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2
Design ofMaterials andProduct
Specifications forPharmaceutical
Dosage Forms
AnkitaKishore, NeerajMishra, JovitaKanoujia,
PremPrakashSingh, andAlokKumarMahor
Abstract
The supply of standard-quality pharmaceutical products to consumers is the
prime accountability of manufacturers. To sustain this, pharmaceutical compa-
nies must comply with all explicit norms and guidelines, producing conventional
to novel drug delivery systems to make them marketable. Reproducibility is the
mandatory criterion in the successful fabrication of dosage forms; therefore,
many new inputs are being carried out, including a quality-by-design (QbD)
approach from the starting material up to the FP.The ICH Q6A guideline explains
specications in terms of analytical procedures, various tests, references and
suitable acceptance criteria, and materials and DP must conform to these speci-
cations. Three types of specications have been set for various developmental
stages of a dosage form: in-process specication, release specication and shelf
life specication. In the ICH Q8 guideline, QbD is well explained. ICH Q6A,
ICH Q6B guidelines and QbD help design the FP within specications.
Identication of critical quality attributes (CQAs), quality target product prole
(QTPP) and necessary process parameters (CPPs) are required for QbD imple-
mentation. It works on identifying risks, executing the design of experiments
(DOE), analysing risks and, nally, dening the design space. A control approach
is used throughout the process to ensure that goods have a constant and predeter-
mined quality. Different guidelines of regulatory authorities also must be fol-
lowed by pharmaceutical companies to get their products approved for marketing.
A. Kishore · N. Mishra · J. Kanoujia
Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP),
Gwalior, Madhya Pradesh, India
P. P. Singh · A. K. Mahor (
*)
Institute of Pharmacy, Bundelkhand University, Jhansi, Uttar Pradesh, India
e-mail: alokmahor522@bujhansi.ac.in
28
Keywords
ICH guidelines · Quality-based design · Specications · Pharmaceutical dosage
forms · Quality target product prole
2.1 Introduction
The production of quality products is the prime focus of the pharmaceutical indus-
try to supply effective and safe medicines to patients Haleem et al. (2015). A quality
product can be designed by considering the quality of raw material (RM) used,
process, equipment, technical knowledge and packaging material, as well as the
guidance documents, regulation and compliance programme Altria (1998). The
quality system model is an essential tool for manufacturing industries to implement
for a better-quality product. When implementing the quality system model, the
design of guidelines, development, strict implementation and promotion are required
to adhere to the standards. These guidelines are a minimum standard and are reeval-
uated and updated as new technology advancements occur Balagué & Saarti (2011).
Designing specications for the RM and FP is a regulatory measure to ensure the
superiority of the pharmaceutical product. The International Conference on
Harmonization of Technical Requirements for the Registration of Pharmaceuticals
for Human Use (ICH) with WHO was established. The ofcials from the United
States, Japan and the European Union (EU) felt the need to harmonise the require-
ments of pharmaceutical products during the International Conference of Drug
Regulatory Authorities. ICH took another initiative in the form of ICHQ6 specica-
tions (quality guideline of ICH), which gives the quality standards for tests and must
be followed by manufacturers for drug substances (DS).
2.1.1 The Objective ofDesign ofMaterials
andProduct Specifications
The pharmacopeial monograph must be followed by a DS or the product manufac-
tured from it. If the monograph is not available, it should nevertheless adhere to the
NDA’s (new drug application) provisions. Disparities in technical requirements
were reduced by ICH standards to harmonise the NDAs. Regulatory agencies of
some potential pharmaceutical markets, including the United States, Japan and the
EU, have taken this initiative. The responses from both regulatory representatives
and the industry were considered for harmonisation. ICHQ6B focuses on develop-
ing specications for biologicals; on the other hand, ICH6A is an ICH guideline
established to provide the specications of new drug molecules and DPs. The single
set of international specications for new drug substance (NDS) and their products
was also issued by the Food and Drug Administration (FDA) (ICH Ofcial website
2023b; Center for Drug Evaluation, Research 2023).
A. Kishore et al.
29
ICHQ6 guidelines focus on determining the essential quality characteristics that
affect the efcacy and safety of a DS or DP and provide references for analytical
procedures. The testing procedures and criteria for accepting the result are consid-
ered in ICHQ6 guidelines. In addition, QbD methodologies and clinical experience
are tools used in setting the specications, and regulatory bodies like the FDA now
request this information (Europa.eu 2023).
All manufacturers must submit specications for approval to regulatory bodies
along with a justication of their acceptance criteria. Systematic characterisation of
RM and FP is the prime requirement for manufacturers and the key to maintaining
quality. As a result, creating specications has become an essential stage in develop-
ing pharmaceutical products (Kumar and Palmieri Jr. 2010).
2.1.2 Product Specification
Product specications serve as a quality benchmark and set the best strategies for
achieving the manufacturer’s objective. The maker must adhere to these require-
ments to meet quality standards. Pharmacopeial monographs, regarded as autho-
rised specications, are a signicant source of veried information (Kumar and
Palmieri Jr. 2010). ICH guidelines provide specic information on multiple aspects
of the product development process, as shown in Table2.1.
The upper and lower specications impact the shelf life of the product. The
applicant must provide suitable analytical validation data in the marketing authori-
sation application (MAA) (Flynn etal. 2022). The specication was evaluated in
terms of quality during the development phase, and the validation of the
Table 2.1 Different guidelines are given by ICH
S.No.
ICH guideline
name Specications related to
References
1 ICHQ1 Stabilities EMA (2018a)
2 ICHQ2 Validity of analytical procedure EMA (2018b)
3 ICHQ3 Impurities in NDS and NDP EMA (2018c, d)
4 ICHQ4 Pharmacopeia EMA (2018e)
5 ICHQ5 Quality of biotechnological product ICH Ofcial website
(2023a)
6 ICHQ6 Specications
7 ICHQ7 Good manufacturing practice
8 ICHQ8 Pharmaceutical development
9 ICHQ9 Quality risk management
10 ICHQ10 Pharmaceutical quality system
11 ICHQ11 Development and manufacture of drug
substance
12 ICHQ12 Life cycle management
13 ICHQ13 Continuous manufacturing of drug
substances and drug products
14 ICHQ14 Analytical procedure development
2 Design ofMaterials andProduct Specications forPharmaceutical Dosage Forms
30
manufacturing process should be established. The upper and lower specication
boundaries impact the shelf life of the product. The likelihood of a batch being
rejected increases with tighter specication limits, whereas the likelihood of accept-
ing a pharmaceutical product of poor quality increases with broader specs (Riley
etal. 2013).
The regulatory bodies are aware of that. However, only a small quantity of data
might be accessible during ling time. Therefore, amended acceptance criteria can
be proposed, and as a result, the industry has the chance to adjust its specications
and provide justication for each process and associated acceptance criterion
(Center for Drug Evaluation, Research 2023).
The specications applied to DP and DS during the development phase are used
to evaluate their quality; for this reason, specications must be carefully designed
with the necessary justication. The RM certicate of analysis (CoA) must include
a detailed description of these specications and a citation to the most recent indi-
vidual monograph from the pharmacopoeia if available. RM manufacturers must be
frequently tested following pharmacopeial guidelines. If standardised specications
are lacking, they typically test their products following all major pharmacopoeias to
guarantee widespread acceptance. End-users rst assess their RM suppliers by con-
ducting complete testing on the rst lots of the products they purchase; subse-
quently, they only regularly conduct identication testing, accepting the certicates
of analysis (CoA) of their suppliers, or they only conduct complete testing on a
limited number of batches under a documented standard operating procedure
(Certicate of Analysis 2023).
2.1.3 Types ofProduct Specification
2.1.3.1 In-Process Specification
Testing standards that must be passed before a drug ingredient or DP is approved for
sale. However, it must be veried that the product’s qualities remain the same from
the in-process to the released state (Center for Drug Evaluation, Research 2023).
2.1.3.2 Release Specification
These specications are the nal requirements of the DS and DP based on the deci-
sion to release or reject the batch. Setting stringent parameters for the product’s
release is more demanding than specifying shelf life. The DP manufacturer sets
these internal requirements to ensure that the DP continues to meet its shelf life
requirements (Kumar and Palmieri Jr. 2010).
2.1.3.3 Shelf Life Specification
The regulatory acceptance standard valid for the pharmaceutical product’s shelf life.
Typically, regulatory authorities accept internal or pharmacopeial specications for
shelf life, to which the product must adhere throughout its entire shelf life (Center
for Drug Evaluation, Research 2023).
A. Kishore et al.
31
2.1.4 Specification Design
During the drug development process, specications are rst created for RM, in-
process materials, intermediates, packaging components and the nal product.
Some of the ICH guidelines help in designing the specications related to the DS
or DP.Updating specications is a continuous process as the manufacturer gains
experience and knowledge about the product and process, and revisions to speci-
cations emerge. The minimum tests required for any DS specication include a
description test, identication, assay and impurity test. Limits for the aforemen-
tioned tests must be justied based on the product’s development data or prior
knowledge. The nalised specications have been approved by the regulatory body
(Pharmaguideline 2019).
2.1.5 Specification Justification
Any specication is incomplete without proper justication. Justify each procedure
when suggesting a specication (ICH Harmonised Tripartite Guideline 2023).
1. Final specications are met by meeting in-process specications considering the
operational variability.
2. Each specication is veried/tested by validated analytical methods to control
analytical variations. The technique should demonstrate specicity.
3. The same established specications were shown to be utilised for analysing sta-
bility samples, scale-up samples and validation samples. However, additional
analysis can be performed during validation to validate/support the manufactur-
ing process.
4. Clinical and preclinical studies directly link with product characteristics/
specications.
2.1.6 Revision ofSpecification
Specications can be updated and revised based on the manufacturer’s experience
with the product and process. However, this must not impact the DP’s safety, efcacy
and identity. Specications may alter due to pharmacopeial changes or revisions.
Such modications must be evaluated for their effect on the drug result. Any speci-
cation updates must follow a change control process, and the necessary regulatory
clearance must be obtained before implementation (Geigert 2019a; Patel etal. 2019).
2.2 ICH Guidelines fortheProduct Specifications
ICH has developed ICH guidelines, which are exceptional in that they bring together
different agencies of regulations and the industries involved in pharmaceutical man-
ufacturing to discuss and create ICH guidelines (Khagga et al. 2019). A rising
2 Design ofMaterials andProduct Specications forPharmaceutical Dosage Forms
32
number of regulatory bodies have started implementing these ICH principles since
the organisation’s founding in 1990. Since then, ICH has steadily adapted to address
increasingly global changes in the pharmaceutical industry (ICH Ofcial web-
site 2023b).
2.2.1 The Mission ofICH
The goal of the ICH is to promote greater global harmonisation so that high-quality,
secure and effective medicines can be produced, licensed and kept in the most
resource-effective way possible while still fullling strict requirements (EMA
2018f; Turner 2019).
2.2.2 Aims oftheICH
ICH guidelines aim to lay consistent framework for technical specications for
human-use pharmaceuticals (Bhavna and Bhargava 2022).
ICH guidelines aim to guarantee that medicines can be manufactured and
licenced quickly, safely and of superior quality (Harron 2013).
The following ICH guidelines are used explicitly in the nal product specica-
tions (Elder 2017):
1. ICH Q6A
2. ICH Q6B
3. ICH Q8 R2
Their details are as follows:
2.2.3 ICH Q6A Guideline
This guideline is about the universal and specic test procedures and acceptable
ranges for their results set for New Drugs and NDP: Q6A: Chemical Substances
(ICH Ofcial website 2023a).
2.2.3.1 Objective
This recommendation aims to contribute as much as possible to developing a singu-
lar collection of international standards for NDP and novel drugs (ICH Ofcial
website 2023a). This guideline deals with specications, like those processes, tests
and approval standards, that are crucial to guarantee the standards of NDS and NDP
both at the time of release and up to their expiration date (Knight 2014).
The ICHQ6A guideline includes NDP along with combination products; if nec-
essary, it can also include a new DS (Kestur etal. 2023). It does not consider any DP
or substances that are in any kind of clinical research developmental stage.
Depending on the situation, this guideline can apply to low molecular weight arti-
cial peptides and semisynthetic or synthetic antibiotics (ICH Ofcial website 2023a;
A. Kishore et al.
33
Knight 2014). The dosage forms involved in this guideline are small-volume paren-
teral and large-volume parenteral (Ain etal. 2020; Bergren and Subbarao 2019),
solid (JBGSR.MS.ID.00087.Text—biogeneric science and research 2023) and liq-
uid oral dosage forms (Jîtcă etal. 2023). Sometimes, the extension can also be done
in topical formulations and inhalational and transdermal drug delivery systems
(Riley and Yang 2020). Some general concepts should be clearly understood as they
are essential in setting harmonised specications. Based on different situations,
these concepts are taken into consideration. This guideline (ICHQ6A) demonstrates
its importance in providing an understanding of the circumstances under which the
following concepts are necessary to be considered (Table2.2):
Under this guideline, NDP and NDS are dened as follows:
Table 2.2 Concepts to be considered for setting harmonisation specications
S.No.
Concept Explanation
References
1 Periodic or skip
testing
• Under this concept, instead of being
performed batch by batch, specic tests are
conducted on previously selected batches at the
time of product release and at particular time
intervals
• All skipped batches must still meet all
requirements for the approval of the product
• Applicability may be on oral solid dosage
forms for microbiological testing and residual
solvent testing
Morris
(2016)
2 Acceptance
criterion for
release vs. shelf
life
• This idea is only specic to DS
• It usually involves setting up more stringent
regulations for a drug’s release than those that
should be regulated throughout its shelf life
Kajiwara
and Shikano
(2020)
3 In-process tests • These tests are carried out while a DS or DP is
being produced
• These tests are only used to make changes in
the processing parameters within a specic range
• Examples such as, this test will apply to the
friability and hardness of core tablets, which later
are going to be coated, but it will not apply to
later after coating on individual weights of a
tablet. Further these coated tablets would be
subjected to nal release testing.
Ng (2022)
4 Design and
development
considerations
• Information collected when developing an
NDP or substance can be utilised to make a base
for specication set. On this base, one can
propose excluding or replacing some tests. For
example:
– Testing for microbes for medicinal
substances and solid pharmaceutical dosage
forms has been shown to resist microbial
growth throughout development
– Depending on its relation to product
performance, tests for particle size come under
this class and can be performed during
developmental stages or as a release test
ICH Ofcial
website
(2023a)
(Continued)
2 Design ofMaterials andProduct Specications forPharmaceutical Dosage Forms
34
S.No.
Concept Explanation
References
5 Limited data
available at ling
• The process of establishing acceptance criteria
may be impacted because only a limited amount
of information may be easily accessible at the
moment of ling
• At the time of ling, safety and effectiveness
should always be the primary considerations for
the acceptance criteria
• When there is a lack of information, the tests
and acceptance criteria that were initially
authorised should be evaluated when new data is
gathered to consider any potential revisions
Chen etal.
(2009)
6 Parametric release • In this, the regulatory authority has permitted
to perform parametric release for some DP in
place of regular release tests
• One example is sterility testing for DP, which
has been terminally sterilised
Pandit etal.
(2019)
7 Alternate method • Alternate methods are the tests that can be
utilised for measuring an aspect when they have a
comparable level of or greater level of quality
control over the DP or DS than the ofcial
method
• For example, tablets that are in stable form at
all times of manufacturing can be released based
on spectrophotometric testing rather than a
chromatographic procedure that is ofcially
approved
Friedel etal.
(2018)
8 Pharmacopoeial
tests and
acceptance
criteria
• If any one test is mentioned in different
pharmacopoeias of different regions and this test
is having differences from each other, then one
harmonisation is needed. This harmonisation is
only possible when all regional regulatory
agencies approve the established processes and
acceptance criteria
De Jong
(2016)
9 Evolving
technologies
• The development of both brand-new analytic
technologies and improvements to already-
existing technologies is ongoing. Such
technologies need to be employed when they are
thought to provide extra quality assurance or
when their usage is otherwise warranted
Schenck
etal. (2020)
10 Effect of DS on
pharmaceutical
product
specications
• Generally speaking, it shouldn’t be necessary
to test the DP for characteristics that are unique
to the medicinal ingredient in the manufacture
• For example, testing for synthesis
contaminants regulated in the medicinal
ingredient and not products of degradation is
typically not considered essential
ICH Ofcial
website
(2023a)
11 Reference
standard (RS)
• RS is frequently described and assessed for its
intended application using methods apart from
those employed in ordinary testing
• For novel DS, RS intended for tests, a
quantitative technique should evaluate the purity,
and the impurities should be adequately
recognised and monitored
Singh etal.
(2018)
Table 2.2 (continued)
A. Kishore et al.
35
2.2.3.2 New Drug Product
A pharmaceutical product type, such as a solution, capsule, tablet, cream, etc., that
has not been registered before in a member state or region and that typically, but not
always, comprises a drug component with excipients.
2.2.3.3 New Drug Substance
The specied therapeutic agent (a new chemical or novel molecular entity) has not
yet been approved in a specic region or member state. It may be a salt, simple or
complex ester of a drug that has already been granted authorisation.
Two types of tests are to be performed when testing these NDPs or new drug
substances (NDS): (1) universal tests and (2) specic tests.
Specic tests for NDP have further been categorised for tablets, oral liquids and
parenteral DP (ICH Ofcial website 2023a).
2.2.3.4 Universal Tests
Some standard tests (Table2.3) must be performed for all NDS and NDP, known as
universal tests (Elder 2013).
2.2.3.5 Specific Tests
In addition to performing universal testing, several specic tests based on the drug
substance and DP must also be carried out. In some circumstances or when new
information becomes available, additional tests can be required in addition to those
that are described in Table2.4 for NDS and Table2.5 for NDP (ICH Ofcial website
2023a; ICH Q 2000).
Table 2.3 Universal tests for new drug substances and new drug products
S.No.
Test name Description
References
1 Description • It tells about the state and colour of NDS and
size, shape and colour of NDP
• Colour should not change during manufacturing
and storage
ICH Ofcial
website
(2023a)
2 Identication • Specic for recognition of any new drug
substance and should be capable of discriminating
even those which have close structures to others
• Identies NDS in NDP by a different set of
testing
ICH Ofcial
website
(2023a)
3 Assay • A technique that indicates stability should be
used to determine the composition of the new
therapeutic drug. It can also be used to quantify
impurities
• In a new drug, product assay determines the
new drug substance’s composition
Rignall (2017)
4 Contamination • Residual solvents and inorganic and organic
impurities are considered impurities
• Organic impurities can also be present due to
the degradation of NDS in NDP manufacturing
• The ICH publications covering contaminants in
NDS and solvent leftovers in pharmaceuticals
provide detailed information for both NDS and
NDP
Parente (2020)
2 Design ofMaterials andProduct Specications forPharmaceutical Dosage Forms
36
Table 2.4 Specic tests for new drug substances (ICH Ofcial website 2023a; Knight 2014; Pandit etal. 2019)
S.No.
Test name Description
References
1 Physicochemical
properties
• Properties include pH, refractive index, melting point, etc. procedures for these tests are specic ICH Ofcial
website
(2023a)
2 Size of particles • Particle size determination becomes a pivotal factor to consider if any NDS is intended for solids or
in suspension
ICH Ofcial
website
(2023a)
3 Polymorphic
forms
• Some techniques for polymorphic studies include the infrared test, differential scanning calorimetry,
thermogravimetric analysis, X-ray diffraction, optical spectroscopy and Raman spectroscopy
ICH Ofcial
website
(2023a)
4 Chiral new drug
substance tests
• When one enantiomeric form predominantly works as a new drug substance, its other enantiomeric
form must be removed from the study and considered an impurity. This test can be considered as written
in the ICH guideline for contaminants in NDS and NDP
Knight
(2014)
5 Water content • This test is crucial when the new drug substance is known to be hygroscopic, susceptible to moisture
degradation or a stoichiometric hydrate. Moisture content acceptance criteria should be set through
specied test procedures, including loss on drying and moisture presence detected through Karl Fischer
titration
Knight
(2014)
6 Inorganic
impurities
• The appropriate test should be selected for testing inorganic impurities (e.g. catalysts) in NDS during
development
• Acceptable ranges for residue on the ignition or sulphated ash should be according to pharmacopoeial
criteria
Knight
(2014)
7 Microbial limits • The overall number of aerobic microbes, the complete number of moulds and yeasts and the lack of
any particular undesirable bacteria (such as Staphylococcus aureus, Pseudomonas aeruginosa,
Salmonella and Escherichia coli) may need to be specied. Under pharmacopoeial guidelines, they
should be established
Pandit etal.
(2019)
A. Kishore et al.