OVERVIEW OF PHARMACEUTICAL
PRODUCT DEVELOPMENT AND ITS
ASSOCIATED QUALITY SYSTEM
1.1 INTRODUCTION
Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow
Chan, Herman Lam, Y. C. Lee, and Xue-Ming Zhang
ISBN 0-471-25953-5 Copyright 2004 John Wiley & Sons, Inc.
1
2 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM
Discovery
research
Product
decision Phase I Phase II Phase III Market
undergo extensive testing to obtain initial safety and efficacy data in animal models.
Upon completion of successful animal safety and efficacy evaluation, submission
to appropriate regulatory bodies is made to gain approval to administer the first
human dose in the clinical phase I trial.
Common Studies Performed on the API and Drug Product. At this stage of the
development, it is important to gain preliminary information of the stability of the
API and drug product. Therefore, open dish (i.e., nonprotected) stability studies
are carried out to understand the chemical and physical stability of both the
API and the drug product. Preliminary packaging stability studies are conducted
to obtain a preliminary assessment of packaging materials that can be used,
and photostability and thermal studies are conducted to determine the light and
thermal stability of the API and drug product.
4 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM
Successful efficacy and safety data will guide the decision to proceed to clinical
phase III in product development. In this stage, the new drug is administered to
a larger population of patients using blinded clinical studies. These studies may
demonstrate the potential advantages of the new compound compared with similar
compounds already marketed. The data collected from this stage are intended
to evaluate the overall benefitrisk relationship of the drug and to provide an
adequate basis for labeling. Phase III studies usually include from several hundred
to several thousand subjects and often include single- or double-blind studies
designed to eliminate possible bias on the part of both physicians and patients.
Positive data from this stage will trigger implementation of a global registration
and commercialization of the drug product.
Impurities Level in New Drug Product. As the new drug product formulation
progresses to this late stage of development, impurity profiles may differ from
those of earlier formulations. The rationale for reporting and control of impurities
in the new drug product is often decided at this stage as are recommended storage
conditions for the product. Degradation products and those arising from excipient
interaction and/or container closure systems will be isolated and identified. The
impurity profile of the representative commercial process will be compared with
the drug product used in development, and an investigation will be triggered if
any difference is observed. Identification of degradation products is required for
those that are unusually potent and produce toxic effects at low levels.
Primary and developmental stability studies help development scientists under-
stand the degradation pathways. These studies are developed to get information
on the stability of the drug product, expected expiry date, and recommended
storage conditions. All specified degradation products, unspecified degradation
products, and total degradation products are monitored in these studies.
Impurities in API. Treatment of the impurities in the API is similar to that for
the new drug product. Impurities in the API include organic impurities (process
and drug related), inorganic impurities, and residual solvents. Quality control
analytical procedures are developed and validated to ensure appropriate detection
and quantitation of the impurities. Specification limits for impurities are set based
on data from stability studies and chemical development studies. A rationale for
the inclusion or exclusion of impurities is set at this stage. The limits set should
not be above the safety level or below the limit of the manufacturing process
and analytical capability.
API Development. The synthetic route will be finalized and a formal primary
stability study will be undertaken to assess the stability of the API.
When a new molecule enters the development phase, in most cases only the
basic information of the new chemical entity is known (e.g., molecular structure
and polymorphic and salt forms). However, we do not know what will happen
when it is formulated and stored at ordinary environmental conditions. In other
words, there is a high degree of variability around what is known about the
molecule and its behavior in a variety of systems. The basic task for development
is to reduce this high variability by conducting a series of controlled experiments
to make this information known and thus predictable. In fact, by the time a
molecule reaches the significant milestone of launch into commercial activities,
most of the behavior and characteristics of the molecule need to be known,
predictable, and in control.
There are multiple paths to achieving the state when a product and a pro-
cess are in control. A pictorial representation of this concept is shown in
Figure 1.2. Simpler molecules may achieve a state of control (predictable state)
early in the development process, while more complex molecules may retain a
high state of variability until late in the process. The goal for development
must be a development path that is documented and performed by qualified
scientists, equipment, facilities, instruments, etc. Development paths that can
be followed are varied, but the final outcome, when a project is transferred to
manufacturing, is a product and a process that are in a well-characterized state
of control.
Development
systems
Manufacturing systems
Launch
Variability
the basic GMP principles is a common part of business practice for an increasing
number of companies. However, the GMPs are silent on explicit guidance for
the development phase in several areas. Thus, companies have been left to make
their own determinations as to how to apply GMPs prior to commercial introduc-
tion of products. More recently, the European Union (EU) and the International
Conference on Harmonization (ICH) have offered a variety of guidances in the
development of API. The ICH Q7A GMP Guidance for APIs includes guidance
for APIs for use in clinical trials. The EU Guideline Annex 13 provides much
more specific guidance to the application of GMPs to investigational medicinal
products. By extension, one can gain perspective on application of GMPs to
the chemistry, manufacturing, and control (CM&C) development process since
it is closely tied to the development, manufacture, and use of investigational
medicinal products.
Regulatory bodies recognize that knowledge of the drug product and its ana-
lytical methods will evolve through the course of development. This is stated
explicitly in ICH Q7A: Changes are expected during development, and every
change in production, specifications, or test procedures should be recorded ade-
quately. The fundamental nature of the development process is one of discovery
and making predictable the characteristics of the API or product. It is there-
fore reasonable to expect that changes in testing, processing, packaging, and
so on will occur as more is learned about the molecule. A high-quality sys-
tem that supports development must be designed and implemented in a way
that does not impede the natural order of development. It must also ensure that
the safety of subjects in clinical testing is not compromised. The penultimate
manufacturing processes must be supported with sufficient data and results from
the development process so that the final processes will be supported in a state
of control.
Processes that are created during development cannot achieve a full state of
validation because the processes have not been finalized. Variation is an inherent
part of this process, and it allows the development scientists to reach conclusions
concerning testing and manufacturing after having examined these processes with
rigorous scientific experiments and judgments. The goal for development is to
arrive at a state of validation entering manufacturing.
If one looks at the various clinical stages of development, there is a ques-
tion as to what practices should be in place to support phase I, II, or late
phase III studies. An all-or-nothing approach to GMPs is not appropriate. There
are certain fundamental concepts that must be applied regardless of the clinical
phase of development. Examples of these include: (1) documentation, (2) change,
(3) deviations, (4) equipment and utilities, and (5), training.
Any high-quality system must be built with an eye to the regulations and
expectations of the regulatory agencies that enforce the system. The U.S. Food
and Drug Administration (FDA) has recently implemented a systems approach
of inspection for ensuring that current GMPs (cGMPs) are followed in the man-
ufacturing environment. The FDA will now inspect by systems rather than by
8 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM
specific facility or product. The premise in this system is that activities in a phar-
maceutical company can be organized into systems that are sets of operations and
related activities. Control of all systems helps to ensure that the firm will produce
drugs that are safe and that have the identity and strength and meet the quality
and purity characteristics that are intended. The goal of this programs activities
is to minimize consumers exposure to adulterated drug products. A company is
out of control if any of its systems is out of control.
The following six systems are identified to be audited in the FDA systems
(GMP subparts are shown in parentheses):
An analysis of the citations of each cGMP system reveals that two subparts are
included in all the citations: Organization and Personnel (subpart B) and Records
and Reports (subpart J). This analysis points to a fundamental precept in the
systems guidance. Having the right number of appropriately qualified personnel
in place along with a strong documentation, records, and reports system are the
foundation of success in implementation of cGMPs in a manufacturing operation.
It therefore follows that the same principles apply to the development processes
that lead to the successful implementation of manufacturing operations.
During the development process, it is important to control variables that affect
the quality of the data that are generated and the ability to recreate the work.
It is important to recognize that by its nature, the development process does
not achieve a complete success rate. That is, many more molecules enter drug
development than transit successfully to the market. Thus, it is reasonable to
develop guidance and practices as to how much control and effort are put into
key activities depending on the phase of development. For example, analytical
methods used to determine purity and potency of an experimental API that is very
early in development will need a less rigorous method validation exercise than
would be required for a quality control laboratory method used in manufacturing.
An early phase project may have only a limited number of lots to be tested; the
testing may be performed in only one laboratory by a limited number of analysts.
The ability of the laboratory to control the method and its use is relatively high,
particularly if laboratory leadership is clear in its expectations for the performance
of the work.
The environment in which this method is used changes significantly when
the method is transferred to a quality control laboratory. The method may be
replicated in several laboratories, multiple analysts may use it, the method may
be one of many methods used in the laboratory, and the technical depth of the
analysts may be less deep than those in the development laboratory. Thus, it
is incumbent on the development laboratory to recognize when projects move
to later phases of development. The developing laboratory must be aware of
the needs of the receiving laboratories as well as regulatory expectations for
CONCLUSIONS 9
1.3 CONCLUSIONS
This introductory chapter gave a quick overview of the drug discovery process.
Normal activities required from molecule discovery to launch of the product are
10 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM
described. Quality systems for drug development must be built with an eye to
the fundamental aspects of the discovery and development processes. There must
be recognition that there is evolution on some standards during development.
The business must have clarity about its purpose and the processes used to run
the business. Quality expectations must be part of the development culture to
ensure compliance with cGMP requirements. Quality and business leadership
must provide a capable environment in which discovery and development occur.