Quality by Design (QbD)

Linda Margata
  Defects in pharmaceutical product quality can be encountered
such as low manufacturing process yield or, more dangerously,
some which may affect the therapeutic performance of the drug
Quality by (or both).

Design (QbD)  The quality of a pharmaceutical product can be defined as an

acceptably low risk of failing to achieve the desired clinical
attributes of the drug
  QbD  a systematic approach to development, which begins
with predefined objectives and emphasizes product and process
understanding and process control, based on sound science and
Quality- by-design (QbD) is
a concept introduced by the quality risk management.
International Conference on  Predefined objectives make up the quality target product profile
Harmonization (ICH) Q8 (QTPP), that is, the summary of the drug product quality
guideline characteristics that ideally should be achieved.
  According to the ICH Q8 guideline, QTPP is a prospective
summary of the quality characteristics of a drug product to
ensure the desired quality, taking into account safety and
QTPP, CPP, & efficacy of that drug product.

CQA ???  Through the scientifically based process of product

development, critical process parameters (CPPs), and critical
quality attributes (CQAs) of the product are identified.
  Intended use in clinical setting, route of administration, dosage
form, delivery systems;

QTPP  Dosage strength(s);

 Container closure system;
  A 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 of solid oral dosage forms are typically those aspects
affecting product purity, strength, drug release and stability.

CQA  For other delivery systems can additionally include more

product specific aspects, such as aerodynamic properties for
inhaled products, sterility for parenterals, and 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.
  CQA is a physical, chemical, biological, or microbiological
property or characteristic that should be within an appropriate

CQA – CPP limit, range, or distribution to ensure the desired product

quality.
Relationship?  CPP is a process parameter whose variability has an impact on
a CQA.
  The identification of a CQA from the QTPP is based on the
severity of harm to the patient if the product falls outside the
acceptable range for that attribute.
QTPP  CQA  QTPP is initially defined, based upon properties of the drug
substance, characterization of the reference product (if it
exists), and intended patient population.
  QTPP for immediate release tablets may include the following
requirements: assay, content uniformity, and dissolution,
hardness, friability, size

Examples  CQA: assay, content, uniformity, dissolution, and degradation

products
 CPPs: compression force and speed used for tableting

The emphasis of the ICH Q8 guideline is to shift pharmaceutical product

development from the empirical, trial- and-error approach, to the scientifically
based process of design space appointment.
  The ICH Q8 guideline describes good practices for
pharmaceutical product development.
 It is often emphasized that the quality of a pharmaceutical
product should be built in by design rather than by testing
ICH Q8 alone.
Guideline  The ICH Q8 guideline suggests that those aspects of drug
substances, excipients, container closure systems, and
manufacturing processes that are critical to product quality,
should be determined and control strategies justified.
  QbD can:
1. facilitate innovation,
2. Increase manufacturing efficiency,

Function of 3. reduce cost/product rejects,

4. minimize/eliminate potential compliance actions,
QbD 5. enhance opportunities for first cycle approval, streamline post
approval changes and regulatory processes,
6. enable more focused inspections, and
7. provide opportunities for continual improvement
Benefits of QbD application for both regulatory agencies and
manufacturers
  The aim of pharmaceutical development is to design a quality
product and its manufacturing process to consistently deliver
the intended performance of the product.
 It is important to recognize that quality cannot be tested into
products

Pharmaceutical  Quality should be built in by design.

Development  Changes in formulation and manufacturing processes during

development and lifecycle management should be looked upon
as opportunities to gain additional knowledge and further
support establishment of the design space.
 Similarly, inclusion of relevant knowledge gained from
experiments giving unexpected results can also be useful.
  Pharmaceutical development should include, at a minimum, the
following elements:
1. Defining the QTPP as it relates to quality, safety and efficacy,
considering e.g., the route of administration, dosage form,
bioavailability, strength, and stability
2. Identifying potential CQAs of the drug product, so that those
Pharmaceutical product characteristics having an impact on product quality

Development can be studied and controlled;

3. 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;
4. Selecting an appropriate manufacturing process
5. Defining a control strategy
  An enhanced, QbD approach to product development would
additionally include the following elements:
1. A systematic evaluation, understanding and refining of the
formulation and manufacturing process, including;
 Identifying, through e.g., prior knowledge, experimentation, and

Pharmaceutical risk assessment, the material attributes and process parameters

that can have an effect on product CQAs;

Development  Determining the functional relationships that link material

attributes and process parameters to product CQAs;

2. 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
 1. Drug Substances

Components of  physicochemical and biological properties (e.g. solubility, water

content, particle size, crystal properties, biological activity, and
the Drug permeability)

Product  The compatibility of the drug substance with excipients.

 The compatibility of the drug substances with each other
 2. Excipients
 The excipients chosen, their concentration, and the characteristics
 Compatibility of excipients with other excipients
Components of  Ability of excipients (e.g., antioxidants, penetration enhancers,

the Drug
disintegrants, release controlling agents) to provide their intended
functionality and to perform throughout the intended drug product

Product shelf life

  A summary should be provided describing the development of
the formulation
 Identification of CQA
Formulation  Bioavailability or bioequivalence studies
Development  Any special design features of the drug product (e.g., tablet
score line, overfill, anticounterfeiting measure as it affects the
drug product) should be identified
  In general, use of an overage of a drug substance to compensate
for degradation during manufacture or a product’s shelf life, or
to extend shelf life, is discouraged.
 Any overage should be justified considering the safety and
efficacy.
Overages  Information should be provided on the:
1. Amount of overage,
2. Reason for the overage (e.g., to compensate for expected and
documented manufacturing losses)
3. Justification for the amount of overage.
  Properties relevant to the safety, performance or
manufacturability of the drug product
Physicochemic  Studies could include:
al and  the development of a test for respirable fraction of an inhaled

Biological product.
 information supporting the selection of dissolution vs.
Properties disintegration
 testing development and suitability of the chosen test
  The selection, the control, and any improvement of the
manufacturing process
 Appropriateness of the equipment used
Manufacturin  process improvement, process validation, continuous process

g Process verification* (where applicable), and any process control

requirements.
Development  microbiological as well as physical and chemical attributes
 critical process parameters that should be monitored or
controlled (e.g., granulation end point)
  intended use of the drug product
 suitability of the container closure system for storage and
transportation (shipping)
Container  integrity of the container and closure
Closure  The choice of primary packaging materials should consider,

System e.g., choice of materials, protection from moisture and light,

compatibility of the materials of construction with the dosage
form (including sorption to container and leaching), and safety
of materials of construction
  The rationale for performing or not performing microbial limits
testing for non sterile drug products
 The selection and effectiveness of preservative systems in
Microbiologica products containing antimicrobial preservative or the
antimicrobial effectiveness of products that are inherently
l Attributes antimicrobial
 For sterile products, the integrity of the container closure
system as it relates to preventing microbial contamination
  The compatibility of the drug product with reconstitution
diluents (e.g., precipitation, stability) should be addressed
 the recommended in-use shelf life, at the recommended storage
Compatibility temperature
 admixture or dilution of products prior to administration (e.g.,
product added to large volume infusion containers)