D3. Pharmaceutical Development, Quality by Design.pptx

PHARMACEUTICAL DEVELOPMENT: QUALITY BY
DESIGN
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Date
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PROMOTING THE QUALITY OF MEDICINES
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 Definition
 Pharmaceutical Development
 Approaches to Pharmaceutical Development
 Elements of Pharmaceutical development
 Quality by Design
Outline
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 ICH Q8(R2)- Pharmaceutical Development
 Pramod K., Tahir M.A., Charoo N.A., Ansari S.H., Ali J. (2016).
Pharmaceutical product development: A quality by design
approach. Int J Pharm Investig; 6(3): 129–138
Reference
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 ICH Q9- Quality Risk Management
 ICH Q10- Pharmaceutical Quality System
 ICH training materials
Reference
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 Quality by Design (QbD)
 A systematic approach to development that begins with predefined
objectives and emphasizes product and process understanding and
process control, based on sound science and quality risk
management
Definition
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 Process Analytical Technology (PAT)
 A system for designing, analyzing, and controlling manufacturing
through timely measurements (i.e., during processing) of critical
quality and performance attributes of raw and in-process materials
and processes with the goal of ensuring final product quality.
Definition
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 Design Space
 The multidimensional combination and interaction of input variables
(e.g., material attributes) and process parameters that have been
demonstrated to provide assurance of quality.
Definition
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 Product lifecycle
 All phases in the life of a product from the initial development
through marketing until the product’s discontinuation.
 Process Robustness:
 Ability of a process to tolerate variability of materials and changes of
the process and equipment without negative impact on quality.
Definition
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 Critical Process Parameter (CPP):
 A process parameter whose variability has an impact on a critical
quality attribute and therefore should be monitored or controlled to
ensure the process produces the desired quality.
Definition
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 Provides an opportunity to present the knowledge gained through the
application of scientific approaches and quality risk management to the
development of a product and its manufacturing process.
 Create a basis of flexible regulatory approaches by reducing uncertainty
 Facilitate risk based regulatory decisions
 Continuous improvements without the need for regulatory review
 ”real time” quality assurance
ICH Q8: Pharmaceutical development
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 The aim of pharmaceutical development is to design a quality product
and its manufacturing process to consistently deliver the intended
performance of the product.
 The information and knowledge gained from pharmaceutical
development studies and manufacturing experience provide scientific
understanding to support the establishment of the design space,
specifications, and manufacturing controls.
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 Pharmaceutical Development section of a dossier
 is intended to provide a comprehensive understanding of the
product and manufacturing process for reviewers and inspectors
 The degree of regulatory flexibility is predicated on the level of
relevant scientific knowledge provided
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 Information from pharmaceutical development studies
 can be a basis for quality risk management
 important to recognize that quality cannot be tested into
products, i.e., quality should be built in by design
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 Design space is proposed by the applicant and is subject to
regulatory assessment and approval.
 Working within the design space is not considered as a change
 Movement out of the design space is considered to be a change
and would normally initiate a regulatory post approval change
process.
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 The product should be designed to meet patients’ needs and the
intended product performance.
 Strategies for product development vary from company to
company and from product to product.
 The approach to, and extent of, development can also vary
Approaches to Pharmaceutical Development
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 An applicant might choose either
 an empirical approach (Minimal approach)
 a more systematic approach to product development (QbD)
 a combination of both
(ICH Q8)
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Approaches to
Pharmaceutical
Development
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 Differing Approaches
to Pharmaceutical
Development
(Appendix 1, ICH Q8)

 A more systematic approach to development (QbD) can include,
for example,
 incorporation of prior knowledge
 Results of studies using design of experiments
 use of quality risk management
 use of knowledge management (see ICH Q10) throughout the
lifecycle of the product.
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 A more systematic approach to development ( QbD)
 can enhance achieving the desired quality of the product
 help the regulators to better understand a company’s strategy
 Product and process understanding can be updated with the
knowledge gained over the product lifecycle
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 Pharmaceutical development should include, at a minimum, the
following elements
 Defining the quality target product profile (QTPP)
 as it relates to quality, safety and efficacy, considering e.g., the route of
administration, dosage form, bioavailability, strength, and stability
 Identifying potential critical quality attributes (CQAs) of the drug
product
 so that those product characteristics having an impact on product quality can
be studied and controlled
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 Pharmaceutical development should include, at a minimum, the
following elements
 Determining the critical quality attributes of the drug substance,
excipients etc., and selecting the type and amount of excipients to
deliver drug product of the desired quality
 Selecting an appropriate manufacturing process
 Defining a control strategy
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 A quality by design approach to product development would
additionally include the following elements:
 A systematic evaluation, understanding and refining of the
formulation and manufacturing process, including;
 Identifying, through e.g., prior knowledge, experimentation, and risk
assessment, the material attributes and process parameters that can have an
effect on product CQAs;
 Determining the functional relationships that link material attributes and
process parameters to product CQAs;
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 Additional elements for QbD approach to product development …..
 Using the enhanced product and process understanding in
combination with quality risk management to establish an
appropriate control strategy which can, for example, include a
proposal for a design space(s) and/or real-time release testing.
• This result, more systematic approach could facilitate continual
improvement and innovation throughout the product lifecycle (See
ICH Q10).
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 Forms the basis of design for the development of the product
 Considerations for the QTPP could include
 Intended use in clinical setting, route of administration, dosage form, delivery
systems;
 Dosage strength(s);
 Container closure system;
Elements of PD- Quality Target Product Profile (QTPP)
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 Considerations for the QTPP …..
 Therapeutic moiety release or delivery and attributes affecting PK 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.
Elements of PD- Quality Target Product Profile (QTPP)
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 CQA:
 is 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
 CQAs are generally associated with the drug substance, excipients, intermediates
(in-process materials) and drug product
 CQAs of SODFs are typically those aspects affecting product purity, strength,
drug release and stability
Elements of PD- Critical Quality Attributes (CQA)
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 CQAs for other delivery systems can additionally include more
product specific aspects, such as
 aerodynamic properties for inhaled products
 sterility for parenterals
 adhesion properties for transdermal patches
 For drug substances, raw materials and intermediates, the CQAs can
additionally include those properties (e.g., particle size distribution,
bulk density) that affect drug product CQAs.
Elements of PD- Critical Quality Attributes (CQA)
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 Linking Material Attributes and Process Parameters to Drug
Product CQAs
 Risk assessment
 is a valuable science-based process used in quality risk management
(see ICH Q9)
 aid in identifying which material attributes and process parameters
potentially have an effect on product CQAs.
Elements of PD-Risk Assessment
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 Risk assessment
 Performed early in the PD process and is repeated as more
information becomes available and greater knowledge is obtained
 Risk assessment tools can be used to identify and rank
parameters (e.g., process, equipment, input materials) with
potential to have an impact on product quality
Elements of PD-Risk Assessment
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 The relationship b/n process inputs (material attributes and
process parameters) and the CQAs can be described in the
design space
 This include an understanding of the linkage and effect of process
parameters and material attributes on product CQAs
Elements of PD-Design Space
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 Parameters needs to considered:
 Selection of Variables
A description of the process parameters and material attributes
considered for the design space and their effect on product quality
 Describing a Design Space in a Submission
 A design space can be described in terms of ranges of material attributes
and process parameters, or through more complex mathematical
relationships.
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 Describing a Design Space in a Submission…
 It is possible to describe a design space as a time dependent function
(e.g., temperature and pressure cycle of a lyophilisation cycle), or as a
combination of variables such as components of a multivariate model.
 Analysis of historical data can contribute to the establishment of a design
space.
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 Unit Operation Design Space
 The applicant can choose to establish independent design spaces for one
or more unit operations, or to establish a single design space that spans
multiple operations
 For example, in the case of a drug product that undergoes degradation in
solution before lyophilisation, the design space to control the extent of
degradation (e.g., concentration, time, temperature) could be expressed
for each unit operation or as a sum over all unit operations.
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 Unit Operation Design Space
 The applicant can choose to establish independent design spaces for one
or more unit operations, or to establish a single design space that spans
multiple operations
 For example, in the case of a drug product that undergoes degradation in
solution before lyophilisation, the design space to control the extent of
degradation (e.g., concentration, time, temperature) could be expressed
for each unit operation or as a sum over all unit operations.
 Design Space Versus Proven Acceptable Ranges
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 It begins with predefined
objectives and requires an
understanding how
formulation and process
variables influence
product quality
Quality by Design (QbD)
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 Involves a thorough understanding of the relationship of product
performance with product attribute and process
 Involves the use of multivariate statistics and design of
experiments technique
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 Application of QbD approach in pharmaceutical product
development
 is systematic, involving multivariate experiments utilizing process
analytical technology (PAT) and other tests to identify critical quality
attributes (CQAs) based on risk assessments (RAs)
 can lead to robust formulations and high success rate in regulatory
approvals
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Figure 1: depicts an
overall QbD system
where RA and risk
control for the product
and process are involved
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• Key steps
for
product
under QbD
Quality by
Design
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 The important components of product development by QbD
are
 target product profile (TPP)
 target product quality profile (TPQP)
 design and development of product
 developing the manufacturing process
 identifying the CQA
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 The components of product development by QbD ….
 assessment and management of the risks involved in the process
 establishment of design space
 defining a control strategy for a product to stay within the design
space.
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 Control strategy
 A control strategy is designed to ensure that a product of required
quality will be produced consistently
 The elements of the control strategy should describe and justify how
in-process controls and the controls of input materials (API &
excipients), intermediates, container closure system, and drug
products contribute to the final product quality
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 Control strategy
 A control strategy is designed to ensure that a product of required
quality
 The controls should be based on product, formulation and process
understanding and should include, at a minimum, control of the
critical process parameters and material attributes
 Sources of variability that can impact product quality should be
identified, appropriately understood, and subsequently controlled
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 Control strategy…
 Process understanding can enable an alternative manufacturing
paradigm where the variability of input materials could be less tightly
constrained
o it can be possible to design an adaptive process step with appropriate process
control to ensure consistent product quality
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 Control strategy…
 Enhanced understanding of product performance can justify the use
of alternative approaches to determine that the material is meeting
its quality attributes.
o The use of such alternatives could support real time release testing
o For example,
 DT could serve as a surrogate for DS for fast-disintegrating solid forms with highly soluble drug
substances
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 Control strategy can include but not limited to
 Control of input material attributes (e.g., API, excipients, primary packaging Ms)
 Product specification(s)
 Controls for unit operations that have an impact on downstream processing or
product quality
 In-process or real-time release testing in lieu of end-product testing (e.g.
measurement and control of CQAs during processing)
 A monitoring program (e.g., full product testing at regular intervals) for verifying
multivariate prediction models
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 Product Lifecycle Management and Continual Improvement
 Provide an opportunity to evaluate innovative approaches to improve product
quality (see ICH Q10) through out product life cycle
 Process performance can be monitored to ensure that it is working as anticipated to
deliver product quality attributes as predicted by the design space including
 Trend analysis of the manufacturing process as additional experience is gained during routine
manufacture
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 Q8(R2) - Example QbD Approach
 Quality Target Product Profile (QTPP)
 Determine “potential” critical quality attributes (CQAs)
 Link raw material attributes and process parameters to CQAs and
perform risk assessment
 Develop a design space
 Design and implement a control strategy
 Manage product lifecycle, including continual improvement
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Product profile
Continuous
improvement
CQA’s
Risk Assessment
Design Space
Control strategy

Quality by Design-Case study
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D3. Pharmaceutical Development, Quality by Design.pptx

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