Mitigating the Risks of Generic Drug Product

Development: An Application of Quality by Design (QbD) and

Question based Review (QbR) Approaches.

Manjurul Kader*

Apotex Inc., 150 Signet Drive, Toronto, Canada

Received: March 18, 2016; Accepted: May 8, 2016 Review Article

ABSTRACT

This paper discusses the challenges and advantages of implementing Quality by Design (QbD) and Question
based Review (QbR) when developing solid dosage formulations and manufacturing processes for generic
drugs. Formulation and process development of a drug product is challenging due to the inherent variability
of the processes. Regulatory agencies, such as the Food and Drug Administration (FDA) in the USA, demand
a QbD approach when developing formulations and processes for new and existing medicinal products. The
QbD approach is described in the International Conference on Harmonization (ICH) Guidance Q8 (R2). The
regulatory reviewers follow the QbR approach during the review of Chemistry, Manufacturing, and Controls
(CMC), which have also adopted some of the elements of the QbD guidance. A systematic application of
scientific principles for developing the formulations and processes for generic drug products following the
QbD approach is outlined below in three main categories. The categories are product understanding, process
understanding, and control strategy. The concept of predefined objectives, quality risk management, and
CMC considerations together with the prior knowledge are discussed in detail. The discussions and
explanations provided in this paper are based on sound scientific principles, as well as, practical experience
applied to resolve product quality and manufacturing issues. Emphasis is given to streamlining formulation
and process development that complies with current QbD and QbR principles in order to prevent commonly
cited deficiencies. Examples are provided as guiding tools for generic formulation and process development.

KEY WORDS: Generic formulation development, Quality by Design, QbD, Quality based Review, QbR, product and
process understanding, Chemistry Manufacturing and Controls, CMC

INTRODUCTION inherent process and material variabilities and

cost of development. The inherent variability
Formulation and process development of drug associated with formulation and development is
products are challenging for the generic driven by several factors. Some of the factors
pharmaceutical industry because of the need to are (i) patent expiration of a number of
get them quickly to the market because of medicinal products within a short span of time,
(ii) increased competition from new entrants as
well as generic versions of the innovator drug
*
Corresponding author: Manjurul Kader, 11907 Rue Calls, products, (iii) enhanced scrutiny by regulatory
Pierrefonds, Quebec, H8Z3K8, Canada, Tel: 647 854 6512,
E-mail: [email protected]

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bodies, (iv) increasingly lower prices due to The required elements for pharmaceutical
government mandated price cuts to make development as described in the ICH QbD
healthcare more affordable, and (v) existing Guidance (4) are (a) defining the quality target
patents of drug substances, drug formulations product profile (QTPP) based on the route of
and their manufacturing processes. administration, dosage form, bioavailability,
strength, and stability, (b) identifying, studying
The two greatest challenges facing the generic and controlling potential critical quality
pharmaceutical industry today are a trend in attributes (CQAs) of the drug product, (c)
decreasing drug prices and increasing regulatory determining the type and amount of excipients
scrutiny. Regulatory bodies, such as the FDA, and their critical material attributes (CMAs), (d)
now require the generic pharmaceutical industry selecting the appropriate manufacturing
to adopt QbD when developing formulations process, (e) establishing the critical process
and processes for a drug product. ICH Q8 (R2) parameters (CPPs) and linking high risk CMAs
Guidance states that QbD “is a systemic and CPPs to drug product CQAs and its
approach to pharmaceutical development and manufacturability using risk assessment tools,
manufacturing that begins with predefined and (f) defining a control strategy.
objectives and emphasizes product and process
understanding and process control, based on The purpose of the guidance is to ensure a
sound science and quality risk management.” desired product performance. There are other
The question is, how can QbD and QbR be elements, such as design space, and process
implemented without impacting time to market analytical technology (PAT), which are not
and cost of development? discussed in this paper. Therefore, an increased
level of product and process understanding is
The benefits of implementing QbD and QbR required to fulfil the objectives of the QbD and
have been discussed previously (1). The QbR approaches. Product and process
McKinsey QbD Report stated that best practice understanding are achieved by a systematic
in product and process development (PPD) application of scientific principles to
could increase net profits by up to 20% (2). formulations and process design. The question
PPD directly determines production cost remains, what does product and process
before and after commercial launch. It accounts understanding mean and how can it be
for 15-50% of the total research time and demonstrated?
development (R&D) expenditure. PPD can also
improve overall equipment effectiveness Product and process understanding is described
(OEE), a standard operational performance in the QbR methodology. Product
measure which is about 35-50% for the understanding is related to the input materials’
pharmaceutical industry compared to 70-90% (e.g. drug substance, excipients, and container
in other comparably regulated industries. and closures) critical attributes. The critical
Downtime in the manufacturing processes adds attributes of the input materials are those which
to production costs. The application of QbD in affect drug product performance. Process
PPD ensures a reduction in wasted time understanding is related to process attributes,
thereby increasing overall profitability. In which are sometimes influenced by the input
addition, the FDA has incorporated some materials and hence affect drug product
elements of QbD in the QbR methodology for performance. The acceptable norms in
CMC for generic drugs (3). demonstrating product and process
understanding are (a) identification of all
possible attributes of the materials and process

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parameters that could impact the drug product DEFINITIONS

performance, (b) determination of high risk
attributes of the materials and process AUC (area under the curve) is a method of
parameters using risk assessment tools, (c) measuring the bioavailability of a drug based on
determination of level, range of the high risk a plot of blood concentrations sampled at
materials attributes and process parameters, (d) frequent intervals. It is directly proportional to
performing actual trials, and (e) analysis of the total amount of unaltered drug in the
experimental data to determine appropriate patient’s blood (7).
range for CQAs, CMAs, and CPPs. Prior
knowledge from developing similar Cmax (maximum plasma concentration) is the
formulations and processes together with peak concentration that a drug achieves in a
design of experiments (DoE) can be accepted specified compartment after the drug has been
as a demonstration of product and process administrated and before administration of a
understanding. Prior knowledge and how it can second dose (7).
be demonstrated is discussed later in this paper.
Control Strategy is a planned set of controls,
The QbD concepts, terminology, and derived from current product and process
differences between the typical versus QbD understanding that ensures process
approach have been discussed previously (5, 6). performance and product quality. The controls
This paper focuses on the development of can include parameters and attributes related to
formulations and manufacturing processes for drug substance and drug product materials and
generic solid dosage forms, as well as, reviews components, facility and equipment operating
questions and deficiencies. Analytical method conditions, in-process controls, finished
development is considered outside the scope of product specifications, and the associated
this paper. A schematic of the QbD approach methods and frequency of monitoring and
in developing the generic formulations and control (4).
manufacturing process is illustrated in Figure 1.
CPPs is a process parameter whose variability
This paper discusses the techniques with has an impact on a critical quality attribute and
relevant examples to fulfill the requirements of therefore should be monitored or controlled to
the QbD and QbR approaches and the science ensure the process produces the desired quality
behind the required elements. The explanations (4).
provided in this paper are based on practical CQAs is a physical, chemical, biological or
experience and approaches applied to resolve microbiological property or characteristic that
product quality issues with scientific rationale. should be within an appropriate limit, range, or
The definitions of some important terms used distribution to ensure the desired product
in this paper are provided below. quality (4).

Figure 1 QbD approach for generic formulation and manufacturing processes

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Process robustness is the ability of a process to RLD Analysis

tolerate variability of materials and changes of
the process and equipment without negative Generic drug product development begins with
impact on quality (4.) a predefined objective. The objective is to
develop a product, which is therapeutically
Quality Risk Management is a systematic equivalent to the RLD. Therefore, the starting
approach for assessing, controlling, point for successful development of a generic
communicating and reviewing risks to the drug product is the complete understanding of
quality of the drug (medicinal) product across the RLD properties. The major components of
the product lifecycle (8). Risk based assessment the RLD analysis, such as composition,
is proportionate to the level of scientific physicochemical characteristics and its CQAs,
understanding of how formulation and dissolution, and biological properties are
manufacturing process factors affect product described below with relevant examples.
quality and performance, and the capability of
process control strategies to prevent or mitigate Composition
the risk of producing a poor quality product.
Drug product formulation and process
QTPP is a prospective summary of the quality development begins with a description of the
characteristics of a drug product that ideally will components and composition of the RLD. The
be achieved to ensure the desired quality, taking descriptions of the components include
into account the safety and efficacy of the drug references to the quality standard of each
product (4). material and their functional category. The
functional aspect of each material is crucial to
Tmax is the time after the administration of a the formulations and process development
drug when the maximum plasma concentration rationale. The quantitative/qualitative com-
is reached i.e., when the rate of absorption position of the RLD is available in the
equals the rate of elimination (7). literature, such as in the product monograph,
the label and patents. An example of describing
QbD and QbR approaches together with the components and composition is outlined in
commonly cited deficiencies and the concept of the manufacturing process development
prior knowledge are described as Product section.
Understanding, Process Understanding,
Control Strategy and Prior Knowledge Physicochemical Characterization
expanded further below.
Physicochemical characterization of the RLD is
PRODUCT UNDERSTANDING carried out to identify potential pitfalls in the
proposed product. Recent and near the end of
The typical components of product the shelf life batches of the reference drug
understanding are (i) analyzing the reference product are characterized to understand the
listed drug (RLD) product, (ii) determining the physical and chemical attributes. Analysis of a
QTPP, (iii) defining drug product CQAs, (iv) near the end of the shelf life batch is critical for
characterizing the drug product components, establishing an impurity profile and dissolution,
and (v) assessing the risk associated with the and for preventing an out-of-specification
input materials and the drug product. The (OOS) situation. Typical elements of the
components of drug product understanding are physicochemical characteristics of the RLD are
discussed below. listed below. These elements are in line with the

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presentation titled “Quality Target Product substance is helpful in designing the

Profile with Examples” (9). formulations and processes of the hygroscopic
and hydrolytic molecules. Water vapor sorption
% Brand name is a gravimetric technique that measures how
% Description quickly and how much of a solvent is absorbed
% Batch Number by a sample.
% Strength
% Expiry date Dissolution
% BCS (Biopharmaceutics Classification System)
Class
% Tablet shape and dimension
The dissolution profile of the proposed drug
% Appearance (description with image) product must be similar to the RLD. A
% Tablet weight discriminatory dissolution test method is used
% Thickness to demonstrate the similarity between the
% Hardness proposed drug product and the RLD.
% Disintegration time (without discs) Discriminatory dissolution test methods could
% Uniformity of dosages unit be used to detect from higher to a lower soluble
% Assay (%) forms and/or transitions from metastable to a
% Dissolution stable form of a drug substance in a drug
% Tablet pH product. A biorelevant dissolution test is also
% Tablet surface area and porosity
performed on a case-by-case basis. The purpose
% Tablet water vapor sorption
% Impurity (A, B, C, D)
is to demonstrate in vitro/in vivo correlations
% Highest Unknown Impurity (IVIVC) and to develop in vitro dissolution
specification (10). In vitro/in vivo correlations are
The critical physicochemical attributes of RLDs generally accepted for BCS Class II, III and
are disintegration and dissolution, which are some BCS Class II drugs. The common factors
discussed in the section on RLD dissolution. associated with dissolution tests are apparatus,
Additionally pH, surface area, porosity, and dissolution media, pH of the dissolution media,
hygroscopicity of the RLD tablet are typically solubility and stability of the drug substance in
analyzed to gain information on the specific the dissolution media, and discriminatory
properties of the drug product. For example, power of the dissolution test method.
changes in pH can significantly influence the
solubility of some drugs. Therefore, a pH In general, United States Pharmacopeia (USP)
modifying excipient may be used with free base dissolution apparatus are preferred for
or salt to adjust the micro-environmental pH. dissolution testing. The four types of USP
The pH in tablets is generally measured using a dissolution apparatus (1-4) for testing solid
pH meter by dissolving the tablet into water. dosage forms are discussed below.
Tablet surface area and porosity of some drugs
influence dissolution and degradation. Surface USP Apparatus 1 is a rotating basket type
area, morphology, and porosity are critical apparatus for which the recommended agitation
attributes for BCS (biopharmaceutical rate is between 50 and 150 RPM and the
classification system) Class II and IV drugs as compendial preference is 100 RPM. It is
dissolution is the rate limiting step for such generally used for testing the dissolution rate of
drugs. Surface area and porosity are generally capsules and tablets. The USP apparatus 1 is
analyzed using the BET (Brunauer, Emmett, preferred for testing immediate release (IR) and
Teller) method. The water adsorption/ modified release (MR) dosage forms. The
desorption nature of the drug product and drug

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agitation ranges are usually used for the influence of the drug substance and excipients.
development of IVIVCs (11, 12). A dissolution medium of pH 6.8 is used to
simulate intestinal fluid (SIF). A higher pH
USP Apparatus 2 is a rotating paddle type (NMT 8.0) is used on a case-by-case basis,
apparatus for which the recommended agitation however, a justification is required if using a
rate is between 25 and 100 RPM and the higher pH. To simulate gastric fluid (SGF), a
compendial preference is 50 RPM. It is dissolution medium of pH 1.2 is used without
generally used for testing the dissolution of enzymes. On a case-by-case basis, enzymes,
tablets and capsules. Similarly to the USP such as pepsin with SGF, and pancreatin with
apparatus 1, it is used for testing IR and MR SIF can be used with justification. For example,
dosage forms. The agitation ranges are usually pepsin is used with SGF for dissolution testing
used for developing IVIVCs (11,12). The USP of some gelatin capsule products. It is reported
apparatus 2 is the most preferred apparatus for that storage conditions, formulation as well as
developing dissolution test methods. analytical test methods influence gelatin
crosslinking (13).
USP Apparatus 3 is a reciprocating cylinder
bio-dis type apparatus and recommended dip Gelatin crosslinking can be caused by extremely
rate is between 10 and 15 RPM. It is generally hot and humid storage conditions, intense
used for testing poorly soluble drugs and MR ultraviolet (UV) or visible lights. Gelatin
dosage forms. The USP apparatus 3 is not crosslinking is caused by the presence of corn
accepted by the Japanese Pharmacopeia. starch, aldehydes, imines, ketones, saccharides
(glucose and aldose sugar) calcium carbonate,
USP Apparatus 4 is flow-through cell apparatus hydrogen peroxide, and dyes (FD&C Red No.
which is generally used for testing 3 or 40 and Blue No. 1) in the formulation or in
multiparticulate dosage forms. the empty gelatin capsules. A barrier film is
formed during storage due to gelatin
The dissolution media are selected based on the crosslinking. The barrier film prolongs the
drug solubility screening. The media should be disintegration time and a subsequent decrease
capable of dissolving 3 times the drug in dissolution rate. Pepsin in the dissolution
substance and must be stable in the media for medium breaks down the crossed-linked barrier
at least 24 hours. The recommended pH range film quicker than acid alone, and hence permits
of the dissolution media for IR and MR the release of the drug. Therefore, USP <711>
formulations is 1.2-6.8 and 1.2-7.5 respectively (Dissolution) recommends the addition of an
(10, 11). Typically, a dissolution test (n=12) is enzyme (e.g. pepsin) to the dissolution medium.
performed using 2 to 3 dissolution media. The However, it is required to demonstrate that a
purpose is to establish the discriminatory power decrease in dissolution is directly related to
of the dissolution test method. crosslinked gelatin shells rather than the
degradation of the drug product. A surfactant,
An aqueous medium with a pH range of 1.2 to such as sodium lauryl sulfate (SLS) can be used
6.8 is commonly used for dissolution tests (11, for water insoluble or sparingly water soluble
12) of IR dosages forms. Use of water as a drug products. However, a justification for the
dissolution medium is discouraged because test need and the amount of the surfactant is
conditions, such as pH and surface tension, can required.
vary depending on the source of water. In
addition, the pH and surface tension may The dissolution test of highly soluble (largest
change during the dissolution test due to the dose dissolved in # 250 ml of water over a pH

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range of 1.2 – 6.8) and highly permeable (extent physiological conditions of the gastrointestinal
of absorption is > 90%) drugs (classified as tract (GI) affect drug product dissolution (15).
BCS Class I) could be replaced by a simple Therefore, a discriminatory dissolution test
disintegration test. The ICH Guidance (14) also method is used to analyze the proposed and
permits the use of a disintegration test as a referenced drug product. The purpose is to
surrogate for the conventional compendial assess the impacts of the excipients CMAs and
dissolution test provided that (i) the drug is levels, and tablet hardness on dissolution rate.
highly soluble, (ii) the intrinsic rate of An example of the RLD dissolution study is
solubilization is rapid, and (iii) the overall drug discussed below.
release rate is dominated by cohesive properties
of the formulation. However, a justification for The dissolution study for an RLD (e.g. a brand
the selection of dissolution versus a named Risedronate sodium 150 mg tablet, batch
disintegration test, as well as, the development XYZ, expiry date month/year of the USA
and suitability of the chosen test is required. market) was carried out across the four
This is generally carried out by establishing a physiological pH ranges. The media used were
relationship between disintegration and USP purified water (deaerated), 0.1N HCl, 0.05M
dissolution. The relationship proves that phosphate buffer pH 4.5 and pH 6.8. During the
disintegration is more discriminating than study, USP Apparatus 2, using an agitation rate
dissolution and therefore a simple of 50 RPM and a volume of 900 ml dissolution
disintegration test could replace the dissolution medium was used. The USP dissolution
test. specification for Risedronate sodium is NLT
80% (Q) dissolved in 30 minutes for tablets
Drug substance solubility, formulations and labeled to contain at least 75 mg. The drug
process variables often influence the dissolution release profile of the RLD in these four
of hydrophobic and poorly water soluble drugs dissolution media is illustrated in Figure 2.
(BCS Class II and IV). The typical formulations
and process variables are excipient attributes The RLD (i.e., the brand named drug) exhibits
(hydrophilic/hydrophobic), levels and grades, very rapid dissolution profiles, $ 85% of the
tablet hardness, surface area and porosity of the drug substance dissolved within 15 minutes, in
drug product. In addition to these factors, the water. Therefore, the dissolution profile of the

Figure 2 pH dissolution profiles of a brand named Risedronate Sodium 150 mg tablets (batch XYZ) in
USP Purified Water, 0.1N HCl, and 0.05 M Phosphate Buffer pH 4.5 and pH 6.8.

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proposed generic drug product considered The absorption of BCS Class III (High
similar and no mathematical evaluation (i.e., f2 solubility/Low permeability, hydrophilic in
calculation) is required. nature) drugs in the GI tract is limited and
controlled by permeability. Cmax and AUC are
Biological Properties the critical in vivo parameters for such drugs.
BCS Class III compounds are eligible for
The RLD biological properties must be biowaiver if the compound dissolves within 15
described according to clinical and minutes at pH of 1.2 to 6.8 tested at 75 RPM.
pharmacokinetics {ADME: absorption (AUC,
Cmax, Tmax), distribution, metabolism, and The absorption of BCS Class IV (Low
elimination}. The bioequivalency of the drug solubility/Low permeability, hydrophobic in
product depends on the absorption site which nature) drugs in the GI tract is poor. Cmax and
for oral dosage forms is the GI tract. The AUC are the critical in vivo parameters for such
criticality of the Cmax and AUC depends on the drugs.
solubility of the drug (based on BCS Class).
The physiology of the GI tract, for example
Drugs classified as BCS Class I (High pH, residence time, and various bile salts can
solubility/High permeability, amphiphilic in influence the biological properties (e.g. Cmax and
nature) are well absorbed in the GI tract. AUC) of the drug molecule. The small intestine
However, the absorption of such drugs is has a high concentration of bile salts with a
controlled by gastric emptying. Highly large surface area due to its villi and micro-villi
permeable drugs are rapidly absorbed in the GI structures. This area serves as the primary site
tract. Therefore, Cmax is the critical in vivo for drug absorption. Therefore, the knowledge
parameter for such drugs and is indicative of of where in the GI tract the drug is absorbed
overall AUC. Compounds belonging to BCS facilitates formulation design. In addition, it is
Class I are eligible for biowaiver, if the useful to understand the impact of food on
dissolution of the compound is >85% within drug absorption, bioavailability (BA) and
30 minutes at pH 1.2 to 6.8 when tested using bioequivalence (BE) when developing the
USP dissolution apparatus 1 without adding formulation. The dissolution of weakly basic
lecithin, bile salts or enzymes in the dissolution drugs is slower at a higher pH because more
media. drugs exist in its unionized form. On the other
hand, weakly acidic drugs dissolve faster at
The absorption of BCS Class II (Low higher pH due to the fact that more drugs exist
solubility/High permeability, lipophilic in in its ionized form. Therefore, meals that
nature) drugs in the GI tract is good and elevate gastric pH can decrease the dissolution
controlled by dissolution. Cmax is the critical in of a weak base by increasing the proportion of
vivo parameter for such drugs. According to the drug existence in its un-ionized state. For
World Health Organization (WHO), certain example, Indinavir, a weak base with pKa
BCS Class II compounds are eligible for (dissociation constant) of 3.7 and 5.9 forms
biowaiver, if the compound is a weak acid with precipitate when gastric pH is elevated during a
a dose:solubility ratio of <250 ml at pH 6.8, meal. The formation of precipitates causes a
and the dissolution is > 85% within 30 minutes significant reduction in AUC and Cmax values of
at pH 6.8 tested at 75 RPM. However, in the the Indinavir in fed versus fasted human
USA the FDA and the EMA (European subjects (16). The biological properties of the
Medicines Agency) in Europe do not allow for RLD are generally available in the product
a biowaver for BCS Class II drugs. monograph and/or in literature.

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Determining the QTPP Determining Drug Product CQAs

The QTPP is a prospective summary of the The QTPP defines the critical and non-critical
quality characteristics of a drug product and attributes of the proposed drug product. The
forms the basis of the development design. The formulations and/or process variables can
RLD analysis determines the QTPP of the potentially alter the critical quality attributes of
proposed drug product. An example for the drug product. An example of determining
determining the drug product QTPP (17) is the drug product CQAs is presented in Table 2.
outlined in Table 1, which is in line with the
presentation entitled “Quality Target Product Table 2 Drug Product Critical Quality Attributes (DP
Profile with Examples (9). CQAs)

DP QUALITY
Table 1 Quality Target Product Profile (QTPP) ATTRIBUTES
TARGET CQA RATIONALE

Formulation and
ELEMENT QTPP TARGET RATIONALE Positive for drug process
Identification No
substance unlikely to have any
Same Dosage impact identity
Dosages Form Tablet
Form.
Appearance
IR/DR design, Not critical for IR
(color and To match RLD No
Dosage Design IR/DR Tablet product
meet label claims. shape)
Route of Same route of Not critical for IR
Oral Size Similar or > RLD No
Administration administration. product
Dosage Strength Hardness To be defined Yes
x and xx Same Strength.
(mg)
NMT 0.8 % @ 100
Weight Physical rev
Attributes Influenced by
Thickness Friability NMT 1.2% @ 200 Yes
formulation and
Similar to the rev.
Physical Attributes Friability compression process
RLD. 500 rev. for info only
parameters
Hardness Disintegratio
Disintegration n (without NMT xx min Yes
discs)
Identification Pharmaceutical
Equivalence Scoring/
Unscored tablet No
Not critical as there is
Requirement: divisibility no score
Assay
meet compendia, Degradation Meets ICH
ICH or other Yes
Dosages uniformity products requirement
Drug Product applicable quality Influenced by CMAs,
Quality Attributes standards. Assay Compendia specs Yes mfg. process and
Dissolution container & closure.
Dissolution in acid Chemical Dosages
and buffer USP <905> Yes
Attributes Uniformity
Degradation products medium provides
idea about the Influenced by
Drug
Residual solvents absorption. Release/ Similar as RLD Yes
formulation, CMAs,
mfg. process &
Dissolution
Bioequivalence parameter
requirement.
IR enabling Tmax in 2 Cmax, AUC, and
Pharmacokinetics hours or less. Tmax similar to the
(pK) Bioequivalent (BE) to RDL.
RLD. Ensures rapid Characterizing drug product components
onset and
efficacy.
Situations in which the The drug product components, such as drug
Contraindication drug might be
contraindicated.
Same as the RLD.
substance and excipients are discussed below.
No plan to study
the drug in a
Use in specific specific
Drug substance
Not to specific group.
populations population as it is
intended for all
groups. The ICH Guidance requirement is to identify
Stability
At least 24 months at For and discuss the physicochemical and biological
room temp. commercialization
Container Closure Commercial
properties of the drug substance and their
HDPE Bottles/Blisters
System requirement influence on drug product performance and its
DR= Delayed release
IR = Immediate release manufacturability (4). The required QbD

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elements for drug substance are (a) manufacturability are discussed below with an
physicochemical and biological properties, (b) example.
degradation pathway (e.g. intrinsic stability), (c)
chemical reactivity, and (d) risk assessment. Polymorphism

Some of the deficiencies in drug substances as Polymorphs of a drug substance that are
cited by the FDA (18) are (i) multiple generally recognized are amorphous, crystalline,
polymorphic forms are reported in the hydrate and solvate (19). However, polymorphs
literature, provide the form used and a suitable refer to crystalline structure of a molecule. By
control to ensure consistency in the drug definition, an amorphous material is not
substance, (ii) include a control for the relevant crystalline. Hydrates and solvates may, or may
enantiomer and diastereomers if the drug not, be crystalline and could have their own
substance is chiral and the enantiomers show polymorphs. The physicochemical properties,
differences in pharmacological effect and/or for example, solubility, hygroscopicity, particle
safety, and (iii) justify the specification for the shape, density, flowability, and compactibility of
full range of particle size distribution (PSD). different polymorphs of a drug substance are
Alternatively, it is possible to show that the different. Therefore, polymorphic forms of the
PSD is not critical to the manufacturing process drug substance influence the performance of
and drug product performance. the drug product and its manufacturability.

The physicochemical and biological properties The thermodynamically most stable polymorph
of the drug substance usually examined include should be chosen for the formulation to ensure
aqueous solubility (as a function of pH), water optimum product performance and
content, particle size, crystal properties (e.g. manufacturability. A thermodynamically stable
polymorphism), biological activity, and polymorph is chemically stable and has the least
permeability. Other physicochemical and potential for conversion to another polymorph
mechanical properties of the drug substance when exposed to a range of manufacturing
include melting point, particle shape, surface processes, such as drying, milling,
area, porosity, pKa, partition coefficient, micronization, wet granulation, spray-drying,
stereoisomers, chemical stability, flowability, and compaction (20). However, occasionally, a
and compressibility. If they are interrelated metastable form is preferred over the stable
some of these properties will be considered in form, since they have better solubility, and
combination. An explanation is required if a bioavailability/ bioequivalency. A metastable
property is not included. For example, pKa may form has a high energy state, low melting point
not be listed because there are no ionizable and high aqueous solubility.
groups in the chemical structure. The product
development report usually describes the Water in pharmaceutical hydrates is generally
polymorphism, solubility, and particle size of present in three different form, for example,
the drug substance. residing in isolated lattice sites, in the lattice
channel sites, which are also referred to as
Physicochemical and mechanical properties of the drug channel water and in the ion-coordinated sites
substance
(20, 21). In isolated lattice sites, water molecules
are in contact with the drug molecule and
Some of the physicochemical and mechanical
therefore, isolated from other water molecules.
properties of the drug substance and their
Channel water is in contact with other water
influence on drug product performance and its
molecules of adjoining unit cells along an axis

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of a unit cell and is mobile in nature. Therefore, reported for an IR formulation containing a
channel water may migrate into and out of the highly soluble drug (24). The drug content in
crystal lattice as a function of ambient humidity. the formulation was low (# 2 mg). The product
Ion-coordinated water participates in an ion was manufactured by wet granulation. The drug
water bond, which is usually stronger than substance was dissolved during the wet
hydrogen bonds present in the molecule. The granulation due to low drug content and high
removal of isolated lattice water generally solubility. The completely dissolved drug
compromises the crystal integrity. In contrast, substance converted to an amorphous form
crystal integrity remains relatively intact upon during the drying cycle. The phase conversion
removal of channel water (21). However, upon of the drug substance caused a loss in potency
the removal of channel water from some drug and an increase in related substances at
substances e.g. Risedronate Hemipentahydrate, accelerated storage conditions. The extent of
the crystal integrity has been reported to be conversion generally depends on the relative
compromised. The hydrate, depending upon stability of the polymorphs, kinetic barriers to
the nature of the water may, or may not, change phase conversion, and applied stress (25).
over time with ambient humidity, temperature,
or other drug product manufacturing and Drug substance phase conversion, however, is
storage conditions (22). Therefore, the generally not a serious concern provided that
metastable polymorph or pharmaceutical the conversion occurs consistently as part of a
hydrate requires special attention during the validated manufacturing process where critical
formulation design regarding the selection of, manufacturing process parameters are well
for example, excipients, as well as, the selection understood and controlled, and where drug
of the manufacturing processes. The influence product BA/BE has been demonstrated (19).
of polymorphic forms on the performance of
the drug product and its manufacturing Drug product stability is affected by various
processes are discussed below. other factors, including the formulation,
manufacturing processes and packaging.
Solid state phase conversion (re-crystallization) Therefore, stability is an important quality
of amorphous or metastable drug substances parameter. The effect of polymorphism on the
during manufacturing processing and/or drug product manufacturing process also
storage has been observed. For example, a depends on the formulation and the
roller compaction process can influence the manufacturing processes (26). For example, the
degradation of acetylsalicylic acid, and milled impact of the drug’s physical and mechanical
Carbamazepine anhydrate converts to dihydrate properties on direct compression for low or
at least four times faster than the unmilled high drug content formulations can be
material during a wet granulation process (23). significant compared to dry granulation.
Mechanical treatments, such as milling, tend to Therefore, paying close attention to the drug’s
accelerate the kinetics of dehydration by polymorphism is critical as it is related to the
generating surface defects and local heating manufacturing processes.
which causes phase conversion.
If different polymorphic forms are known, it is
Phase conversion of a drug substance may take required to specify which polymorphic form
place immediately or, over time, during storage, was chosen and provide supporting evidence
at accelerated conditions (40ºC/75% RH). This for the claim. The identification of the
is a common occurrence for amorphous polymorphic form is usually determined using
materials. Drug substance conversion was different analytical methods, for example, using

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a Fourier Transform Infrared Spectroscopy (crystalline form), pKa, lipophilicity and high
(FTIR). It collects simultaneously high spectral melting point of the drug substance, lack of
resolution data over a wide spectral range and solute-solvent interaction, changes in pH, fluid
measures how well a sample absorbs light at contents, and motility, as well as, the residence
each wavelength). X-ray Powder Diffraction time in the GI tract influence the solubility and
(XRPD) is a rapid analytical technique primarily in vivo dissolution of an oral solid dosage forms.
used for phase identification of a crystalline For example, a drug substance with an aqueous
material. Differential Scanning Calorimetry solubility of <100 μg/ml is reported to present
(DSC) determines where the energy of a sample dissolution and absorption limitations (32).
is absorbed or released as it is heated, cooled, Therefore, solubility screening of the drug
or held at a constant temperature. substance is a pre-requisite of the formulation
Thermogravimetric Analysis (TGA) measures and process development, and for any
the change in weight of a sample as it is heated. application for a biowaiver. Solubility
Information on drug substance polymorphism information of the drug substance is available
is generally available in the Drug Master File in the literature, for example, in the Martindale,
(DMF) and/or in the literature. An example of the Extra Pharmacopeia, the Merck Index,
the selection of a polymorphic form is given Florey’s Analytical drug profiles and on the
below. internet (aqueous solubility is available on
Medline®).
A drug substance such as Carbamezepine is
known to exhibit polymorphism and four However, there are concerns for using the
anhydrous polymorphs and a hydrate, as well solubility information from the literature or the
as, other solvates have been reported in the internet because the reported solubility data is
literature (27, 28, 29, 30). The four polymorphic generally based on using water as the
forms of Carbamezapine have been identified dissolution media at room temperature and at
through XRPD analysis (27). Among the four one pH only. Therefore, it is essential to
polymorphs, Form III is the most stable form determine the drug substance solubility
at room temperature, and is therefore experimentally. Solubility screening is
commonly used in tablet formulations (31). The performed using multiple media, such as, acid
manufacturing process is a direct compression/ and buffer. The media usually represents all
dry granulation process and is not expected to physiologically relevant pH ranges, for example,
cause phase conversion during processing. pH 1.1, pH 2-3, pH 4-5, pH 6.8, and pH 7.5 at
Therefore, Form III was chosen for 37ºC. To determine the dose:solubility ratio, the
development, and was expected to be stable highest single dose strength is divided by the
throughout its shelf life under normal solubility of the compound over the pH range
environmental conditions. The XRPD data of of 1.1 to 7.5 at 37°C. The drug substance is
the drug substance confirmed that the considered “highly soluble,” if the
polymorph was Form III. dose:solubility ratio is <250 ml. The reason for
comparing the solubility < 250 ml or > 250 ml
Solubility is that typically, 250 ml of fluid is present in the
upper GI-tract when administering the drug in
Drug substance solubility is often referred to a fasted state. The goal is to determine the
according to its BCS Class. The solubility of the optimal solubility and stability of the drug
drug substance influences the selection of the substance and to meet the FDA BCS
excipients and drug product manufacturing classification system (33). The solubility
process, stability, and dissolution testing design. screening decision tree is illustrated in Figure 3.
Several factors, for example, polymorphism

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Particle size and its distribution influence the

dissolution and absorption (Cmax and AUC) of
the drug product, as well as, its manufac-
turability. For example, Cmax and AUC of a drug
product containing a drug substance with 100
μm particle size were significantly lower
compared to the <50 μm (34). Particle size is
indicative of compressibility and flowability i.e.,
flow and cohesiveness. Therefore, particle size
usually impacts quality parameters, such as assay
and dosage uniformity in formulations with a
low drug content, as well as, the compression
force of formulations with a high drug content.
The particle size of a cohesive/milled/
micronized drug substance is of greater concern.
Figure 3 Solubility screening diagram For example, the mean particle size of the
micronized Griseofulvin has been reported to
increase during the com-paction process based
The solubility in media with different pH also on drug loading (35). The surface area of a
indicates the pH dependent release nature of particle decreases with increasing particle size
the drug substance. The solubility information leading to a decrease in the dissolution rate. In
guides the selection of excipients and addition to an increase in particle size, the
manufacturing processes together with the author experienced excessive wafer build up in
stability of the drug substance. For example, the granulation chamber during dry
Poloxamer 470 (a nonionic triblock copolymers granulation (roller compaction) process of a
composed of a central hydrophobic chain of micronized drug substance.
polyoxypropylene flanked by two hydrophilic
chains of polyoxyethylene), Meglumine (an
amino sugar derived from sorbitol with pKa Therefore, for some drugs, particle size
value of 9.60) is used as a solubilizing agent for specification and its test method is a mandatory
poorly water soluble drugs, and potassium requirement. In general, laser diffraction, image
bitartrate (the potassium acid salt of tartaric and sieve analysis techniques are employed to
acid) is used as a buffering agent to ensure examine the particle size of a drug substance.
optimal release of the pH dependent drug However, different particle sizes have been
substance. An example of aqueous solubility as obtained for a specific batch when analyzed
a function of the pH of a drug substance is using different techniques. In addition,
shown in Table 3. different particle sizes can be obtained based on
the method used for measuring the particle size.
Particle size and particle size distribution

A discussion about the drug substance particle

size is mandatory irrespective of the impact on For example, different particle size are obtained
the drug product performance and its for a specific batch when analyzed using wet or
manufacturability. The criticality of the drug dry methods by a Malvern particle size analyzer.
substance particle size depends on (i) drug Therefore, it is required to use validated test
substance solubility, drug product dissolution, method to analyze particle size. Particle
and bioavailability/bioequivalence (ii) dosage fragility, nature of agglomeration and particle
strength (iii) drug content in the formulation habits of the material influence the selection of
and (iv) manufacturing process, such as, direct particle size test method. An example of drug
compression >dry granulation >wet granulation.

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Table 3 Aqueous Solubility

AQUEOUS SOLUBILITY AS A FUNCTION OF pH AT 37<C

SOLUBILITY USP TERMINOLOGY Sol.b
Solvent Final pHa
(mg/ml)

>1 g/ml Very soluble 0.1 N, HCl, pH = 1 1.0 47.2 mg/ml

100-1000 mg/ml Freely soluble 0.05 N HCl, pH = 2 1.7 49.2 mg/ml

33.3-100 mg/ml Soluble 0.15 M acetate buffer, pH = 4 3.7 56.8 mg/ml

10-33.3 mg/ml Sparingly soluble 0.15 M phosphate buffer, pH = 6 5.8 60.8 mg/ml

1-10 mg/ml Slightly soluble 0.15 M phosphate buffer, pH = 8 7.8 56.0 mg/ml

0.1-1 mg/ml Very slightly soluble

<0.1 mg/ml Practically insoluble

a
Refers to the pH of aqueous media following addition of drug substance.
b
Solubility measures were carried out on polymorphic Form I (the most stable form)
Note: hypothetical values are used for dose/solubility calculation.
The calculated dose/solubility volume: 32 mg (highest strength) ÷ 47.2 mg/ml (minimum concentration of drug) = 0.68 ml. Based on the
BCS Classification system the drug is highly soluble as the dose/solubility volume is less than 250 ml. Considering the strength (low and
high), a drug substance could be classified as high soluble or low soluble, for example, Acyclovir 200 mg tablet belongs to BCS class III
(high solubility - low permeability), whereas Acyclovir 800 mg tablet belongs to BCS class IV (low solubility - low permeability).

substance particle size discussion is outlined humans/animals or a suitable cell line (e.g.,
below. Caco 2 cells). However, determination in Caco
2 cells is only applicable to passively absorbed
When the water solubility of a drug substance substances and is used for additional
(e.g. Captopril) is 160 mg/ml at 25°C (CAS confirmation. Permeability data from humans is
62571-86-2), it is categorized as a highly soluble preferred and animal data is only used if no
drug (BCS Class III). The drug content in the other data can be found. The probable reasons
formulation is 27.0% W/W. The highest dosage for below 90% bioavailability are degradation in
strength is 100 mg tablet. The manufacturing the GI-tract, first pass effect, solubility limited
process is dry granulation. The particle size of a bioavailability, and poor absorption.
highly soluble drug is not critical to the drug
product performance (14). Therefore, the Lipinski’s “The Rule of 5” can be used to
particle size specification of the drug substance predict the permeation of a drug substance.
(e.g. Captopril) is not proposed based on the ‘The Rule of 5' predicts that poor absorption or
drug content in the formulation, manufacturing permeation of a drug substance is more likely,
process (dry granulation), and particle size of when (i) there are more than 5 H-bond donors,
the dug substance will not be controlled during (ii) there are more than 10 H-bond acceptors,
routine release test. (iii) the molecular weight is greater than 500
g/mol, and (iv) the Log P (Clog P) is greater
Permeability than 5 (or Mlog P > 4.15) (36). An example of
the drug substance permeability discussion is
The permeability of a drug substance influences provided below.
its absorption. Information on permeability for
some drug substances can be found in the A drug substance, e.g., Clopidogrel bisulfate has
literature, e.g.,, the Martindale, the Merck Index 2 H-bond donor and 8 H-bond acceptor. Its
and Florey’s Analytical drug profiles and on the partition coefficient, Log P is 3.89 in
internet (permeability or bioavailability is octanol/water, pH 7.4 at 25°C and it has a
available on Medline). A drug substance is molecular weight of 419.90 g/mol (37).
considered “highly” permeable, if the Therefore, according to “The Rule of 5” the
permeability is >90%, measured in permeability of Clopidogrel bisulfate is good.

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However, following an oral administration, the selections and manufacturing processes. For
bioavailability of Clopidogrel bisulfate is example, direct compression is selected based
reported to be about 50% due to its poor water on the measured angle of repose (AoR is < 30°)
solubility (38). and the compressibility index (CI is <10%) of
the drug substance and drug content (i.e., 40%
W
Water content and hygroscopicity /W) in the formulation. Therefore, no adverse
impact on the drug product quality attributes
It is expected to include a test (e.g. Karl Fischer and its manufacturability is anticipated.
titration) for water content when appropriate.
Water exists as bound and free water in a Compactability
molecule. Generally, the free water associated
with the drug molecule and excipient can Together with other factors e.g., formulation
influence dissolution, stability (chemical composition and compression press speed,
degradation e.g., hydrolysis), pow-der flow, drug substance compactability influences
manufacturability and microbial growth. compression force and tablet hardness. Drug
Typically water is not a reactant except in ester substance bulk density is one of the indicators
hydrolysis, however, it accelerates most for compactability. Compactability is critical for
reactions by bringing the molecules together high drug content formulations especially when
due to an increase in plasticity and molecular compressibility of the drug substance is poor or
mobility in the system. Highly soluble and moderate.
highly hygroscopic drugs have a tendency to
change polymorphic forms during storage at The physical properties of the drug substance
ambient conditions. A partial change in the have the least impact in a wet granulation. The
polymorphic form (e.g. crystalline to physical and mechanical properties of the drug
amorphous) generally causes faster dissolution. substance are often masked during the wet
Tablets and excipients in the formulation are granulation process (19).
examined using a XRPD method to confirm
the change in polymorphic form, if any. The DS Degradation Pathways: Forced Degradation/
acceptance criteria for water content in such Stress Testing
drugs are usually justified by the effects of
hydration or water absorption. In some cases, a It is required to describe the degradation
loss on drying analysis is also adequate. Drug pathways of the drug, generally demonstrated
substance hygroscopicity is usually used to through forced degradation studyes/stress
justify the selection of the excipients grade, testing. A stress test is performed in both
level, and manufacturing process together with solution and solid state for a specific storage
the packaging. The hygroscopicity of the drug time or until a certain degradation is observed.
substance is generally analyzed using a dynamic The purpose of such a test is (i) to demonstrate
vapor sorption (DVS) method and is available the intrinsic stability of the drug substance, (ii)
in the DMF (drug master file) and/or in the to identify environmental factors (ambient
literature. temperature, humidity, light) and oxygen
affecting the stability of the drug product, (iii)
Flowability to determine the potential degradates and assess
if they can be formed during manufacture or
Drug substance flowability influences blend storage of the drug, (iv) to validate the stability
uniformity (BU), uniformity of dosages unit indicating power of the analytical method, and
(DU), assay, and granulate compressibility. The (v) to justify the selection of primary packaging
flowability property is used to justify excipient

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material that protects the drug product during at elevated temperatures. The selection of an
storage and transportation. acid or a base and their concentration depends
on the stability of the drug substance. The drug
The four main degradation mechanisms are substance solution is subjected to various pH
hydrolytic, oxidative, heat, and photolytic values e.g., 2, 7, 10–12 at room temperature for
degradation. Therefore, typically the drug two weeks or up to a maximum of 15%
substance is subjected to these conditions degradation (40) to assess the hydrolytic
during forced degradation studies. The degradation. Typically, hydrochloric acid or
preferred level of degradation depends on the (i) sulfuric acid at a concentration of 0.1 M to 1 M
suitable reagents, (ii) concentration of the for acid hydrolysis and sodium hydroxide or
reagents such as acid, base, or oxidizing agent, potassium hydroxide at a concentration of 0.1 M
(iii) test conditions e.g. varying temperature and to 1 M for base hydrolysis is used (43). For
humidity, and (iv) length of exposure. During lipophilic drugs e.g., thiopental, inert co-
stress testing, degradation is controlled to a solvents are generally used to solubilize the drug
desired level to ensure that the drug substance is substance. The selection of cosolvent depends
not subject to over- or under- stressing. Over- on the functional groups present in the drug
stressing a sample may lead to the formation of molecule.
secondary degradants that would not be seen in
formal shelf-life stability studies and under- Oxidation
stressing may not serve the purpose of stress
testing. Therefore, a generic approach for stress Oxidative degradation is complex. Hydrogen
testing is applied to achieve purposeful peroxide is used predominantly for oxidation
degradation that is predictive of long-term and degradation tests because it mimics the possible
accelerated storage conditions, which is between presence of peroxides in the drug and/or
5-20% degradation (39, 40, 41, 42). The 5 – 20% excipients. Other oxidizing agents such as metal
range covers the generally permissible 10% ions, oxygen and light are also used. The
degradation for small molecule drug products. selection of an oxidizing agent, its
The typical stability limits for small molecule concentration, and conditions depends on the
drug product is 90 to 110% of the label claim drug substance. Typically the drug substance
(43). Generally, 10% degradation is preferred by solution is subjected to 0.1%-3% hydrogen
some pharmaceutical scientists to validate the peroxide at neutral pH and room temperature
analytical method for small drug molecules. The for seven days or up to a maximum of 20%
stress conditions are selected based on prior degradation (42). Metals ions e.g., iron and
knowledge of a compound. For instance, low copper are found in some drug substances and
concentration of a base is generally used for a some excipients. Therefore, metal ions are
compound containing an ester group as the added to the solution of the drug substance to
compound is very labile to base hydrolysis. The determine whether the drug substance will be
samples are analyzed at different time intervals catalytically oxidized or not. Oxidative
as it generally provides information on the degradation influenced by light is discussed
progress of degradation and help to distinguish below in the photostability section.
primary degradants from secondary ones.
Heat
Acid and base hydrolysis
Thermal stress testing e.g., dry or wet heat is
Acid and base hydrolytic stress testing are generally more strenuous than recommended in
carried out for drug substances and drug the ICH Q1A accelerated testing conditions.
products in solution at ambient temperature or Samples of solid-state drug substances and drug

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products are exposed to dry or wet heat, from weak functional groups such as carboxylic
whereas liquid drug products are exposed to dry acids. Moisture, temperature, and pH may
heat. Generally, the effect of temperature is greatly impact the rate of hydrolysis. Drug
studied in 10°C increments at 75% or greater substances containing functional groups such as
relative humidity (44). In the event that the amide (Acetaminophen, Oxazepam), carbamic
stress conditions produce little or no ester (Loratidine), lactone (Warfarin), imide
degradation due to the stability of a drug (Barbiturates), acetal (Erythromycin), imine
molecule, it is required to ensure that the stress (Diazepam, Oxazepam) are susceptible for
applied is in excess of the energy applied by hydrolytic degradation.
accelerated conditions (40°C for 6 months)
before terminating the stress study. Oxidation

Photostability Oxidation reactions are often catalyzed by

oxidizing agents such as peroxides, metals,
Testing photostability is an integral part of stress atmospheric oxygen, light, and free-radical. The
testing, especially for photolabile compounds. reactive impurities in excipients play a key role
The recommended conditions for photostability in oxidation either as a primary source of
testing are described in ICH Q1B Photostability oxidants, trace amounts of metals, or other
Testing of New Drug Substances and Product contaminants. Three primary mechanisms for
(45). Samples of a solid/liquid drug product, are oxidative degradation are nucleophilic and
exposed to a minimum of 1.2 million lux hours electrophilic, electron transfer, and
and 200 watt hours per square meter light. The autoxidation. Peroxides are a common impurity
same samples are exposed to both white and in many excipients, such as Povidone,
UV light. The temperature is controlled to Crospovidone, Hydroxypropylcellulose (HPC)
minimize the effect of temperature changes etc. Nucleophilic and electrophilic oxidation is
during exposure. The light-exposed samples are generally initiated by the peroxides present in
examined for any changes in physical properties the drug substance and in the excipients.
e.g. appearance, clarity, color of solution, and Electron transfer oxidation is typically mediated
for assay and degradants. The information is by the transition metal ions presents in the
used to specify the appropriate storage excipients. Oxidizing agents can produce free
conditions on the container labels. radicals in the presence of atmospheric oxygen
and light. The free radicals then react with
Understanding common degradation pathways oxygen to form peroxy radicals. The peroxy
helps in designing stable formulations and radicals then react with the oxidative substrate
processes and to avoid OOS situations. A to yield further complex radicals affecting the
discussion about the common degradation stability of the drug product. A free radical often
pathways (e.g. hydrolysis/thermolytic, initiate chain reaction called autoxidation, which
oxidation, and photolytic) is not required. could be autocatalytic and non- Arrhenius.
However, the three common degradation
pathways of the drug substance or drug product Photolytic
are briefly discussed below.
Drug substances containing functional groups
Hydrolysis such as carbonyl, nitro-aromatic, aryl, vinyl,
thiol, or halogens are susceptible for photo
Hydrolysis accounts for the majority of reported labile degradation (46). Photo labile degradation
drug degradations. Hydrolysis is common for a is also influenced by the intrinsic
broad category of organic molecules derived photosensitivity of the counter ions present in

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the salt form. Aromatic (toluenesulfonic acid) substance and the excipient is stored at different
and/or carbonyls (oxalic acid) counter ions conditions, such as non-stress, thermal, heat and
shows higher photo degradation compared to humid, and light. After the defined time, the
non-aromatic counter ions (47). The stored sample is analyzed using a stability
explanation is that oxalic acid, the carbonyl indicating test method to determine the percent
counter ions and toluenesulfonic acid, the impurities and remaining potency. The common
aromatic counter ions have the higher tendency methods to examine the chemical reactivity are:
for photo degradation due to the inherent (i) chromatographic analysis e.g. HPLC, (ii)
property. Hydrated salts are more susceptible to DSC, and (iii) TGA. However, an orthogonal
photo labile degradation compared to their confirmatory technique is required with DSC to
anhydrous counterparts. Anhydrous salts determine the chemical reactivity. Sometimes
containing aromatic/carbonyl counter ions are the information from literature is used to justify
also susceptible to photo labile degradation. chemical reactivity between the drug substance
Solid-state photo degradation of amlodipine and excipients instead of performing the
camsylate is lower compared to that of experiment.
amlodipine besylate (48). The photostability of
prazosin salts are prazosin hydrochloride Determining DS critical material attributes (CMAs)
anhydrous >prazosin camsylate anhydrous-
prazosin-free base >prazosin hydrochloride The critical attributes of a drug substance are
polyhydrate >prazosin tosylate anhydrous generally identified by their physicochemical and
>prazosin oxalate dihydrate- prazosin tosylate mechanical properties, intrinsic stability, and
monohydrate (49). chemical reactions with the excipients. The
typical critical attributes of the drug substance
Chemical reactivity affecting drug product CQAs and its
manufacturability for explicit tracking in risk
Generally, excipients facilitate the release of the assessment are: (i) polymorphism, (ii) solubility
drug substance, as well as, stabilize it against (BCS Class), (iii) particle size, (iv) intrinsic
degradation. However, excipients can also stability, and (v) water content and
accelerate the degradation of the drug product. hygroscopicity.
The interaction between the drug substance and
excipients influences the instability and Excipients
bioavailability/bioequivalency of the drug
product. The reactive impurities of the Excipients affects critical attributes of a drug
excipients as well as the moisture content of the product such as bioavailability and stability, as
drug substance and excipients often influence well as, manufacturability. Mannitol may
the instability of the drug product. Some of the influence drug absorption and thus the
known incompatibilities between the excipients bioavailability of a drug product. The probable
and drug substance are Meglumine with explanation is that Mannitol influences gastro-
Glipizide (50) and Magnesium Stearate with intestinal motility due to contraction and can
Clopidogrel (51). Therefore, regulatory bodies decrease the transit time in the small intestine
require evidence of compatibility between the which may impact drug absorption and thus its
drug substance and excipients. bioavailability (52, 53). Excipients such as
surfactant (Poloxamer) and polymers
Typically, the binary mix of the drug substance (Povidone/Polyvinylpyrrolidone) can impact
and excipient are analyzed to examine the the metabolizing cytochrome p-450 enzymes.
chemical reactivity between the drug substance
and excipients. The binary mix of the drug

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The requirements for excipients as stated in the and thus affects powder beds mechanical
ICH QbD Guidance (4) are: properties and tablet die wall friction. Physical
attributes, such as particle size, surface area,
a) The excipients chosen, their concentration, porosity, surface morphology, and viscosity of
and the characteristics that can influence the excipients have the potential to impact drug
drug product performance (e.g. stability, product manufacturing process and quality
bioavailability) or manufacturability are attributes. Sometimes commonly used
discussed. Compatibility of excipients with excipients such as, starch is modified by
other excipients, if relevant, should be chemical or mechanical methods to enhance its
established. Excipient compatibility with functionality. For example, starch can be
other excipients is specific to the modified chemically through carboxy-
preservative. methylation to enhance hydrophilicity and
b) The intended functionality of the excipients crosslinking to reduce solubility. The source of
throughout the drug product shelf life starch, particle size, amount of sodium chloride
should be demonstrated. The excipients for (reaction by-product), viscosity, degree of
which the functionality should be substitution and cross-linking effect the
demonstrated are antioxidants, penetration functionality of the modified starch e.g.
enhancers, disintegrants, and release pregelatizied starch, sodium starch glycolate etc.
controlling agents. The author has observed differences in
c) The information on excipient performance disintegration, and experienced capping during
can be used to support the justification of compression due to differences in liquid uptake
the drug product specification. and settling volume (15 versus 30) of
d) Information to support the safety of disintegrants e.g., Croscarmellose sodium.
excipients, when appropriate, should be
cross referenced. All possible excipients that could be used in the
proposed formulation are typically categorized
Formulations and process design protocols into soluble, insoluble, and hydrophobic
must capture the above points. The materials. The purpose is to ensure the quality
experimental trial outcomes are discussed in the and robustness of the proposed formulation and
development report required for the CMC its manufacturability. For example, inorganic/
review. Usually, drug substances and drug insoluble/hydrophobic excipients are generally
product attributes and its manufacturability are avoided in formulating BCS Class II and IV
used to justify the appropriateness of excipient drugs. Instead hydrophilic excipients together
selection. An understanding of pharmaceutical with solubilizers/surfactants are chosen to
hydrates as excipients and their impact on optimize dissolution and drug absorption. The
product quality and its manufacturing process is dissolution profile of the RLD and the
often helpful. Some of the commonly used proposed drug product are frequently used to
hydrates as excipients are, magnesium stearate, rationalize the selection of the disintegrant and
lactose, glucose, dextrose or calcium control releasing agents used in the proposed
diphosphate. Use of magnesium stearates in the formulation. An example of excipient
solid dosage formulation is always critical. description is described below.
Differences in the hydration state i.e., water of
crystallization between batches of magnesium Croscarmellose Sodium NF
stearate impacts its lubrication properties (54).
The physical properties of magnesium stearate Croscarmellose sodium NF is a crosslinked
vary between batches due to its hydration state polymer of carboxymethyl cellulose sodium

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(NaCMC) and is an odorless, white or grayish It is one of the so called super disintegrants and
white powder. It is an anionic water insoluble used at a concentration up to 5% W/W of tablet
compound which is highly alkaline, and weight. The disintegration mechanism of
hygroscopic in nature. The pKa of Croscarmellose Sodium is swelling and wicking.
Croscarmellose Sodium NF is 4.17. It swells to It is suitable for both direct compression and
4 to 8 times its original volume in contact with dry granulation. In addition to its disintegrant
water in less than 10 seconds. It has a bulk property, the addition of a large amount of this
density of 0.529 g/cc, and specific surface area super disintegrant in the formulation of
of 0.81–0.83 m2/g (55). micronized drugs prevents the agglomeration of
the drug substance during compression.
In general, Croscarmellose Sodium NF is
nontoxic and nonirritant in nature. However, Risk assessment
oral consumption of large amounts of
Croscarmellose Sodium may have a laxative The ICH QbD Guidance requirements for risk
effect, although the quantities used in solid assessment of the input materials, as well as,
dosage formulations are unlikely to cause such a process parameters are summarized below (4):
problem. The reactive impurities present in
Croscarmellose Sodium are nitrite (NO2) and a) Critical material attributes (CMAs) and
nitrate (NO3). These reactive impurities can critical process parameters (CPPs) impacting
react with functional groups, such as dialkyl, drug product CQAs is linked.
alkylaryl, diaryl, cyclic secondary amines, N- b) Risk assessment is typically performed early
alkylureas, N-alkylcarbamates, and N- in the pharmaceutical development process
alkylamides to form N-nitroso compounds (e.g. and repeated as more information becomes
nitrosamines or nitrosamides). The nitrosamines available and greater knowledge is obtained.
or nitrosamides are the drug substance The risk assessment tools mentioned in the
degradates. Drug substance potency decreases guidance are the Ishikawa (fishbone) diagram
due to the formation of nitrosamines or and the failure mode and effects analysis
nitrosamides. In addition to the potency loss, (FMEA).
nitrosation at trace levels can also be c) Risk assessment could be based on prior
carcinogenic (56). Croscarmellose Sodium also knowledge and initial experimental data.
reacts with weakly basic drugs in the presence of
moisture causing loss in disintegration capacity. The two basic elements of risk assessment are
Therefore, the ability of the disintegrant to fully the identification of hazards and evaluation of
push apart the tablet matrix is reduced and risk associated with exposure to those hazards.
hence dissolution is slowed down. The change Three fundamental questions are often helpful
in interparticulate bonding of the disintegrant is in defining risk. The questions are (i) what might
believed to cause a decrease in dissolution rate. go wrong (ii) what is the likelihood (probability)
Croscarmellose Sodium is not compatible with that it will go wrong and (iii) what are the
strong acid or with soluble salts of irons and consequences (severity)? (8)
other metals, such as aluminum, mercury, and
zinc. It loses its disintegration capacity when The CMAs of the drug substance are
used in wet granulation or in direct compression determined considering the impact on the
with other hygroscopic ingredients e.g. sorbitol biological properties (e.g. bioavailability), drug
(57). product critical quality attributes and its
manufacturing process. The typical CMAs of
the drug substance for explicit tracking in risk

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assessment are: polymorphism, particle size, Manufacturing process selection

chemical reactivity, impurity, and water content.
Generally, the drug product development report The requirement is to select an appropriate
describes the impacts of the drug substance manufacturing process based on scientific
CMAs on drug product CQAs and its rationale. The purpose is to mitigate the
manufacturability. A control strategy needs to potential effects of the drug substance and
be outlined to control the identified CMAs of excipients attributes on drug product
the drug substance. An example of the performance as well as on unit operations.
quantitative risk assessment is outlined in Table Sometimes the manufacturing process of the
4, considering the impacts of the drug substance RLD is referred to justify the manufacturing
CMAs on drug product CQAs and its process selection of the proposed drug product.
manufacturability. A risk priority number (e.g. The manufacturing process of the RLD could
low/medium/high) is used for the assessment. be available in the literature or patents.
Sometimes reverse engineering study is also
PROCESS UNDERSTANDING performed to determine the manufacturing
process of the RLD. Some of the examples of
The common elements of process manufacturing process selection are: (i) since the
understanding are: (i) manufacturing process solubility of the drug substance is poor, a solid
selection, (ii) drug product and manufacturing dispersion/hot melt extrusion process is
process development, and (iii) risk assessment. employed to improve the dissolution and
absorption of the drug product, (ii) a dry/wet
The elements of process understanding along granulation process is suitable when the flow
with the container and closures system are property of the drug substance is poor;
discussed below. however, dry granulation is preferred for
reasons of cost, (iii) a hot melt/wet granulation
process is selected as the drug substance shows

Table 4 Risk assessment of DS attributes on DP CQAs

DP CQA
DS CMA MANUFACTURING
DU ASSAY DT DISSOLUTION STABILITY
Polymorphism
Chemical Stability
Degradant/Impurity
Particle Size
Hygroscopicity/
Water Content

Low: No investigation is required or not applicable

Medium: Investigation may be required

High: Investigation is required

DU: Uniformity of Dosages Unit

DT: Disintegration

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reduced crystallinity after processing (e.g. faster rate leading to improved drug absorption.
milling, micronization), (iv) a direct However, micronized/fine particles have a
compression/dry granulation process is selected greater tendency to form agglomerates which
because the drug substance is susceptible to can decrease the dissolution rate. Therefore, an
hydrolytic degradation, and (v) encapsulation initial risk assessment of the proposed
approach is chosen as the drug substance has a formulation is performed to identify potential
low melting point. Besides formulation problems that could affect the CQAs of the
optimization, stringent environment and drug (e.g. assay, dosage uniformity,
process controls are required for any drug disintegration, dissolution, and impurities). The
substance susceptible to hydrolysis/ typical ways to perform an initial formulation
oxidation/photolytic degradations to ensure risk assessment are a cause-and-effect diagram,
desired drug product performance and its such as the Ishikawa (fishbone) diagram and
manufacturability. quantitative risk mapping. A risk priority
number, such as low, medium, or high is
Drug product development employed for quantitative risk assessment.
Initial formulation risk assessments are often
The ICH QbD Guidance requires an initial based on prior information of the input
formulation risk assessment to identify the materials’ attributes together with knowledge of
focus of the drug development. The goal is to developing similar dosage forms, as well as, the
meet the QTPP. Formulation parameters, such unit operations. An example of an initial
as pH dependent solubility of the drug formulation risk assessment is shown in Table 5.
substance, drugs forming insoluble complexes
with the GI contents, instability in the GI tract, The QbR requirements for the drug product
and physicochemical interaction that could developments are: (i) what attributes the drug
affect in vivo absorption (58). In general, the drug product should possess, (ii) how the drug
is micronized to increase the dissolution rate product was designed to have these attributes,
and thereby the absorption of BCS Class II and (iii) how alternative formulations or
IV drugs. mechanisms were investigated, (iv) how the
excipients and their grades were selected, and (v)
The micronized/fine particles have a large how the final formulation was optimized.
specific surface area and hence dissolve at a

Table 5 Initial formulation risk assessment using prior knowledge

INPUT MATERIAL MANUFACTURING PROCESS

DP QA Excipient Major Magnesium

DS Disintegraton
Grade and Excipient Stearate Blending Lubrication Compacting Coating Pkg.
PS Level
Ps Ratio Level
Physical Attributes
Hardness
Assay
DU
Dissolution
Degradation/
Stability

Low: No investigation is required or not applicable

Medium: Investigation may be required
High: Investigation is required

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Formulation development b) The information required for using an

overage are: (i) the amount of overage (ii) the
The required elements of the formulation reason for the overage (e.g. to compensate
development as detailed in the ICH QbD for expected and documented manufacturing
guidance (4) are: losses) and (iii) a justification for the amount
of overage.
a) The drug product CQAs is identified. c) The overage should be included in the batch
b) The evolution of the formulation design formula.
from initial concept up to the final design
should be summarized. Typical formulation related deficiencies (59) are:
c) The excipient ranges, if any, included in the (i) Ethylcellulose is listed as a binder instead of a
batch formula should be justified; this rate controlling agent, provide data to
justification can often be based on the demonstrate that the amount of Ethylcellulose
experience gained during development or used has no impact on the drug release profile,
manufacture. (ii) it was concluded that high polymer content
d) Formulations used in clinical safety and can prevent the drug substance from
efficacy and in any relevant bioavailability or undergoing physical changes, such as re-
bioequivalence studies should be provided. crystallization, clarify if the drug substance
Any changes between the proposed remains as crystalline form or transforms to
commercial f or mulation and the amorphous form, (iii) provide the excipient
formulation(s) used in pivotal clinical batches compatibility (chemical and physical changes)
and primary stability batches should be study report performed during the
clearly described and the rationale for the pharmaceutical development, and (iv) clarify the
changes provided. difference in the acceptance criteria of the
e) Information from comparative in vitro studies excipient (name) between the vendor’s and
(e.g. dissolution) or comparative in vivo yours.
studies (e.g. bioequivalence) that links clinical
formulations to the proposed commercial Therefore, the formulations and process design
formulation should be summarized and a protocol must integrate the QbD requirements
cross-reference to the studies (with study and the possible QbR deficiencies discussed
numbers) should be provided. The results of above. The findings are discussed in the
the in vitro/in vivo correlation (when development report to expedite the CMC
performed) and a cross-reference to the review and to thereby reduce the approval time.
studies (with study numbers), should be One of the main goals of formulation design is
provided. to overcome the identified limitations of the
f) Any special design features of the drug drug substance, such as poor solubility or
product should be identified and a rationale susceptibility to degradation.
should be provided for their use. The special
design features include tablet score line, The solubility of some drugs is pH dependent,
overfill, and anti-counterfeiting measures. and sometimes the drug has a tendency to
crystallize or precipitate during dissolution. For
Overages example, dissolution of some weakly basic drugs
(e.g. Quetiapine Fumarate) slows down due to
a) Use of an overage of a drug substance is its pH dependent solubility. The probable
discouraged. reasons for this release problem are the variable

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pH of the GI tract and/or precipitation or formulation(s) are determined based on the lab
crystallization of the free base during scale trials. The prospective formulation(s) are
dissolution. Sometimes the pH of the GI tract then scaled up to a 5 to 20 kg batch size or
increases as a result of antacid or food more, depending on tablet weight and the
consumption. The slow or incomplete drug experimental design. Typical evaluations
release impacts drug bioavailability/ performed at the pilot scale trials are: (i)
bioequivalence. Therefore, the formulation is blending time and blender speed (ii) granulate
often optimized to mitigate the described physical and chemical (blend uniformity) quality
degradation pathways of such drugs. The attributes (iii) compression force and (iv) tablet
common ways to improve the performance of physical and quality attributes. The evaluations
such drugs is to modify the micro- of blend characteristics include particle size
environmental pH or to add an antioxidant in distribution, bulk density (BD), tapped density
the formulation to limit oxidative degradation. (TD), and blend uniformity of 6 or 10 locations
Acidic excipients, such as Tartaric Acid/Citric from the blender, and granules flowability. The
Acid/Fumaric Acid are often used in the evaluations of the tablet physical attributes
formulations of such drugs to overcome gastric include tablet weight (n=20), hardness,
pH interaction. The addition of these excipients thickness, and friability (6 g or more). The
in the formulation of such drugs ensures quality attributes that are examined at this stage
optimal bioavailability/bioequivalence. are dosage uniformity (n=10 or 20), impurity
Therefore, the choice of pH modifying profile, and dissolution (n=12). Composite
excipients along with its levels for such drug is samples from the beginning, middle, and end of
critical. the operation are generally analyzed for
evaluation purpose.
Several formulations around the target are
usually examined through initial trials. The trials The lead formulation(s) is often selected based
are performed to determine the robustness and on tablet hardness, dosage uniformity, impurity
sensitivity of the formulation and its impact on profile, and dissolution rate. Typically statistical
drug product CQAs. In general, the formulation assessment is performed to compare the quality
variables are identified based on prior attributes of the experimental batches and RLD.
knowledge and/or using the design of One of the statistical assessments is to calculate
experiment (DoE). The other typical the p value. The p values must > 0.05 to
considerations for initial formulation design are demonstrate that quality attributes of the
the patent on the drug substance, drug product experimental batches is comparable to the RLD.
formulations, and its manufacturing process. Statistical analyses are performed to justify that
The common components of formulation the proposed formulation is comparable to the
development are identification of lead RLD.
formulation, determination of excipient CMAs,
and risk assessment. These elements are The development report documents the
outlined below. summary of each unit operations along with the
equipment and the process parameters used. It
Identifying the lead formulation also documents the in-process and quality
attributes obtained from all the trial batches.
In general, laboratory and pilot scale The report identifies the processing problems
experiments are performed to determine the observed and the actions taken to overcome the
lead formulation(s). The quality attributes that problems. This information is often useful for
are examined during the lab scale trials are tablet investigating future deviations. The activities
hardness and dissolution. The prospective

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Table 6 Screening study

PATTERN DS* DILUENT 1 DILUENT 2 BINDER DISINTEGRANT LUBRICATION

1 !!!!++ -1 -1 -1 -1 +1 +1
2 !!++!! -1 -1 +1 +1 -1 -1
3 !+!+!+ -1 +1 -1 +1 -1 +1
4 !++!+! -1 +1 +1 -1 +1 -1
5 000000 Target Target Target Target Target Target
6 +!!++! +1 -1 -1 +1 +1 -1
7 +!+!!+ +1 -1 +1 -1 -1 +1
8 ++!!!! +1 +1 -1 -1 -1 -1
9 ++++++ +1 +1 +1 +1 +1 +1
*Theoretical low (-) and high (+) assay

performed at this stage are generally used to drug performance and its manufacturability.
justify formulation robustness and sensitivity. The report is also expected to document
equipment and process parameters used for
Determining excipients CMAs each trial. The evaluated result is used to justify
the grades of the excipients.
Excipient grade and level influence drug
product performance and its manufacturability. Excipient Levels
Therefore, experimental trials are performed to
evaluate the impact of different grades and Experimental trials are designed and performed
levels of excipients on product quality and unit to assess the effect of the generally used
operations. Experimental trials determine the excipients, for example, diluent, binder,
CMAs of the major excipients affecting drug disintegrant/solubilizer, glidant, and lubricant
product performance and its manufacturability. levels on drug product in-process and quality
Prior knowledge of CMAs of the selected attributes and on unit operations. The
excipients and manufacturing process in experimental trials are designed based on the
question is often used as QbD checklist for worst case scenario of the drug substance assay
excipient. (theoretical low and high assay values) or using
the design of experiment (DoE) model e.g.
Excipient Grades screening study. In a worst case scenario, the
major excipient levels are calculated based on
Physical properties, for example, particle size, the drug substance theoretical low and high
loss on drying, and flow of different grades of assay values. The other technique that can be
the same excipients are different. Formulations used is a screening study. An example of a
are designed and performed using at least two screening study based on low (-) and high (+)
grades of the major excipients to evaluate the levels of excipients is outlined in Table 6.
impact on product quality attributes and its
manufacturability. The in-process quality The summary report documents the trial
attributes that are examined during the trials findings and describes the impact of excipient
include weight (n = 20), hardness, thickness, levels on the drug product quality attributes
and friability (6 g or more), capping, cracking, (physical and chemical). It also describes the
and disintegration. Dosage uniformity (n = 10), manufacturability of the drug and the
the impurity profile, and dissolution (n= 6 or equipment and process parameters used. The
12) are analyzed to evaluate the product evaluated result justifies the excipient levels with
performance. The product development report a target quantity that could be used in future.
describes the impact of the excipient grades on

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Table 7 Risk assessment of formulation variables

DP CQAs
ELEMENT MANUFACTURING JUSTIFICATION
DU Assay DT Dissolution Stability
Excipient compatibility
Major excipient PS Influence scale up
Excipient Impurity Impact unit
operations, tablet
Major excipient Grade & hardness, BU, DU,
Level DT and dissolution
Glidant Level
Lubricant Level

The goal is to keep an option for continual c) Critical process parameters are identified,
improvement. monitored and controlled.
d) Significant differences between the
Risk assessment manufacturing processes used to produce
batches for pivotal clinical trials (safety,
Chemical reactivity, excipient grades and levels efficacy, bioavailability, and bioequivalence)
trials identify the risks of the CMAs on drug or primary stability studies and the process
product quality and its manufacturability. for commercial manufacturing should be
Generally recognized CMAs of the excipients discussed. The information should include,
for explicit tracking in risk assessments are for example, (i) identity (e.g. batch number)
particle size, flow, hygroscopicity, and reactive and use of the batches produced (e.g.
impurities. An example of assessing the risks of bioequivalence study batch number), (ii)
formulation variables is described in Table 7. manufacturing site, (iii) batch size, and (iv)
any significant equipment differences (e.g.
The formulation development studies and the different design, operating principle, or size).
risk assessment together determine the most e) A description of the measurement systems
likely formulation that will ensure problem free applied during monitoring and collection of
scale-up and subsequent process validation. CQAs/CMAs/ CPPs.
Therefore, the prospective formulation is used f) An assessment of the ability of the process to
during the manufacturing process development reliably produce a product of the intended
study to finalize the ranges for the critical quality e.g. the performance of the
process parameters of each unit operation. manufacturing process under different
operating conditions, at different scales, or
Manufacturing process development with different equipment.
The elements of the manufacturing process The purposes of the manufacturing process
development as expressed in the ICH QbD development are to (i) enable scale-up and
Guidance are listed below (4). decrease variations in drug product quality and
its manufacturability using a science-based
a) The selection, the control, and any approach, (ii) provide flexibility for future
improvement of the manufacturing process process improvement, (iii) enhance process
should be explained. understanding, (iv) to reduce risk through risk
b) The selection of the manufacturing process, assessment, and (v) justify the drug product
appropriateness of the components and specification.
equipment used should be discussed.

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A manufacturing process development study for operating principle of the equipment. Special
non-problematic drug substances and attention is required if the manufacturing
noncritical dosage forms is optional. For equipment is not within the same SUPAC (scale
example, an immediate release dosage form is up and post approval changes) equipment class
manufactured using a direct compression of the bio or submission batch. The factors
process. The formulation contains a drug considered in blending scale-up are (i) geometric
substance that is highly soluble, stable, and similarity: ratio of all lengths constant (constant
flows well. The other components, for example, fill ratio), (ii) dynamic similarity: maintenance of
diluent, binder, disintegrant, and lubricant are forces (Froude number), and (iii) kinematic
commonly used grades and are recognized in similarity: maintaining a consistent number or
the national formulary or other acceptable revolutions. Experimental trials examine the
quality standards. Their levels in the formulation impacts of the process parameters of each unit
are supported by the the Inactive Ingredient operations on drug product quality attributes
Database (IID) limits. The drug load in the (in-process and CQAs) and its processability.
formulation is between >10% to <50% W/W. In Trial findings determine the ranges of the
such cases, a manufacturing process critical process parameters of each unit
development study may not be required operations. Identification of the CPPs of
provided that it could be justified based on prior different unit operations is summarized below.
knowledge.
Identifying the critical process parameters
Typical deficiencies pertaining to the (CPPs)
manufacturing process development (59) are (i)
to clarify how the critical process parameters Typical CPPs of different unit operations and
(CPPs) were identified, monitored, and/or their probable impact on the drug product in-
controlled for each unit operation, provide a process quality attributes and CQAs, and the
summary table to adds clarity and facilitates drug’s manufacturability are discussed below.
review, (ii) drug content in the final blend is low,
the manufacturing process is a direct De-agglomeration or milling
compression process, provide available
information regarding the segregation potential Screen size and impeller speed used during
of the blend under your manufacturing milling can affect the drug substance (e.g. phase
conditions, and the possible impact on the conversion of metastable drugs) and the
content uniformity, (iii) for the pre-lubrication segregation of low drug content formulation. In
and lubrication blending of the commercial general, smaller screen size and moderate
batch, establish your mixing time in relation to impeller speed is used to de-agglomerate the
the scale-up effect from a 5 cu. ft. to a 80 cu. ft. cohesive/micronized drug substance. The
blender, and (iv) provide data to justify your objective is to ensure uniform dispersion of the
tablet hardness range, especially its impact on drug substance without impacting its crystal
friability, shipping, and dissolution at the structure.
extremes of the proposed hardness range.
Blending

A scale-up plan should be based on the risk Critical parameters of the blending process are
assessment of each variable and the process bin fill, mixing order, blending time, and blender
understanding gained during pilot scale and speed. The bin fill depends on several factors,
prior knowledge. One of the considerations for for example, (i) drug substance and excipients
scale-up manufacturing is the design and flowability (ii) drug content in the formulation

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and (iii) the manufacturing process. The bin fill The granule produced using each experimental
is especially critical for the direct compression trial is analyzed for physical characterization.
process which depends on drug content in the The physical characteristics analyses determine
formulation. The recommended bin fill for the compaction parameters as well as the in-
mixing the cohesive/micronized/ fines and free process acceptance limits of particle size
flowing drug substance and excipients is 60% distribution (sieve analysis), density, and flow.
and 80% respectively of the blender working
capacity. A blend time analysis method is used Compression
to evaluate blending time. Blend time analysis is
performed by collecting the blend sample from Typical critical parameters of the compression
the identified dead spots of the blender at process are compression speed and
different time points. The collected blends are compression force. In addition, sometimes
usually examined for density, flow, blend feeder speed may influence the segregation of
uniformity, compressibility, and dosage low drug content formulation leading to OOS
uniformity. dosage uniformity and assay. Compression
speed influences blend flow and thereby impacts
Dry Granulation (Roller Compaction) tablet weight, hardness, and dosage uniformity.
Compression force influences tablet hardness,
The purpose of compaction is to produce disintegration, and dissolution. Trial plans, such
quality granules to ensure optimum flow and as low weight – high weight (LW – HW), low
compressibility. Compaction process para- speed – high speed (LS – HS) and low hardness
meters control the physical quality attributes of – high hardness (LH – HH) are designed and
the granules, such as particle size and their performed to determine the ranges of the
distribution, bulk and tapped density and flow. compression parameters. The analysis of the
Particle size and shape along with the density tablet physical quality attributes, for example,
influence the flow and compressibility of the weight, hardness, thickness, friability, and
granules. Granules flow and compressibility disintegration of each experiment determines
influence blend and dosage uniformity, and the tablets in-process quality attributes along
compression force and speed, and thereby with the compression speed. This also provides
impact drug product quality attributes, such as a guideline for pre and main compression force.
tablet weight, hardness, friability, disintegration,
and dissolution. Generally recognized critical Coating
parameters of the compaction process are
compaction force (CF), roller speed (RS), and There are two types, i.e., functional and non-
roller gap (RG). An example of identifying the functional film coating. The degree of criticality
CPPs of the roller compaction process is of the non-functional coating is less compared
outlined in Table 8 using a partial factorial to the functional coating. Sometimes, a seal coat
design of experiment (DoE) model. is applied based on the drug substance and the
coating solution/dispersion attributes. The
Table 8 Partial factorial DOE design: compaction objective of a seal coat is to ensure the
parameter evaluation robustness of the product. Triethyl citrate
(TEC) is commonly used as a plasticizer in
TRIALS
1
PATTERN
--+
CF (kN/cm) – X1 RG (mm) – X2
-1 -1
RS (rpm) – X3
+1
aqueous based delayed release coating. TEC is
2 -+- -1 +1 -1 slightly acidic in nature, and so can influence the
3 000 Target Target Target degradation of the drug substance (e.g.
4
5
+--
+++
+1
+1
-1
+1
-1
+1
Pantoprazole) during the coating process (60).

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Table 9 Delayed release coating process parameters

PARAMETERS RANGES CONTROLS COMMENTS

Coating Dispersion
Dry polymer on the tablet per cm2 area Yes Yes Ensure delayed release
Plasticizer on dry polymer Yes Yes Provides elasticity to polymer.
Total quantity of insoluble excipients Yes Yes Ensure film mechanical strength
Total solid contents Yes Yes Governs solidification, impacts film mechanical strength
Mixing time Yes Yes To ensure dispersion quality.

Coating Process
Pan Load Yes Yes Ranges based on study
Spray Rate Yes Yes Ranges based on study
Gun Distance No Yes Fixed for specific pan load
Gun Angle No Yes Fixed
Pan Speed Yes Yes Machine controlled in Auto Mode
Atomizing and Pattern Air Pressure No Yes Fixed based on study
Exhaust Air Temp. Yes Yes Based on study
Inlet Air Humidity Yes Yes Impact film mechanical strength of hygroscopic core.

High susceptibility to hydrolysis coupled with an risk assessment tools to establish the CPPs and
acidic environment influence the degradation. their impact on CQAs. However, establishing
Therefore, a seal coat is applied to protect the the critical process parameter ranges using a risk
tablet core of such drug substances. In this case, assessment tool is optional for non-problematic
the seal coat does not contain TEC as a generic formulations and process development.
plasticizer. The goal is to ensure that the reactive An example of determining the impact of
ingredient, for example, TEC, in the final critical process parameter(s) of unit operations
coating formulation does not come into contact on drug product CQAs is presented in Table 10
with the core tablet. An example of identifying using FMEA risk assessment tool.
the critical parameters of the delayed release
coating process is described in Table 9. The RPN and criticality number provides
guidance for ranking potentials failures in the
Worst case scenarios, e.g., extreme low and order they should be addressed.
extreme high together with risk assessments are
used to establish the ranges of the critical Formulation and process selection
process parameters of each unit operation.
The formulation and manufacturing process
development studies determine the final
Risk assessment: impact of the CPPs on DP formulations and manufacturing processes for
CQAs the bioequivalence/stability/submission batch.
The drug product CQAs manufactured using
The risk assessment tools for pharmaceutical the optimized formulation and processes are
manufacturing process development are compared with the RLD. The QbR questions
described in the guidance (4, 8). They are failure with respect to composition of the drug product
mode effects analysis (FMEA), failure mode are: (i) what are the components and
effects criticality analysis (FMECA), and hazard composition of the final product and their
operability analysis (HAZOP) (8). FMEA quality standard? What is the function of each
focuses on how and when a system will fail, not excipient, (ii) does any excipient exceed the
if it will fail. Regulatory bodies accept both Inactive Ingredients Database (IID) limit for
approaches, such as worst case experiments and this route of administration, and

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Table 10 Risk Assessment: Impact of CPPs on DP CQAs

CRITICALITY

CRITICALITY
Potential

**
Failure Mode/ Potential Cause Design/Control

RPN

RPN
Unit Op Effects of S O Detection D S O D
CPPs of Failure Strategy
Failure

Develop screen
size guideline
Poor de-
considering drug
agglomeration Drug substance
Release test substance
Screen size . 5 particle size is not 1 5 25 5 5 1 1 5 5
(Assay, DU) particle size,
Impact assay considered.
drug content and
and DU.
manufacturing
process.

Link
development
Scale up batch size
batch size to
Blending is not considered
Mixing is not submission/clinic
during initial
uniform. Over al study batch
development.
or under size and to the
Equipment
Bin fill, blender compaction of commercial
malfunctions due to 3 BU/DT/Hard
speed and blending the blend. 5 3 45 15 batch size. 5 1 1 5 5
motor problem. ness
time Impact BU, Check list to
Timer malfunction.
DU, DT, ensure
No instruction to
hardness and preventive
check blender
dissolution maintenance,
speed and time as
calibration of the
the time is preset.
blender speed
and time.

Ribbon
density.
High/low
Determine
density
granules physical
granules.
attributes (PSD,
Irregular
Compaction force Compaction BD, TD) in-
granules size Sieve
Roller (CF), Roller gap parameters are not process criteria
(big and 5 5 analysis 3 75 25 5 1 3 15 5
Compaction (RG), optimized with a based on the
small). BD and TD
Roller speed (RS) range. impact of the
Segregation
target and
potential,
extreme
Impact flow
parameters.
and
compressibilit
y (hardness)

Determine
hardness ranges
Poor quality
Hardness/ Impact tablet based on
5 granules cause 5 Dissolution
Compression compression force porosity and 5 125 25 compression 5 1 5 25 5
variation in test
and speed dissolution speed and
compression force.
dissolution test
result.

Ranking

1 3 5 7

Severity (S) Low: Deviation Reprocessing Batch Rejected Recall

Repeated: 1 out
Occurrence (O) Unlikely: 1 out of 500 Occasional: 1 out of 100 Regular: 1 out of 10
of 20

Always before During the release

Detectability (D) During in-process test or before the next unit operation During stability test
operations test
**
Risk Priority Number RPN = S*O*D, Criticality = S*O

(iii) do the differences between this formulation (ii) function(s) of each excipient (iii) excipient
and the reference listed drug (RLD) present levels with reference to the IID limit for the
potential concerns with respect to therapeutic route of administration (iv) potential differences
equivalence? Therefore, the product and between the selected formulation and the RLD
process development summary report describes with respect to therapeutic equivalence, if any,
the (i) component and compositions of the final and (v) comparative formulation of the
product with reference to the quality standard proposed drug product and the RLD.

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Regulatory bodies accept the differences in demonstrate the integrity of the container
excipients with a justification. An example of and closure.
component and composition, and a c) The choice of primary packaging materials
comparative formulation of the proposed drug should be considered e.g. choice of materials,
product are presented in Tables 11 and 12 protection from moisture and light,
respectively. compatibility of the materials of construction
with the dosage form (including sorption to
Table 11 Components and composition of the proposed container and leaching), and safety of
drug product materials of construction. Justification for
secondary packaging materials should be
QTY (mg/TAB) REFERENCE TO
COMPONENT
IID
QTY
FUNCTION QUALITY included when relevant.
xx mg xy mg STANDARD
USP/BP/EP/
DS X X1 -- Active
In-house The QbR questions related to the container
Excipient 1 X X2 -- Diluent NF/EP/ In-house
closures are: (i) rationale for choice of the
Excipient 2 X X3 -- Binder NF/EP/ In-house
Excipient 3 X X4 -- Disintegrant NF/EP/ In-house
container closure system i.e. what specific
Excipient 4 X X5 -- Glidant NF/EP/ In-house container closure attributes are necessary to
Excipient 5 X X6 -- Lubricant NF/EP/ In-house ensure product performance, (ii) what container
Tablet weight (mg) Xx xy
closure system(s) is proposed for packaging and
storage of the drug product? Has the container
closure system been qualified as safe for use
Table 12 Comparative formulation of the proposed drug
product
with this dosage form, and (iii) is the container
closures suitable for use with respect to
PROPOSED performance, functionality and safety. Relevant
RLD FUNCTION JUSTIFICATION
DP compendial test and controls for the container
DS DS Active Diluent, binder and disintegrant
used in the proposed drug closure are USP <381> (Elastomeric Closures
Excipient 1 Excipient x Diluent product and RLD are different.
However, the diluent, binder for Injections), <87> (Biological Reactivity
Excipient 2 Excipient x Binder and disintegrant used in the
proposed drug product are Tests, In Vitro), <660> (Containers – Glass),
Excipient 3 Excipient x Disintegrant

Excipient 4 Excipient x Glidant

established and recognized for
solid dosages formulation. In
<661> (Containers- Plastics), and <671>
Excipient 5 Excipient 5 Lubricant
addition, the desired drug
product performance and its
(Containers – Performance Testing). These
Excipient 6 Diluent
manufacturability have been
established.
tests are intended to demonstrate the identity,
x is used to differentiate material differences between the proposed performance, suitability, compatibility and
and RLD formulation. safety of the container closures. Generally,
deficiency is cited, if this information is not
mentioned.
Container and closures system
Environmental factors, such as moisture,
The ICH QbD Guidance requirements for the oxygen, and light often influence the
container and closures systems are (4): hydrolytic/oxidative/photo degradation of the
drug product. Therefore, the drug must be
a) The choice and rationale for selection of the protected by an effective barrier to prevent or
container and closures system particularly the control the negative influence of environmental
primary packaging for the commercial factors. For example, the moisture ingress often
product are discussed. influences the appearance (e.g. discoloration)
b) The choice of materials for primary and tablet softening or hardening as well as
packaging should be justified. The discussion hydrolytic degradation. Degradations adversely
should describe studies performed to affects assay; dissolution and impurity profile of

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the drug product thereby compromising its effectiveness of the container and closures
safety, purity and efficacy. Therefore, in general, barrier property.
high humidity territories warrant extra
precautions. The high density polyethylene (HDPE) bottle is
the preferred packaging format for tablets and
A justification for the selection of the container capsules in the USA and Canada. The most
and closures system is required. Intrinsic common packaging for Europe and the rest of
stability of the drug substance and distinctive the world (ROW) is blister. Understanding the
quality attributes of the primary packaging container and closures barrier properties and
component influence the selection of the the packaging processes provide the basis for
container and closures system. The quality selecting the right container and closures. The
attributes of the container and closures are barrier properties of some commonly used
physicochemical stability and barrier property container and closures and typical critical
against environmental factors (e.g. moisture, aspects of the packaging process are briefly
oxygen, and light). The other two aspects of discussed below.
container and closures selection are its child
resistance property and security (e.g. anti- HDPE Bottle package
counterfeiting, tamper evident). The child
resistance property of the container and Water vapor transmission rate (WVTR) and
closures is a legal requirement for the USA and oxygen vapor transmission rate (OVTR)
Canada with few exceptions. However, child influence the selection of the HDPE bottles.
resistance of the container and closures is not Theoretical WVTR of a standard 60cc HDPE
mandatory in all European countries. In some bottle when stored at 40ºC/75% RH (relative
European countries, the requirement is product humidity) is equal to 1 mg of water per day.
specific. In addition to protection against Therefore, RH conditions within a standard
environmental factors, the selection of the 60cc HDPE bottle could re-equilibrate to 50%
container and closures system depends on the within 1 day, even if a product is packaged
cost of goods (CoGs), market trend, and under low water vapor conditions. The OVTR
preferred pack size/patient compliance. of the HDPE, Polypropylene (PP), and PVC
Selecting the right container and closures from (polyvinyl chloride) bottle is 102 {g.mm/(
the beginning minimizes stability failure and m2.day)}, 89 g.mm {g.mm/( m2.day)}, and 4
regulatory review questions. It also ensures the {g.mm/( m2.day)}, respectively.
best product shelf-life.
In addition to permeation through the walls, the
Stable products are not sensitive to key vulnerability in a HDPE bottle is the screw-
environmental factors. Therefore, the relevant topped closure even when a lid induction seal is
scientific data pertaining to the intrinsic stability used. Moisture and oxygen levels in the
of the drug product and barrier property of the container head space can be significant enough
container and closures are sufficient to show to affect the stability of some drugs. The author
the acceptability of the drug product’s experienced a decrease in the dissolution rate of
physicochemical integrity during storage. weakly basic drugs (e.g. Domperidone Maleate,
However, for moisture/oxygen/light sensitive pKa of 13.4) in presence of Croscarmellose
drugs (e.g. Pantoprazole), it is required to Sodium NF due to the presence of
demonstrate that the container and closures environmental moisture in the bottle head
provide an effective barrier. Stability data at space. Therefore, desiccants are used to prevent
different storage conditions supports the moisture mediated degradations. The adsorb/
absorb capacity of the desiccant varies

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depending on storage conditions. For example, PVC is the most commonly used base film in
silica gel is efficient in absorbing moisture at blister packs. The WVTR of the PVC film of
high RH, but inefficient at lower RH. However, 250 microns is about 3.72 g/(m² d) at 38°C and
it is the opposite for molecular sieve desiccants. 90% RH (61). The PVC film is commonly used
The molecular sieve is approved for to pack stable drugs. The use of PVC in some
pharmaceutical products in the EU, but not in European countries is restricted by regulations
the USA for commercial products. The amount due to its disposal concern. The common
of desiccant required to maintain relative disposal method of PVC is incineration that
humidity within a specified range over the produces toxic gas.
product’s shelf-life can be calculated. The
calculation uses the WVTR of the container’s Other blister films with superior barrier
material of construction and the rate of properties are available on the market. Blister
moisture adsorbed by the desiccants. An films with enhanced barrier properties are
oxygen-impermeable seal (e.g., induction heat PVC/PVdC (polyvinyl dichloride),
seal) is used for oral solid dosage forms prone PVC/PCTFE (polychlorotrifluroethylene), and
to oxidative degradation. The induction seal is cold form.
also used to ensure security of the packaged
drug product. A secondary pack component can For PVdC coated PVC film, PVdC layer is
augment light protection. specified in gsm. The weights of commonly
used PVdC coating are 40 gsm, 60 gsm, 90 gsm,
The opacity of the container does not and 120 gsm. The PVC/PVdC film is offered
necessarily mean that it will protect the product with or without a middle layer of polyethylene
from light. HDPE bottles are generally (25µ PE). The polyethylene is used with a
opacified with titanium dioxide pigment to heavier coating of 60 gsm, 90 gsm or 120 gsm
prevent light transmission. However, HDPE to improve the thermoforming characteristics
bottles still allow significant light transmission of the blister cavity. The PVC/PVdC coated
because the light is scattered both internally and film provides medium to high barrier
externally. Therefore, HDPE bottles are not protection. Depending on the weights of PVdC
used to pack light sensitive drugs. coating, the WVTR of the PVC/PVdC coated
film is varied between 0.6 g/(m²d) to 0.2
Blister packages g/(m²d) at 38°C and 90% RH (62). PVC/PVdC
coated films are easy to form, but PVdC tends
Three types of pharmaceutical blister package to release gas during blister forming. The
are commonly used. They are: (i) thermoform released gas is sticky in nature and is also
(ii) cold form and (iii) tropical blister. The two reported to damage the blister formats (63).
components of a blister are forming/base film
and lid foil. The polymers influence the Depending on the thickness of the PCTFE
characteristics of the commonly used blister film, the WVTR of the PVC/PCTFE film is
films and the critical aspects of the blister between 0.05 g/(m²d) to 0.45 g/(m²d) at 38°C
packaging parameters. The intrinsic moisture and 90% RH. Generally, sustained/controlled
and oxygen transmission properties of release products and rapidly dissolving drugs
commonly used single polymers are different. are packaged using PVC/PCTFE blister film.
The intrinsic transmission rate is the The draft angle of the blister mold for
characteristic of each polymer (grade) and PVC/PCTFE film is generally designed to be 5°
represents the thickness independent barrier to avoid non-uniform blister formation. A plug
performance (commonly called “the assist is required if blister depth is >6 mm to
transmission rate of a one micron thick film”).

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avoid malformation. The most common a channel is formed between the lid foil and
problem of the PCTFE film is the curl base films due to overheating during sealing.
formation towards the PCTFE side of the The formed channel allows water/oxygen vapor
blister. Therefore, during the blistering process to pass into the blister pockets, which facilitates
low heat is applied to the PCTFE side to the degradation of the drug product. Therefore,
minimize curl formation. the sealing temperature is controlled to ensure
optimum sealing, which is generally tested by
The product contact requirements for performing a leak test.
PVC/PVdC and PVC/PCTFF are different for
the USA and Europe. In the USA, the product The appropriate container and closures are
contact may only br PVC whereas either PVC selected based on the primary packaging
or PVdC is acceptable in Europe. materials quality attributes and the drug
substance intrinsic stability. The developed drug
Commonly used lid foils are hard aluminum, products are packaged using the selected
soft aluminum, paper/aluminum, paper/PET/ container and closures. The packaged product is
aluminum. Hard aluminum is the most widely then placed in stability following the ICH
used push-through lid foil in Europe. stability guideline (44, 64). The product placed
Paper/PET/aluminum is predominantly used in stability is then analyzed at different intervals
in the USA for peel-push (child resistant) to assess the integrity, safety, and purity of the
blister. The product contact requirement for lid drug product. The data is also used to
foil is that the heat seal lacquer must be non- demonstrate the suitability of the container and
reactive and non-toxic. The heat seal lacquer closures.
non-reactive and non-toxic information is
available in the open part of the DMF. The science based analysis of the drug
substance attributes, drug product formulation
The cold form blister provides a nearly absolute and manufacturing process, and the packaging
barrier against moisture, oxygen, and light. The components discussed above provide the
cold form blister generally contains three layers. highest confidence for product integrity.
These are (i) OPA (oriented polyamide)/
aluminum/PVC (ii) OPA/aluminum/nylon and CONTROL STRATEGY
(iii) OPA/aluminum/PP. The presence of
aluminum in the cold form blister ensures best The ICH QbD Guidance requires the design of
protection from light. Cold form blister control strategy to ensure consistent quality of
materials are mostly used to pack drug products the drug product. The elements of control
that are extremely sensitive to moisture, oxygen, strategy should describe and justify how in-
or light. process controls and the controls of input
materials e.g., drug substance and excipients,
Some other critical aspects of blister packaging intermediates e.g., in-process materials,
are: (i) blister tip thickness, (ii) sealing container and closure system, and drug product
temperature, and (iii) outer seal width. The contributes to final product quality. A control
preferred blister tip thickness is one fourth of strategy can include, but is not limited to, the
the base film original thickness. However for following as outlined in the Guidance (4).
stable products, the tip thickness could be up to
one sixth of the original thickness. An outer a) Control of input material attributes (e.g. drug
seal width of 3 mm is optimum for substance, excipients, primary packaging
moisture/oxygen sensitive products. Generally, materials) based on an understanding of their
impact on processability or product quality;

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b) Product specification(s); Ascorbic acid, Thioglycerol, Propyl gallate in

c) Controls for unit operations that have an the formulation.
impact on downstream processing or % Introduce an antioxidant (e.g. BHA or
product quality (e.g. the impact of drying on Tetrahydrofuran (THF)) as an impurity in
degradation, particle size distribution of the the drug substance, if possible.
granulate on dissolution); % Assign hold time for each unit operations to
d) In-process or real-time release testing in lieu limit the exposure to environmental oxygen,
of end-product testing, for example, moisture and temperature.
analyzing CQAs (blend and dosage % Ensure minimum head space in the bottle by
uniformity) during processing; selecting the right size bottle for each count
e) A monitoring program (e.g. full product and use of desiccant.
testing at regular intervals) for verifying
multivariate prediction models. The controls discussed above are generally
included either in the master production
Control strategy pertaining to the test method document or in the release testing specification
and testing frequency of the input materials is as appropriate. In general, drug specific tests
out of the scope of this paper. Control strategy (e.g. polymorphism, particle size, optical
for the input materials, unit operations, and rotation, water content, impurities, and residual
drug product is briefly discussed below. solvent) are captured in the control strategy.

Drug substance The typical control strategy for stabilizing photo

labile degradation is the addition of light
The control strategy for a drug substance is absorbing agents, such as pigments, colorants,
determined based on the risk assessment or UV absorbers in the formulation or use of
pertaining to intrinsic stability, particle size, appropriate packaging components. The
impurity, chemical reactivity, and their impact effectivity of the light absorbing agents are
on drug product CQAs as well as its pigments > colorants > UV absorbers. The
manufacturability. For example, sometimes, the ideal packaging component for extreme photo
oxidative degradates (>1%) derived from the labile drugs is aluminum foil.
drug substance are controlled to prevent or
minimize the impact on drug product quality. Excipients
The ways to control the oxidative degradates
(>1%) of the drug substance and their The specifications for excipients are included
interaction with peroxides and/or USP/NF compendial monographs. Sometimes,
environmental factors are discussed below. additional specifications, such as particle size
and viscosity are included in the release testing
% Set a tighter limit for the oxidative degradates to control excipients with critical functional
derived from the drug substance and the roles or specific grades (e.g. povidone, guar
reactive impurities of the excipient based on gum). For non-compendial excipients, the
the annual rate of change. development report must provide a description
% Perform real time analysis (i.e. prior to use) of the tests performed to control identity and
of the excipient containing reactive impurity. quality along with the validation of the test
% Add Butylated hydroxyanisole (BHA), method. Special attention is given to control
Butylated hydroxytoluene (BHT), and monitor the reactive impurities of the
Ethylenediaminetetraacetic acid (EDTA),

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excipients to ensure the product purity, safety attributes/utilization expertise, drug product
and efficacy. specific expertise, and policies/procedures in
place. An example to justify the use of prior
Drug product knowledge is provided in Table 14.

Usually the drug product specification includes CONCLUSION

the tests, procedures, and acceptance criteria
used to control quality, identity, strength, and There are challenges in implementing QbD and
purity of the drug product. QbR when developing formulations and
processes for generic drugs. However, there are
The risk assessments are usually the basis for benefits when adopting QbD, for example it is
the control strategy. An example of determining possible to select the optimum formulations
the control strategy for input materials and unit and processes with a reasonable confidence.
operations using risk assessment and mitigating Building in QbD to the development process
the risks is outlined in Table 13. minimizes answers to regulatory review
questions and hence, first cycle approval. It can
PRIOR KNOWLEDGE reduce the time for preparing common
technical documents (CTD) and also reduce
Prior knowledge is one of the important overall product and process development costs.
elements of the QbD approach, which is Finally, it will allow for continuing
generally the starting point for subsequent improvements throughout the product life-
assessment. Prior knowledge could be used cycle. The application of QbD minimizes the
during the risk assessment of the drug risks of failing bioequivalence studies, scale-up,
substance, excipient selection, formulation and validation, and stability studies. It is required to
process design. However, it cannot be spend considerable time during the product and
generalized as a standard set of information for process characterization phase compared to the
all applications. It is relevant to the submission execution of the trials. The key to making QbD
if it (i) clearly delineates similarities and and QbR implementation a success is the
differences, (ii) properly links CQA’s with appropriate product and process
CMA’s and CPP’s, (iii) justifiable/qualifiable characterization based on sound scientific
based on scientific rationale, (iv) supported by principles together with risk assessment. The
relevant data, and (v) can fill the gaps/missing- other requirements for successful
links, as applicable. Outside information and implementation of the approach are a strong
industry or in-house information could be used commitment by top management, appropriate
as prior knowledge. The typical sources of planning, and focused project management.
outside information are: published literature,
research articles, review papers, DISCLOSURE AND CONFLICTS OF INTEREST
patents/intellectual properties, reference books,
RLD label, and suppliers (equipment/material) The author reports no declarations of interest.
technical data sheets. The pertaining industry or
in-house information are capability (equipment ACKNOWLEDGEMENTS
and technology available, process know-how),
The author would like to thank Naresh Talwar,
dosage form/drug delivery system specific prior
PhD., Satya Sarker, PhD., and George Hammer
submissions, dosage form/drug delivery system
for their valuable suggestions and time to
specific expertise, specialized material
review the paper.

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Table 13 Risk assessment and mitigating risks by control strategy

RANGES USED PROPOSED
IMPACT ON RISK FOR OPERATING CONTROL
MATERIAL/PROCESS CMA/CPPS
PROCESS/CQAS LEVEL BIO/STABILITY RANGE STRATEGY
BATCH (Min – Max)
INPUT MATERIALS
Polymorphic
Mfg. Process, Dissolution
From
Particle size
BU, DU, hardness, dissolution
(µm)
Drug Substance
Impurity
Stability
(oxidative) Ranges based on
Parameter used for
Mfg. process, dissolution, the successful
Water content bio or stability Specification limits
degradation, microbial growth experimental trials
study batch
and bio batch
Particle size BU, DU
Major Excipients Peroxide Stability
Metal Ions Stability
Primary Packaging Assay, dissolution,
WVTR/OVTR
Materials degradation

UNIT OPERATIONS
Screening Screen size BU, DU
Compaction CF, RG, RS Compression, dissolution
Blend time, Appearance, BU, DU,
Final Blending
blender rpm dissolution
Compression Sticking, picking, hardness,
speed dissolution
Compression
Core tablet
Dissolution
hardness
Coating
dispersion Dissolution
mixing time
Coating
dispersion Micro growth
holding time
Air flow rate Ranges based on Acceptance or
Parameter used for
the successful operating parameter:
Gun distance bio or stability
experimental trials Fixed or ranges with
study batch
Pan Speed and bio batch target

Spray Rate

Delayed Release Coating Atomizing and

Pattern Air
Pressure
Exhaust Air Film Integrity and dissolution
Temp
Inlet Air
Humidity
% of polymer
applied on per
sq. cm of
tablet
Coating
weight gain

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Table 14 Prior knowledge justification

PROPOSED
ELEMENTS EXAMPLE PRODUCT COMMENT
PRODUCT
DRUG SUBSTANCE

Chemical Name A C NA

Polymorphism Do not exist Do not exist Similar

Chiral Center None None Similar

Class I, Soluble at pH 1.2 to Class I, Soluble at pH 1.2 to

BCS Class/Solubility Similar
7.5 7.5

pKa 6.0 7.0 Similar

Partition Coefficient Log P: 0.5 at 25<C, pH: 7.0 Log P: 0.6 at 25<C, pH: 6.8 Similar

D50:40-60µm D50: NMT50µm

Particle Size Comparable
D90: NMT 90µm D90: NMT80 µm

Water Content LT 2.0% LT2.5% Comparable

FORMULATION

Drug Content 15 %W /W 20 %W /W Comparable

Binder Content 12% /W W

10% W /W Comparable

Disintegrant

Wicking (Porosity and Wicking (Porosity and

Mechanism Same
capillary action) capillary action)

Content 5% /W W
4% /W W

Major Diluent and Binder

3:2 2:1 Comparable
Ratio

Glidant 0.5% /W W
0.8% /W W
Comparable

Lubricant 2.0% 1.8% Comparable

MANUFACTURING

Batch Size 300 kg 280 kg Within ± 10%

Process Dry Granulation Dry Granulation Same

Pre-blending time 15 minutes 12 minutes Comparable

Final blending time 5 minutes 5 minutes Same

In-process criteria

Tablet shape Modified Caplet Caplet Similar

Tablet weight 220 mg 200 mg Comparable

Tablet hardness 10 – 18 kp 8 – 16 kp Similar

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