Journal of Pharmaceutical Sciences 109 (2020) 2131-2144

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Journal of Pharmaceutical Sciences

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General Commentary

Comprehensive Temperature Excursion Management Program for

the Commercial Distribution of Biopharmaceutical Drug Products
Kashappa Goud Desai*, James D. Colandene, Monica Adams
Biopharmaceutical Product Sciences, GlaxoSmithKline, 1250 S Collegeville Road, Collegeville, Pennsylvania 19425

a r t i c l e i n f o a b s t r a c t

Article history: Biopharmaceutical drug products may be exposed to temperatures outside of the intended storage
Received 11 March 2020 temperature range (typically 2e8
C) during commercial distribution due to uncontrolled variables and
Revised 14 April 2020 unexpected events. Pharmaceutical companies are expected to ensure that product quality and stability
Accepted 14 April 2020
are not negatively impacted by temperature excursions defined as being acceptable for the product. It is
Available online 18 April 2020
imperative that all firms involved in the distribution understand key elements of the temperature
excursion management program in place to overcome the challenges of global distribution and comply
Keywords:
Biopharmaceutical drug product with regulatory requirements. Proactive implementation of a comprehensive temperature excursion
mAb management program is expected to help achieve successful commercial distribution. In this article,
Commercial distribution important aspects related to the key elements of a comprehensive temperature excursion management
Temperature excursion
program are summarized, including standard stability testing, regulatory expectations related to the
Thermal cycling
Stability testing justification of temperature excursions, thermal cycling studies to assess and support potential tem-
Regulatory expectations perature excursions (including how/when thermal cycling study data is used to support temperature
Good distribution practices excursions), good distribution practices to minimize temperature excursions and use of theoretical
Mean kinetic temperature
methods/mathematical simulation models to assess temperature excursions. A comprehensive temper-
ature excursion management program is expected to ensure product quality and help minimize, assess,
and justify temperature excursions more efficiently, ensure regulatory compliance and avoid business
impact caused by the loss of products or inadequate supply.
© 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction environments and transportation processes on product quality and

Biopharmaceutical drug products (e.g., recombinant proteins
and monoclonal antibodies) are distributed under controlled-
temperature storage/transportation conditions to ensure that
quality, safety and efficacy of the drug is not negatively impacted
throughout the shelf-life of the product.1e3 Successful commercial
distribution of drug products has been faced with formidable
challenges associated with global shipping environments,
including varying environmental conditions (e.g., different climatic
zones and seasonal changes), mode used to control the tempera-
ture, and region-specific differences (e.g., number of drop-off
points and country-specific regulations/procedures).4e12
A typical commercial distribution model involves several storage
facilities and transportation processes necessary to ship the drug
product from manufacturing site to the end user (Fig. 1). Precautions
should be taken to minimize the effects of global shipping
* Corresponding author.
E-mail addresses: kashappa-goud.x.desai@gsk.com, kghdesai@yahoo.com
(K.G. Desai).
stability. Pharmaceutical companies are expected to adhere to the
good storage and transportation practices/compendial standards
put forth by the global regulatory agencies (e.g., GDPs and United
States Pharmacopoeial chapter <1079>).3,9,13e17 Despite complying
with the GDP requirements, there may be periods of time during
storage or transportation wherein the product is exposed to tem-
peratures outside of the intended storage temperature.1,3,18 Given
that biopharmaceutical drugs are more sensitive to elevated tem-
perature than chemical drugs,3,19e21 a short-term temperature
excursion may directly affect product quality or affect the stability
trajectory within its established shelf life.12,17,18 Therefore, the onus
is on the pharmaceutical company to assess the impact and justify
the short-term temperature excursions.
Global regulatory agencies have unique requirements/expecta-
tions related to stability data needed to support potential short-
term temperature excursions associated with the commercial dis-
tribution of biopharmaceutical drug products. For example, stan-
dard stability data generated from the accelerated storage
conditions can be used to evaluate and justify the impact and justify
short-term temperature excursions in the United States, Europe,
Japan, Switzerland and Canada.3,21e25 Firms operating

https://doi.org/10.1016/j.xphs.2020.04.006
0022-3549/© 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
2132 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
Drug Product Manufacturing
(and/or Labeling) Sites
Excursion Management
Scope for Temperature
Distribution Centers
Program
Shipping / Transportation
Storage
Affiliate
Wholesaler (Distributor)
Government
Pharmacy
Pa ent: Pa ent
Physician
Pharmacy to
Handling
and Use
Hospital
Patient
Figure 1. A typical distribution model for biopharmaceutical drug products. The dis-
tribution model may vary in some cases (e.g., public health emergency). The scope for
temperature excursion management program is shown in the figure.
commercially in these regions may also utilize development sta-
bility studies to assess for impact of thermal cycling conditions that
may not be covered by standard stability data and internally apply
the data for decisions on excursion allowances. In contrast, the
Australian and Brazilian regulatory agencies expect pharmaceutical
companies to assess the impact of short-term exposure to temper-
atures outside of the intended storage temperature range on sta-
bility of drug product through formal thermal cycling protocols on
commercial-scale current Good Manufacturing Practice (cGMP)
drug product batches and use this stability data to support potential
temperature excursions.3,12,25,26
The objective of this article is to summarize important aspects to
establish a comprehensive global temperature excursion manage-
ment program, including standard stability testing, regulatory ex-
pectations related to the justification of temperature excursions,
thermal cycling studies to assess and support potential tempera-
ture excursions (including how/when thermal cycling study data is
used to support temperature excursions), GDPs to minimize tem-
perature excursions and use of theoretical methods/mathematical
simulation models to assess temperature excursions. The infor-
mation provided in this article may be useful for the pharmaceu-
tical companies to design a temperature excursion management
program, deal with temperature excursions, and understand dif-
ferences in global regulatory expectations/requirements. Biophar-
maceutical products (e.g., recombinant proteins and monoclonal
antibodies) shipped under frozen conditions (e.g., frozen liquid
drug product) and cell and gene therapy products are beyond the
scope of this article and therefore, topics covered in the current
article are not applicable to the distribution of these products.
What is Temperature Excursion?
As per the World Health Organization (WHO) model guidance,
temperature excursion is “an excursion event in which a time
temperature sensitive pharmaceutical product is exposed to tem-
peratures outside the range(s) prescribed for storage and/or
transport”.1,24 The temperature ranges for storage and transport
may be the same or different and determined by the product
manufacturer based on stability data.24
It is difficult to obtain an estimate of the magnitude of occur-
rence of temperature excursions as the events are not usually re-
ported in the literature. However, there is high potential for
temperature excursions during distribution due to unpredictable
random events associated the global distribution processes.
What Are the Potential Impacts of Temperature Excursions?
Biopharmaceutical drugs are sensitive to temperature excursions
(exposure to elevated or subzero temperatures) that may occur
during transportation, storage and handling of drug products.
Exposure to temperatures outside of the intended storage conditions
has the potential to cause protein degradation. For example, expo-
sure to elevated or subzero temperatures during storage, handling, or
patient use has been shown to impact product quality attributes for
some biopharmaceuticals.27e29 At elevated temperature, conforma-
tional destabilization or partial-to-complete unfolding of proteins
may occur, which may lead to the formation of aggregates via non-
covalent interactions.30e32 The temperature excursion events may
also lead to unintentional exposure to freeze/thaw cycles. Freeze/
thaw stresses can cause protein aggregation due to partitioning of
the protein molecule to ice-water interface, adsorption to the
container surface (solid-water interface), cryo-concentration, and
change in pH due to non-uniform crystallization of buffer.33e36
To protect the patient, acceptable temperature excursions need
to be defined to ensure that drug product quality or stability is not
impacted. Loss of a high-value product due to unacceptable tem-
perature excursions can have a significantly negative impact, both
financially (e.g., reduced profitability) and socially (e.g., loss of
reputation, credibility and goodwill). Impromptu due diligence
work on temperature excursions may require reallocation of re-
sources and extra time, which may impact productivity and output.
Therefore, fully understanding and defining what excursions are
acceptable for commercialization and having a distribution system
in place to avoid “unacceptable excursions” is critical.
Key Elements of Comprehensive Temperature Excursion
Management Program
Several factors related to storage, transportation, environmental
conditions, and region-specific custom clearance hurdles can
contribute to temperature excursions. A comprehensive tempera-
ture excursion management program can be designed by inte-
grating key elements (Fig. 2) into the overall management program.
A comprehensive temperature excursion management program is
expected to not only help minimize, assess, and justify temperature
excursions, but also ensure regulatory compliance and provide
several benefits (e.g., avoid regulatory citations, improve efficiency,
and minimize/avoid business impact caused by the loss of products
or inadequate supply).
The temperature excursion management program is applicable to
transportation and storage events that occur during distribution from
the manufacturing site to the first customer (e.g., wholesaler or
distributor) (Fig. 1). The pharmaceutical company usually has direct
control over the distribution (with direct responsibility for method of
shipping) from the time a shipment leaves the manufacturing site and
reaches the first customer location (the point at which the direct
chain of custody is complete). The first customer is then directly
responsible for shipping the drug product to the next destination
point (e.g., pharmacy) under appropriate conditions. The pharma-
ceutical company may still retain indirect control of this distribution
segment, through contractual agreements with the first customer to
ensure that the drug product is shipped under intended conditions.
Temperature excursions that occur during distribution from the first
customer to the pharmacy are typically addressed by the first
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144 2133

Standard Stability Testing Program

Standard Stability is defined as the capacity of the drug product to

Stability
Testing remain within established specifications to maintain its identity,
strength, quality, and purity through the shelf-life.37 Stability
testing is a key component of new drug development and product
lifecycle management phases (Fig. 3). The International Council
Regulatory for Harmonisation of Technical Requirements for Pharmaceuticals
Use of Expectations for Human Use (ICH) Q5C guideline (Quality of Biotechnological
Theoretical Regarding the
Assessment Justification of Products: Stability Testing of Biotechnological/Biological Prod-
Methods Temperature
Temperature Excursions
ucts) provides a general guidance on the body of stability data
Excursion required to register drug products in the ICH regions.21 This
Management standard stability testing is the primary type of testing performed
Program to understand how the quality of a drug changes under the in-
fluence of environment factors (e.g., temperature, humidity and
light).22,24,37 This knowledge is necessary to make decisions
regarding the conditions under which the drug product is to be
stored, transported, and used.3,11,21,22,24,37
Good Storage Thermal Assessment of drug product stability starts at the preclinical
& Distribution Cycling
Practices Studies stage and continues through all clinical phases of the product to
understand the stability trajectory of the product and satisfy reg-
ulatory requirements (where applicable, this may include estab-
lishing shelf-life). Stability typically continues after commercial
Figure 2. Key elements of comprehensive temperature excursion management approval through an annual stability testing program.
program.
The ICH Q5C recommends to conduct stability studies under
customer (e.g., replacement of the drug product if the shipment ar- accelerated and stress conditions as these may provide useful
rives under inappropriate conditions). support data for establishing the expiration date, provide
Patient handling and use (from pharmacy to patient as shown in product stability information for future product development,
Fig. 1) is not typically within the scope of the temperature excursion assist in validation of analytical methods for the stability pro-
management program, because continued monitoring at this point gram, and generate information which may help elucidate the
is typically not feasible. For patient use, appropriate handling and degradation profile of the drug product.11 Stability studies under
storage conditions and allowed time out of cold storage should stress conditions are useful to establish temperature and time
clearly defined in the product Instructions for Use. Appropriate allowances during drug product manufacturing and to deter-
protection from light exposure should also be considered as part of mine whether accidental exposures to conditions outside of the
Instructions for Use. Temperature excursion queries that may arise intended storage conditions (e.g., during transportation) are
during this stage due to improper handling (as communicated by deleterious to the product. Accelerated and stress stability also
the drug product user) may be handled by the manufacture's help evaluate which specific test parameters may be the best
Medical Information department, which may have data on file to indicators of product stability.11 Also, stability studies under
provide information in response to specific questions on temper- accelerated/stress conditions may reveal protein degradation
ature excursions (e.g., information based on in-use stability, pathways; if so, such changes should be monitored under pro-
development thermal cycling and stress study data, etc.). posed storage conditions.11 Intended, accelerated and stress
Depending on the query, other departments such as Quality and conditions used to assess the stability are described in ICH Q1
Pharmacovigilance/Safety may become involved in the response. (R2) guideline.11

IND / IMPD
Submission

NDA
Drug Preclinical Phase I Phase II Phase III Submission, Commercial
Discovery Development Clinical Trial Clinical Trial Clinical Trial Review and Manufacturing
Approval

Stability Testing to Support Formulation Stability Testing to Support Post-approval

Development and Clinical Trials Marketing Authorization Testing to
(Phase I and Phase II) (New Drug Application / NDA) Monitor Stability
Trajectory

Figure 3. Stability testing program used to support new drug development and product lifecycle management phases. IND: Investigational New Drug Application; NDA: New Drug
Application; IMPD: Investigational Medicinal Product Dossier.
2134 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
Table 1
Regulatory Expectations Applicable to Several Regions with Respect to the Justification of Temperature Excursions and Author's Perspectivea
Region(s) Regulatory Expectations
United States, Europe, Regulatory expectations regarding the primary stability
Canada, Japan, & Switzerland data package needed for a registration application
within these regions are described in ICH and/or
individual agency's guidelines. In brief, the stability
data from the accelerated and intermediate (if
applicable) storage conditions can be used to
evaluate the effect of short-term excursions outside
the label storage conditions. The ICH Q5C guideline
states that the stability data should be generated by
considering the external conditions which can affect
the product's potency, purity and quality. Health
Canada guideline states that the short-term
temperature excursions outside the intended storage
conditions may be acceptable provided stability data
and scientific/technical justification exist
demonstrating that product quality is not affected.
Australia Department of Health Therapeutic Goods
Administration (TGA) recommends performing
temperature cycling study on cGMP drug product
batches to assess the impact of short-term excursion
outside of the intended storage temperature range on
stability trajectory of the drug. The TGA's
recommendations regarding the design of the
temperature cycling study are summarized below.
Following an excursion outside of the intended storage
temperature range (2e8
C), the drug product may
only be supplied after the TGA has assessed the
stability data to support the release. This data may be
submitted as part of an initial application for
registration or as a variation to permanently allow
ongoing release within defined conditions.
The agency recommends including at least one cycle
above (and if desired, below) the intended storage
conditions (e.g., 5
C and þ30
C) in the cycling
study. Multiple cycles may be included if desired. The
duration of the cycle should mimic or exceed the
maximum likely duration of a shipping excursion.
The thermal cycling should be conducted at the
beginning of shelf-life and the samples should be
stored at the intended long-term storage conditions
for the remainder of the shelf life. Stability
assessment should be conducted at the end of the
shelf-life. Preferably, thermal cycling should be
performed on 3 batches of commercial scale product.
For already-registered products, the thermal cycling
can be incorporated into the design of the annual
stability study.
If a thermal cycling study has not been conducted, the
pharmaceutical company will need to provide a
justification with sufficient supporting evidence as to
why the product quality has not been impacted
following an excursion.
Brazil Brazil National Sanitary Surveillance Agency (ANVISA)
has recently updated the regulations for biological
products. Resolution No. 50 of September 20, 2011, as
amended by Resolution No. 25 of May 14, 2013,
includes procedures and conditions for conducting
stability studies for registration or post-registration
changes of biological products. As per this resolution,
the potential impact of excursions outside the
recommended storage conditions (e.g., high
temperatures and/or freezing) on the quality of drug
product must be evaluated through a stress study.
The stress study must be conducted with at least one
batch of the finished biological product.
For liquid drug products, a study must be conducted to
determine the product's freezing temperature, in
case it is foreseen that the product will be exposed to
temperature below 2
C.
The stress study is not a mandatory documentation to
file a biological product registration application in
Brazil. After an excursion has occurred, a report of the
stress study must be submitted with the stability data
obtained up to the end of the product's final validity
Author's Comments Reference(s)
11,21e24,46,51
Although the standard stability data generated
under accelerated storage conditions can be
used to support shipping excursions above
8
C, the knowledge gap with respect to the
impact of temperature excursions below 2
C
would exist. The regulatory guidelines do not
contain any recommendations about the
assessment of short-term temperature
excursions on the stability trajectory of drug
products through a thermal cycling study.
Therefore, the onus is on the pharmaceutical
companies to assess and justify the
temperature excursions below 2
C.
12
In addition to standard stability testing,
performing a formal thermal cycling on
commercial-scale cGMP drug product
batches is a regulatory requirement to justify
potential temperature excursions.
Unique recommendations included in the TGA
guideline regarding the design of thermal
cycling study and approach to the data
collection will have to be met by the
pharmaceutical companies.
Justification to utilize or release a commercial
batch in this region solely based on stability
data generated at accelerated storage
conditions or through development thermal
cycling studies (those not performed under
formal stability protocol on a cGMP batch),
may not be accepted in this region.
The authors recommend performing thermal
cycling as part of development stability
studies prior to executing a formal thermal
cycling as part of a formal stability program
using cGMP clinical or commercial batches to
verify that the risk to product quality is low
ahead of time.
78
Similar to TGA's expectation, the ANVISA also
recommends assessing the impact of short-
term temperature excursions on stability
trajectory of drug product through thermal
stress study. The only difference between the
expectations of 2 agencies is that the ANVISA
recommends performing the study on at
least one cGMP batch of drug product, while
the TGA imply performing the study on 3
cGMP batches of drug product.
Though stress study is not a mandatory
requirement to file a biological product
registration application in Brazil, it would be
prudent to plan and conduct the study ahead
of time.
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144 2135

Table 1 (continued )

Region(s) Regulatory Expectations Author's Comments Reference(s)

period to demonstrate that the product

characteristics have not been negatively impacted by
the excursion. The submitted report and data will be
analyzed for the freight clearance.
Ireland A standard operating procedure should be established
for the management of temperature excursions. After
an excursion, the event should be promptly and
thoroughly investigated. After completion of the
investigation, the outcome should be documented.
The impact of temperature excursion on product
quality should be ascertained and documented. The
product stored within the affected area should be
quarantined until the outcome of the investigation is
known. If a recall may be required, the HPRA should
be notified immediately. Corrective actions should be
identified and implemented following the
investigation to prevent reoccurrence.
ASEAN Data from the standard stability testing at accelerated
storage condition may be used to evaluate the effect
of short-term excursions outside the intended
storage conditions. The procedures should be
established for handling temperature excursions.
India Written procedures should be established for handling
of temperatures excursions outside the labeled
storage conditions. After an excursion occurs, the
cause for the excursion should be investigated.
51
There is no clarity in the guideline regarding the
studies to be conducted to support potential
temperature excursions. However, it is
reasonable to expect that the agency may ask
for a proper justification such as
development data to support the excursion.
11,21,24,54,79
The ASEAN Pharmaceutical Product Working
Group (PPWG) was established by the ASEAN
Consultative Committee for Standards and
Quality (ACCSQ). The ASEAN harmonized
with the ICH guidelines [ICH Q1A (R2), ICH
Q5C], which state that the standard stability
data at accelerated storage conditions can be
used to support shipping excursions above
8
C. However, the onus is on the
pharmaceutical companies to assess and
justify the temperature excursions below
2
C. The ASEAN guideline does not
specifically discuss thermal cycling studies.
80
The guideline does not specifically discuss
thermal cycling studies. However, it is
reasonable to expect that the agency may ask
for a proper justification and data to support
the excursion.

ICH: The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; cGMP: current Good Manufacturing
Practice; HPRA: Health Products Regulatory Authority; ASEAN: The Association of Southeast Asian Nations (ASEAN) was established on August 8, 1967.
The Member States are Brunei Darussalam, Cambodia, Indonesia, Lao PDR, Malaysia, Myanmar, Philippines, Singapore, Thailand and Viet Nam.
a
Regulatory expectations summarized in this table are based on guidelines published by the agencies.

Regulatory Expectations Regarding the Justification of Freeze-Thaw Studies

Temperature Excursions
The regulatory expectations applicable to several regions with
respect to the justification of temperature excursions and the
author's perspective are summarized in Table 1. Key takeaway mes-
sages from the global regulatory guidelines are that specific thermal
cycling studies (initial development thermal cycling and formal
thermal cycling on commercial-scale cGMP drug product batches)
are essential to assess the potential impact of short-term excursions
on the stability trajectory of drug product to support potential tem-
perature excursions/comply with global regulatory requirements.
Freeze-thaw studies, typically performed during formulation
development (to select a formulation that is stable to freeze-thaw
stresses) and in some cases as part of stability studies, are useful
to consider with respect to thermal cycling risk when the cycling
includes temperatures below 0
C. Depending upon the sensitivity
of drug product to freeze-thaw stresses, appropriate thermal
cycling conditions can be selected to minimize the risk/product
quality impact.
Historical Temperature Excursions

Thermal Cycling Studies to Assess the Impact of Temperature
Excursions on Drug Product Quality and Stability: Key
Considerations
It is beneficial to assess the impact of thermal cycling on stability
of drug product through a development stability study prior to
performing formal thermal cycling on commercial-scale cGMP drug
product batches. The development stability study will help assess
the risk associated with the thermal cycling conditions and the
findings can be used to select temperature/time conditions for
thermal cycling on commercial-scale cGMP drug product batches. It
is advisable to take several key factors (described below) into the
consideration when designing the thermal cycling studies (devel-
opment thermal cycling and formal thermal cycling on cGMP
batches).
Excursion conditions that may be encountered during the
distribution of drug product can be envisaged from the historical
knowledge/experience of similar products. Therefore, it is
important to collate and consider the historical excursion infor-
mation from the commercial distribution of existing biopharma-
ceutical drug products (e.g., number of excursions, excursion
temperature and excursion duration) when selecting the cycling
temperatures and duration of exposure. An example of summary
of hypothetical historical temperature excursions is shown in
Table 2 (this hypothetical example is for illustration and expla-
nation purposes only). This historical information shows that the
majority of excursions occurred between 8.1 and 25
C, and
relatively fewer excursions occurred above 25
C and below 2
C.
Based on this information, thermal cycling between 5
C and
25
C for reasonable durations would cover maximal future
2136 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144

Table 2 leverage the existing knowledge on protein degradation (generated

A Hypothetical Example of Information on Historical Temperature Excursionsa through the stability testing at accelerated storage conditions) to
Temperature Range Number of Excursions in One Year define the upper temperature limit and duration of exposure for
8.1 to 25
C 25
the thermal cycling study. In the case of liquid drug product, the
25.1 to 30
C 5 rate of protein degradation at 30
C is expected to be higher than
>30
C 2 that at 25
C and the level of degradation often depends upon the
1.9 to 0
C 11 exposure time. Including both 25
C and 30
C exposures for a
0.1 to 5
C 6
reasonable timeframe in the thermal cycling study allows to cover
5 to 10
C 2
maximal future excursions in the 9e30
C temperature range.
Minimum excursion temperature and duration of exposure at the minimum
excursion temperature are 8
C and 1 h, respectively.
Maximum excursion temperature and duration of exposure at the maximum Examples of Thermal Cycling Conditions
excursion temperature are 33
C and 3 h, respectively.
This type of information may be useful in selecting thermal cycling conditions for Based on expectations of the global regulatory agencies and type
the product of interest.
of drug product (lyophilized or liquid), examples of conditions for
Intended storage temperature is 2e8
C.
a
Assumed to have occurred during commercial distribution of existing bio- thermal cycling studies (applicable to both development thermal
pharmaceutical drug products. cycling and thermal cycling on commercial-scale cGMP drug
product batches) are proposed in Table 3. However, the actual up-
per and lower exposure temperatures and corresponding exposure
temperature excursions. If there is no historical knowledge on duration should be defined based on the expected ability of the
excursions, then temperature/time profiles of the shipping vali- drug product to withstand high/low temperatures as well as the
dation studies may be used to understand about the potential intended shipping conditions for the product. The proposed studies
excursions. are expected to determine the impact of short-term exposure of
drug product to temperatures outside of the intended storage
Protein Degradation Profiles temperature range (2e8
C) on product quality and stability. Hu-
midity control is not required in the study as the main objective of
The rate of protein degradation outside of the intended storage the thermal cycling study is to assess the impact of temperature
temperature range (2e8
C) may vary depending upon the sensi- stress only. The relative short exposures to minor variations in
tivity of molecule, type of formulation (lyophilized or liquid), and absolute humidity during distribution is considered to have a
exposure temperature and time. Therefore, it is important to negligible impact on drug product quality.

Table 3
Examples of Conditions for Thermal Cycling of Biopharmaceutical Drug Products (Lyophilized Drug Product in Vial, Liquid Drug Product in Vial and Liquid Drug Product in
Syringe) and Author's Perspective

Sample Thermal Cycling Conditions Author's Comments

A: Lyophilized Drug Product in Vial

Stressed/test sample Expose samples of drug product to 20
C for 2 days and 30
C The cumulative duration of exposure to the lower (20
C) and
for 2 days in each cycle. Perform 3 cycles before storage at 2 upper (30
C) temperature is 6 days. These thermal cycling
e8
C for long-term stability testing. It will be useful to store conditions are intended to cover the majority of potential
the test samples at accelerated storage conditions (e.g., 25
C) excursions. If 30
C is unacceptable for product quality or is
for short-term stability testing (6 months) to understand considered too close to the glass transition temperature (Tg)
protein degradation phenomenon not detectable at 2e8
C. of the lyophilized product, then 25
C can be used as the
upper temperature limit in the thermal cycling studies.
B: Liquid Drug Product in Vial
Stressed/test sample Expose samples of drug product to 20
C for 2 days and 25
for The lower temperature should be selected based on product
2 days in each cycle. Perform 3 cycles before storage at 2e8
C specific need as some liquid formulations may not contain
for long-term stability testing. It will be useful to store the cryoprotectant(s) or eutectic transition of some excipients
test samples at accelerated storage conditions (e.g., 25
C) for (e.g., NaCl) may occur around 20
C and impact product
short-term stability testing (6 months) to understand protein quality. It is advisable to assess the impact of short-term
degradation phenomenon not detectable at 2e8
C. exposure to temperatures below 0
C on product quality and
stability through a development study before selecting the
lower temperature. Exposing the drug product to 30
C for a
reasonable time frame in one of the 3 cycles will help support
temperature excursions in the 26
Ce30
C range.
C: Liquid Drug Product in Syringe
Stressed/test sample Expose samples of drug product to 5
C for 2 days and 25
C for Syringe may have little or no head space (between stopper and
2 days in each cycle. Perform 3 cycles before storage at 2e8
C product). Freezing and thawing of the product in syringe
for long-term stability testing. It will be useful to store the during thermal cycling may cause stopper movement (see
test samples at accelerated storage conditions (e.g., 25
C) for Plunger Movement Concern for Syringes section). Assessing the
short-term stability testing (6 months) to understand protein impact of short-term exposure to temperatures below 0
C on
degradation phenomenon not detectable at 2e8
C. product quality and stability, and container closure integrity
through a development study will be helpful to select the
lower temperature. If stopper movement during freezing is
considered high risk toward container-closure integrity, then
understanding the freezing point depression due to
excipients and the protein concentration is important.
Controls for thermal cycling studies: Samples stored at intended storage temperature (2e8
C) without cycling for the duration of the study, and sample stored at the
upper/lower cycling temperature (25
C/30
C/5
C/20
C) for the duration of time that thermal cycled samples were exposed to these temperatures. These samples
are intended to assess the impact of storage at these temperatures without temperature transition on the stability trajectory of drug product. Standard stability data at
intended and accelerated storage conditions can also be leveraged.
Thermal cycling chamber: If a single chamber capable of providing both the upper and lower cycling temperatures is used, then the duration of exposure starts from the
time the chamber reaches the target temperature.
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
Stability Testing and Analysis
After cycling between exposure temperatures, the samples are
stored at the intended storage conditions for the remainder of the
shelf-life of the product (control samples may be stored at the
upper/lower cycling temperature). As with any formal stability
study, at predetermined time points, the samples are pulled and
analyzed by validated/qualified stability indicating assays. The
long-term stability testing is performed till the end of the shelf-life
of the drug product to understand the potential impact on the
stability trajectory. The results of stability indicating assays must
meet the acceptance criteria. However, the ICH definitions may be
used to define significant changes.
The overall knowledge of drug product stability (stability data
from standard stability studies at accelerated storage conditions,
thermal cycling studies and shipping validation studies) can be
used to predict the effect of temperature excursions on drug
product quality during distribution and to establish shipping and
distribution control strategy documents. The overall knowledge
can also be used to pre-define the acceptable and unacceptable
levels of temperature excursions with respect to product quality.
Well-established GDPs help achieve commercial distribution of
drug products without or minimal temperature excursions.
Timing of Formal Thermal Cycling on Commercial-Scale cGMP Drug
Product Batches
There is no ideal time to perform formal thermal cycling on
commercial-scale cGMP drug product batches (required to comply
with the Australian and Brazil regulatory requirements) as it de-
pends upon the stage and scenario of project (e.g., risk associated
with the study, availability of development stability data, submis-
sion timing of regulatory application, etc.). However, it would be
prudent to perform the formal study at the appropriate moment as
part of the overall stability testing program to ensure that sufficient
stability data is available prior to submitting new drug application
in Australia and Brazil. If the study is performed too early, it might
be invalid if critical changes (e.g., changes in formulation, primary
container, or distribution) are made and the study will have to be
repeated. The thermal cycling should be performed on drug prod-
uct batches manufactured using a process that is representative of
the commercial process.
The potential window for performing formal thermal cycling on
the commercial-scale cGMP drug product batches is during the
phase (typically during Phase 3 clinical studies) when standard
stability testing is performed (Fig. 3) to support marketing autho-
rization (primary batches of drug product used for formal stability
studies can be used for the thermal cycling study). This strategy
gives sufficient time before the commercial launch to design a
robust cold supply chain and temperature excursion management
for the product based on the outcome of the thermal cycling study
(product quality and stability impact caused by the short-term
excursions outside of the intended storage temperature). It also
allows to leverage the knowledge gained from the study to define
the time out of cold storage allowances for the distribution and
patient handling or storage. However, the study can also be per-
formed using Process Performance Qualification batches or one of
the commercial batches after approvals in the USA, Europe, or other
regions (if there is enough lag phase before submitting new drug
application in Australia or Brazil).
Number of cGMP Drug Product Batches
Formal thermal cycling should be performed on at least one
commercial-scale cGMP drug product batch. However, some
2137
regulatory agencies (e.g., Australian regulatory agency) may prefer
3 drug product batches. Performing formal thermal cycling on 3
cGMP drug product batches will comply with the current Austra-
lian and Brazil regulatory requirements and help determine the
consistency in stability trends between pre- and post-stress con-
dition samples.
Plunger Movement Concern for Syringes
While product degradation is always a concern with temperature
excursions, container-closure integrity and maintaining a sterile
barrier is also of concern. For example, avoiding frozen conditions
that are below the glass transition temperature of the rubber stop-
pers (55 to 65
C) is advisable to ensure that stoppers maintain a
proper seal (below the glass transition temperature, rubber stoppers
may lose their elastic properties and become brittle).38,39
Pharmaceutical companies are expected to perform container-
closure integrity testing (this can also be in lieu of sterility
testing) as part of the stability testing protocols to comply with the
regulatory requirements. The plunger of a pre-filled syringe must
maintain sterility barrier to ensure drug product stability and ste-
rility throughout the shelf-life of the drug product. Therefore, it is
important to understand the effects of varying air pressure or
freeze/thaw events due to temperature excursions (thermal
cycling) on plunger movement and potential breaches to the
integrity of the sterile barrier.
Most stoppering processes leave a residual air bubble (head-
space) in the pre-filled syringe between the drug product and
stopper. Temperature excursions that lead to freezing (during
exposure at subzero temperature) and thawing events during dis-
tribution can cause stopper movement due to expansion of water
upon freezing (see the stopper movement after 1 freeze-thaw
cycles in Fig. 4 for an example). The potential concern associated
with multiple times stopper movement during distribution is the
breaching of the sterility barrier (see schematic diagram in Fig. 5).
However, breaching of the sterility barrier depends upon the
magnitude of stopper movement in the syringe. A study was done
to assess the impact of difference in atmospheric pressure during
air transportation on the level of stopper movement and integrity
of sterility.40 It was found that the sterility barrier could be
breached if the plunger moves past the second rib of the stopper
(for a stopper containing 3 ribs).40 The study was performed using
3-mL, 10-mL and 20-mL syringes and the maximum stopper
movement did not exceed one stopper rib distance for the typical
minimum aircraft ambient cabin pressure.40 The magnitude of
plunger movement was found to be influenced by the size of the
syringe and stopper, the level of headspace in the syringe (the
greater the headspace the greater was the plunger movement at a
given ambient pressure) and ambient pressure (gradual increase in
the plunger movement with increasing ambient pressure).40,41
If freezing in a syringe is known to move the stopper beyond an
acceptable point, or the risk of freezing relative to extent of stopper
movement is unknown, then the lower temperature limit allowed
for excursions should be based on the freezing temperature of the
formulation (in order to avoid freezing) as the excipients and pro-
teins have a depressive effect on freezing point (this limit may be
below 0
C).
How/When Thermal Cycling Study Data is Used to Support
Temperature Excursions
Thermal cycling study data (from development studies and in
some cases from formal thermal cycling on cGMP drug product
batches) and associated impact toward product quality and stability
may be included in a New Drug Application (NDA). Pharmaceutical
2138 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144

After Thawing (1X)

Before Freezing After Freezing (1X) Plunger Returned to Original
(Initial) Plunger Movement = ~ 1 rib / ~ 1.7 mm Position

1 cm 1 cm 1 cm

0.5 cm 0.5 cm 0.5 cm

1st rib of the
0 cm 1st rib of the 0 cm 2nd 0 cm 1st rib of the
2nd
plunger 2nd
plunger plunger

mAb solution Frozen mAb Thawed mAb

formulation formulation

Pre-filled Syringe (1 mL)

Containing mAb Solution

Figure 4. Pictures showing the plunger position before freezing (initial), after freezing at 20
C and after thawing (at room temperature) of a mAb formulation inside a syringe.

companies may set internal temperature excursion allowances based
on thermal cycling studies and standard stability testing data at
accelerated storage conditions to support potential temperature
excursions. The process regarding how and when the thermal cycling
study data is used to support potential temperature excursions vary
depending upon the location/region of the destination point.
In the event of temperature excursion during distribution from
the manufacturing site to the wholesaler/distributor located in
major countries (e.g., United State, European country, Canada and
Japan), an internal Quality representative or qualified person will
review and assess the temperature/time data of a shipment against
the internal allowances. If excursion(s) are within the internal al-
lowances, the shipment is released for transport to the next
destination. The Quality representative or qualified person may
reach out to technical expert(s) within the company to determine
the product quality impact and suitability for release when the
event falls outside of defined allowances. The internal process (e.g.,
handling of shipping excursions) may be reviewed by the regula-
tory agencies during pre-approval inspections and/or post-
approval inspections/audits.
In the case of Australia, temperature excursion allowances based
on formal thermal cycling on cGMP drug product batches and
technical justification must be submitted in the NDA (or as part of
the post-approval variation if the data is submitted after approval of
the drug) and obtain approval from the Department of Health
Therapeutic Goods Administration (TGA). The condition of
registration would be that the first 5 batches received in the
Australian market must be released by the TGA upon receipt of the
appropriate documentation (e.g., Quality Control records and cold-
chain temperature monitoring information). Thereafter and
depending on the outcome of the first 5 batches, the TGA will
determine whether to continue the batch release via the agency or
waive the requirement. If the TGA decides that batch release does
not have to be via the agency, then the onus is on the pharma-
ceutical company to review temperature/time profile of a shipment
to identify excursion and release the batch provided the excursion
falls within the TGA approved allowances. If the temperature
excursion falls outside of the TGA approved allowances and the
company believes that product is acceptable to release to market, a
variation needs to be submitted to the agency with a justification to
obtain a batch specific exemption.
In the case of the Brazil market, development and formal ther-
mal cycling study data along with a technical justification is pro-
vided to the customs in the event of a temperature excursion for
evaluation and clearance of the shipment.
Cold Supply Chain Management: Good Distribution Practices
to Minimize Temperature Excursions and Ensure Global
Compliance
Maintaining a robust cold-chain during distribution of drug
product from the manufacturing/labelling site to the intended

1st movement 2nd movement 3rd movement

Initial / Starting Stopper Movement Stopper Back to Stopper Movement Stopper Back to Stopper Movement Stopper Back to
Position (1 rib of the stopper) Initial Position (1 rib of the stopper) Initial Position (1 rib of the stopper) Initial Position

Microbes / spores

Figure 5. Schematic diagram showing the movement of microbe/spore as a result of multiple times movement of stopper inside a syringe. The stopper movement can be caused by
expansion and contraction of an air bubble inside a syringe during air transport (due to difference in atmospheric pressure) or multiple freeze-thaw cycles.
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
destination is essential to ensure product quality and regulatory
compliance, prevent financial loss or liability, and improve supply
chain efficiency. Therefore, the cold supply chain management
plays a key role in achieving this goal and it defines how
temperature-sensitive products are packaged, transported and
stored to ensure that the product remains within its recommended
conditions throughout the distribution process. However, this task
is often complex due to formidable challenges associated with the
global distribution process (e.g., remote locations, multiple ex-
change and drop-off points, different climate zones and seasonal
changes, and lengthy clearance procedures at customs end). Taking
a holistic approach for the cold-chain management (summarized
below) is necessary to achieve intended goals.
Global Regulations and Expectations
It is challenging to ensure global compliance because of several
requirements and expectations regarding the temperature-
controlled distribution (e.g., regulations, guidelines, technical re-
ports, standards, and recommendations). As a result, there is a
potential risk of non-compliance with some of the regulations,
guidelines, or standards. Therefore, design and governance of the
cold-chain should be based upon a combination of global regula-
tory requirements/expectations (defined by the agencies of
different countries or regions) and industrial standards/best prac-
tices (developed by several organizations, Table 4).
Thermal Packaging Systems
Thermal packaging systems are an important element of the
cold-chain distribution. Three types of basic thermal packaging
systems are usually used to maintain the product in the intended
storage temperature rangedactive (thermal system that use me-
chanical or electric systems powered by an energy source to
maintain intended storage temperature), passive (thermal system
that use phase change materials such as ice or dry ice to maintain
intended storage temperature) and hybrid (thermal system that
use a combination of phase change materials as a source of
energy and thermostatic controls to maintain proper product
temperature).42e44
Underdesigning the thermal packaging system by selecting low-
cost components may result in frequent temperature excursions.
Overdesigning thermal packaging to achieve 100% success rate to
withstand against all environmental conditions and unpredictable
hurdles may result in large, heavy and expensive systems. There-
fore, a balanced approach is advisable to select the custom thermal
packaging system by taking several factors (e.g., advantages, dis-
advantages, capabilities and thermal performance of the system,
payload, shipping routes, physical performance of the packaging,
environmental impact, system cost and stability profile of drug
product) into the consideration.42e45 Qualification of the selected
thermal packaging system is also an important element of the GDPs
and it should be validated against rigorous global standards to
ensure that it can maintain the temperature within the intended
storage temperature range (2e8
C).1,13,14,23,24,46e62
Innovative Technologies/Solutions
Temperature monitoring during distribution is necessary to
ensure that the product remains within the intended storage
temperature range during cold-chain distribution. Innovative
temperature monitoring technologies/solutions have been intro-
duced to have greater visibility and control over the shipping
conditions throughout the cold-chain distribution.2,4,7,9,63,64 Ship-
ping drug product inside passive coolers along with advanced
2139
temperature monitoring system provides several benefits,
including real-time temperature monitoring of product, ability to
adjust temperature during shipment when temperature start to go
outside of the intended storage temperature range and precise
tracking of the shipment.7,9,63,64 Next generation automated
monitoring systems not only enable to monitor and track storage
and transport conditions, but can also provide controlled envi-
ronments throughout the cold-chain distribution.2,9,63,65 Using
innovative technologies with shipments can ensure optimal prod-
uct handling and successful timely delivery.2,9,63 Therefore, the
cold-chain logistics of pharmaceutical companies should evolve
continuously by adopting innovative technologies for monitoring
temperature during distribution. Integration of innovative tech-
nologies into the cold supply chain is in alignment with the GDPs.
Documentation and Standard Operating Procedures (SOPs)
Proper documentation of aspects related to the cold-chain
management (e.g., documentation related to storage, transport,
precautions, warnings, agreements if applicable, records of in-
vestigations and actions taken, time out of cold storage allowance,
etc.) is necessary to comply with the global regulatory expectations
and meet international industrial standards.1,7,9,14,24,46,47,58,65 The
SOPs to receive, store and transport drug products and to ensure
the quality of cold-chain management should be in place and
effective.1,7,9,14,24,46,47,58,65
Personnel Training
Training is an essential element of the cold-chain management
and all personnel involved in the cold-chain distribution activities
(e.g., handling, storage and transport) should be trained by quali-
fied persons. The training should be provided based on written
SOPs and the personnel should receive initial and continuing
training relevant to their tasks.1,7,9,14,24,46,47,58,65 The trainings
should be assessed periodically as applicable to evaluate the
effectiveness of the training (actions taken). Proper records on
training (e.g., details of topics covered, participants trained, and
actions taken) should be maintained.1,7,9,14,24,46,47,58,65
Quality of External Logistics Companies
Many pharmaceutical companies turn to external logistics firms
that have required technology, infrastructure and systems for cold-
chain distribution of drug products. However, the quality of service
provided by the third-party logistics firms may vary. Therefore, it is
important to set selection criteria (e.g., transportation and ware-
housing cost, logistic infrastructure and warehousing facilities,
customer service and reliability, network management, material
handling capabilities, quality control and inspection, automation of
processes, innovation and effectiveness of cold-chain processes,
and information technology applications for tracking and tracing)
and assess the third-party logistics firms against the criteria before
making a selection to ensure that the service is efficient, cost-
effective and un-disruptive.
Shipping Validation
Global distribution environments vary significantly, especially
when a drug product is shipped between different climatic zones.
Seasonal changes, the method of transportation, and the number of
drop-off points can also vary. Shipping validation studies should be
conducted under real-time shipping conditions (i.e., temperature,
mode of transport, shipping duration, and shipping containers and
packing representative of the minimum and maximum load) to
2140
Table 4
Regulatory Requirements/Expectations Defined by the Agencies and Standards/Best Practices Developed by Several Organizations Regarding Storage and Distribution
Practices
Organization/Pharmacopeia/Agency and Applicable
Document
United States Pharmacopeia Chapter <1079> Good
Storage and Shipping Practices
European Guideline on GDPs
Australian Code of Good Wholesaling Practice
Health Canada Guidelines (GUI-0069) for
Temperature Control of Drug Products during
Storage and Transportation
China Good Supply Practice Standards for
Pharmaceutical Products
Indian Guidelines on Cold-Chain Pharmaceutical
Products
Irish Guide to Control and Monitoring of Storage
and Transportation Temperature Conditions for
Medicinal Products and Active Substances
Malaysian Guidelines on GDPs
Russian Code of Good Practice in the
Pharmaceutical Industry
K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
Summary References
46
This chapter provides the requirements related to several aspects of good storage
and distribution practices, including labelling, quality management, storage
management, distribution management, excursion assessment, and risk
management. All persons and companies involved are responsible and
accountable to ensure that the practices are followed, which will help facilitate
the movement of drug products throughout a supply chain that is controlled,
measured, and analyzed for continuous improvements. The pharmaceutical
company is expected to be adaptive to potential changes as innovative solutions
evolve and integrate them in developing strategies for GDPs, controls, and
procedures.
47
The European Commission has issued revised guideline on the November 5, 2013. It
provides the requirements related to several aspects of GDPs (quality
management system, personnel, premises and equipment, documentation,
operations, outsourced activities, self-inspections, transportation, complaints and
returns/recall and provisions for brokers) to ensure compliance and product
quality. All persons and companies involved must comply with the requirements
described in the guideline.
48
This code is applicable to manufacturers, wholesalers, manufacturer's agents,
importers and distributors who store and/or supply medicines included in
Schedules 2, 3, 4 and 8 of the Standard for the Uniform Scheduling of Drugs and
Poisons or other applicable State or Territory poisons legislation. This code of
Practice sets out standards applicable to transport, buildings and grounds,
facilities, personnel, stock handling and control, complaints and records and all
involved are responsible to apply these standards to ensure that the medicines
are stored and distributed in accordance with the label requirements of the
sponsor, State and Territory legislation and this code.
23
All persons and companies involved in the storage and transportation of drug
products are expected to comply with the recommendations (applicable to
warehousing and storage, product transportation, containers, receiving and
documentation) to ensure that appropriate storage and transportation conditions
are maintained from the point of manufacturing up to the delivery of the drug
products to the final distribution point. The maintenance of the chain of storage
and transportation conditions should be supported by written agreements
among the distributor, the importer, the wholesaler, and the transportation
provider. The responsibility of each party is to ensure that the required storage
and transportation conditions are met through their respective GMP activities.
Alternative means of complying with the intent may be considered with
appropriate scientific justification.
49
China Food and Drug Administration issued revised guideline that contains higher
standards on Good Supply Practice for Pharmaceutical Products and it came into
effect as of July 13, 2016. As per the guideline, pharmaceutical wholesalers and
retailers are required to establish a comprehensive quality control system,
dedicated qualified quality management personnel to handle quality control
matters, and conduct internal audits periodically. All persons and companies
involved are expected to take effective quality control measures related to
purchase, storage, sale, and transportation of drugs to ensure the quality of drugs
and establish the drug traceability system in accordance with the relevant
requirements of the state to achieve the traceability of drugs.
50
Organization of Pharmaceutical Producers of India Guidelines on Cold-Chain
Pharmaceutical Products provides standard operating procedures for various
stakeholders. The booklet includes guidelines for storage and handling at airports
and seaports, customs clearance and sample testing by the Assistant Drug
Controller Office, transportation in refrigerated vans, and handling of cold-chain
products by distributors and retailers.
51
The document provides guidance to manufacturers, wholesalers and transporters in
relation to conditions for cold storage/cold-chain and controlled temperature
storage. All involved must implement controls described in this guideline to
ensure continuity of the ‘cold-chain’ while the products are in their care and
comply with the requirements for controlled temperature storage.
52
The guideline describes the principles on several aspects (quality management,
personnel, premises and equipment, stock handling and control, transportation,
complaints, recall, counterfeit products, outsourced activities, self-inspection,
records and documentation) for those involved in the supply chain in conducting
their activities to ensure the maintenance of high standards of quality assurance
and integrity of the distribution processes. The principles, where applicable,
should be adapted to meet individual company's needs. Alternative practices can
be adopted provided that those practices are shown to achieve an outcome that is
equivalent to or better than the provisions described in the guideline.
53
The main objective of the Code is self-regulation of the pharmaceutical industry in
the Russian Federation, as well as the establishment of fair, open and honest rules
of competitive cooperation in the pharmaceutical industry. All persons and
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144 2141

Table 4 (continued )

Organization/Pharmacopeia/Agency and Applicable Summary References

Document

Singapore Guidance Notes on GDPs
South African Good Wholesaling Practice for
Wholesalers
World Health Organization (WHO) Model Guidance
for the Storage and Transport of Time- and
Temperature-Sensitive Pharmaceutical Products
International Safe Transit Association (ISTA)
Standards 7E and 20
Parenteral Drug Association (PDA) Technical
Reports 39 and 46
International Air Transport Association (IATA)
Standards
manufacturers involved in the storage and distribution should comply with the
new rules described in this document.
54
This guide is applicable to all steps involved and covers controls appropriate for
storage and distribution of products. Those involved should implement the
recommended controls to ensure that the quality and integrity of the products
are maintained throughout the distribution chain.
55
This guideline outlines Good Warehousing Practices for all parties involved in the
supply chain of pharmaceutical products. The practices are applicable to
pharmaceutical products which move through the supply chain from the
manufacturer to the end user and backwards because of the return or recall. All
parties involved in the wholesaling process should adhere to the practices
described in the guideline.
24
The document outlines the principal requirements for the safe storage and
distribution of time- and temperature-sensitive pharmaceutical products
(TTSPPs) and gives a balanced overview of the major aspects of good storage and
distribution practice for TTSPPs. The guidelines are based upon existing
regulations and best practice guidance from a wide range of international
sources. The guidelines are applicable in less-developed countries as well as in
the industrialized world.
56,57
Biopharmaceutical products should be shipped using containers and packaging
methods that have undergone a rigorous design and performance qualification
processes. The ISTA is a global organization, which has created relevant standards
(7E and 20) for qualifying the shipping containers. The ISTA standard 7E is the
first data-based thermal profile. Standard 20 outlines how to create test protocols
and the tests include design testing, thermal qualification, physical qualification
and thermal qualification. Combined with Standard 20, 7E thermal profiles can be
used for comparative analyses of shipping package thermal properties. It is
noteworthy to mention that the ISTA 7E profiles only apply to North America and
related regions. Therefore, it's essential to refer to region-specific regulatory
standards to ensure global compliance.
1,14,58
The PDA has introduced technical reports that provide guidance to all involved on
the essential principles and best practices for transporting temperature-sensitive
products. The guidance provided in the technical reports is useful to develop own
process which should comply with the global regulatory requirements.
59e61
The IATA is the industry's global trade association, which has developed standards
and solutions to ensure a safe and harmonized air transport system. Chapter 17
“Air Transport Logistics for Time and Temperature Sensitive Healthcare Products”
in the IATA perishable cargo regulations provides the requirements for the
transportation of time and temperature sensitive healthcare cargo shipments.
The chapter also sets out standards such as the use of the IATA Time and
Temperature Sensitive label. This label is mandatory for the transportation of
health care cargo shipments and provides several benefits (e.g., better
identification, faster supply chain transit handling, greater reliability and
accuracy, and decreases risk).

GDPs: Good Distribution Practices.

evaluate the ability of the shipping containers to maintain the
intended temperature and to evaluate the impact of shipping on
the physical integrity and drug product quality.62,66,67 Simulated
shipping studies can be used, but must be sufficiently representa-
tive of the commercial shipping conditions.66 Pharmaceutical
companies are expected to provide detailed information about the
method and the results (e.g., physical integrity, temperature pro-
files, product quality pre- and post-shipping, etc.) of shipping
validation in the manufacturing process validation section of the
market application dossier.
Specific guidance regarding the shipping validation studies can
be found in the Parenteral Drug Association (PDA) Technical Re-
ports (PDA Technical Report No. 53: Guidance for Industry: Stability
Testing to Support Distribution of New Drug Products, PDA Tech-
nical Report No. 58: Risk Management for Temperature-Controlled
Distribution and PDA Technical Report No. 72: Passive Thermal
Protection Systems for Global Distribution: Qualification and
Operational Guidance).15,68,69 It is noteworthy to mention that the
specific procedures are at the discretion of each biopharmaceutical
company to design studies based on the intended shipping process,
but the evaluation method should include worst-case shipping
conditions with respect to distance, duration, temperature, mode of
transportation and vibration. Also, the drug product used in the
shipping studies should be manufactured using a process repre-
sentative of the commercial process, same formulation and pack-
aged in the same container closure system as that proposed for
commercial batches.
Rational Use of Theoretical Methods/Mathematical
Simulation Models
As per the ICH Q1A guideline, mean kinetic temperature (MKT)
is defined as “a single derived temperature which, if maintained
over a defined period, would afford the same thermal challenge to a
drug substance or drug product as would have been experienced
over a range of both higher and lower temperatures for an equiv-
alent defined period”.11,46 In other words, the MKT is a calculated
fixed temperature that simulates the effects of temperature varia-
tions over a period of time.46 It expresses the cumulative thermal
stress experienced by a product at varying temperatures during
storage and distribution (see the equation below).46
2142 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
DH=R
Tk ¼ 0 1
B RTDH RTDH DH C
B ð1Þ RTðnÞ C
lnBe þ e n þ/e C
ð2Þ
@ A
Where Tk is the mean kinetic temperature; DH is the heat of acti-
vation (assumed to be 83.144 kJ per mole); R is the universal gas
constant (8.3144  103 kJ per mole per degree); T1 is the value for
the temperature recorded during the first time period; T2 is the
value for the temperature recorded during the second time period;
Tn is the value for the temperature recorded during the nth time
period (n being the total number of storage temperatures recorded
during the observation period). Note all temperatures, T, are abso-
lute temperatures in degrees Kelvin (K).
Seevers and co-workers evaluated the use of MKT in evaluating
temperature exposure outside refrigerated storage condition dur-
ing the distribution process.70 Calculated MKT was found to be not
sensitive to the impact of excursions that may occur if the baseline
is a long period of time such as storage segment.70 In the case of
shorter baseline periods of time (e.g., transportation or distribution
segments), it was noted that an excursion can have a significant
impact on the resulting MKT, but this would not necessarily have a
significant impact on product quality.70
It appears that the use of MKT in the distribution environments
is limited to temperatures for which there is actual stability data to
support the finding. The MKT analysis must be based on sound
science and existing stability data should be taken into the
consideration or used for comparison. The MKT and its use in dis-
tribution applications is expected to evolve as guidance, regula-
tions, and technologies progress.
Recently, Clenet applied kinetic analysis models on forced
degradation data to predict the long-term vaccine degradation of
the freeze-dried products under specific temperature excursions.71
The kinetic-based approach was found to accurately predict the
impact of temperature excursions on vaccine degradation.71 The
accurate prediction requires appropriate controlled temperature
monitoring, so that the real temperature/time profiles can be used
in the kinetic analysis. If this kind of kinetic model is integrated into
electronic temperature-time monitoring devices, real-time infor-
mation on temperature excursions and their impact on protein
degradation could be obtained.71 It is reasonable to predict that the
advanced kinetics and stability modeling approaches can be a very
useful tool in evaluating the temperature excursions, especially in
remote areas. This kind of analysis can also be used to support the
conclusions gained from the standard stability testing or thermal
cycling study.
Arrhenius equation-based mathematical simulation model has
been used to understand product's stability performance.72 The
mathematical simulation model was based on stability data at
intended and accelerated storage conditions, Arrhenius equation
and first-order kinetic equation.3,72 Using this approach, a mathe-
matical simulation of the product degradation was run which
showed the product stability performances.3,72 Based on this
approach, a relationship between time and temperature could be
established.73 This approach shows how much time is acceptable at
a defined temperature for a given product before it undergoes
significant/unacceptable degradation. Based on this information, it
is possible to determine the potential degradation that may have
been caused by the temperature excursions is acceptable or
unacceptable.
Arrhenius kinetic models are more widely used for small
molecule drugs. While Arrhenius kinetic model may be applicable
to some biopharmaceutical product quality attributes (Arrhenius
kinetic model has been used to understand temperature-
dependent chemical degradation of proteins, such as oxidation
and deamidation),74 they may not be applicable to others (e.g., non-
Arrhenius aggregation behavior has been demonstrated for some
proteins).74,75 Interestingly, Arrhenius kinetics has been demon-
strated for some physical reactions of protein molecules (i.e.,
without changes in covalent bonds).74,76,77
In summary, the use of theoretical methods/mathematical
simulation models to evaluate the impact of temperature excur-
sions on quality and stability of temperature-sensitive products can
provide useful information that can be used in conjunction with the
actual stability data to justify temperature excursions.
Concluding Remarks
Global regulatory agencies expect that pharmaceutical com-
panies distribute biopharmaceutical drug products to the intended
destination in a manner that ensures that the product quality and
stability are not negatively impacted by temperature excursions.
The regulatory expectations and industrial practices regarding the
justification of temperature excursions and global distribution
process have evolved in recent years.
Successful distribution of biopharmaceutical drug products is a
challenging task due to several uncontrolled variables and unex-
pected events associated with the global distribution process. It is
imperative for all firms involved to understand and overcome the
challenges of global distribution. A proactive and comprehensive
temperature excursion management program is necessary to
ensure that drug product reaches the end user without compro-
mising quality, stability and efficacy of the product and patient
safety. The comprehensive temperature excursion management
program can be designed by integrating key elements of the
product lifecycle management and global distribution processes in
the program.
Standard stability testing at accelerated storage and stress
conditions may reveal protein degradation pathways which can be
leveraged to select conditions for thermal cycling studies. Thermal
cycling studies should be conducted by taking several key factors
into the consideration to assess the impact of the short-term
exposure of drug product to conditions outside the intended stor-
age temperature on product quality and stability and use this data
to pre-define temperature excursion allowances and support po-
tential temperature excursions. A robust cold-chain model is
necessary to prevent/minimize temperature excursions during
distribution. It is advisable to consider key elements of the global
distribution process when designing the model for cold-chain
distribution. Theoretical assessment methods or mathematical
simulation models provide useful information regarding the impact
of temperature excursions on the quality and stability of
temperature-sensitive products and it is advisable to use them in
conjunction with the actual stability data to justify temperature
excursions.
A comprehensive temperature excursion management program
is expected to not only help minimize, assess, or justify tempera-
ture excursions more efficiently, but also ensure regulatory
compliance.
Disclaimer
This article reflects the views of the authors only and should not
be construed to represent regulatory authority's, GlaxoSmithKline's
or any other applicable International Organizational's views or
practices. GlaxoSmithKline is not responsible for author's views
expressed in this article. Regulatory expectations/ standards/dis-
tribution practices summarized in this article are based on the
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144
current environments and these may evolve with time. Therefore,
the readers are advised to seek most recent information from
relevant sources.
Acknowledgements
The authors thank Alan Forthman (Supply Chain Solutions),
Michael Schwartz (CMC Regulatory Affairs, USA), Jamie Fox (Reg-
ulatory Compliance, USA), Deidre Malton (Regulatory Affairs Op-
erations, Australia) and Monique Lellis Prado (LOC Quality, Brazil),
GlaxoSmithKline, for sharing their opinions.
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