirit of merry-making, not in the least
elegant or sophisticated. To our knowledge there is no other music of
equal merit and charm composed in this spirit expressly for the
piano. Schubert is unique among the great composers in having
treated dance forms and rhythms thus strictly as dances.

V
All the work of Weber and most of that of Schubert fall within the
lifetime of Beethoven. The three great men constitute the foundation
of the pianoforte music of the great German composers of the next
generation. But Beethoven’s influence is largely spiritual, as Bach’s.
There was nothing more to be done with the sonata after he finished,
and long before his death the progress of pianoforte music had taken
a new turn. It is not inconceivable that before very long Beethoven’s
sonatas will be regarded as the culmination and end of a period of
growth, just as the music of Bach is already regarded; that he will
appear materially related only to what came before him, and to have
died without musical heir. The last sonatas rested many years
generally unknown. His peculiar and varied treatment of the
pianoforte in them found few or no imitators. The technique of the
instrument that Schumann and Chopin employed was not
descended from him; rather from Weber on the one hand and from
Mozart and Hummel on the other.

Even in the matter of form he exercised hardly more than a spiritual

influence, as regards pianoforte music alone. Schumann and Chopin
both wrote sonatas, but the sonatas of neither show kinship to those
of Beethoven. The Brahms sonatas are more closely related to
Weber than to Beethoven. The Liszt sonata in B minor and the Liszt
concertos are constructed on a wholly new plan that was suggested
by Berlioz; and the two long works of César Franck are not even
called sonatas. The sonata in pianoforte music alone had had its
day. The form remained but the spirit had fled. If music came back to
it at all, it came back to sit as it were among ruins.

The change which came over music was but the counterpart of the
change which came over men and over society. It was evident in
literature long before it affected music. It might in many ways be said
to have reached music through literature. The whole movement of
change and reformation has been given the name Romantic. It was
accompanied in society by violent revolutions, prolonged
restlessness, the awakening of national and popular feeling. It is
marked in literature and in music by intensely self-conscious
emotion, by an appeal to the senses rather than to the intellect, by a
proud and undisguised assertion of individuality.

Most great music is romantic music. The preludes of Bach, the little
pieces of Couperin, a great deal of Haydn, Mozart, and Beethoven
have a personal warmth which is essentially romantic. Music draws
its life more directly from emotions than the other arts. But there are
signs in the music of these men of an objective, an external ideal, to
which they have conformed the expression of their emotions. They
do not work upon the spur of emotional excitement alone. That is but
the germ from which their music starts. They have a power to
sustain. They work with music; and the ideas which they choose to
work with are chosen from a thousand others for the possibilities
they contain of expansion, of alteration, of adaptability to the need of
the work as a whole. Within the limits of this work emotional
inspiration plays its part, adding here and there a bit of harmony, a
new phrase. These are romantic touches. These reveal the quick or
the inert nature back of the music. But back of it all the architectural
brain presides, building a structure of broad design, or of exquisite
proportions. The ideal is commonly known as classical; and these
composers are properly called classical.

The Romantic composers, on the other hand, treasure their moods.

They enshrine their separate inspirations. It is the manner of their
time. They are, as we have said, emotionally self-conscious. This is
one of the marks by which we may know them. The architectural
ideal loses their devotion. They lack, in the first place, the prime
desire to sustain, in the second place, the power. The change shows
itself distinctly in the works of Weber and Schubert, both of whom
are recognized as the first of the Romantic composers.

Take, for example, the sonatas of Weber. The movements are, as we

have ventured to suggest, like broad pictures. They are a series of
figures, of colors and shadows, like tapestries. They conform to the
rules of form, but they have little or nothing of the spirit of it. They
seem to cover the outlines of a story. They suggest the theatre. So
little is their form all-sufficing that we are tempted to fit each with a
chronicle taken from olden days of knighthood. At last Weber does
so himself—gives us stories for two of his compositions.

And the sonatas of Schubert, what a ruin are they! Moments of hot
inspiration, of matchless beauty; well-nigh hours of fatal indifference
and ignorance. On the other hand, he has left us short pieces which
the publishers must needs call impromptus for lack of any other
name; ‘Musical Moments,’ each the full and perfect expression of a
single, swift inspiration. His muse whispers in his ear and before she
has flown away he has written down what she prompted. She makes
short visits, this muse. So much the worse for him if she starts him
upon a sonata. He is soon left with nothing but a pen in his hand.

Weber with his stories, Schubert with his short forms, are the
prototypes of most of the Romantic composers to come. We shall
find everywhere signs of the supremacy of the transient mood.
Stories will be lacking, at least in pianoforte music; but there will be
titles, both vague and specific, labelling the mood so that the music
may exert an added charm. There will be something feverish,
something not entirely healthy in it all. As we shall see, composers
will expend their all in a single page. Yet there will come a warmth
and a now sad, now wild poetry.

The virtuosi, and Weber among them with his showy polaccas and
rondos, speak of the change. They appeal to the general public.
They are sensationalists. The aristocratic amateurs will no longer
hold musicians in dependence. There is a mass of people waking
into life. The crowd makes money, it buys pianos; it will pay to hear a
man, or a woman, perform on the household instrument. It will
submit to the intoxicating, swift fingers, to the display of technique.
Not that the aristocratic amateurs were always less open to such
oratorical persuasion; but the public now holds the money bags, and
it will pay to hear fingers, to see flying arms and streaming hair. Who
will care to hear a man improvise a fugue in five parts? How will they
judge virtue but by virtuosity?

On the other hand, men will begin to write about their art, to defend
their new ideals, to criticize and appreciate the outpourings of each
genius as he comes along, to denounce the virtuosi who have
nothing to show but empty show. A musician holds a place now as a
man, a man of the world and of affairs. He makes a name for himself
as a poet, a critic, a satirist. And on the verge of all this new
development stand Weber and Schubert; the brilliant, witty patriot,
the man who spent his energy that a national opera might be
established in the land of his birth; and the man who had no thoughts
but the joy of his art, the warmth of music, no love but the love of
song, the singer of his race and his companions.
 FOOTNOTES:
[31] Les pianistes célèbres. 2d edition, Paris, 1878.
 CHAPTER VI
MENDELSSOHN, SCHUMANN AND
BRAHMS
Influence of musical romanticism on pianoforte literature—
Mendelssohn’s pianoforte music, its merits and demerits; the
‘Songs without Words’; Prelude and Fugue in D minor; Variations
Sérieuses; Mendelssohn’s influence, Bennett, Henselt—Robert
Schumann, ultra-romanticist and pioneer; peculiarities of his style;
miscellaneous series of piano pieces; the ‘cycles’: Carnaval, etc.
—The Papillons, Davidsbündler, and Faschingsschwank; the
Symphonic Études; Kreisleriana, etc., the Sonatas, Fantasy and
Concerto—Johannes Brahms; qualities of his piano music; his
style; the sonatas, ‘Paganini Variations,’ ‘Handel Variations,’
Capriccios, Rhapsodies, Intermezzi; the Concertos; conclusion.

The progress of German pianoforte music is consistent and

unbroken from the death of Schubert down to the end of the
nineteenth century. All composers, both great and small, with the
exception of a few who would have had music remain in the forms of
Haydn, Mozart, and Beethoven, even at the price of stagnation little
better than death, submitted themselves and their art to the
influences of the Romantic movement which had placed so distinct a
mark on the music of Weber and Schubert. We meet with relatively
few long works. The best of these are frankly called Fantasies,
claiming little relation to the sonata. Hundreds of sets of short pieces
make their appearance. Rarely have the separate pieces in a set any
conventional or any structural relation. The set as a whole is given a
name, simple and generic, or fantastical. We meet ‘Songs Without
Words,’ ‘Fantasy Pieces,’ ‘Melodies for Piano,’ ‘Nocturnes,’ ‘Ballads,’
‘Novelettes,’ ‘Romances,’ ‘Night Poems,’ ‘Love Dreams,’
‘Rhapsodies,’ ‘Diaries,’ and ‘Sketch-books.’ There are Flower, Fruit,
and Thorn pieces, Flying Leaves, Autumn Leaves, and Album
Leaves, even the ‘Walks of a Lonely Man’ and Nuits Blanches.

Most of these short pieces conform to one of three types. Either they
are moods in music, in which case they have no distinctive features;
or they are genre pieces, a diluted, watery (usually watery) picture
music; or, by reason of the constant employment of a definite
technical figure, they are études or studies. Most of them are mild
and inoffensive. Few of them show marked originality, genuine fervor
or intensity of feeling. They are evaporations rather than
outpourings; and as such most of them have been blown from
memory. A cry against this vigorous wind of Time, harsh and
indiscriminating as in many cases it may appear to be, is hopeless.
Not refinement of style nor careful workmanship can alone save
music from the obliterating cyclone. One may as well face the fact
that only a few men’s moods and reveries are of interest to the
world, that sentimentality must ever dress in a new fashion to win
fresh tears and sighs.

I
The sweetest singer of songs without words was Felix Mendelssohn-
Bartholdy. He sang the sweetest stories ever told. He was thoroughly
prosperous in his day; he was even more than that, he was
admirable and worshipful. The whole of his life reads much like the
accounts of Mozart’s early tours. He was the glass of fashion and the
mold of form in music; not only in pianoforte music, but in orchestral
and vocal music as well. One might continue the quotation, and
remark how the observed of all observers is now quite, quite down;
but one may never say that his music is out of tune and harsh. Its
very mellifluousness is what has condemned it. It is all honey,
without spice. For this reason it has become the fashion now to slight
Mendelssohn, as it once was to revere him.

This is unjust. His pianoforte music is such an easy mark for

epigrams that truth has been sacrificed to wit. There is much in it that
is admirable. Some of it will probably come to life again. Indeed, it
has not all the appearance of death now, choked as it may seem to
be in its own honey. A few of the ‘Songs Without Words,’ the Prelude
and Fugue in E minor, opus 35, some of the short capriccios and the
Variations sérieuses still hold a high place in pianoforte literature.

The mass of his music, however, has fallen into disgrace. This is not
wholly because the world ate too much of it and sickened. One does
not look askance at it as one looks at sweets once immoderately
devoured and henceforth distressful even to the eye. One sees
weakness and defects to which its fate may be attributed.

At the basis lies a monotony. His melodies and harmonies are too
unvaryingly alike. He is a slave to milky mannerisms. The curves of
his melodies are endlessly alike; there is a profusion of feminine
endings, dwellings in commonplaceness, suspensions that have no
weight. His harmonies are seldom poignant. His agitation leads no
further in most cases than the diminished seventh. To this he comes
again and again, as regularly or as inevitably as most Romanticists
went to tombstones for their heroics. The sameness of melody, the
threadbare scheme of his harmonies, these mark a composer with
little great creative force.

In the pianoforte music one finds even a lack of ingenuity. He has

nothing to add to the resources of the instrument. He knew himself to
be sterile in pianoforte figures. The ‘Songs without Words’ show but
two or three types of accompaniment, and these are flat and
monotonous. There are the unbroken chords, usually without a trace
of subtlety in line, such as we find in the first, the fifteenth, the
twenty-first, the thirty-seventh, and numerous others. There are plain
chords, usually triads, monotonously repeated, as in the tenth,
twentieth, twenty-second, and thirty-ninth, flat with the melody, or in
syncopation as in the fourteenth and seventeenth. There are the
rocking figures such as one finds in all the ‘Gondola’ songs, in the
so-called ‘Spring Song,’ and in the thirty-sixth. Only rarely does he
give to these figures some contrapuntal flexibility, as in the fifth and
in the thirty-fourth, known as the ‘Spinning Song,’ and in the
eleventh.

There are many songs which have no running accompaniment,

which are in the simple harmonic style of the hymn tune. These are
usually extremely saccharine. The few measures of preludizing with
which they begin are monotonously alike—an arpeggio or two, as if
he were sweeping the strings of his harp, as in the ninth and the
sixteenth. Some, however, are vigorous and exciting, like the
‘Hunting Song’ (the third), and the twenty-third, in style of a folk-
song.

It is the lack of variety, of ingenuity and surprise which makes the

‘Songs without Words’ so extraordinarily sentimental and inanimate
as a whole, both to the musician and to the pianist. The
workmanship is always flawless, but there is little strain to pull it out
of perfect line. Mendelssohn had considerable skill in picture music.
The overture to ‘Midsummer Night’s Dream’ and the overture
suggested to him by his visit to Fingal’s Cave are successful in this
direction. It is worthy of note that at least two of the best of the
‘Songs without Words’ are in the nature of picture music—the so-
called ‘Hunting’ and ‘Spinning’ songs. The gondolier songs likewise
stand out a little from the rest in something like active charm. These
offer him an external idea to work on and he brings to his task a very
neat and sensitive, though unvaried, technique.

He had also a gift, rather special, for light and tripping effects. It does
not often show itself in the ‘Songs without Words.’ There is one in C
major, published after his death, which shows him to advantage in
this vein, and the light ‘Spring Song’ has a touch of it. Among his
other pieces the Rondo Capriccioso in E major and the little scherzo
in E minor stand out by virtue of it.

Of the longer pieces we need touch upon only two. These are the
Prelude and Fugue in E minor and the Variations sérieuses. The