Journal of Pharmaceutical Sciences 112 (2023) 2981−2990

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Journal of Pharmaceutical Sciences

jo urn a l h om ep ag e : w [Link] harms ci.o rg

Perspective

Industry Perspective on Temperature Cycling Studies to Meet

Regulatory Temperature Excursion Support Requirements:
Survey Outcome and Recommendations
Claudia Aranaa, Junyan Jib, Elisabeth Krugc, Jing Liud, Lori McCaigd, Bob Rozaieskie,
Camilla Santosf, Jessica Sloang, Amy M. St. Charlesh, Frank Wiegeshoffi,*
a
Bristol Myers Squibb, New Brunswick, NJ, USA
b
Genentech (A Member of the Roche Group), South San Francisco, USA
c
Eli Lilly and Company, Indianapolis, IN, USA
d
Seagen Inc., Bothell, WA, USA
e
Merck & Co., Inc., Rahway, NJ, USA
f
Amgen Inc., West Greenwich, RI, USA
g
Biogen Inc., Cambridge, MA, USA
h
Pfizer Inc., Chesterfield, MO, USA
i
AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Temperature cycling stability studies can be appropriately designed and utilized to ensure that drug product quality, effi-
Received 2 June 2023 cacy, and safety are not compromised when materials are subjected to short term temperature excursions from intended
Revised 20 September 2023 storage that may occur during e.g., shipping, transport, or patient use. Some countries, such as Australia and Brazil,
Accepted 20 September 2023
impose specific regulations that specify the need to conduct stability studies that are supportive of “real world” excur-
Available online 27 September 2023
sions as part of licensing approval requirements. These temperature cycling stability studies extend beyond what is
described in ICH Guidelines Q1A(R2) and Q5C, and companies may be challenged in designing studies that not only sat-
Keywords:
isfy country specific regulations, but also satisfy all global regulatory health authority expectations. This article focuses on
Stability
Temperature excursion
responses to a cross-industry survey conducted within the International Consortium for Innovation and Quality (iqcon-
Thermal cycling [Link]) member companies, regarding practices related to temperature cycling stability studies, in order to deter-
Shipping excursion mine how these requirements are being interpreted and met. The results indicate that while there is no one-size-fits-all
Biologics approach to performing temperature cycling stability studies, there are common and best practices that can be followed
Best practices to satisfy global health authority regulatory guidelines and requirements.
Drug product Purpose: The purpose of this paper is to describe the outcome of an industry survey and common/best practices on
Regulatory expectations temperature cycling stability studies performed on drug product (DP) to satisfy the requirements established for mar-
keting authorizations in Australia and Brazil or any other countries that may have similar requirements. The frame-
work is proposed within the context of late phase and commercial development of common biological and/or large
molecule modalities, such as monoclonal antibodies (mAbs, including bispecific antibodies), fusion proteins, complex
proteins, oligonucleotides, and antibody-drug conjugates (ADCs), but many of the general principles involved may be
applied to other therapeutics, such as Virus Like Particles (VLP), gene or cell therapies (GTx or CTx), or vaccines.
For the purposes of this paper, temperature cycling stability studies refer to studies that are designed, in part,
to support short term temperature excursions that drug product may be subjected to during shipping and
storage activities and is outside of the labeled storage condition of the product.
© 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Introduction new investigational drug substances and products, to provide evi-

dence of how the quality of the drug substance or drug product varies
ICH Guidelines Q1A(R2) and Q5C address information to be sub- with time under the influence of a variety of environmental factors
mitted in a core stability data package in registration applications for such as temperature, humidity, and light, and establish a retest
period or shelf-life, and recommended storage conditions.1,2 While
there is general mention that data from accelerated or intermediate
* Corresponding author.
storage conditions can be used to evaluate the effect of short-term
E-mail address: [Link]@[Link] (F. Wiegeshoff).

[Link]
0022-3549/© 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.
2982 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990

Table 1
Temperature cycling stability study requirement comparison.

Requirement ICH Q1A (R2) stability testing of ANVISA RDC No. 412 20 Aug 2020 TGA stability testing for prescription
new drug substances and medicines 6 Mar 2017
products 6 February 2003
ICH Q5C stability testing of
biotechnological/biological
products 30 November 1995

Temperature cycling study Does not explicitly require or Yes, to support deviations to storage Yes, to support deviations to storage
describe conditions conditions
Number of Batches N/A At least one Preferably three
Manufacturing Scale N/A Representative of commercial scale Commercial scale
Cycle description N/A Representative of the temperature Representative of temperature devi-
deviation. Further cycle design ation (magnitude of time and tem-
examples or description not given. perature), examples given. At least
one cycle, multiple may be
included.
Storage at long-term storage N/A Yes Yes
condition through shelf life
Justification required if study not N/A Yes Yes
conducted or completed

excursions outside the label storage conditions, such as during ship- The survey comprised 45 questions (please see supplementary online
ping or handling, there is no further guidance with respect to addi- material).
tional studies that may support real world excursions that could be
encountered. Additionally, the ICH guidelines do not address specific
national or regional expectations. Some countries have incorporated Results
more specific requirements for temperature cycling stability studies
for drug product into their regulations or guidance documents. Out of 21 biopharmaceutical/biotech companies contacted 13
Table 1 details a comparison of temperature cycling stability study responded. Fig. 1 provides an overview of the product types included
requirements from ICH, ANVISA (Brazil’s regulatory authority) and in the responses.
TGA (Australia’s regulatory authority).1−4 The majority of the survey participants indicated that they strive
In response to industry questions, the Temperature Excursion to use a common world strategy approach when designing tempera-
Stability IQ Working Group was formed in 2018 to develop a ture cycling stability studies, however, alternative strategies have
corresponding guidance. The IQ Working Group authored a also been utilized, as demonstrated in Fig. 2. Where a common world
survey for industry with the intent to gather information from strategy is not being carried out, companies may instead be using
IQ member companies on how these requirements are being separate strategies to address each specific country requirement or a
interpreted and to recommend common practices on temperature common regional strategy, where the requirements of Australia and
cycling stability for fulfillment of global regulatory requirements, Brazil are coupled together and used in conjunction with other stud-
if appropriate. ies that support other world markets.
In general, temperature cycling stability studies are performed
throughout product development and those early studies augment
Method data generated in either the registration phase for global markets or
in a post-approval/ lifecycle stage of the product to enable a success-
To evaluate both general temperature cycling stability study prac- ful submission in Australia and Brazil.
tices and those used to address Brazil’s and Australia’s requirements, The following sections present all available data received from the
a survey was circulated to IQ consortium member companies. responses for the key topics from the survey.

Figure 1. Overview of product types included in company response.

 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990 2983

Figure 2. Summary of how responding companies currently address requirements.

Material and Batches Temperature Cycling Stability Study Design

About 50 % of the responding companies use materials from three Two study designs were described by the survey participants:
batches to meet the preference set out by the Australian and Brazil
agencies in a combined approach, whereas the other 50 % submitted  In the first study design type, one or two temperatures (one above
data for one batch only (Fig. 3). If materials from multiple batches are the storage condition and if desired one below) are included
used, a bracketing/ matrixing strategy to support multiple product within a single cycle (or block) followed by placing the materials
strengths or presentations is often employed (e.g., fill volume/head- at the long-term temperature conditions.
space; container/closure systems).  The second design type utilizes a multi-step temperature profile
The majority of responding companies utilize drug product mate- (more than 2 temperatures) in multiple cycles with subsequent
rials available throughout the development life cycle, such as batches placement of the material at the long-term temperature condi-
supporting toxicological studies, development batches, or GMP tions.
batches, as long as the batches meet representativeness criteria, in
the design of temperature cycling stability studies. However, all com-
Tables 2 and 3 show a summary of the cycling conditions used by
panies reported eventually also utilizing commercial scale materials
the companies on the same sample; the actual study design, (e.g., the
in temperature cycling stability studies (either ICH/primary/registra-
order in which the cycles were applied before placing the material on
tion materials or process validation (PPQ) batches) (Fig. 4).
long-term stability to the end of shelf-life) may not be reflected as it

Figure 3. Summary of number of batches being utilized in design of temperature cycling studies.
2984 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990

Figure 4. Summary of material being utilized in design of temperature cycling studies.

Table 2 studies as part of product development and characterization. Ship-

Minimum and maximum conditions in a single cycle (or block). ping validation studies may also incorporate multiple forms of stress.
Temperature [ C] Days Modality

Company 1 50 180 Gene / Cell Therapy Products

Testing Strategy
5 2
Company 2 20 7 Monoclonal Antibody As indicated in Fig. 6, the overwhelming majority of companies
25 32 include all shelf-life specification tests into the testing program. Very
30 32
few also conduct additional characterization on the product. One
Company 5 20 30 Virus Like Particles (VLPs) | Antibody
25 30 Drug Conjugate | Vaccine company only performs these studies with a minimal subset of stabil-
Company 11 25 14 Monoclonal Antibody | Antibody Drug ity indicating tests.
Conjugate | Fusion Proteins/Bi-specific If changes to critical quality attributes (CQAs) are observed on the
Proteins/More Complex Proteins stressed material, most companies perform investigations as part of
Company 13 25 30 Monoclonal Antibody | Antibody Drug
Conjugate | Fusion Proteins/Bi-specific
their quality system obligations (out-of-trend/ out-of-specification).
Proteins/More Complex Proteins However, if the change does not impact meeting the specification
acceptance criteria no action is taken. If the specification acceptance
criteria are not met, then companies either restrict the allowance for
depends on the specific product characteristics. Of companies using a excursions or look for alternatives to control their shipping process
single cycle or block design (Table 2), two companies only test for (e.g., shipping containers). One company exposes additional subsets
high temperature in a single cycle followed by the end of shelf-life of batches to shorter or longer excursion periods as a contingency.
study.
In order to mimic or exceed the maximum likely duration of “real-
life” temperature excursions and be prepared for both low and high Data Package Used for Submission
excursions, most companies investigate the effects of temperature
excursions by performing multiple alternating low and high temper- How much data is provided to the agencies may depend on the
ature excursions versus exposing the product to a single excursion at submission strategy a company pursues. On the extremes, one com-
one or both extreme temperatures. pany is generating full shelf-life data prior to submission, while four
The cycling in all the above study designs is then followed companies have the excursion study started, but do not provide any
through the end-of-shelf-life at the recommended storage condition. stability data when submitting. The remaining companies submit
More than 50 % of the companies do not have a requirement in with the data available at the time of filing, ranging from 3 to 12
which timeframe after manufacture the temperature cycling study months. The companies that submit with no or less than full shelf-life
should start. For those companies that recommend a start date for data from the cycling study typically provide additional available
the temperature cycling study, most of the companies will schedule data upon request of the health authorities. Only one company com-
the study within the first six months after manufacture (Fig. 5). mits to provide the data to the agencies prior to launch.
While drug product may be subjected to stress factors other than
temperature excursions during shipping (such as light exposure, Additional Considerations for Temperature Cycling Stability Studies
vibrations, etc.), these factors are typically outside of the scope of the
temperature cycling stability studies discussed here. Temperature, To explore acceptability of utilizing data generated for accelerated
light and other stress conditions are evaluated in forced degradation studies as part of the developmental stability program in lieu of the
 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990 2985

Table 3
Minimum and maximum conditions in multiple cycles.

Cycling Temperature [°C] Days per Cycle No of Cycles Modality

Company 1 30 3 3 Monoclonal Antibody | Fusion Proteins/Bi-specific Proteins/

30 3 3 More Complex Proteins
Company 2 20 2 3 Monoclonal Antibody
Company 3 20 7 3 Monoclonal Antibody | Antibody Drug Conjugate | Gene / Cell
30 14 1 Therapy Products | Peptides | Enzymes | Fusion Proteins/Bi-
40 1 1 specific Proteins/More Complex Proteins
Company 6 70 3 4 Monoclonal Antibody | Antibody Drug Conjugate | Vaccine |
20 4 3 Gene / Cell Therapy Products | Peptides | Enzymes | Oligo-
5 4 3 nucleotides | Virus Like Particles (VLPs) | Fusion Proteins/Bi-
5 3 3 specific Proteins/More Complex Proteins | Nanoparticles
25 3 3
30 3 3
Company 7 0.5 7 2 Monoclonal Antibody | Peptides | Fusion Proteins/Bi-specific
15 24 1 Proteins/More Complex Proteins
25 2.5 1
25 1 4
35 1 1
Company 8 25 2 3 Monoclonal Antibody
30 2 3
Company 9 20 3 3 Peptides | Enzymes | Monoclonal Antibody | Antibody Drug
0 30 1 Conjugate | Oligonucleotides
5 3 6
10 30 1
25 3 3
Company 10 5 3 1 Monoclonal Antibody | Oligonucleotides
15 4 5
30 0.2 11
30 4 3
40 0.6 1
Company 11 20 1 4 Monoclonal Antibody | Antibody Drug Conjugate | Fusion Pro-
5 1 4 teins/Bi-specific Proteins/More Complex Proteins
Company 12 25 2 3 Monoclonal Antibody | Antibody Drug Conjugate | Fusion Pro-
teins/Bi-specific Proteins/More Complex Proteins

temperature cycling stability studies to support excursion, additional functionality as part of their testing strategy in the temperature
questions were included into the survey. cycling stability studies. Those companies that do not include device
functionality testing (25 % of the responding companies) support this
Device Stability approach by utilizing excursion studies performed separately in the
device design verification study. If device testing is included, func-
If the commercial product includes a device, all companies con- tional tests like break-out and gliding forces measurement, delivered
sider the impact of excursions on the functionality of the device volume, and functional hands-on-tests like trigger button actuation
delivery system (Fig. 7). However, not all companies include device are the most used tests (Fig. 8).

Figure 5. Requirements surrounding timing of temperature cycling study start.

2986 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990

Figure 6. Type of testing being performed on temperature cycling study.

Modeling  that a universally applicable recommendation for a successful

temperature cycling stability study design cannot be identified
While all companies were supportive of robust and scientifically since varied strategies have been successful.
sound strategies, such as modeling, to reduce the resources needed  that all companies have common challenges when designing tem-
to conduct stability testing, currently, the majority of companies do perature cycling stability studies.
not incorporate reduced testing strategies into temperature cycling  that all companies were supportive of robust and scientifically
stability study design (Fig. 9). Only two out of 13 companies used sound strategies, such as modeling, to reduce the resources
Arrhenius modeling to reduce the number of stability studies. needed to conduct stability testing.

With regards to the second and third bullet above, current

Discussion and Conclusion approaches to meeting the guidelines issued by Australia and Bra-
zil place a high burden on the organizations with respect to the
Companies are responsible for designing stability studies to sup- competing needs to supply material for temperature cycling sta-
port temperature excursions that may occur during handling and/or bility studies to support temperature excursions while building
transport of the product. A variety of general articles exist regarding launch supply to meet patient needs. Incorporation of science
such studies, with differing degrees of specificity to biologics and and risk-based approaches, in choice of material, study design, or
fewer with reference to specific regional requirements.5−10 use of stability models, may improve time to market while ensur-
The survey responses highlight the following commonalities: ing safe and efficacious drugs as intended by current guidelines.

Figure 7. Addressing the temperature influence on the device.

 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990 2987

Figure 8. Functionality test applied.

Table 4 details common challenges that companies are currently development should be considered in study designs for these types
facing with discussion on possible solutions to overcome these of products. Additionally, cycling temperature impact on device func-
challenges. tionality should also be considered, e.g., a battery powered device
The approach to the design of temperature cycling stability stud- may not tolerate frozen storage.
ies depends on the prior knowledge about the molecule (e.g., suscep- The varied responses in the survey also highlight the need for con-
tibility to degradation), the type of product presentation (liquid/ tinued discussion with regulatory health authorities and potential
lyophilized/ vial/ prefilled syringe), recommended storage condition alignment of guidance and regulations. Table 7 summarizes the con-
(frozen versus refrigerated), as well as the intended transportation siderations for potential discussion with agencies for the temperature
routes (e.g., by land, water, air) and the shipping containers. All these cycling stability study design based on the responses obtained in the
factors influence the design of the excursion program to be executed survey.
to meet the Australia and Brazil submission requirements. However, In summary, while a universally applicable recommendation for a
some common practices were identified and are detailed in Table 5. successful temperature cycling study design cannot be identified, a
Using these common practices, it may be possible to create a few reflection of science and risk-based approaches in material selection,
general temperature cycling designs based on common product cate- study design, and use of stability models in the guidelines may pro-
gories, with justification of specific design based on product knowl- vide distinct advantages to the ability to meet the guidelines for Aus-
edge. Table 6 summarizes a few temperature cycling stability study tralia and Brazil, and other global markets, more efficiently while
designs for traditional biologic products, such as mAbs, ADCs or pep- providing evidence and understanding of the impact of temperature
tides. The recommended example temperature cycling conditions in excursions on the drug product. The following case study is presented
the table are based on general scientific knowledge as well as the sur- which demonstrates that consideration of the above can result in a
vey outcome. With the suggested cycling conditions below, tempera- successful overall global strategy that was accepted by Brazil and
ture can be controlled using commonly available stability chambers. Australia.
The proposed cycling designs can be seen as a starting point. The
decision about acceptable cycling conditions normally starts after Case Study Molecule - Global Strategy Including Brazil and
commercially representative material is available. Specific conditions Australia
for each product should be driven by product stability knowledge
acquired through the development. If the product is part of a combi- In the following example, one member company established a
nation product or device, there will be additional considerations. For general approach incorporating many of the responses from success-
example, the impact of freezing temperatures on container closure ful studies as described in this publication. The conditions covered by
integrity for a prefilled syringe product, as well as any knowledge the temperature cycling stability study were designed to confirm
gained from the characterization of siliconization during the proposed allowances outside of the recommended storage

Figure 9. Summary of companies that incorporate reduced stability testing strategies.

2988 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990

Table 4
Common challenges.

Challenge Proposed Solution and Justification

Temperature cycling stability study Incorporation of science and risk-based approaches, in choice of material, study design, or use of stabil-
material needs limit supply to patients ity models, may improve time to market while ensuring safe and efficacious drugs as intended by
current guidelines.
Consideration should be given to matrixing and bracketing approaches if different presentations
(strength, presentations) are intended for commercialization.
Limited success/experiences using stabil- As stability modeling approaches are used in study design and stability data evaluation elsewhere in the
ity modeling approaches registration of drug products (in support of the stability data package, or in establishment of shelf-
life) their role in the design of temperature cycling stability studies for excursion assessments should
be considered as well. While acknowledging that biological medicines can be subject to multiphasic
and non-linear degradation, there exist stability models11−15 that have proven useful to define sta-
bility over relevant ranges. These stability models in addition to other stability knowledge might be
used to assess excursions.
Limited success using prior knowledge If changes throughout development are viewed as a continuum supported by comparability studies,
utilization of earlier development studies are justifiable in lieu of conducting a dedicated tempera-
ture cycling stability study using commercial batch material. Good scientific justifications exist to
leverage previously generated data in addressing the temperature excursion requirements, especially
when these data are combined with mathematical models (e.g., Arrhenius or other models11)
Interpretation of current guidelines The design of the study should be based on, and supported by, the product knowledge gained through
across regions for different type of the development process. An understanding of the stability and degradation behavior is built through
products stability studies conducted at long-term, accelerated or stress conditions. Fundamental principles for
the molecule, such as melting temperature (Tm), eutectic temperature of frozen mass (Te), glass tran-
sition temperature of frozen mass (Tg’) or dry mass (Tg), may be considered and helpful to identify
regions of greater or lesser concern and justify the choice of temperatures used for cycle design. The
quality target product profile, including the presentation (e.g., liquid or lyophilized drug product),
recommended storage condition (frozen, refrigerated, or controlled room temperature), and drug
product administration (including clinical or home use environment) may also drive the need for a
particular cycling design.
Application of current guidelines to new The current guidance/regulations were established at a time when biological drug products primarily
modalities consisted of mAbs and vaccines, which have traditionally had intended storage conditions of refriger-
ation (or possibly room temperature). In the past decade, new modalities have emerged with frozen/
ultracold intended storage and these materials are in a frozen solid state during shipping. Exposure to
Zone I-IV temperatures would often mean that a phase change from a frozen solid to a liquid has
occurred as part of the excursion. As these exposure types would often have a higher probability of
adverse impact on the drug product, as it is a more stressed excursion, temperature cycling stability
studies outlined by current guidance may not be needed to support shipping and storage excursions.
Instead, studies where the impact to the quality attributes of the material is examined as a result of
subjecting the material to phase changes may be more appropriate than a study that cycles above and
below the intended storage condition. It is recommended that these additional factors be considered
and alternative supportive stability data and/or alternate studies to those outlined in this paper may
be utilized to support shipping and storage excursions of the products. The existing standard may
require updates for these new modalities.

temperature of 5 °C, in order to support time needed for manufac- that was cycled to multiple temperatures below the recommended
ture, packaging, shipping operations, and distribution. Additionally, storage condition, followed by elevated temperatures for pre-deter-
the conditions also support if a designated allowance for the end- mined durations, and then cycled back to the recommended condi-
user-convenience time is necessary and to encompass allowances for tion of 5 °C to be monitored through the end-of-shelf-life.
potential unexpected temperature excursions. The study started with The approach is used as the single global strategy and has been
a single drug product batch representative of the final commercial approved in global submissions, including by TGA and ANVISA.
manufacture process (e.g., Process Performance Qualification batch) Although a specific amount of data to support temperature

Table 5
Common practices.

Category Common practice

Minimum number of batches used in temperature 1

cycling stability studies
Temperature cycling stability study Place material at long term condition after temperature cycling exposure for duration of shelf life in order to
demonstrate continued compliance to specifications within the established shelf life.
The use of temperature cycling approaches provides data to support varying temperatures encountered dur-
ing transportation. The data supports continued use of the product and mitigates rejection of material subject
to a temperature excursion such as during shipping.
When end-user convenience time is a part of the label claim, it should be included in the temperature cycling
stability study design. The end-user convenience time is the storage of the product for a period of time at a
second temperature (usually ambient temperature) prior to administration. Such a ‘patient use period’ or ‘in-
use allowance’ adds convenience for end-users and improves patient experience.
Testing Strategy and Data Assessment Utilize shelf-life specification test methods and utilize them according to typical ICH testing intervals.
Additional characterization testing may be considered in order to gain a deeper product stability knowledge.
Changes to CQAs should be scientifically understood with appropriate controls in place to monitor.
If specifications are not met, temperature excursions during shipping could be entirely restricted if required.
 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990 2989

Table 6
Example cycling designs3 for biologic products stored in vials.

Product presentation Nominal storage temperature Recommended temperature cycling condition

Liquid Refrigerated (2−8 °C) 20 °C1 for 3 days, 25 °C or 30 °C for 3 days, 3 cycles
Liquid Frozen (below 0 °C) N/A2
Lyophilized Refrigerated (2−8 °C) 20 °C for 3 days, 25 °C or 30 °C for 3 days, 3 cycles
Lyophilized Controlled room temperature 20 °C for 3 days, 40 °C for 3 days, 3 cycles
1
20 °C as an example frozen condition, generally above from Tg’ or Te. Note: low temperature cycle may be above the freezing point if the product or container-closure are not
stable for freeze/thaw cycling.
2
N/A = not applicable. Many frozen mass phase transition temperatures should be considered to determine cycling conditions for frozen stored DP. Each product should be
assessed individually.
3
long term stability to be evaluated after the temperature cycling, including end-user-convenience time, if required.

excursions is defined for the initial market application (IMA) for shelf-life may be granted, or temperature excursions may not be
approval, the data provided at the IMA submission typically has allowed by TGA due to the limited data set at the initial submis-
included the completion of temperature cycling prior to the initia- sion. The intended shelf-life claim is approved by TGA once a full
tion of the stability study at the long-term storage condition. While set of temperature cycling data including the end of shelf-life has
ANVISA is more open to the information provided, a shortened been provided.

Table 7
Considerations for agency discussion based on survey responses.

Study design based on survey responses Considerations for discussions with the agencies

Study Setup  Expose material to cycling conditions (low and A cycling approach (versus a block excursion) reduces the
high temperature compared to long-term stor- risk if multiple temperature excursions are experienced
age/shipping temperature) considering the during the same shipment.
knowledge about potential shipping excursions.
 The excursion study is followed by storage at the
long-term storage condition
 Patient convenience period needs to be included
at the long-term storage condition, if applicable.

Study Setup  Best to use material within six months of N/A

manufacture Utilizing material in early stages of the shelf life reflects
the real-world scenario of product being shipped. It
also allows for assessing the impact of an early excur-
sion on the full shelf life.
Material from Number of Batches  Material from one commercial scale batch per Brazil requires data from one batch, Australia prefers data
Exposed to Temperature Excursion presentation from three batches, both agencies agree on commercial
 Consider matrixing and bracketing for different scale in the to be marketed presentation (i.e., incl.
strengths, presentations, manufacturing sites, etc. device if applicable).
Consideration should be given to matrixing and brack-
eting approaches if different presentations (strength,
presentations) are intended for commercialization.
Consideration should be given to the possibility of pro-
viding the stability of multiple product presentations
by supporting the choice of a worst case for excursion
followed by long-term stability (e.g., highest concentra-
tion as a worst case for aggregation growth).
Parameters Tested  shelf-life specification tests for drug product only Additional drug product testing as demanded by product
might be executed.
Consideration could be given to not including device
testing if data for device performance are available that
cover excursion temperatures (e.g., from device devel-
opment).
Timepoints Tested  Prior to excursion, directly after excursion, fol- Consideration should be given to possibility for reduced
lowed by the regular timepoints at the long-term timepoint design for the long-term storage condition.
storage condition (ICH interval)

Data Evaluation  Data will be evaluated against (anticipated) shelf- Data need to be (re-) evaluated against commercial speci-
life specifications fications granted by the authorities.

Data Package Submitted to Agencies  Full shelf-life data set is not needed at time of ini- Full dataset needs to be generated for subsequent sub-
tial submission mission or response to questions to avoid the risk of
reduced shelf-life for product that experienced an
excursion.
Consideration should be given on whether data for
non-cycled batches that are bridged by comparability
studies could be utilized to support the full shelf life
while additional data are generated for the batches that
had experienced the cycling conditions.
2990 C. Arana et al. / Journal of Pharmaceutical Sciences 112 (2023) 2981−2990

Declaration of Competing Interests 2. International Conference on Harmonization Q5C Quality of Biotechnological Prod-
ucts: Stability Testing of Biotechnological/Biological Products. Available from:
[Link] Accessed 2023 May
The authors declare that they have no known competing financial 8th.
interests or personal relationships that could have appeared to influ- 3. Resolution - RDC NO. 412. Ministry of Health National Health Surveillance
ence the work reported in this paper. Agency. Available from: [Link]
RDC_412_2020_.pdf/04f596d3-90ef-4e0f-86bb-16ae08925291. Accessed 2023
May 8th.
Acknowledgments 4. Stability testing for prescription medicines. TGA Health Safety Regulation. Available
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