USP General Chapter <1049.
1>
Design of Stability Studies for
Biotechnology Product Development
An Executive
Summary and Lifecycle Management
Introduction to a new USP General Chapter
that provides guidance and considerations for
biotechnology product stability studies.
Overview
Camilla Santos, PhD
Director, Product Quality Biotechnology or biological medicinal products are inherently complex, often requiring
Amgen specialized technologies and procedures to ensure their quality, safety, and efficacy.
One essential requirement for any medicinal product is that stability be maintained
Vice Chair
USP Biologics Stability Expert Panel throughout its shelf life and until it is administered to the patient.
Biotherapeutics are typically sterile and stored as drug substance in a frozen condition
and as final product refrigerated in glass vials or syringes, using rubber stoppers and
plungers. The common long-term storage condition of the refrigerated drug product
is 5°C without humidity control and is highly dependent upon the demonstration of
container closure integrity. A closed container protects from ingress of contaminants
as well as ingress/egress of moisture. Because the container protects the product
from moisture ingress/egress, it is often unnecessary to further evaluate product under
Lori McCaig, PhD controlled humidity conditions at the long-term storage condition.
Independent Consultant
In addition, since many products may be exposed to various temperatures throughout the
Member intended shelf life (i.e., one temperature during long-term storage and other temperatures
USP Biologics Stability Expert Panel during processing, packaging, resulting from transportation excursions, or during use), the
effect of temperature must be studied at more than one storage condition. Studies performed
under stressed conditions also serve to assess the possible product degradation pathways.
Figure 1: USP Chapter <1049.1> aligns with regulations
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USP GENERAL CHAPTER <1049.1> DESIGN OF STABILITY STUDIES FOR
BIOTECHNOLOGY PRODUCT DEVELOPMENT AND LIFECYCLE MANAGEMENT
This article explores the new United States Pharmacopeia
Figure 2: Common storage conditions
(USP) General Chapter <1049.1> Design of Stability Studies
for Biotechnology Product Development and Lifecycle
Management, which is supplemental to USP General
Chapter <1049> Quality of Biotechnological Products:
Stability Testing of Biotechnological/Biological Products.
It provides guidance regarding the overall strategy and
lifecycle management of biotechnology product stability
testing with a focus on streamlining programs and
achieving sustainable commercial product expiries.
The new proposed General Chapter <1049.1> aligns
with the US Code of Federal Regulations, FDA Guidance
Documents, ICH Guidance Documents, and WHO
Figure 3: Study design to support Market Application Guidelines (Figure 1), while addressing the complexity
of the actual design of expiry setting studies as well as
various other stability studies necessary for product
characterization, market registration, and patient/
physician use for biotechnology derived or biological
medicinal products and devices. It will be available for
public comment in Pharmacopeial Forum 46(3), which will
be available online May 1, 2020.
General Concepts for Biologic Product Stability
General information about design considerations for stability
studies can be found in ICH and FDA Guidance Documents;
special considerations for biologics are discussed within
Figure 4: Container: orientation, container closure USP <1049.1>. Included are recommendations and
guidance for stability studies, such as:
• Common storage conditions (Figure 2)
• Testing frequency and study duration (Figure 3)
• Container orientation and closure (Figure 4)
• Ensuring the study is representative of products in
the clinic and on the market
• Stability test methods and stress testing
For many biologics, data at accelerated or stressed
conditions may not be predictive of the behavior at the
long-term storage condition due to non-Arrhenius kinetics
of the product attributes. When selecting accelerated
or stressed conditions, consideration should also be
given to avoid temperatures near important transition-
“When selecting accelerated or stressed temperatures where degradation will be less stable or
unpredictable. Moreover, while the clinical shelf-life is
conditions, consideration should also be given often extrapolated using real-time recommended storage
condition data, it is always necessary to confirm the
in order to avoid temperatures near important
extrapolated shelf-life because it may not be predictive of
transition-temperatures where degradation will the actual shelf life.
be less stable or unpredictable. ” With respect to stability containers, drug substance
stability samples may be stored in containers of smaller
size than the bulk provided the containers have the same
materials of construction and closure system.
USP GENERAL CHAPTER <1049.1> DESIGN OF STABILITY STUDIES FOR
BIOTECHNOLOGY PRODUCT DEVELOPMENT AND LIFECYCLE MANAGEMENT
Figure 5: Summary of Stability Data Expected in MA
Drug product stability samples are stored in the will ensure that the clinical shelf life is supported by
marketed containers. Studies evaluate the impact to stability data through extrapolation with confirmation at
product of container orientation and determine if there the extrapolated shelf life. In the later clinical stages, the
are any differences due to contact with the container stability of three primary lots each of drug substance
and closure system. If no differences are detected, a and drug product are necessary to support commercial
single orientation can be used (typically inverted for liquid product expiry, with additional lots to support validation
product). Syringes are typically stored horizontally to (i.e., Process Performance Qualification [PPQ]) if not
expose the liquid product to the needle and the plunger, already included in the primary lots.
and to maximize the air–liquid interface and exposing the
product to the most stressful condition. It is important For biologics, the commercial expiry is typically two
that sterility is maintained through shelf life; thus, to three years, so the primary stability studies must
container-closure integrity is a major focus, especially for be initiated well in advance of the market application
single-use parenteral administration, which typically lacks because commercial expiry is based on real-time stability
preservatives or antioxidants within the formulation. data from the primary lots. The primary lots also may be
used for any required special studies (e.g., accelerated
Product Lifecycle Stage Considerations condition and stress studies). Typical accelerated/stress
USP <1049.1> also provides guidance on appropriate stability studies include the following (see also Figure 8):
studies throughout the product lifecycle. Stability studies
support the development of the product and clinical studies, • Chemical stress to inform how the product will
and data to support registration and expiration dating, as well behave, especially during the processing conditions
as a commitment to ongoing monitoring, are expected in the • Mechanical stress, which may point to any necessary
marketing authorization application (Figure 5). transportation restrictions
During the pre-clinical stage (see Figure 6), a single • Temperature cycling to determine optimal storage
stability lot can be used that, at a minimum, covers the temperature and support temperature excursions
age of the product used in toxicology studies. Many during manufacture, transport, and use
times, this study is extended to get an early read on the • Photostability to determine the effect of exposure to light
sustainability of the intended drug product and, if the
product and process remain unchanged for commercial • Reconstitution for lyophilized products
sale, the lot used may be used as a primary stability lot. These and other special studies contribute to product
For the clinical stages (see Figure 7), it is important understanding and provide information to support
to set the strategy for the stability program early. This manufacturing, transportation and use limits and controls.
USP GENERAL CHAPTER <1049.1> DESIGN OF STABILITY STUDIES FOR
BIOTECHNOLOGY PRODUCT DEVELOPMENT AND LIFECYCLE MANAGEMENT
Figure 6: Lifecycle management: Post-approval changes
“Statistical modeling is used to evaluate
stability data.”
Statistical Modeling and Specifications
The knowledge gained from the stability program
contributes to the setting of specification acceptance
criteria and is used to determine the expiry periods
for drug substance and drug product. Several factors
When the drug product has multiple presentations, should be considered when evaluating this information,
additional stability lots must be considered, although including whether the test methods are quantitative or
it may be possible to utilize a bracketing strategy to qualitative, whether the attributes change over time,
limit the number of stability studies needed. At the what the regulatory or pharmacopoeia requirements
time of the market application, it is not unusual to have are for the regions where the product will be marketed,
limited real-time data from these studies, particularly the manufacturing capability at release for both the
for biologics. Therefore, it is important that the primary drug substance and drug product, and the internal and
clinical lots have the desired expiry at the time of the external handling, storage, and patient use conditions.
application and comparability demonstrated for new
Statistical modeling is used to evaluate stability data. The
presentations. Stability data will continue to be provided
degradation observed can be linear or non-linear, and the
through the market application review period as well as in
statistical method chosen should fit the data as simply
supplemental submissions and in annual updates.
as possible. It is important to account for and include
For commercial products, an ongoing stability program is as many sources of variability as possible to ensure the
required, including both drug substance and drug product specification acceptance criteria are not set too tight
(see Figure 9). For a frozen drug substance, it is common and that they account for the real world of commercial
to study the stability at a condition where change may manufacturing. Expiry is based on the real-time data at
be seen, which could be at a temperature higher than the recommended storage condition, supported by data
the recommended storage condition. This information is at the accelerated storage condition. Shelf-life estimates
typically provided within the market application and in are based on where the model and the specification limits
annual updates. The drug product is typically evaluated intersect. Product is expected to meet the specifications
at its intended, long-term storage condition. Depending through shelf-life and often beyond shelf-life. Shelf life
on the stability data provided in the market application, can be extrapolated in the clinical space, but always must
when justified the frequency and testing may be reduced be confirmed with real-time data analysis. For biologics, it
for drug substance or drug product ongoing stability is required to evaluate at least one lot, in real time and at
protocol design. For example, the three-month and nine- all storage temperatures, that reaches expiry during the
month timepoints can be dropped, and the test methods marketing authorization review. Statistical assessments
may include only those for stability-indicating attributes. also may be used to establish trend limits (e.g., for an
If there is a desire to extend the shelf life, or to support ongoing monitoring/stability trending program or in
post-approval changes, additional studies may be comparability assessments for post-approval changes).
needed (Figure 10). If a major change involves the drug
substance, the study will include the recommended
Summary
storage conditions, as well as accelerated and stressed The new USP <1049.1> provides guidance and
conditions; the drug product made from the modified considerations specific to biotechnology product stability
drug substance should be studied at its recommended to help streamline development programs and achieve
storage condition (either upfront or as a commitment). sustainable commercial product expiries. The scope
For major changes to the drug product, such as changes includes stability of the product throughout its shelf
to the formulation, container, or long-term storage life until labeled expiry, from the moment it leaves the
condition, the primary stability study design is also company until administered to the patient and it applies
typically repeated to evaluate the modified drug product. to drug substance, drug product, and drug device
For both drug substance and drug product post-approval combinations. A holistic approach is outlined, providing
changes, risk-based stability designs and comparability broad application to the many variations of biotechnology
are used to leverage existing stability data and shelf life. products on the market.
