Excipients QBD
Excipients QBD
Excipients QBD
Incorporation of
Pharmaceutical Excipients
into Product Development
using Quality-by-Design
(QbD)
First Version
2020
FOREWORD
The International Pharmaceutical Excipients Council (IPEC) is an international industry
association formed by excipient manufacturers, distributors and end-users. At the current writing,
there are regional pharmaceutical excipient industry associations located in the Americas,
Europe, Japan, China, and India. IPEC’s objective is to contribute to international excipient
standards development and harmonization, new excipient development and introduction, and
best practice and guide development concerning excipients.
IPEC has three major stakeholder groups;
1. Excipient manufacturers and distributors, defined as suppliers in this document
2. Pharmaceutical manufacturers, defined as users in this document
3. Public health and regulatory authorities
This Guide is intended to be voluntary, to indicate best practice, and to be globally applicable.
However, it should be recognized that the rules and regulations applying to excipients will vary
from region to region and country to country. In addition, the rules and regulations are continually
evolving. It is the responsibility of users of the Guide to determine whether there are any additional
legal or regulatory requirements, in addition to the recommendation given in this Guide, applicable
to a particular region or country in which they are doing business.
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FOREWORD........................................................................................................................... 1
ACKNOWLEDGEMENTS ....................................................................................................... 5
1 INTRODUCTION.............................................................................................................. 6
1.1 Purpose ...................................................................................................................... 6
1.2 Scope.......................................................................................................................... 6
1.3 Principles Adopted..................................................................................................... 7
2 BACKGROUND AND GENERAL GUIDANCE ................................................................. 8
2.1 An introduction to Drug and Drug Product Development......................................... 8
2.2 Quality-by-Design .................................................................................................... 10
2.3 Excipients................................................................................................................. 15
2.4 Pharmaceutical products......................................................................................... 18
3 INCORPORATION OF EXCIPIENTS INTO THE FORMULATION .................................. 20
3.1 Excipient selection................................................................................................... 20
3.2 Formulation and Process Design and Development............................................... 21
3.3 Risk assessment...................................................................................................... 21
3.4 Design of Experiments............................................................................................. 23
3.5 Design Space and Control Strategy ........................................................................ 23
4 EXCIPIENTS IN QUALITY-BY-DESIGN ......................................................................... 25
4.1 Introduction .............................................................................................................. 25
4.2 Excipient Impact Categorization.............................................................................. 30
4.3 Critical Material Attributes ....................................................................................... 31
4.4 Analysis of the Design of Experiments (DoE) ......................................................... 34
4.5 Scale-up.................................................................................................................... 35
5 LIFECYCLE MANAGEMENT ......................................................................................... 36
5.1 Continued monitoring .............................................................................................. 36
5.2 Multivariate Analysis (MVA)..................................................................................... 36
5.3 Continued product verification ................................................................................ 37
5.4 Detection of product/excipient drift and out-of-trend results ................................. 37
5.5 Excipient-related Special Cause Variation in Production ....................................... 37
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Table of Tables
Table 1: The criticality of Lactose Particle Size Distribution in different dose forms ...... 32
Table of Figures
Figure 1 Pharmaceutical Drug Development Timelines .................................................... 8
Figure 2 ICH Quality Roadmap [21].................................................................................. 11
Figure 3 Reducing Product Variability [21]...................................................................... 13
Figure 4 Simple Process Capability Model ...................................................................... 30
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1.1 Purpose
This Guide’s intent is to:
• introduce Quality-by-Design (QbD) and pharmaceutical formulation development
concepts to excipient manufacturers and suppliers,
• provide an explanation of how changes in pharmaceutical formulation practices, due to
the introduction of QbD, impact excipient manufacturers and suppliers,
• provide understanding for excipient manufacturers and suppliers as to what excipient
users will likely require when applying QbD principles during product development, and
• provide understanding to excipient users and regulatory agencies regarding what may or
may not be possible when considering the impact of excipient variability in the application
of QbD principles during product development.
This Guide includes recommendations related to impact of excipient variability on drug product
quality during development and to justify management of excipient variability in the control
strategy.
It contains useful explanations and suggestions for pharmaceutical excipient makers and users.
1.2 Scope
This Guide is applicable to excipient use throughout the pharmaceutical product development
process using a Quality by Design (QbD) approach described by the International Conference on
Harmonization (ICH) Q8 [2] as well as other applicable ICH Guidelines such as ICH Q9 [3], Q10
[4], Q11 [5], and Q12 [6].
Persons using this Guide should apply appropriate risk management principles to ascertain what
options may apply for excipients in their intended use. This Guide’s intent is to enhance
communication between excipient maker and excipient user related to QbD relevant information.
The excipient maker and excipient user should discuss and negotiate the necessary parameters
for control and who will accept responsibility for the testing.
The QbD concepts in this guide are applicable to both new drug applications and generic drug
applications. The pharmaceutics primer in Sections 2 and 3 is based primarily on small molecule
oral solid dose form development but the general principles introduced in Sections 4 and 5 can
be applied in other development areas, including biologics.
Other relevant guides may complement this guide, such as:
• IPEC Qualification of Excipients for Use in Pharmaceuticals [7]
• IPEC Excipient Composition Guide [8]
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An initial regulatory review takes place prior to commencing development and is then ongoing
throughout the clinical testing, prior to submitting the marketing application, and post launch.
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For drug products manufactured using continuous processing methods, scale-up may refer to
increased throughput in the existing processing line, addition of a like-for-like or a new line, or a
larger continuous processor. It will be necessary to demonstrate that longer running times,
increased throughput, or increased capacity do not adversely impact product quality design space
or control strategy. In batch manufacturing, as scale increases, the number of experimental
batches decreases such that smaller scale design of experiments (DoE) cannot be replicated,
which confirms the importance of continued verification and monitoring using multivariate analysis
in QbD. DoE applies to both continuous manufacturing and batch processing.
2.2 Quality-by-Design
QbD is a systematic approach to pharmaceutical drug product design and development, taking
into account the many variables associated with drug product manufacture including a full
understanding of ingredients (APIs and excipients), their inherent variability, and the processes
and equipment used during their manufacture. QbD is part of the larger Quality Planning initiative
proposed by J. M. Duran in the mid-1980s [20]. QbD is NOT new but the concepts are being more
frequently adopted by the pharmaceutical industry. The basic elements of QbD as they relate to
the pharmaceutical industry include:
• scientific, risk-based, holistic, and proactive approaches to pharmaceutical development,
• deliberate design effort from product conception through commercialization, and
• understanding how material attributes and process parameters relate to finished drug
product performance.
In 2009, QbD was included in the ICH Q8(R2) Guideline and eventually became one of the
cornerstones of the ICH Quality Roadmap:
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It was also one of the cornerstones of the US FDA’s ‘Quality in the 21st Century’ initiative. The
basic philosophy is that, “Quality cannot be tested into a product or operation, it must be built in
during the whole development and manufacturing cycle.”
QbD is based on the premise that during development of pharmaceutical finished products,
pharmaceutical companies invest time and effort up-front to identify and obtain enhanced
understanding of the material attributes and critical process parameters (CPPs) which
significantly affect product CQAs.
This should result in more robust products and processes, and may reduce the post approval
regulatory burden. For example, it may be possible to show that changes within the design space
(see below) will no longer require prior approval, but will simply be reported in the annual report.
When used effectively, QbD will ensure that every drug product batch manufactured within the
design space conforms to specifications and that the control strategy is still valid, thus potentially
eliminating the need to reject, rework, or recall batches due to out-of-specification (OOS) failure.
Results from manufactured batches can be leveraged to support a continued verification program.
Regulatory process validation guides [14,15] seek to provide additional flexibility for process
validation approaches across the process life-cycle (e.g., through the application of continued
process verification).
Although formulations designed and manufactured for safety testing and early phase clinical trials
may not require the same level of understanding and process optimization as required for the final
commercial product, experience gained from such formulations can provide a scientifically valid
framework for identifying key process and formulation parameters, and thus facilitate effective
process optimization used to support a robust commercial formulation (i.e., the design space).
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Thus, the design space concept, when utilized and approved by the appropriate regulatory/health
authority, would permit the drug product manufacturer to continue to optimize the formulation and
process within the design space during routine commercial manufacture, e.g. through the use of
evolutionary operations (EVOP) or an equivalent technique and reporting such changes through
appropriate regulatory mechanisms without the need for prior authorization.
2.2.3 Control Strategy
Control strategy is defined in the ICH Q8 (R2) document as follows:
“A planned set of controls derived from current product and process understanding that
ensures process performance and product quality. The controls can include parameters and
attributes related to drug substance and drug product materials and components, facility and
equipment operating conditions, in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control. (ICH Q10).”
The control strategy is developed from the design space. It is the total of in-process controls,
finished product testing, and any other checks and balances that control final product quality and
consistency. ICH Q10 highlights the importance of effective processes for maintaining the control
strategy through the product lifecycle.
2.2.4 Change Control
Products are subject to numerous changes throughout their lifecycle, and ideally subject to on-
going multivariate monitoring. Univariate change control based on compliance risks cumulatively
builds inherent risk of hidden drift, which may lead to unexpected failures and possibly invalidating
models and the control strategy. Enhanced understanding using a QbD approach also will likely
provide information supporting design space expansion.
Note: Expansion of the design space requires prior authorization.
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- Define the CQAs 1 as formalized in the quality target product profile2 (QTPP).
- Characterize API properties (pre-formulation).
- Review relevant prior knowledge.
- Identify potential manufacturing approaches.
- Identify potential excipients (from excipient compatibility studies).
- Design potential formulations and processing.
- Complete initial risk assessment to identify potential excipient CMAs and CPPs.
Note: ensure dialog with the supplier to identify needs and determine risks
- Define the DoE.
- Evaluate robustness of the formulation and process to determine if formulation
and/or process changes may be needed.
- Finalize risk assessment.
- Establish the design space and control strategy (optional).
- Scale-up
Note: There may be more than one scale-up.
- Confirm design space and control strategy for commercial manufacture.
- Submit marketing authorization application.
Note: There are other activities that will be undertaken in support of QbD formulation
development, including, but not limited to: analytical method development (chemical, physical
and microbiological), stability, bioequivalence, etc.
A new product development project incorporating QbD is outlined in Annex A.
1
ICH Q8(R2) def ines a CQA as: a ‘physical, chemical, biological or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to ensure the desired
product quality’.
2
ICH Q8(R2) def ines a QTPP as ‘A prospective summary of the quality characteristics of a drug product
that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the
drug product’. The quality target product profile forms the basis of design for the development of the
product. Considerations for the quality target product profile could include: intended use in clinical
setting, route of administration, dosage form, delivery, systems; dosage strength(s); container closure
system; therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics
(e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being
developed; drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for
the intended marketed product.
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It is essential to monitor for trends instead of waiting for out-of-specification (OOS) results. MVA
can contribute to an early warning system that enables effective management review (Quality
Assurance instead of reliance on Quality Control). Potential risk from excipient variability can be
addressed by further development batches to expand the excipient experience domain before
production, if the risk is deemed unacceptable. Alternatively, if the risk is deemed acceptable,
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4.1 Introduction
As defined in Section 2.3.1, excipients are substances, other than the API, which are included in
the manufacturing process or are contained in the finished pharmaceutical dosage form. After a
prototype formulation and process have been developed, emphasis shifts to assessing impact of
excipient variability on finished product quality. Excipient suppliers and users should identify and,
if possible, control relevant excipient material attributes, which may not be included in
pharmacopeial specifications. Reliance on pharmacopeial compliance alone may not be sufficient
for QbD.
In part, QbD seeks to minimize the risk that excipient variability will adversely affect finished
product quality. The impact of excipient variability will depend on the excipient role in the
formulation and the finished product CQAs. Formulation and process development scientists
should anticipate lot-to-lot and supplier-to-supplier variability in excipient properties and address
the following potential areas of concern:
1. unknowns and uncertainty,
2. complexity,
3. common vs special cause variation,
4. finished product criticalities,
5. excipient, process, and product drift, and
6. ensuring representative sampling of excipient variability to inform design robustness and
determine control strategy [see Excipient QbD Sampling Guide, 10].
4.1.1 Unknowns and Uncertainty
A pharmaceutically plausible formulation is not a guarantee against quality excursions. The
design quality depends on how well the product performs against predictions based on (known)
design inputs. Unknowns may subsequently adversely affect product quality. Unknowns may be
unknown to the user, the excipient manufacturer, or both. Risk management requires that the
impact of unknowns (uncertainty) be minimized by involving all stakeholders, including excipient
suppliers. Excipient unknowns include:
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Pharmaceutical product development, control, and regulation have traditionally relied on simple
rules, such as fixed formulae, fixed processes, and (over-)reliance on pharmacopeial compliance.
Some of the many degrees of freedom (variability) associated with excipients have been
illustrated in the preceding discussion of excipient unknowns, and they are complemented by
additional degrees of freedom from processes and operating procedures. The resulting
unpredictable emergent behaviors means that the excipients (and API), even if fully compliant,
represent a reservoir of potential special cause variation. Finished product quality may
unexpectedly and disproportionately become susceptible to the impact of excipient variability.
SCV is attributable to a specific disturbance. Removing all special causes leaves the intrinsic
system noise, CCV. Deming’s reference to inherent system change is consistent with finished
product criticalities.
Due to the complexity of excipients, and the products into which they are formulated, excipients
represent a reservoir of special cause variation in the finished product, which must be addressed
by the designer. As SCV is, by definition, unpredictable, it is not experimentally accessible during
development, and must be factored into the control strategy. Paradoxically, the more rigid or fixed
the system is, the more susceptible it is to the impact of excipient variability. Flexibility built into
the system to cope with SCV then becomes a criterion of design quality. There is little benefit in
having products that work perfectly so long as nothing changes. Products are subject to
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Proximity to performance margins or failure points also increases excipient variability impact risk.
Good examples can be found with design-critical rate-controlling polymers in modified release.
The higher the level of gelling-matrix-former in a hydrophilic matrix tablet formulation, the lower
the impact from variability in the excipient attributes. If faster drug release is required, it is
generally advisable to maintain a high level of a polymer having different viscosity (molecular
weight) or chemistry rather than reduce the original polymer to a level where the impact of
excipient variability is greater. Similarly, maintaining a high loading of a more permeable rate-
controlling controlled release film-coating is preferable to reducing the level of a low permeability
coating to the point where it is more susceptible to the impact of both the coating precision and
variability of the excipient attributes.
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Such drift may not be detectable by univariate change control; hence, the value of continued
multivariate monitoring. Pharmaceutical product change control is nearly always univariate.
Product performance is checked before and after the change to confirm that the product remains
within specification and that the change has had no effect on CQAs. This may be formalized as a
comparability protocol to cover foreseeable events such as switching excipient suppliers. The
weakness of this approach is that other product attributes may change, which are not reflected in
specification parameters or the CQAs. After several supplier changes and process adjustments,
sequentially qualified one step at a time, the system may have drifted and the next change triggers
an unexpected problem. Past performance is not predictive of future performance. Ideally,
specification parameters or CQA monitoring should be complemented with multivariate
monitoring.
Note: The presenting excipient variability may not be causative. Excipients and their
variability may not have changed but are now within range of a criticality and starting to
correlate with finished product quality excursions.
Impact from drift can be illustrated by simple process capability models as shown in Figure 4.
Process capability is essentially the ratio of specification range relative to range of variability,
usually quantified as ±3 standard deviations (±3σ), assuming only common cause variation. It is
a measure of the ability of the process to yield product within limits. For the purposes of illustrating
the combined impact of drift, variability and criticality, only a single limit is needed. This
corresponds to an unknown limit within the product beyond where excipient variability will impact
product CQAs.
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In Figure 4a: the criticality limit is on the right-hand side. Excipient variability impact is not seen
as it is well to the left of the criticality limit. The process capability is >1, and the product can
tolerate some drift, with the 3σ limit being well away from the criticality. The excipient would be
regarded as non-critical, as there is no discernible impact on product CQAs.
Figure 4b shows the 3σ limit drifting to the criticality limit. The process capability now has a value
of one, and the previously non-critical excipient is now critical. Excipient variability is starting to
correlate with product quality excursions. Detectability is low as incidence of excursions will still
be parts per million, assuming a normal distribution. Further drift (Figure 4c and 4d) increases the
incidence of quality excursion, and the process is no longer capable of producing product within
limits.
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• Performance excipients have one or more material attributes which have direct,
proportional and immediate impact on finished product quality. These are what would
traditionally be regarded as critical excipients and are titrated into a formulation for specific
performance.
• Variability in material attributes of basic excipients has no direct or immediate impact on
finished product quality, above a minimum threshold. Such excipient attributes are
generally taken for granted by users and only result in dissatisfaction if not present or
insufficient. It is more appropriate to think of these excipients as potentially critical (below
threshold) rather than non-critical.
The application of Kano Analysis to excipients in QbD has been published by Carlin & Wilson [35]
and is discussed in more detail in Annex B.
The degree of control via CMAs should be commensurate with risk from variability in such
excipient attributes to the product quality and manufacturability: i.e. a higher degree of
specification for excipients associated with higher risk. Excipient criticality in any formulation may
be a continuum rather than a binary state.
CMAs are specific to a finished product and must be distinguished from application-specific FRCs.
FRCs are potential CMAs. For example, in solid dose forms, particle size distribution (PSD) is an
FRC, which only becomes a CMA if additional or tighter limits need be imposed in addition to
pharmacopeial or grade specifications to control performance or the finished product quality.
PSD is irrelevant where excipients are in solution but are likely critical in solid dose forms. Table
1 illustrates the spectrum of criticality for Lactose PSD across a dosage form range.
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Attributes ensuring compliance with pharmacopeial specification are not CMAs, but minimum
standards with limited relevance to fitness for purpose in specific applications. CMAs are
complementary to compliance. Reliance on pharmacopeial compliance alone implies no CMAs
are required, but this requires justification for products more complex than simple solutions.
CMAs should be discussed early in development with suppliers to ensure that desired limits,
ranges, or distributions are within process capabilities. Suppliers also may be able to suggest
other potential CMAs for specific applications.
CMAs are complementary to CPPs in controlling finished product quality. A fixed formula with a
fixed process will be entirely dependent on CMAs as there are no compensatory controls. For
example, a granulation process with a target performance endpoint (CPP), such as torque, may
not need CMAs for the granulation excipients. However, the same process with a fixed endpoint,
such as granulation time, may be dependent on CMAs.
CMAs can be used to either: -
The latter affords greater sourcing flexibility in that wider ranges or distributions can be used
where compensatory process controls exist. Formulation control can also be applied by both user
and manufacturer:
• Users can blend grades varying in CMAs to achieve a consistent, desired CMA.
• Manufacturers can supply standardized performance using agreed methods and an
agreed diluent (batch-to batch compositional variability, but consistent performance in
target application).
CMAs should be ranked in terms of severity of impact on patient safety (CQAs) followed by
severity of impact on manufacturability. Detectability may be a secondary consideration but
probably is of limited value in ranking CMAs given the potential for special cause variation, which
is inherently unpredictable, even probabilistically. Failure to rank means that a reviewer will be
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If the excipient manufacturer has not changed anything (or the user has not precipitated the crisis
by changing excipient supplier), it is worth asking the excipient manufacturer what process or
excipient variations are covered by product specifications. This could include different sites or
equipment trains/scales. A representative selection of excipient batches can then be introduced
into the user’s production to identify “good” or “bad” batches in terms of the presenting quality
issue. Specifying preferred excipient batch types should be accompanied by appropriate
characterization to identify a CMA to distinguish “good” from “bad”. The advantage of adding a
CMA is that no prior regulatory approval is required. In the longer term (the next window of
regulatory opportunity), a variation can be filed containing corrective formulation and/or process
options, together with justification for retiring the now redundant added CMA if appropriate.
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4.5 Scale-up
Having successfully completed the DoE and established the Design Space and Control Strategy,
one of the next steps in the project progression will likely be to scale up the formulation and
process. Scale-up, in pharmaceutical projects, may not be predictable. In addition, there are
regulatory restrictions on how large a scale-up can be undertaken at one time. Generally, the
maximum scale-up allowed by regulatory authorities is not more than a ten-fold batch size
increase (for batch processed formulations) can be undertaken in one step without having to
undertake bioequivalence testing in human subjects (or appropriate animals for veterinary
products).
It should be confirmed that after scale-up the Design Space and Control Strategy are still valid.
However, this should not require repeating the original full DoE. With the increased understanding
obtained during the initial DoE, and using experience of the unit operations in general, it may be
possible to use a partial DoE to confirm the applicability of the Design Space and Control Strategy
at the new scale of manufacture.
Once the continued applicability of the Design Space and Control Strategy are confirmed, further
manufacture at the new scale can commence. If, however, the Design Space and Control Strategy
are not confirmed at the new scale, further assessment is required. The options available include:
• data assessment to determine if a more restricted Design Space and Control Strategy
would be applicable and can be scientifically justified based on available data,
• perform additional experiments to provide the necessary data to identify and scientifically
justify an acceptable Design Space and Control Strategy for the new scale, and
• formulation and process redesign to address the issues identified during scale-up.
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Excipient users should also be aware of the risk of unpredicted events, including out of trend
(OOT) and out of specification (OOS, failure), due to special cause variation (SCV). Unfortunately,
prior compliance is not predictive of such events, thus, continued monitoring as part of the control
strategy is essential to provide early warning. However, the onset of SCV may not always be
easily detectable and can be difficult to distinguish from background CCV.
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Principle Component Analysis (PCA) is one of the more commonly used techniques where
large datasets with correlated measures are organized into a smaller set of uncorrelated
variables, the principal components, PCs. If two or three PCs are sufficient to explain variability,
then variability can be visualized in two or three dimensions. Mathematically, larger numbers of
PCs can be used if required.
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The following overview of the pharmaceutical development process illustrates the incorporation
of QbD throughout the project lifecycle. It describes a de novo product development project and
is applicable to innovator or generic products.
Note: all stages should be fully documented using appropriate protocols and reports.
1. Define the QTPP: required product specifications, in vivo performance requirements, and
any commercial requirements (including dosage strength(s), packaging, etc.).
2. Review of all the available information on the API relevant to the route of administration
and the likely dosage form (including preformulation studies).
Note: Preformulation comprises all physicochemical and biopharmaceutical studies
undertaken on the API, alone or in combination with excipients, which support the
formulation and process design, and development.
3. Identify likely excipients.
4. Identify likely formulations and processing options.
5. Review relevant information (prior knowledge) on excipients and processing options.
6. Identify potential product CQAs.
7. Assess variability of materials
8. Identify all potential CMAs relating to both the API and excipients used in, and CPPs
relating to, the manufacture of the formulation(s).
9. Carry out a risk assessment regarding the potential CMAs and CPPs drawing on
appropriate experience and knowledge (including the scientific literature).
10. Undertake preliminary experiments (if necessary) to confirm the criticality of any quality
attributes or process parameters for which the risk assessment is not clear.
11. Establish the DoE at small scale (1x).
12. Execute the DoE for the small scale.
13. Analyze the results from the executed DoE.
14. Review the results and confirm there is nothing lacking in the DoE
15. Establish the design space for the small scale.
16. Establish the CMAs, CPPs and product CQAs and control strategy for manufacture at the
small scale.
17. Establish the DoE for the intermediate scale (10x).
Note: this will likely be a subset of the small-scale DoE.
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KANO ANALYSIS
Kano Model
Kano models relate customer satisfaction to the degree of sufficiency of product or service design
attributes. Kano models are used to guide investment in research and development (R&D). A
simple two element Kano model divides design attributes into performance and basic:
• Fuel economy is a performance attribute, the higher the miles per gallon the greater the
customer satisfaction, and vice versa. The more important the fuel economy is to the buyer
the steeper the gradient of the performance correlation.
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Rigid categorization of excipients is not as important as awareness of the potential for multiple
modes of impact from specific attributes and their interactions. An individual excipient may have
both performance and basic attributes, dependent on the application or finished product.
Kano Performance
A Kano performance attribute correlates with the degree of satisfaction, generally the more the
better, and vice versa. A performance attribute is generally synonymous with a performance
excipient. An excipient falling into this category is typically titrated into the formulation to deliver a
specific product performance. An example would be the rate-controlling polymer in a sustained
release product, where the lower the rate-controlling polymer concentration the faster the release,
and vice versa.
Ignoring interactions, the impact of a performance excipient in a finished product will be a function
of its concentration (c), and expression of the relevant excipient attribute (x), i.e. sufficiency,
strength or effectiveness. Variability in x can directly impact product performance, and such
excipients would traditionally be regarded as critical, with attribute (x) being a potential CMA.
𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷 = ∫(𝒄𝒄, 𝒙𝒙) 𝒐𝒐𝒐𝒐 𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷𝑷 = ∫ 𝒙𝒙 for fixed formulae
Interactions will result in dependency on other formulation or process variables. For Kano
performance excipients a range is preferred rather than a single concentration, in order to offset
variability in x, in which case x becomes less critical. By using a range, the manufacturer of a
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The second type of excipient attribute in the basic category are those with no correlation to product
quality above a minimum threshold. The so-called “non-critical” excipient is a misnomer, as the
attributes exhibit a threshold between critical and non-critical ranges. The lack of impact of
variability is illustrated by the flat-line response, where variability is well away from the level below
which there is dissatisfaction. A good test of “non-criticality” is to range the concentration
downwards. If there is no impact on CQAs, it suggests a margin or reserve of performance. Never
titrate down to point of failure during development as this guarantees susceptibility to excipient
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