FORMULATIONS
METHODOLOGIES
• TRADITIONAL FORMULATION APPROACH
• The traditional or the conventional approach for pharmaceutical formulation is based on
the trial and error, where the focus of formulation is the adjustment of one
individual factor at a time while fixing all other factors. The adjustment of the
individual factor is usually based on the experience of the formulator.
• Gaining knowledge of the relationships between the factors and response is not
emphasized in the conventional approach. Thus, the formulations resulting from the
traditional approach are also called as the experience-based formulations.
• The desired properties of formulation are obtained by changing one factor and holding
all others fixed. Some initial experiments with selected levels of the ingredients based
on the experience are carried out.
• The succeeding experiments are based on the results obtained after each
experimentation in the direction of increase (or decrease) of the response (properties).
• In this way a maximum (or minimum) of property is reached. Since
in this approach, the factors for product properties are optimized one
by one, the approach is also called as one factor at a time (OFAT)
approach. This is called as the sequential approach of formulation
development.
• After formulating a product, if it is not the desired one, then the
center of attention is another, but one specified factor. One by one, by
controlling the other factors at a constant level, effort is made to
accomplish a desired product/formulation in OFAT approach.
• With the OFAT approach, optimized output could not be obtained.
The reason for OFAT failure is that the multiple responses
(properties) of a product are related differently to factors. The
traditional OFAT approach has certain other limitations.
• LIMITATIONS OF THE TRADITIONAL APPROACH
• In OFAT, the experimental process is unplanned and based on hit and trial.
• Approach is less effective since it may improve but never approaches to the
optimal setting of the factors and properties.
• Development is sequential where the factors are adjusted one by one for each
product property.
• OFAT is unable to estimate effect of each factor independent of the existence
of the effect of other factors. Thus, the factor interaction remains
unrevealed.
• This approach cannot obtain the information on two factor
interactions, which may be synergistic or antagonistic.
• OFAT requires larger number of experimentations to obtain
information helpful to make formulation decision
• The product of OFAT is not knowledge-based.
• OFAT is time consuming, laborious and costly.
• The OFAT approach cannot help in achieving a product with
aspirational or desired quality.
• COMPUTER-AIDED FORMULATION
• Computer-aided formulation or artificial intelligence-based formulationsare new
approaches and powerful tools for pharmaceutical formulation which work by using the
artificial intelligence and computational approaches.
• These are coupled with visualization and statistical validation and robust optimization
methods.
• Currently, *DESIGN OF EXPERIMENT (DOE) and *ARTIFICIAL NEURAL
NETWORK (ANN) strategies have found rapidly increasing applications in optimization
against classical OFAT approach.
• These approaches require computerized decision support systems that recognize relationship
existing between the factors and the responses.
• Computational approaches can reduce the formulators’ effort by automatically generating
knowledge (of relationships between factors and responses) directly from data, which are
obtained from the planned experimentation using different settings (levels) of the factors. Thus,
the resulting formulations are called as the knowledge-based formulations.
• The newer approaches allow simultaneous optimization of all properties,thus are also called as the
simultaneous optimization approaches. Such approaches plan the complete set of experiments,
called as experimental design or matrix before hand.
• This matrix is generated by the mathematical and statistical algorithmsin DoE by providing a
range of the levels of the factors. However, this matrix system is not a requirement for the ANN
approach.
• The number of experiments is based on the number of factors and precision in prediction for the
optimized levels of the factors. The experiments are carried out according to the plan (matrix
or grid), the data are entered in a decision support system (software) and the resultsare
fitted to a mathematical model.
• The response values can be predicted by using a range for the settings ofvariables (formulative,
process and machine). A wide range of possible choices (factor settings) is available for a product
in a matrix.
ADVANTAGES AND APPLICATIONS
OF THE ADVANCED APPROACHES
• FORMULATION DESIGN FOR COMPLEX FORMULATIONS
• The complex formulations, which have several properties or severalfactors are
the major candidates for such approaches.
• DEVELOPMENT OF NEW PRODUCTS
• The new products for which much information or experience is notavailable can
easily be developed using these approaches.
• REVEALING OF THE INTERACTION BETWEEN DIFFERENT VARIABLES
• The advanced formulation approaches reveal interactions between the factors which may be
antagonistic or synergistic for a particular property.
• Information could be obtained by which, a factor may totally be excluded from the system
without compromising on the quality of the product. This is called as the breakthrough
which can only be achieved with the computer-aided formulation approaches.
• ENHANCEMENT OF PRODUCT QUALITY AND PERFORMANCE AT LOW COST
• The advanced approaches require lesser number of experiments for optimization of a
product or process thus require lesser materials and time for the optimized formulation
development.
• SHORTER TIME TO MARKET
• Since an optimized product can be developed with lesser time, the product can be placed in market
in a shorter time. This could provide an edge in the market competition.
• IMPROVED CUSTOMER RESPONSE
• With the improved quality products, the consumers have more confidence on the product.
• IMPROVED COMPETITIVE EDGE
• Lesser time for a research product from bench to bedside, improved product quality and the
improved consumer confidence in the product leads to the improved competitive edge for a
pharmaceutical company that uses computer-aided approaches.
• RECOMMENDED BY FDA/EQUIVALENT REGULATORY
AUTHORITIES
• The use of the advanced formulation approaches is recommended by FDA, equivalent
regulatory authorities of several countries and the standard setting organizations for
formulation design, process validationand developing control plans.
• REGULATORY FLEXIBILITY
• The regulatory authorities recommend the use of advanced approaches because these
generate the “design space”.
• Re-working on the factor levels demonstrated within the design space isnot considered as a
“change” in product or process, which would not initiate a regulatory post approval change
process.
• Thus, these approaches provide a regulatory flexibility which is a great incentive for
pharmaceutical industry
• ROLE IN SCALE-UP AND POST APPROVAL CHANGE (SUPAC)
• The advanced computer-aided approaches provide information which are helpful
for appropriate scale up of the products. Due to the generation of design space,
the post approval changes are also possible without initiating the
investigational new drug (IND) or new drug application (NDA).
• MISCELLANEOUS APPLICATIONS
• Due to the above advantages, the advance formulation approaches have
wide applications in the following field:
❑ Formulation design for pharmaceutical products
❑ Optimization of pharmaceutical formulation
❑ Optimization of pharmaceutical process
❑ Pharmaceutical process validation
❑ Industrial scale up
❑ Cost reduction
NEED OF THE ADVANCED FORMULATION APPROACHES
• The failure of the traditional approaches to optimize the output hascreated the need for the use of
advanced formulation approaches.
• Coping with the following is becoming increasingly difficult for thepharmaceutical formulations by
the traditional approaches:
- Increasing pressure for developing new products quickly to copewith market competition
- Products with more stringent quality standards
- Partial or totally unavailability of historical knowledge for the new formulations
- Optimization process is multi-dimensional (some properties arerequired to be minimum while others
to be maximum).
- Existence of opportunity to improve the formulation operations and resulting profitability by
streamlining the formulation designtasks.
- Formulation requires experimentation which is expensive in termsof laboratory and staff time and in
terms of opportunities missed through slow response to new customer requirements
- Use of the advanced formulation approaches has been recommended by the FDA, regulatory
authorities and standards setting organizations.
- Recently, the drug regulatory authority of Pakistan (DRAP) requires QBD data in a document
called as the common technicaldocument (CTD). The CTD has all the required information on a
product and is submitted to DRAP for evaluation for the product registration.
DESIGN OF EXPERIMENT
• Design of experiment (DoE) is one of the computer-aided approaches
which is carried out systematically, identifies critical variables,
reveals factor interactions and helps obtain combinations of
variables to accomplish optimum response with lesser number of
experiments.
• DoE is statistical approaches using the algorithms, which are based onthe following components:
• FACTORIAL ANALYSIS AND THE ANALYSIS OF VARIANCE (ANOVA)
• The factorial analysis and the ANOVA give the information on the statistically significant factor(s) and their
interactions, individually for allproperties included in a study.
• PRINCIPLE COMPONENT ANALYSIS (PCA)
• The PCA supplements the findings of the ANOVA and shows the principle, major and core factors
for the individual properties.
• POLYNOMIAL REGRESSION
• The regression is used to predict the best combination of the factors toforecast the best properties.
• RESPONSE SURFACE METHODOLOGY (RSM)
• The RSM composes of several mathematical algorithms which help inthe optimization of the properties. In
this approach, two factors are related simultaneously to a given property to show their combined effect on the
property.
• This DoE approach finds the relationship between the factors and properties statistically.
EXPERIMENTAL STRATEGY FOR FORMULATION DESIGN IN DOE
• Though a general procedure to execute DoE is available, yet this can be applicable to ANN as well.
• The different phases in the DoE procedure are the:
• *DISCOVERY, * BREAKTHROUGH, *OPTIMIZATION, AND *VALIDATION
(CONFIRMATION).
• DISCOVERY
• Discovery studies has two components, brain storming and pilot study.
• Discovery is the first step in DoE, where all the possible factors which may affect the formulation
are considered.
• Brainstorming on the problem under study is the basic tool which is carried out in a group of
experts.
• ISHIKAWA FISHBONE DIAGRAM is used as a team brainstorming tool to evoke ideas for as
maximum as possible factors (causes) which may affect a particular output.
• The property/response is placed at the right of a straight line which iscalled as spine or
backbone.
• Categories of the factors are drawn and connected to the backbone through angled lines
in such a way that the illustration resembles a fishbone. Thus, a fishbone graphically
explains all the possible factors ofa particular property.
• The factors are classified as the real variables (values of which can be changed), fixed
variable (values which can be changed but deliberately fixed due to technologic
limitations).
• BREAKTHROUGH STUDIES
• Screening studies under breakthrough phase are more statistically- intensive and planned than
pilot study. Screening study helps narrowing down the large number of factors to a few critical
factors.
• In screening study, a factor can be studied at 2-levels, lower and higher. In this simplest study,
the number of experimental runs is minimum. Full factorial, optimal, Plackett-Burman or
Taguchi design use more levels of a factor and have own advantages or limitations.
• This phase of DoE is called as breakthrough because usually the factors which are considered
theoretically the most important for a property are revealed to be otherwise.
• OPTIMIZATION
• Optimization of the properties is carried out using RSM. Several tools available under RSM
are central composite design, Box Behnken, 3- fatorial level and optimal design.
• These designs generate different matrix (a planning to perform experiments) for different
levels of factors for RSM. Sometimes an experiment performed without matrix is analyzed
using data’s “history”for RSM.
• VALIDATION
• Under validation, based on the predicted levels of factors given for predicted
optimized properties of a formulation, a real formulation is manufactured.
• An agreement between the predicted and the real formulation properties at the
suggested factor level is the success. Sometimes, the output is not achieved
according to the prediction. In this case, design augmentation is employed,
which simply may be addition of another factor level in the previous factor
levels or can be replication of whole design.
• Statistical approach becomes more difficult for more than three or four inputs
since the formulator is tempted to oversimplify the problem in order to model it.
Statistics also often requires the assumption of a functional form (for example,
linearity) in order to generate a model and such assumptions can be inappropriate
for complex tasks like formulation.
• ARTIFICIAL NEURAL NETWORK
• Alternative to statistical approach, artificial neural network (ANN), a
biologically inspired mathematical construct (algorithm) mimics the learning
of human brain through modeling of and pattern recognition within data.
• In ANN, the complexity of biological neural architect is highly abstracted as
enormous processing elements (PEs), analogous to neurons (called artificial
neurons, nodes or units) connected to other PEs, comparable to synapse through
coefficients (weights), similar to signal strength (threshold) and the outputs
representing axons.
BIOLOGICAL NEURONS AND THEIR ANALOGOUS IN ARTIFICIAL NEURALNETWORK
BIOLOGICAL NEURONS ARTIFICIAL NEURAL ANALOGOUS
Neuron Processing elements/nodes/units
Synapse Node to node connection
Signal strength (threshold) Weights/coefficients
Axons Outputs
Dendrites Inputs
Learning Training (process of finding cause-
and-effect relationship within a givendata)
Complex functionality Highly abstracted (simplified)
Slow speed Fast speed
Numerous neurons (n=109) Few neurons (n=102 – 103)
• Pattern of connectivity among the ANN units is equivalent to a mammalian neural
architect. A typical ANN forms input and output layers and at least one or more hidden layers.
• ANN works by reducing the error between observed and predicted outcomes by adjusting the
weight. Like biological neural learning, it acquires knowledge from a learning process responsible
for adapting theconnection strength (weight value) to input stimuli.
• Mathematically, it detects the underlying patterns in data that recognizes the functional
relationships between factors and responses and predicts optimum levels of factors from a
limited input data.
• Finding the relationships between the cause-and-effect is called the training. ANNs are
particularly suitable for complex and non-linear systems for which the conventional approach
is more exhausting.
• Use of ANN for optimization does not require any prior knowledge. The neural network makes
no assumptions about the functional form of the relationships; it simply generates and assesses a
range of models to determine one that best fits the experimental data provided to it.
• As such, increasingly, (ANNs) are used to model a complex behavior in problems like
pharmaceuticals formulation and processing. The models generated by neural networks allow
“what if” possibilities to be investigated easily. Even lesser number of experimentations is
required in ANN, than that required by DoE.
ASSOCIATED TERMINOLOGY WITH COMPUTER-AIDED
FORMULATIONS
• QUALITY BY DESIGN
• Quality by design (QBD) is a structured and organized method for determining
relationship between factors affecting a process and the response(s)/of that process.
• Under QBD, a thorough investigation of the variables associated with materials, product design,
process, etc. is necessary for understanding effect of factors and their interactions on the outputs
by designed set of experiments to achieve outputs with desired and predefined specifications.
• QBD helps achievement of certain predicable quality with desired and predetermined
specifications through relating critical material attributesand critical process parameters to
critical quality attributes of drug product.
• Simply, the QBD provides understandings for process, output (product)and process control. For
QBD the first step is to set the predefined objectives, standards and specifications.
• The main aim of QBD is to achieve a product according to or as close as possible to the
desired quality attributes. The QBD uses multivariate experiments to understand product
and process to establish a design space through design of experiment.
• QBD for health products is required by US FDA and the equivalent authorities of
several countries. The real cause-and-effect or the effectof factors and factor
interaction is difficult to understand with the conventional ‘hit and trial’ approach
which is termed as one factor at a time (OFAT) approach.
• The QBD is achieved by the computer-aided approaches such as design of experiment
(DoE) or DoE-combined with artificial neural network (ANN).
• Limitations includes the difficulty in accomplishing, and the lack of acceptance by Pharmaceutical
industry.
• QBD was introduced under ICH. ICH guidelines Q8 (on Pharmaceutical Development), Q9
(on Quality Risk Management), and Q10 (on Pharmaceutical Quality System) assist
manufacturers to implement Quality by Design into manufacturing operations or process
development. QBD relies on the concept of design space.
• PROCESS ANALYTICAL TECHNIQUE
• The process analytical technique (PAT) is the system for designing, analyzing and
controlling manufacturing through timely measurements,during processing of critical
quality and performance attributes of raw materials and processes with the goal of
assuring final product quality.
• Risk assessment of the critical processing variables is also noted for process under PAT.
• PAT for health products is required by US FDA and the equivalent authorities of several
countries. Like QBD, the PAT is accomplished by the design of experiment (DoE) or
DoE-combined with artificial neural network (ANN). Six sigma (6σ) is related
terminology to QBD and PAT.
• Six sigma is the accomplishment of a level of quality of outputs (products)
where the number of defects are not more than 3.4 per million produced.
This is near zero defect in products. This is a level of quality where
99.9997% of the products are free of defect and thus are called as products
with near zero defects.
• With the help of QBD and PAT employing DoE and ANN, it is now possible to
achieve such products with 6σ quality. FDA and other equivalent drug
regulatory authorities are requiring now the use of all these approaches to
improve the quality of the drugs and medical devices.
• The innovative pharmaceutical companies are measuring their overall
performance using QBD, PAT and 6σ approaches, which was earlier based on
quality assurance, quality control, current good manufacturing practices, and the
total quality concept. QBD, PAT and 6σ have emerged as the new GMP’s
concepts for the 21st Century.
• MULTI-OBJECTIVE OPTIMIZATION
• Closeness of the properties of a product to its pre-set (desired) criteria for the critical attributes
is called optimization. Optimization is achieving the desired properties of a product.
• The latest computer-aided approaches, such as DoE and ANN optimize the several properties
of a product simultaneously, thus it is also called as the multi-objective optimization or
simultaneous optimization.
• For instance, an optimized tablet formulation is that which is with a high hardness
(crushing strength), low disintegration time, has certain dissolution profile and is robust
towards (small) deviations (errors) in process conditions, mixture variable settings or in
the environment.
• In a robust formulation, despite small variations, the values of the properties remain at
(almost) the same level or deviate with only within an acceptable range. It is of course
desirable to accomplish a product which maintain exactly the same values of properties (or
specifications) during and after production, storage before use, or during use, but this may be
costly and is not always needed or achievable.
• Many methods are available to search for such a compromise variablesetting. A
pharmaceutical formulation usually, is optimized with a compromise between cost and
quality.
• This robustness aspect can also be extended towards environmental factors like temperature
and (more importantly) humidity. It can be predicted the shelf-life of a formulation under
certain conditions is or what the desired conditions are to keep a product stable during a
certaintime on a desired quality level.
• When there is only one response or property, the goal is often to searchfor a maximum or a
minimum or property response. However, in practice the optimization is challenging and
difficult to accomplish because optimization problems usually require simultaneous
optimizingthe multiple properties.
• Sometimes, the optimization requires adjusting qualitative parameters, e.g., setting zero
order release. This complexity in simultaneous optimization is dealt with undertaking a
compromise on certain properties. Usually, it may be necessary to trade off properties during
such experimentation, to sacrifice one characteristic in order to improveanother, e.g., to
accept a tablet with lesser hardness in order to achieve the desired dissolution profile.
• Thus, the primary objective may not be to optimize absolutely but to compromise
effectively and thereby to produce the best formulation under a given set of restrictions.
• The optimization procedure can be simplified by discarding highly correlated responses with
other responses. Statistical approach called Principal Component Analysis (PCA) is used to
select these key responses.
• The ANN finds the critical factor by recognizing (“learning”) the pattern in the data. The
above information is used for optimization. Achieving optimization is difficult as the product
must meet specification which arecomplex to accomplish.
• DESIGN SPACE
• The above computer-aided experimentation generates the “design space” which according to FDA
is the multidimensional combination andinteraction of input variables (factors, e.g., material
attributes) and process parameters that have demonstrated to provide optimum responses
(outputs).
• Design space is a region where specifications are consistently met. Thus,design space is a
graphical optimization plot of multi-factors and properties under study. Design space provides the
allowable operating boundaries within which, the process factors can vary with little risk of
producing off-grade product.
• Design space is a processing window that provides a high level of confidence that 99% of the
output population meet (or exceed) specifications. Design space provides assurance of quality.
Thus, findingthe design space is the aim of optimization.
• Design space is proposed by the applicant of a new drug (pharmaceutical
industry) to the regulatory authority and is subjected to regulatory
assessment and approval.
• The future working on the factor levels demonstrated within the design space
is not considered as a “change” in product or process which would not initiate
investigational new drug application (INDA) or a regulatory post approval
change process.
• In such cases, bioavailability/bioequivalence studies are required. Any of the
following conditions is considered as change: Change in manufacturing site,
change in manufacturing method, change in raw material suppliers, minor
modification in formulation and modification in the product strength.
IMPLEMENTATION OF COMPUTER-
AIDED APPROACHES IN R&D
• Though, currently the Quality by design is a mandatory part of the modern
pharmaceutical quality, but the major limitation for its adoption and
implementation in the pharmaceutical industry is the lack of its understanding.
• Pharmaceutical companies traditionally, are tuned to emphasize the final
product and outcome, with a little attention on the science-based
understanding of a process required for an end product.
• The majority of pharmaceutical companies perceive implementation of QBD
as challenging and believe that there is a need for an easy guidance from
regulatory agency for implementation of QBD.
• The following are the challenges, related to industry (1-4) and regulatoryauthority (5-10)
for QBD implementation.
1. An uncertainty and lack of understanding over investment requirements for QBD
implementation.
2. An internal disconnect between cross functional areas of industry,such as R&D and
manufacturing or quality and regulatory departments.
3. Lack of knowledge and technology to execute QBD in industry.
4. Reliance on suppliers and contract manufactures – how QBD couldbe adopted by these third parties.
5. Lack of favorable interactions of regulatory agency with industrydoes not facilitating QBD
adoption.
6. Lack of tangible guidance on QBD from agency for industry.
7. Lack of the regulator’s preparedness to handle the QBDapplications.
8. Inconsistency of treatment of QBD across regulatory authority.
9. The regulatory benefits from QBD approach does not inspireconfidence.
10. A disconnect among international regulatory bodies.
COMPARISON OF COMPUTER AIDED APPROACHES WITH THAT OF THE OFAT
PARAMETER OFAT DOE/QBD/PAT/ANN
Product development Empirical approach Designed/scientificapproach
Fixed manufacturingprocess Adjustable based on designspace
Manufacturing process
Process control In-process control QBD, PAT tools
Specifications Based on batch data/history Based on productperformance
QC by in-process and finished QC by risk-based approachwith real
QC strategy product testing time release test
Life cycle management Reactive Preventive
Information regardingFormulation Knowledge-based built intoproduct
and rich in understanding
Little information
Process Static process allowing nochange Flexible process allowingchange
Robustness, reduced variation,
Focus Reproducibility identification ofcritical control
point
Quality Assured by testing Designed based