Design of Experiments

• https://www.youtube.com/watch?v=Srq9Q-yd1Rk&t=33s intro
• https://www.youtube.com/watch?v=NoVlRAq0Uxs&t=765s – JMP
• https://www.youtube.com/watch?v=10ikXret7Lk experimental
designs
• https://www.youtube.com/watch?v=ZoaUu6iRE64 – Simply explained
 Introduction
• In order to develop high-quality pharmaceutical products, a traditional
approach based the univariate or trial and error method was used in the past
that led to several problems like non-reproducible, high-cost, and time
consuming methods.
• To overcome these drawbacks, a new concept of the Design of Experiment
(DoE) was introduced. DoE is a statistical element of the Quality by Design
(QbD) approach introduced by British statistician Sir Ronald Fisher in 1925.
• The basic objectives of DoE are screening, optimization, and robustness. It
involves the execution of experimental design on the basis of suitable variables
along with statistical evaluation of obtained responses and exploration of the
design space using mathematical or graphical approach.
• The statistical evaluation empowers to build up the quality of finished products
and helps to meet the increasing demands for product of superior quality and
standards.
Introduction
• Many of the current statistical approaches to designed experiments
originate from the work of R. A. Fisher in the early part of the 20th
century.
• Fisher demonstrated how taking the time to seriously consider the
design and execution of an experiment before trying it helped avoid
frequently encountered problems in analysis.
• Key concepts in creating a designed experiment include blocking,
randomization, and replication.
Key concepts
• Blocking: When randomizing a factor is impossible or too costly,
blocking lets you restrict randomization by carrying out all of the trials
with one setting of the factor and then all the trials with the other
setting.
• Randomization: Refers to the order in which the trials of an
experiment are performed. A randomized sequence helps eliminate
effects of unknown or uncontrolled variables.
• Replication: Repetition of a complete experimental treatment,
including the setup.
Definition
• Design of experiments (DOE) is defined as a branch of applied statistics
that deals with planning, conducting, analyzing, and interpreting
controlled tests to evaluate the factors that control the value of a
parameter or group of parameters.
• DOE is a powerful data collection and analysis tool that can be used in a
variety of experimental situations.
• Design of experiments (DOE) is a systematic, efficient method that
enables scientists and engineers to study the relationship between
multiple input variables (aka factors) and key output variables (aka
responses).
• It is a structured approach for collecting data and making discoveries.
When to use?
• To determine whether a factor, or a collection of factors, has an effect
on the response.
• To determine whether factors interact in their effect on the response.
• To model the behavior of the response as a function of the factors.
• To optimize the response.
Why use DOE?
DOE is useful:
• In driving knowledge of cause and effect between factors.
• To experiment with all factors at the same time.
• To run trials that span the potential experimental region for our
factors.
• In enabling us to understand the combined effect of the factors.
• Quality by Design (QbD) and Design of Experiments (DOE) are both
methodologies used in the field of process and product development,
but they differ in their approaches and objectives.
Quality by Design (QbD)
• QbD is a systematic approach to product and process development
that focuses on designing quality into the product from the beginning.
• It involves identifying critical quality attributes (CQAs) of the product,
understanding the factors that affect those attributes, and designing a
manufacturing process that can consistently produce a product with
the desired quality.
• QbD aims to understand and control the sources of variability that can
affect product quality by using scientific principles, risk assessment,
and statistical tools.
• Implementing QbD early in the drug development process enables a
proactive and systematic approach to ensuring quality.
• It helps identify critical factors, optimize processes, and minimize
variability, ultimately leading to more consistent and reliable
pharmaceutical products.
The key features of QbD include:
• Product and process understanding
• Risk assessment and mitigation
• Design space and control strategy
Product and process
understanding:
• QbD emphasizes a thorough understanding of the product and the
process, including the identification of critical process parameters
(CPPs) and critical material attributes (CMAs) that can impact product
quality.
Risk assessment and mitigation
• QbD involves a proactive assessment and management of risks
throughout the product lifecycle.
• It includes identifying potential risks to product quality, developing
strategies to mitigate those risks, and implementing control measures
to ensure consistent quality.
Design space and control
strategy

• QbD involves establishing a design space, which is a multidimensional

combination and interaction of input variables (e.g., process
parameters) that have been demonstrated to provide assurance of
quality.
• A control strategy is then developed to maintain the process within
the design space.
Design of Experiments (DOE):
• DOE is a statistical technique used to systematically investigate and
analyze the relationship between process variables (factors) and the
output (response) of a process.
• DOE involves designing a series of experiments where different
factors are deliberately varied, while keeping other factors constant,
to understand their individual and combined effects on the process
output.
• The goal of DOE is to optimize process performance, improve product
quality, and understand the factors that have the most significant
impact.
Key aspects of DOE include:
• Factorial designs: DOE often uses factorial designs where multiple factors and
their interactions are studied simultaneously. By systematically varying the
levels of factors, the experiment allows for the estimation of main effects and
interaction effects.
• Response surface methodology (RSM): RSM is frequently employed in DOE
to model and optimize the relationship between factors and response. It
helps identify the optimal factor settings that result in the desired response.
• Statistical analysis: DOE employs statistical analysis techniques to analyze the
experimental data and draw conclusions about the significance of factors and
their effects. This allows for the identification of critical factors that have the
most significant impact on the process or product.
Step by Step approach for a
successful QbD Development
• Developing Quality by Design (QbD) involves a systematic and step-by-step
approach to ensure the quality of pharmaceutical products. Here is a general
outline of the process:
1. Define the Target Product Profile (TPP)
2. Identify Critical Quality Attributes (CQAs)
3. Identify Critical Material Attributes (CMAs)
4. Identify Critical Process Parameters (CPPs)
5. Establish a Design Space
6. Develop a Control Strategy
7. Conduct Risk Assessment and Mitigation
8. Implement Continuous Improvement and Knowledge Management
 Identify Critical
Define the Target Identify Critical Quality
Material Attributes
Product Profile (TPP) Attributes (CQAs)
(CMAs)

Develop a Control Establish a Design Identify Critical Process

Strategy Space Parameters (CPPs)

Implement Continuous
Conduct Risk
Improvement and
Assessment and
Knowledge
Mitigation
Management
1. Define the Target Product
Profile (TPP):
• Identify the desired characteristics and quality attributes of the final
product.
• Consider factors such as dosage form, route of administration,
strength, stability, and patient requirements.
2. Identify Critical Quality
Attributes (CQAs):
• Determine the specific product attributes that significantly impact
safety, efficacy, or quality.
• Use scientific knowledge, regulatory guidelines, and patient needs to
identify CQAs.
3. Identify Critical Material
Attributes (CMAs):

• Assess the characteristics of raw materials, excipients, and

components used in the manufacturing process.
• Determine the material attributes that can impact the quality of the
final product.
• Examples of CMAs include particle size, polymorphic form, moisture
content, and chemical composition.
4. Identify Critical Process
Parameters (CPPs):

• Determine the key variables that need to be controlled within specific

limits to ensure product quality.
• Use scientific understanding, prior knowledge, and experimentation
to identify CPPs.
• Examples of CPPs include temperature, pressure, mixing speed, drying
time, and sterilization conditions.
5. Establish a Design Space:
• Conduct experiments and studies to identify the acceptable ranges
and interactions of CPPs.
• Use statistical analysis and modeling techniques to establish a
multidimensional design space.
• The design space represents the range of process parameters that
provide assurance of quality.
6. Develop a Control Strategy:
• Define a control strategy to ensure the manufacturing process
operates within the established design space and meets quality
standards.
• Include process controls, in-process testing, monitoring, and
corrective actions in the control strategy.
• The control strategy should address potential risks and deviations
from the design space.
7. Conduct Risk Assessment and
Mitigation:
• Perform a systematic risk assessment to identify potential risks to
product quality.
• Use tools such as Failure Mode and Effects Analysis (FMEA) and
Hazard Analysis and Critical Control Points (HACCP).
• Develop risk mitigation strategies to minimize or eliminate identified
risks.
8. Implement Continuous
Improvement and Knowledge
Management:
• Continuously monitor and analyze data throughout the product
lifecycle.
• Use the knowledge gained to improve processes, optimize controls,
and update the design space if necessary.
• Incorporate feedback and lessons learned to enhance product quality
and process understanding.
Implementation
• Quality by Design (QbD) principles can be implemented at various
phases of drug development, but it is most effective when incorporated
from the early stages.
• The ideal phase to begin implementing QbD is during the development
of the manufacturing process and formulation.
• Here are the key stages where QbD can be applied:
• Preclinical Development
• Formulation Development
• Process Development
• Process Validation
• Commercial Manufacturing
Preclinical development
• During preclinical development, QbD principles can be applied to the
formulation development and process design.
• The identification of CQAs and CMAs can begin based on the desired
characteristics of the product.
• Initial risk assessments can be conducted to understand potential
risks and challenges associated with the product and process.
Formulation development
• QbD can be employed during
formulation development to understand
the impact of formulation factors on
product attributes.
• Design of Experiments (DOE) techniques
can be used to systematically vary
formulation components and optimize
their effects on CQAs.
• The design space can be explored to
identify the acceptable ranges of
formulation variables that achieve the
desired product quality.
Process Development
• QbD is highly applicable during process development to understand
the impact of process parameters on product quality.
• CPPs can be identified using scientific knowledge, prior experience,
and experimentation.
• DOE can be employed to study the effects of process parameters on
CQAs and optimize the process design.
Technology Transfer and Scale-
Up
• QbD principles play a crucial role in technology transfer and scale-up
activities.
• The knowledge gained from the earlier stages can be used to ensure a
successful transfer of the optimized process to a larger scale.
• Risk assessments can be performed to identify potential challenges
and develop mitigation strategies during the scale-up process.
Process Validation
• QbD principles guide the development of a robust control strategy for
process validation.
• The established design space and control strategy are used to set
acceptance criteria and ensure consistent product quality during
validation studies.
Commercial Manufacturing
• QbD principles continue to be applied during commercial
manufacturing to maintain process control and monitor product
quality.
• Ongoing monitoring, data analysis, and continuous improvement are
employed to optimize the manufacturing process and update the
design space if necessary.
Is QbD necessary for drug
development?
• While Quality by Design (QbD) is not mandatory for drug development in a
regulatory sense, it is highly recommended and considered good practice by
regulatory agencies and industry experts.
• QbD provides a systematic and science-based approach to ensure the quality
of pharmaceutical products throughout their lifecycle.
• Implementing QbD principles offers several benefits:
• Enhanced Understanding
• Consistent Product Quality
• Risk Reduction
• Process Optimization
• Regulatory Compliance
• Continuous Improvement
Enhanced Understanding
• QbD promotes a deeper understanding of the product and its critical
quality attributes (CQAs), manufacturing processes, and associated
risks.
• This knowledge enables better control and mitigation of potential
issues.
Consistent Product Quality
• By designing quality into the product and process from the beginning,
QbD helps ensure consistency and reliability in product quality.
• It minimizes variability and reduces the likelihood of batch failures or
deviations.
Risk Reduction
• QbD incorporates risk assessment and mitigation strategies, helping
identify and address potential risks early in the development process.
• This proactive approach minimizes the chance of quality issues and
improves patient safety.
Process Optimization
• QbD encourages the optimization of manufacturing processes by
identifying critical process parameters (CPPs) and establishing a
design space.
• This leads to improved efficiency, reduced waste, and cost savings.
Regulatory Compliance
• QbD aligns with regulatory expectations and guidelines, such as those
provided by the International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH).
• Demonstrating a thorough understanding of product quality and
employing a robust control strategy helps meet regulatory
requirements.
Continuous Improvement
• QbD emphasizes continuous improvement and knowledge
management throughout the product lifecycle.
• Ongoing monitoring, data analysis, and feedback loops allow for
process refinement and optimization.
• While QbD may require additional upfront effort and resources, its
implementation can result in long-term benefits, including improved
product quality, reduced risks, and increased efficiency.
• It promotes a proactive and science-based approach to drug
development, leading to safer and more reliable pharmaceutical
products.
Specific tools recommended for
the development of Quality by
Design (QbD)
• Several tools and methodologies can be employed during Quality by Design (QbD)
development to facilitate data analysis, experimentation, risk assessment, and
process optimization.
• Here are some commonly used tools:
• Design of Experiments (DOE)
• Failure Mode and Effects Analysis (FMEA)
• Fishbone Diagram (Ishikawa Diagram)
• Control Charts
• Risk Assessment Matrices
• Statistical Analysis Software
• Quality Tools (e.g., Pareto Analysis, Cause-and-Effect Diagram)
• Process Analytical Technology (PAT)
Design of Experiments (DOE)
• DOE is a statistical tool used to systematically vary process parameters
and formulation components to understand their impact on product
quality.
• It helps identify critical process parameters (CPPs) and establish the
relationship between variables and critical quality attributes (CQAs).
Failure Mode and Effects
Analysis (FMEA)
• FMEA is a systematic approach
used to identify potential failure
modes and their effects on
product quality.
• It assesses the severity,
occurrence, and detectability of
failures and helps prioritize risks
for mitigation.
 Fishbone Diagram (Ishikawa
Diagram)
• A fishbone diagram is a
visual tool used to
identify and categorize
potential causes of
problems or quality
deviations.
• It helps identify the root
causes of issues and
facilitates problem-
solving.
Control Charts
• Control charts are
statistical tools used to
monitor process
performance and detect
variations or trends
over time.
• They help assess
process stability and
identify potential out-
of-control situations
that may affect product
quality.
Risk Assessment Matrices
• Risk assessment matrices provide a visual representation of identified
risks, their likelihood, and severity.
• They help prioritize risks based on their potential impact on product
quality and guide risk mitigation strategies.
Statistical Analysis Software
• Various statistical analysis software packages, such as Minitab, JMP, or
R, can be used for data analysis, design of experiments, and statistical
modeling.
• These tools facilitate data visualization, regression analysis, and
optimization of process parameters.
Quality Tools
• Quality tools help identify and analyze the causes of quality issues.
• Pareto analysis and cause-and-effect diagrams (also known as
fishbone or Ishikawa diagrams) are commonly used to identify the
most significant factors contributing to a problem.
• Example: Pareto Analysis, Cause-and-Effect Diagram
Process Analytical Technology
(PAT)
• PAT involves the use of real-time process monitoring and control
tools, such as spectroscopy, chromatography, or near-infrared (NIR)
analysis.
• PAT enables continuous monitoring of critical process parameters and
facilitates real-time adjustments to maintain product quality.
References:
1. Beg, S., Hasnain, M. S., Rahman, M., & Swain, S. (2019). Introduction to quality by design (QbD):
fundamentals, principles, and applications. In Pharmaceutical quality by design (pp. 1-17). Academic Press.
2. Fukuda, I. M., Pinto, C. F. F., Moreira, C. D. S., Saviano, A. M., & Lourenço, F. R. (2018). Design of
experiments (DoE) applied to pharmaceutical and analytical quality by design (QbD). Brazilian journal of
pharmaceutical sciences, 54.
3. Mishra, V., Thakur, S., Patil, A., & Shukla, A. (2018). Quality by design (QbD) approaches in current
pharmaceutical set-up. Expert opinion on drug delivery, 15(8), 737-758.
4. ICH Guidelines: The ICH guideline Q8 (R2) describes the QbD process specifically for drug product; ICH Q11
guides the QbD development of the active substance.
5. Ter Horst, J. P., Turimella, S. L., Metsers, F., & Zwiers, A. (2021). Implementation of Quality by Design (QbD)
principles in regulatory dossiers of medicinal products in the European Union (EU) between 2014 and 2019.
Therapeutic innovation & regulatory science, 55, 583-590.
6. Pharmaceutical QbD: Omnipresence in the product development lifecycle,
https://www.europeanpharmaceuticalreview.com/article/77392/pharmaceutical-qbd-omnipresence-in-the-
product-development-lifecycle/
7. https://www.slideshare.net/VaishnaviBhosale6/design-of-experiments-pharma