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Introduction
Design is a process of originating a conceptual solution to a
requirement and expressing it in a form from which a product may be produced or
a service delivered.
Development is realization of design in the form of
prototype and subsequent improvements in the prototype to make product and
further innovations in the product. So development
is creation and improvement.
In pharmaceutical development (product
and process) this clause has huge implications. The entire process of
pharmaceutical development is lengthy and complex and the end product/process
must comply with all the regulatory and statutory requirements, requirements of
the product and customers’ requirements.
Though it is difficult to justify the
exclusion from this clause the clause may be excluded if no developmental work
is undertaken and product has been received through technology transfer from
other source or product manufactured for quite a long time (i.e., initial
consistency proved and approval from national regulatory authority) with no process
improvements. This clause may also be excluded by the contract manufacturing
firms. However, it is applicable for new projects whether they are technology
transfer or new facility setup.
Pharmaceutical Development:
Quality cannot be tested into product;
it should be built in or should be by design.
The above statement reflects the present
regulatory expectation with pharmaceutical products. ICH Q8 states, ‘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.’
Different elements of pharmaceutical development include,
– Defining an objective
– Determination of
critical quality attributes (CQA)
– Risk assessment
– Development of
experimental design (Design of Experiment)
– Designing and
implementing control strategy
– Continuous
improvement.
The process of pharmaceutical
development and regulatory expectation are emphasized in different regulatory
guidance documents for clear interpretation and harmonized approach. The major
work in the field has been done by International
Conference on Harmonization (ICH).
FDA’s Guidance on Process Validation has stressed scientific approach for entire
pharmaceutical development and process validation.
FDA’s PAT (Process Analytical Technology) initiative also emphasizes
on Quality to be designed in the process
than tested into product.
The following documents shall be considered for successful pharmaceutical
development:
FDA’s Guidance Document on Process Validation: The document encourages the use of modern pharmaceutical development concepts, quality risk management and quality
system at all stages of
manufacturing process lifecycle. The lifecycle concept links product and
process development, qualification and commercial manufacturing processes, and
maintenance of the process in a state of control during routine commercial
production.
The guide describes process validation
activities in three stages:
Stage
1: Process Design
Stage
2: Process Qualification
Stage
3: Continued process verification
The guidance emphasizes, ‘Before any batch from the process is
commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will
consistently produce APIs and drug products meeting those attributes relating
to identity, strength, quality, purity, and potency. The assurance
should be obtained from objective information and data from laboratory-,
pilot-, and/or commercial-scale studies. Information and data should demonstrate
that the commercial manufacturing process is capable of consistently producing
acceptable quality products within commercial manufacturing conditions’.
ICH Q10: This guideline applies to
the systems supporting the development
and manufacture of pharmaceutical drug substances (i.e., API) and drug
products, including biotechnology and biological products, throughout the
product lifecycle.
The product lifecycle is divided into
following stages:
- Pharmaceutical Development
- Technology Transfer
- Commercial Manufacturing
- Product Discontinuation
The enablers of QMS (Knowledge Management and Quality Risk Management) are applicable for all the stages of product lifecycle, including pharmaceutical development.
The document describes four elements to promote the lifecycle approach to product quality. the four elements are:
- Process performance and product quality monitoring system;
- Corrective action and preventive action (CAPA) System;
- Change Management system;
- Management review of process performance and product quality.
ICH Q9: This document offers a systematic approach to quality
risk management. The document proposes integration of quality risk management
into industry and regulatory operations which included pharmaceutical
development. Annexure II of the document gives examples of situations in which
QMS can be useful.
ICH Q8: This document entirely focuses
on pharmaceutical development and provides insight to regulatory expectations.
The guide states that, ‘It is important to recognize that quality cannot be
tested into products; i.e., quality should be built in by design’.
The guide also emphasizes on the concept
of design space.
The guide states, ‘The design and
conduct of pharmaceutical development studies should be consistent with their
intended scientific purpose. It should be recognized that the level of
knowledge gained, and not the volume of data, provides the basis for
science-based submissions and their regulatory evaluation’.
The annexure Pharmaceutical Development
provides further clarification of key concepts along with the principles of
quality by design.
ICH Q6: The document assists in the establishment of a single set of global specifications for new drug substance and new drug product. It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures for new drug substance.
FDA’s Guidance Document on PAT: The
document provides insight and emphasizes on improving pharmaceutical development,
manufacturing and quality assurance through innovation in product and process
development, process analysis and process control.
The goal of PAT is to enhance
understanding and control the manufacturing process. PAT proposes different
tools which have to be considered during process/product development.
The table below simplifies the requirements of Clause 7.3
Design
and development planning
|
Defining
an objective of development project
Determination
of critical quality attributes (CQA)
Risk
assessment
Development
of experimental design (Design of Experiment)
Designing
and implementing control strategy (Method validation)
|
Design
and development inputs
|
Pharmacopeia/
Regulatory Requirements
Requirements
of the product (quality, safety and efficacy requirements, container closure
system, delivery system, stability etc).
Previous
experience with similar processes and products
Published
literature and current status
Market
viability
|
Design
and development outputs
|
Critical
Quality Attributes and specifications
Resources
and capabilities
Design
and Development stages
Timelines
Experimental
Design and statistical tools
Study
Protocols/ Drawings
Responsibilities
and Authorities
|
Design
and development review
|
Review
to see outputs are rational and unambiguous.
Progress
of the project
Managing
changes in project
|
Design
and development verification
|
Paper
based review to check that the output of design and development planning such
as specifications, layouts, drawings, test protocol and study design, test
methods and procedures are meeting the input requirements. Exercise which
ensures that each requirement in the inputs is accounted for in the outputs.
|
Design
and development validation
|
Physical,
chemical, biological verification of the product. Product of design and
development exercise (prototype) is tested for all the specifications and
parameters such as safety, efficacy, purity, stability etc.
|
Design
and development changes
|
Changes
in design and development plan arising due to review, verification,
validation and better understanding of process/product. These changes are
identified, captured, reviewed, verified and validated. The records are
maintained in project plan.
|
Verification
and validation has important role to play in software development. For better understanding
of the concept in software development refer General Principles of Software
Validation; Final Guidance for Industry and FDA Staff.
References:
ICH: Pharmaceutical
quality system Q10
ICH: Quality Risk Management
Q9
ICH: Pharmaceutical
Development Q8
ICH: Specifications: Test
procedures and acceptance criteria for new drug substances and new drug
products Q6
FDA: Guidance for Industry- Process Validation: General Principles and Practices
FDA: Guidance for Industry PTA- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance
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