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

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

It is difficult to obtain an estimate of the magnitude of occur-

rence of temperature excursions as the events are not usually re-
Drug Product Manufacturing
ported in the literature. However, there is high potential for
(and/or Labeling) Sites
temperature excursions during distribution due to unpredictable
random events associated the global distribution processes.

Excursion Management
Scope for Temperature
Distribution Centers What Are the Potential Impacts of Temperature Excursions?

Program
Shipping / Transportation

Storage
Biopharmaceutical drugs are sensitive to temperature excursions
Affiliate (exposure to elevated or subzero temperatures) that may occur
Wholesaler (Distributor) during transportation, storage and handling of drug products.
Government 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
Pharmacy patient use has been shown to impact product quality attributes for

Pa ent: Pa ent
Physician some biopharmaceuticals.27e29 At elevated temperature, conforma-

Pharmacy to

Handling
and Use
Hospital 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
Patient also lead to unintentional exposure to freeze/thaw cycles. Freeze/
thaw stresses can cause protein aggregation due to partitioning of
Figure 1. A typical distribution model for biopharmaceutical drug products. The dis- the protein molecule to ice-water interface, adsorption to the
tribution model may vary in some cases (e.g., public health emergency). The scope for
container surface (solid-water interface), cryo-concentration, and
temperature excursion management program is shown in the figure.
change in pH due to non-uniform crystallization of buffer.33e36
To protect the patient, acceptable temperature excursions need
commercially in these regions may also utilize development sta- to be defined to ensure that drug product quality or stability is not
bility studies to assess for impact of thermal cycling conditions that impacted. Loss of a high-value product due to unacceptable tem-
may not be covered by standard stability data and internally apply perature excursions can have a significantly negative impact, both
the data for decisions on excursion allowances. In contrast, the financially (e.g., reduced profitability) and socially (e.g., loss of
Australian and Brazilian regulatory agencies expect pharmaceutical reputation, credibility and goodwill). Impromptu due diligence
companies to assess the impact of short-term exposure to temper- work on temperature excursions may require reallocation of re-
atures outside of the intended storage temperature range on sta- sources and extra time, which may impact productivity and output.
bility of drug product through formal thermal cycling protocols on Therefore, fully understanding and defining what excursions are
commercial-scale current Good Manufacturing Practice (cGMP) acceptable for commercialization and having a distribution system
drug product batches and use this stability data to support potential in place to avoid “unacceptable excursions” is critical.
temperature excursions.3,12,25,26
The objective of this article is to summarize important aspects to Key Elements of Comprehensive Temperature Excursion
establish a comprehensive global temperature excursion manage- Management Program
ment program, including standard stability testing, regulatory ex-
pectations related to the justification of temperature excursions, Several factors related to storage, transportation, environmental
thermal cycling studies to assess and support potential tempera- conditions, and region-specific custom clearance hurdles can
ture excursions (including how/when thermal cycling study data is contribute to temperature excursions. A comprehensive tempera-
used to support temperature excursions), GDPs to minimize tem- ture excursion management program can be designed by inte-
perature excursions and use of theoretical methods/mathematical grating key elements (Fig. 2) into the overall management program.
simulation models to assess temperature excursions. The infor- A comprehensive temperature excursion management program is
mation provided in this article may be useful for the pharmaceu- expected to not only help minimize, assess, and justify temperature
tical companies to design a temperature excursion management excursions, but also ensure regulatory compliance and provide
program, deal with temperature excursions, and understand dif- several benefits (e.g., avoid regulatory citations, improve efficiency,
ferences in global regulatory expectations/requirements. Biophar- and minimize/avoid business impact caused by the loss of products
maceutical products (e.g., recombinant proteins and monoclonal or inadequate supply).
antibodies) shipped under frozen conditions (e.g., frozen liquid The temperature excursion management program is applicable to
drug product) and cell and gene therapy products are beyond the transportation and storage events that occur during distribution from
scope of this article and therefore, topics covered in the current the manufacturing site to the first customer (e.g., wholesaler or
article are not applicable to the distribution of these products. 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
What is Temperature Excursion? reaches the first customer location (the point at which the direct
chain of custody is complete). The first customer is then directly
As per the World Health Organization (WHO) model guidance, responsible for shipping the drug product to the next destination
temperature excursion is “an excursion event in which a time point (e.g., pharmacy) under appropriate conditions. The pharma-
temperature sensitive pharmaceutical product is exposed to tem- ceutical company may still retain indirect control of this distribution
peratures outside the range(s) prescribed for storage and/or segment, through contractual agreements with the first customer to
transport”.1,24 The temperature ranges for storage and transport ensure that the drug product is shipped under intended conditions.
may be the same or different and determined by the product Temperature excursions that occur during distribution from the first
manufacturer based on stability data.24 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 Author's Comments Reference(s)

11,21e24,46,51
United States, Europe, Regulatory expectations regarding the primary stability Although the standard stability data generated
Canada, Japan, & Switzerland data package needed for a registration application under accelerated storage conditions can be
within these regions are described in ICH and/or used to support shipping excursions above
individual agency's guidelines. In brief, the stability 8
C, the knowledge gap with respect to the
data from the accelerated and intermediate (if impact of temperature excursions below 2
C
applicable) storage conditions can be used to would exist. The regulatory guidelines do not
evaluate the effect of short-term excursions outside contain any recommendations about the
the label storage conditions. The ICH Q5C guideline assessment of short-term temperature
states that the stability data should be generated by excursions on the stability trajectory of drug
considering the external conditions which can affect products through a thermal cycling study.
the product's potency, purity and quality. Health Therefore, the onus is on the pharmaceutical
Canada guideline states that the short-term companies to assess and justify the
temperature excursions outside the intended storage temperature excursions below 2
C.
conditions may be acceptable provided stability data
and scientific/technical justification exist
demonstrating that product quality is not affected.
12
Australia Department of Health Therapeutic Goods In addition to standard stability testing,
Administration (TGA) recommends performing performing a formal thermal cycling on
temperature cycling study on cGMP drug product commercial-scale cGMP drug product
batches to assess the impact of short-term excursion batches is a regulatory requirement to justify
outside of the intended storage temperature range on potential temperature excursions.
stability trajectory of the drug. The TGA's Unique recommendations included in the TGA
recommendations regarding the design of the guideline regarding the design of thermal
temperature cycling study are summarized below. cycling study and approach to the data
Following an excursion outside of the intended storage collection will have to be met by the
temperature range (2e8
C), the drug product may pharmaceutical companies.
only be supplied after the TGA has assessed the Justification to utilize or release a commercial
stability data to support the release. This data may be batch in this region solely based on stability
submitted as part of an initial application for data generated at accelerated storage
registration or as a variation to permanently allow conditions or through development thermal
ongoing release within defined conditions. cycling studies (those not performed under
The agency recommends including at least one cycle formal stability protocol on a cGMP batch),
above (and if desired, below) the intended storage may not be accepted in this region.
conditions (e.g., 5
C and þ30
C) in the cycling The authors recommend performing thermal
study. Multiple cycles may be included if desired. The cycling as part of development stability
duration of the cycle should mimic or exceed the studies prior to executing a formal thermal
maximum likely duration of a shipping excursion. cycling as part of a formal stability program
The thermal cycling should be conducted at the using cGMP clinical or commercial batches to
beginning of shelf-life and the samples should be verify that the risk to product quality is low
stored at the intended long-term storage conditions ahead of time.
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.
78
Brazil Brazil National Sanitary Surveillance Agency (ANVISA) Similar to TGA's expectation, the ANVISA also
has recently updated the regulations for biological recommends assessing the impact of short-
products. Resolution No. 50 of September 20, 2011, as term temperature excursions on stability
amended by Resolution No. 25 of May 14, 2013, trajectory of drug product through thermal
includes procedures and conditions for conducting stress study. The only difference between the
stability studies for registration or post-registration expectations of 2 agencies is that the ANVISA
changes of biological products. As per this resolution, recommends performing the study on at
the potential impact of excursions outside the least one cGMP batch of drug product, while
recommended storage conditions (e.g., high the TGA imply performing the study on 3
temperatures and/or freezing) on the quality of drug cGMP batches of drug product.
product must be evaluated through a stress study. Though stress study is not a mandatory
The stress study must be conducted with at least one requirement to file a biological product
batch of the finished biological product. registration application in Brazil, it would be
For liquid drug products, a study must be conducted to prudent to plan and conduct the study ahead
determine the product's freezing temperature, in of time.
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
 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.
51
Ireland A standard operating procedure should be established There is no clarity in the guideline regarding the
for the management of temperature excursions. After studies to be conducted to support potential
an excursion, the event should be promptly and temperature excursions. However, it is
thoroughly investigated. After completion of the reasonable to expect that the agency may ask
investigation, the outcome should be documented. for a proper justification such as
The impact of temperature excursion on product development data to support the excursion.
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.
11,21,24,54,79
ASEAN Data from the standard stability testing at accelerated The ASEAN Pharmaceutical Product Working
storage condition may be used to evaluate the effect Group (PPWG) was established by the ASEAN
of short-term excursions outside the intended Consultative Committee for Standards and
storage conditions. The procedures should be Quality (ACCSQ). The ASEAN harmonized
established for handling temperature excursions. 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
India Written procedures should be established for handling The guideline does not specifically discuss
of temperatures excursions outside the labeled thermal cycling studies. However, it is
storage conditions. After an excursion occurs, the reasonable to expect that the agency may ask
cause for the excursion should be investigated. 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
Freeze-thaw studies, typically performed during formulation
The regulatory expectations applicable to several regions with development (to select a formulation that is stable to freeze-thaw
respect to the justification of temperature excursions and the stresses) and in some cases as part of stability studies, are useful
author's perspective are summarized in Table 1. Key takeaway mes- to consider with respect to thermal cycling risk when the cycling
sages from the global regulatory guidelines are that specific thermal includes temperatures below 0
C. Depending upon the sensitivity
cycling studies (initial development thermal cycling and formal of drug product to freeze-thaw stresses, appropriate thermal
thermal cycling on commercial-scale cGMP drug product batches) cycling conditions can be selected to minimize the risk/product
are essential to assess the potential impact of short-term excursions quality impact.
on the stability trajectory of drug product to support potential tem-
perature excursions/comply with global regulatory requirements.
Historical Temperature Excursions

Thermal Cycling Studies to Assess the Impact of Temperature Excursion conditions that may be encountered during the
Excursions on Drug Product Quality and Stability: Key distribution of drug product can be envisaged from the historical
Considerations knowledge/experience of similar products. Therefore, it is
important to collate and consider the historical excursion infor-
It is beneficial to assess the impact of thermal cycling on stability mation from the commercial distribution of existing biopharma-
of drug product through a development stability study prior to ceutical drug products (e.g., number of excursions, excursion
performing formal thermal cycling on commercial-scale cGMP drug temperature and excursion duration) when selecting the cycling
product batches. The development stability study will help assess temperatures and duration of exposure. An example of summary
the risk associated with the thermal cycling conditions and the of hypothetical historical temperature excursions is shown in
findings can be used to select temperature/time conditions for Table 2 (this hypothetical example is for illustration and expla-
thermal cycling on commercial-scale cGMP drug product batches. It nation purposes only). This historical information shows that the
is advisable to take several key factors (described below) into the majority of excursions occurred between 8.1 and 25
C, and
consideration when designing the thermal cycling studies (devel- relatively fewer excursions occurred above 25
C and below 2
C.
opment thermal cycling and formal thermal cycling on cGMP Based on this information, thermal cycling between 5
C and
batches). 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 2137

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

Number of cGMP Drug Product Batches Thermal cycling study data (from development studies and in
some cases from formal thermal cycling on cGMP drug product
Formal thermal cycling should be performed on at least one batches) and associated impact toward product quality and stability
commercial-scale cGMP drug product batch. However, some 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 registration would be that the first 5 batches received in the
on thermal cycling studies and standard stability testing data at Australian market must be released by the TGA upon receipt of the
accelerated storage conditions to support potential temperature appropriate documentation (e.g., Quality Control records and cold-
excursions. The process regarding how and when the thermal cycling chain temperature monitoring information). Thereafter and
study data is used to support potential temperature excursions vary depending on the outcome of the first 5 batches, the TGA will
depending upon the location/region of the destination point. determine whether to continue the batch release via the agency or
In the event of temperature excursion during distribution from waive the requirement. If the TGA decides that batch release does
the manufacturing site to the wholesaler/distributor located in not have to be via the agency, then the onus is on the pharma-
major countries (e.g., United State, European country, Canada and ceutical company to review temperature/time profile of a shipment
Japan), an internal Quality representative or qualified person will to identify excursion and release the batch provided the excursion
review and assess the temperature/time data of a shipment against falls within the TGA approved allowances. If the temperature
the internal allowances. If excursion(s) are within the internal al- excursion falls outside of the TGA approved allowances and the
lowances, the shipment is released for transport to the next company believes that product is acceptable to release to market, a
destination. The Quality representative or qualified person may variation needs to be submitted to the agency with a justification to
reach out to technical expert(s) within the company to determine obtain a batch specific exemption.
the product quality impact and suitability for release when the In the case of the Brazil market, development and formal ther-
event falls outside of defined allowances. The internal process (e.g., mal cycling study data along with a technical justification is pro-
handling of shipping excursions) may be reviewed by the regula- vided to the customs in the event of a temperature excursion for
tory agencies during pre-approval inspections and/or post- evaluation and clearance of the shipment.
approval inspections/audits.
In the case of Australia, temperature excursion allowances based Cold Supply Chain Management: Good Distribution Practices
on formal thermal cycling on cGMP drug product batches and to Minimize Temperature Excursions and Ensure Global
technical justification must be submitted in the NDA (or as part of Compliance
the post-approval variation if the data is submitted after approval of
the drug) and obtain approval from the Department of Health Maintaining a robust cold-chain during distribution of drug
Therapeutic Goods Administration (TGA). The condition of 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 2139

destination is essential to ensure product quality and regulatory temperature monitoring system provides several benefits,
compliance, prevent financial loss or liability, and improve supply including real-time temperature monitoring of product, ability to
chain efficiency. Therefore, the cold supply chain management adjust temperature during shipment when temperature start to go
plays a key role in achieving this goal and it defines how outside of the intended storage temperature range and precise
temperature-sensitive products are packaged, transported and tracking of the shipment.7,9,63,64 Next generation automated
stored to ensure that the product remains within its recommended monitoring systems not only enable to monitor and track storage
conditions throughout the distribution process. However, this task and transport conditions, but can also provide controlled envi-
is often complex due to formidable challenges associated with the ronments throughout the cold-chain distribution.2,9,63,65 Using
global distribution process (e.g., remote locations, multiple ex- innovative technologies with shipments can ensure optimal prod-
change and drop-off points, different climate zones and seasonal uct handling and successful timely delivery.2,9,63 Therefore, the
changes, and lengthy clearance procedures at customs end). Taking cold-chain logistics of pharmaceutical companies should evolve
a holistic approach for the cold-chain management (summarized continuously by adopting innovative technologies for monitoring
below) is necessary to achieve intended goals. temperature during distribution. Integration of innovative tech-
nologies into the cold supply chain is in alignment with the GDPs.
Global Regulations and Expectations
Documentation and Standard Operating Procedures (SOPs)
It is challenging to ensure global compliance because of several
requirements and expectations regarding the temperature- Proper documentation of aspects related to the cold-chain
controlled distribution (e.g., regulations, guidelines, technical re- management (e.g., documentation related to storage, transport,
ports, standards, and recommendations). As a result, there is a precautions, warnings, agreements if applicable, records of in-
potential risk of non-compliance with some of the regulations, vestigations and actions taken, time out of cold storage allowance,
guidelines, or standards. Therefore, design and governance of the etc.) is necessary to comply with the global regulatory expectations
cold-chain should be based upon a combination of global regula- and meet international industrial standards.1,7,9,14,24,46,47,58,65 The
tory requirements/expectations (defined by the agencies of SOPs to receive, store and transport drug products and to ensure
different countries or regions) and industrial standards/best prac- the quality of cold-chain management should be in place and
tices (developed by several organizations, Table 4). effective.1,7,9,14,24,46,47,58,65

Thermal Packaging Systems Personnel Training

Thermal packaging systems are an important element of the Training is an essential element of the cold-chain management
cold-chain distribution. Three types of basic thermal packaging and all personnel involved in the cold-chain distribution activities
systems are usually used to maintain the product in the intended (e.g., handling, storage and transport) should be trained by quali-
storage temperature rangedactive (thermal system that use me- fied persons. The training should be provided based on written
chanical or electric systems powered by an energy source to SOPs and the personnel should receive initial and continuing
maintain intended storage temperature), passive (thermal system training relevant to their tasks.1,7,9,14,24,46,47,58,65 The trainings
that use phase change materials such as ice or dry ice to maintain should be assessed periodically as applicable to evaluate the
intended storage temperature) and hybrid (thermal system that effectiveness of the training (actions taken). Proper records on
use a combination of phase change materials as a source of training (e.g., details of topics covered, participants trained, and
energy and thermostatic controls to maintain proper product actions taken) should be maintained.1,7,9,14,24,46,47,58,65
temperature).42e44
Underdesigning the thermal packaging system by selecting low- Quality of External Logistics Companies
cost components may result in frequent temperature excursions.
Overdesigning thermal packaging to achieve 100% success rate to Many pharmaceutical companies turn to external logistics firms
withstand against all environmental conditions and unpredictable that have required technology, infrastructure and systems for cold-
hurdles may result in large, heavy and expensive systems. There- chain distribution of drug products. However, the quality of service
fore, a balanced approach is advisable to select the custom thermal provided by the third-party logistics firms may vary. Therefore, it is
packaging system by taking several factors (e.g., advantages, dis- important to set selection criteria (e.g., transportation and ware-
advantages, capabilities and thermal performance of the system, housing cost, logistic infrastructure and warehousing facilities,
payload, shipping routes, physical performance of the packaging, customer service and reliability, network management, material
environmental impact, system cost and stability profile of drug handling capabilities, quality control and inspection, automation of
product) into the consideration.42e45 Qualification of the selected processes, innovation and effectiveness of cold-chain processes,
thermal packaging system is also an important element of the GDPs and information technology applications for tracking and tracing)
and it should be validated against rigorous global standards to and assess the third-party logistics firms against the criteria before
ensure that it can maintain the temperature within the intended making a selection to ensure that the service is efficient, cost-
storage temperature range (2e8
C).1,13,14,23,24,46e62 effective and un-disruptive.

Innovative Technologies/Solutions Shipping Validation

Temperature monitoring during distribution is necessary to Global distribution environments vary significantly, especially
ensure that the product remains within the intended storage when a drug product is shipped between different climatic zones.
temperature range during cold-chain distribution. Innovative Seasonal changes, the method of transportation, and the number of
temperature monitoring technologies/solutions have been intro- drop-off points can also vary. Shipping validation studies should be
duced to have greater visibility and control over the shipping conducted under real-time shipping conditions (i.e., temperature,
conditions throughout the cold-chain distribution.2,4,7,9,63,64 Ship- mode of transport, shipping duration, and shipping containers and
ping drug product inside passive coolers along with advanced packing representative of the minimum and maximum load) to
2140 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144

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 Summary References

Document
46
United States Pharmacopeia Chapter <1079> Good This chapter provides the requirements related to several aspects of good storage
Storage and Shipping Practices 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
European Guideline on GDPs 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
Australian Code of Good Wholesaling Practice 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
Health Canada Guidelines (GUI-0069) for All persons and companies involved in the storage and transportation of drug
Temperature Control of Drug Products during products are expected to comply with the recommendations (applicable to
Storage and Transportation 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 Good Supply Practice Standards for China Food and Drug Administration issued revised guideline that contains higher
Pharmaceutical Products 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
Indian Guidelines on Cold-Chain Pharmaceutical Organization of Pharmaceutical Producers of India Guidelines on Cold-Chain
Products 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
Irish Guide to Control and Monitoring of Storage The document provides guidance to manufacturers, wholesalers and transporters in
and Transportation Temperature Conditions for relation to conditions for cold storage/cold-chain and controlled temperature
Medicinal Products and Active Substances 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
Malaysian Guidelines on GDPs 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
Russian Code of Good Practice in the The main objective of the Code is self-regulation of the pharmaceutical industry in
Pharmaceutical Industry 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

manufacturers involved in the storage and distribution should comply with the
new rules described in this document.
54
Singapore Guidance Notes on GDPs 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
South African Good Wholesaling Practice for This guideline outlines Good Warehousing Practices for all parties involved in the
Wholesalers 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
World Health Organization (WHO) Model Guidance The document outlines the principal requirements for the safe storage and
for the Storage and Transport of Time- and distribution of time- and temperature-sensitive pharmaceutical products
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
International Safe Transit Association (ISTA) Biopharmaceutical products should be shipped using containers and packaging
Standards 7E and 20 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
Parenteral Drug Association (PDA) Technical The PDA has introduced technical reports that provide guidance to all involved on
Reports 39 and 46 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
International Air Transport Association (IATA) The IATA is the industry's global trade association, which has developed standards
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 conditions with respect to distance, duration, temperature, mode of
intended temperature and to evaluate the impact of shipping on transportation and vibration. Also, the drug product used in the
the physical integrity and drug product quality.62,66,67 Simulated shipping studies should be manufactured using a process repre-
shipping studies can be used, but must be sufficiently representa- sentative of the commercial process, same formulation and pack-
tive of the commercial shipping conditions.66 Pharmaceutical aged in the same container closure system as that proposed for
companies are expected to provide detailed information about the commercial batches.
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 Rational Use of Theoretical Methods/Mathematical
market application dossier. Simulation Models
Specific guidance regarding the shipping validation studies can
be found in the Parenteral Drug Association (PDA) Technical Re- As per the ICH Q1A guideline, mean kinetic temperature (MKT)
ports (PDA Technical Report No. 53: Guidance for Industry: Stability is defined as “a single derived temperature which, if maintained
Testing to Support Distribution of New Drug Products, PDA Tech- over a defined period, would afford the same thermal challenge to a
nical Report No. 58: Risk Management for Temperature-Controlled drug substance or drug product as would have been experienced
Distribution and PDA Technical Report No. 72: Passive Thermal over a range of both higher and lower temperatures for an equiv-
Protection Systems for Global Distribution: Qualification and alent defined period”.11,46 In other words, the MKT is a calculated
Operational Guidance).15,68,69 It is noteworthy to mention that the fixed temperature that simulates the effects of temperature varia-
specific procedures are at the discretion of each biopharmaceutical tions over a period of time.46 It expresses the cumulative thermal
company to design studies based on the intended shipping process, stress experienced by a product at varying temperatures during
but the evaluation method should include worst-case shipping storage and distribution (see the equation below).46
2142 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144

kinetic model has been used to understand temperature-

DH=R dependent chemical degradation of proteins, such as oxidation
Tk ¼ 0 1 and deamidation),74 they may not be applicable to others (e.g., non-
B RTDH RTDH DH C Arrhenius aggregation behavior has been demonstrated for some
B ð1Þ RTðnÞ C
lnBe þ e n þ/e C
ð2Þ
proteins).74,75 Interestingly, Arrhenius kinetics has been demon-
@ A
strated for some physical reactions of protein molecules (i.e.,
without changes in covalent bonds).74,76,77
Where Tk is the mean kinetic temperature; DH is the heat of acti- In summary, the use of theoretical methods/mathematical
vation (assumed to be 83.144 kJ per mole); R is the universal gas simulation models to evaluate the impact of temperature excur-
constant (8.3144  103 kJ per mole per degree); T1 is the value for sions on quality and stability of temperature-sensitive products can
the temperature recorded during the first time period; T2 is the provide useful information that can be used in conjunction with the
value for the temperature recorded during the second time period; actual stability data to justify temperature excursions.
Tn is the value for the temperature recorded during the nth time
period (n being the total number of storage temperatures recorded Concluding Remarks
during the observation period). Note all temperatures, T, are abso-
lute temperatures in degrees Kelvin (K). Global regulatory agencies expect that pharmaceutical com-
Seevers and co-workers evaluated the use of MKT in evaluating panies distribute biopharmaceutical drug products to the intended
temperature exposure outside refrigerated storage condition dur- destination in a manner that ensures that the product quality and
ing the distribution process.70 Calculated MKT was found to be not stability are not negatively impacted by temperature excursions.
sensitive to the impact of excursions that may occur if the baseline The regulatory expectations and industrial practices regarding the
is a long period of time such as storage segment.70 In the case of justification of temperature excursions and global distribution
shorter baseline periods of time (e.g., transportation or distribution process have evolved in recent years.
segments), it was noted that an excursion can have a significant Successful distribution of biopharmaceutical drug products is a
impact on the resulting MKT, but this would not necessarily have a challenging task due to several uncontrolled variables and unex-
significant impact on product quality.70 pected events associated with the global distribution process. It is
It appears that the use of MKT in the distribution environments imperative for all firms involved to understand and overcome the
is limited to temperatures for which there is actual stability data to challenges of global distribution. A proactive and comprehensive
support the finding. The MKT analysis must be based on sound temperature excursion management program is necessary to
science and existing stability data should be taken into the ensure that drug product reaches the end user without compro-
consideration or used for comparison. The MKT and its use in dis- mising quality, stability and efficacy of the product and patient
tribution applications is expected to evolve as guidance, regula- safety. The comprehensive temperature excursion management
tions, and technologies progress. program can be designed by integrating key elements of the
Recently, Clenet applied kinetic analysis models on forced product lifecycle management and global distribution processes in
degradation data to predict the long-term vaccine degradation of the program.
the freeze-dried products under specific temperature excursions.71 Standard stability testing at accelerated storage and stress
The kinetic-based approach was found to accurately predict the conditions may reveal protein degradation pathways which can be
impact of temperature excursions on vaccine degradation.71 The leveraged to select conditions for thermal cycling studies. Thermal
accurate prediction requires appropriate controlled temperature cycling studies should be conducted by taking several key factors
monitoring, so that the real temperature/time profiles can be used into the consideration to assess the impact of the short-term
in the kinetic analysis. If this kind of kinetic model is integrated into exposure of drug product to conditions outside the intended stor-
electronic temperature-time monitoring devices, real-time infor- age temperature on product quality and stability and use this data
mation on temperature excursions and their impact on protein to pre-define temperature excursion allowances and support po-
degradation could be obtained.71 It is reasonable to predict that the tential temperature excursions. A robust cold-chain model is
advanced kinetics and stability modeling approaches can be a very necessary to prevent/minimize temperature excursions during
useful tool in evaluating the temperature excursions, especially in distribution. It is advisable to consider key elements of the global
remote areas. This kind of analysis can also be used to support the distribution process when designing the model for cold-chain
conclusions gained from the standard stability testing or thermal distribution. Theoretical assessment methods or mathematical
cycling study. simulation models provide useful information regarding the impact
Arrhenius equation-based mathematical simulation model has of temperature excursions on the quality and stability of
been used to understand product's stability performance.72 The temperature-sensitive products and it is advisable to use them in
mathematical simulation model was based on stability data at conjunction with the actual stability data to justify temperature
intended and accelerated storage conditions, Arrhenius equation excursions.
and first-order kinetic equation.3,72 Using this approach, a mathe- A comprehensive temperature excursion management program
matical simulation of the product degradation was run which is expected to not only help minimize, assess, or justify tempera-
showed the product stability performances.3,72 Based on this ture excursions more efficiently, but also ensure regulatory
approach, a relationship between time and temperature could be compliance.
established.73 This approach shows how much time is acceptable at
a defined temperature for a given product before it undergoes Disclaimer
significant/unacceptable degradation. Based on this information, it
is possible to determine the potential degradation that may have This article reflects the views of the authors only and should not
been caused by the temperature excursions is acceptable or be construed to represent regulatory authority's, GlaxoSmithKline's
unacceptable. or any other applicable International Organizational's views or
Arrhenius kinetic models are more widely used for small practices. GlaxoSmithKline is not responsible for author's views
molecule drugs. While Arrhenius kinetic model may be applicable expressed in this article. Regulatory expectations/ standards/dis-
to some biopharmaceutical product quality attributes (Arrhenius tribution practices summarized in this article are based on the
 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144 2143

current environments and these may evolve with time. Therefore, 24. WHO Technical Report Series, No.961. Annex 9. Model guidance for the storage
and transport of time- and temperatureesensitive pharmaceutical products.
the readers are advised to seek most recent information from
http://www.who.int/medicines/areas/quality_safety/quality_assurance/Model
relevant sources. GuidanceForStorageTransportTRS961Annex9.pdf; 2011.
25. Rios M. Product stability testing: developming methods for new biologics and
emerging markets. BioProcess Int. 2015;13(5):1-5.
Acknowledgements 26. Ministry of Health. National health surveillance agency. Resolution - RDC No.
50, of September 20, 2011 http://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2
013/rdc0050_20_09_2011_rep.html.
The authors thank Alan Forthman (Supply Chain Solutions), 27. Vlieland ND, Nejadnik MR, Gardarsdottir H, et al. The impact of inadequate
Michael Schwartz (CMC Regulatory Affairs, USA), Jamie Fox (Reg- temperature storage conditions on aggregate and particle formation in drugs
ulatory Compliance, USA), Deidre Malton (Regulatory Affairs Op- containing tumor necrosis factor-alpha inhibitors. Pharm Res (N Y). 2018;35(2):
42.
erations, Australia) and Monique Lellis Prado (LOC Quality, Brazil), 28. Nejadnik MR, Randolph TW, Volkin DB, et al. Postproduction handling and
GlaxoSmithKline, for sharing their opinions. administration of protein pharmaceuticals and potential instability issues.
J Pharm Sci. 2018;107(8):2013-2019.
29. Jiskoot W, Nejadnik MR, Sediq AS. Potential issues with the handling of bi-
References ologicals in a hospital. J Pharm Sci. 2017;106(6):1688-1689.
30. Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways,
1. Technical Report No 39 (Revised 2007). Guidance for Temperature Controlled induction factors and analysis. J Pharm Sci. 2009;98(9):2909-2934.
Medicinal Products: Maintaining the Quality of Temperature Sensitive Medicinal 31. Hawe A, Kasper JC, Friess W, Jiskoot W. Structural properties of monoclonal
Products through the Transportation Environment. Parenteral Drug Association; antibody aggregates induced by freeze-thawing and thermal stress. Eur J Pharm
2007. Sci. 2009;38(2):79-87.
2. Bishara RH. Cold chain management - an essential component of the global 32. Brader ML, Estey T, Bai S, et al. Examination of thermal unfolding and aggre-
pharmaceutical supply chain. Am Pharm Rev. 2006;9(1):105-109. gation profiles of a series of developable therapeutic monoclonal antibodies.
3. Ammann C. Stability studies needed to define the handling and transport Mol Pharm. 2015;12(4):1005-1017.
conditions of sensitive pharmaceutical or biotechnological products. AAPS 33. Kreilgaard L, Jones LS, Randolph TW, et al. Effect of Tween 20 on freeze-
PharmSciTech. 2011;12(4):1264-1275. thawing- and agitation-induced aggregation of recombinant human factor
4. Robertson J, Franzel L, Maire D. Innovations in cold chain equipment for im- XIII. J Pharm Sci. 1998;87(12):1597-1603.
munization supply chains. Vaccine. 2017;35(17):2252-2259. 34. Strambini GB, Gonnelli M. Protein stability in ice. Biophysical J. 2007;92(6):
5. Brison M, LeTallec Y. Transforming cold chain performance and management in 2131-2138.
lower-income countries. Vaccine. 2017;35(17):2107-2109. 35. Pikal-Cleland KA, Cleland JL, Anchordoquy TJ, Carpenter JF. Effect of glycine on
6. Ashok A, Brison M, LeTallec Y. Improving cold chain systems: challenges and pH changes and protein stability during freeze-thawing in phosphate buffer
solutions. Vaccine. 2017;35(17):2217-2223. systems. J Pharm Sci. 2002;91(9):1969-1979.
7. Hoffmann A. Challenges of cold supply chain. https://eipg.eu/wp-content/ 36. Kueltzo LA, Wang W, Randolph TW, Carpenter JF. Effects of solution conditions,
uploads/2013/07/seminar-armin-presentation-eipg-madrid.pdf. processing parameters, and container materials on aggregation of a mono-
8. McLean D. Cold chain shipping: protecting temperature sensitive products. clonal antibody during freeze-thawing. J Pharm Sci. 2008;97(5):1801-1812.
https://www.pda.org/docs/default-source/website-document-library/chapters/ 37. Lucas TI, Bishara RH, Seevers RH. A stability program for the distribution of
presentations/metro/cold-chain-shipping—protecting-temperature-sensitive- drug products. Pharm Technol. 2004;28(7):68-73.
products-diane-mclean.pdf?sfvrsn¼6. 38. Nieto A, Roehl H, Brown H, Nikoloff J, Adler M, Mahler H-C. Evaluation of
9. Hager R. The global cold chain: ensuring the integrity and compliance of bio- container closure system integrity for frozen storage drug products. PDA J
materials generated in clinical trials. BioProcess Int. 2012;10(10):24-28þ65. Pharm Sci Technol. 2016;70(2):120-133.
10. https://en.a3p.org/qualification-approach-for-the-validation-of-real-word-ship 39. Zeng Q, Bucci A, Ho L. Time temperature superposition evaluation and
ping-in-single-use-systems-the-wave-53/. modeling for container closure system's seal performance at low temperatures.
11. International conference on harmonisation of technical requirements for PDA J Pharm Sci Technol. 2020;74(1):27-40.
registration of pharmaceuticals for human use. ICH harmonised tripartite 40. Olivas J. Syringe plunger movement during air shipments. In: Pre-filled Syringes
guideline. Stability testing of new drug substances and products Q1A(R2). Forum. 2008. La Jolla, CA, USA.
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ 41. Kinney S, Wagner A. United States Patent Number US 7,328,549 B2. In: Process
Quality/Q1A_R2/Step4/Q1A_R2_Guideline.pdf; 2003. for Aseptic Vacuum Filling and Stoppering of Low Viscosity Liquids in Syringes.
12. Australian Government, Department of Health. Therapeutic goods adminis- 2008.
tration, stability testing for prescription Medicines. https://www.tga.gov.au/ 42. https://www.pharmalogisticsiq.com/logistics/articles/cold-chain-packaging-
sites/default/files/stability-testing-prescription-medicines.pdf; 2017. systems-comparison-of-active.
13. United States Pharmaceopaedia: (Chapter 1079): Good Storage and Shipping 43. https://www.berlinpackaging.com/white-papers/shipping-temperature-sensi
Practices. U.S. Pharmacopeia; 2011. USP 34 e NF 29 www.usp.org. tive-materials-considerations-in-packaging-selection/.
14. Technical Report No. 46. Last Mile: Guidance for Good Distribution Practices for 44. Romero B. Upgrading of traditional cold chain shipping systems using 2-8
C
Pharmaceutical Products to the End User. Parenteral Drug Association; 2009. phase change materials. Pharm Outsourcing. 2012;13(1).
15. Technical Report No. 53. Guidance for Industry: Stability Testing to Support Dis- 45. https://www.coldchaintech.com/white-paper/.
tribution of New Drug Products. Parenteral Drug Association; 2011. 46. U.S. Pharmacopeial Convention. United States Pharmacopoeia. USP <1079>
16. Taylor J, Holloway I. Transportation of biological products: European regula- Good Storage and Shipping Practices. www.pharmacopeia.cn/v29240/usp2
tions and guidance. Am Pharm Outsourcing. 2007;8(3). 9nf24s0_c1079.html.
17. Bedu-Tessier M, Boudy V, Demouy A, et al. Temperature excursions to which 47. European Commission Health and Consumers Directorate-General (European
medicinal products are exposed. Dealing with these excursions in order to Government). Guidelines on Good Distribution Practice of Medicinal Products for
manage these correctly. STP Pharma Prat. 2017;27(6):309-341. Human Use (2013/C 343/01); 2013. https://eur-lex.europa.eu/LexUriServ/
18. Kumar N, Jha A. Temperature excursion management: a novel approach of LexUriServ.do?uri¼OJ:C:2013:343:0001:0014:EN:PDF.
quality system in pharmaceutical industry. Saudi Pharm J. 2017;25(2):176-183. 48. National Coordinating Committee on Therapeutic Goods. Australian code of
19. Morrow T, Felcone LH. Defining the difference: what makes biologics unique. good wholesaling practice for Medicines in schedules 2, 3, 4 and 8. Effective 1
Biotechnol Healthc. 2004;1(4):24-29. April 2011. https://www.tga.gov.au/sites/default/files/manuf-medicines-cgwp-
20. Patel J, Kothari R, Tunga R, Ritter NM, Tunga BS. Stability considerations for schedule2-3-4-8.pdf.
biopharmaceuticals: Overview of protein and peptide degradation pathways, 49. China Food and Drug Administration. Good supply practice for pharmaceutical
Part 1: Overview of protein and peptide degradation pathways. BioProcess Int. products. Effective 07-13-2016. http://en.pkulaw.cn/Display.aspx?lib¼law&
2011;9(1):20-31. Cgid¼276012.
21. International Conference on Harmonisation of Technical Requirements for Regis- 50. Organisation of Pharmaceutical Producers of India. OPPI guidelines on cold
tration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. chain pharmaceutical products. https://www.indiaoppi.com/sites/default/files/
Quality of Biotechnological Products: Stability Testing of Biotechnological/Biolog- PDF%20files/OPP%20Guidlines%20on%20Cold%20Chain%20Pharmaceutical%20
ical Products Q5C; 1995. https://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products%20-%20%28June%201%2C%202010%29%20Final.pdf; 2010.
Products/Guidelines/Quality/Q5C/Step4/Q5C_Guideline.pdf. 51. Health Products Regulatory Authority (HPRA) Guide to Control and Monitoring of
22. U.S. Department of Health and Human Services, Food and Drug Administration. Storage and Transportation Temperature Conditions for Medicinal Products and
Center for drug evaluation and research (CDER). Guidance for industry Q1A(R2) Active Substances; 2017. IA-G0011-2 https://www.hpra.ie/docs/default-source/
stability testing of new drug substances and products. https://www.fda.gov/ publications-forms/guidance-documents/ia-g0011-guide-to-control-and-moni
downloads/drugs/guidances/ucm073369.pdf; 2003. toring-of-storage-and-transportation-conditions-v2.pdf?sfvrsn¼18.
23. Health Canada/Health Products and Food Branch Inspectorate. GUI-0069: 52. National Pharmaceutical Regulatory Division Ministry of Health Malaysia.
Guidelines for Temperature Control of Drug Products during Storage and Trans- Guidelines on Good Distribution Practice. third ed.; 2018. https://www.npra.gov.
portation; 2011. https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/ my/images/seranta/2017/gdp/DRAFT_GUIDELINE_ON_GDP_3rd_Edi_2018_311
dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/docs/GUI-0069-eng.pdf. 02017.pdf.
2144 K.G. Desai et al. / Journal of Pharmaceutical Sciences 109 (2020) 2131-2144

53. Federal Antimonopoly Service of the Russian Federation. Code of Good Practice in 68. Technical Report No. 58. Risk Management for Temperature-Controlled Distri-
the Pharmaceutical Industry; 2016. http://en.fas.gov.ru/upload/documents/Code bution. Parenteral Drug Association; 2012.
%20of%20Good%20Practice%20in%20the%20Pharmaceutical%20Industry.pdf. 69. Technical Report No 72. Passive Thermal Protection Systems for Global Distri-
54. Health Sciences Authority. Guidance Note on Good Distribution Practice; 2015. bution: Qualification and Operational Guidance. Parenteral Drug Association;
https://www.hsa.gov.sg/content/dam/HSA/HPRG/Manufacturing_Importation_ 2015.
Distribution/Guidance%20documents%20for%20Industry/GUIDE-MQA-013-01 70. Seevers RH, Hofer J, Harber P, Ulrich DA, Bishara R. The use of mean kinetic
0.pdf. temperature (MKT) in the handling, storage, and distribution of temperature
55. South African Health Products Regulatory Authority. South African Good sensitive pharmaceuticals. Am Pharm Outsourcing. 2009;10(3):30-39.
Wholesaling Practice for Wholesalers (V2); 2016. https://www.sahpra.org.za/ 71. Clenet D. Accurate prediction of vaccine stability under real storage condi-
documents/44a724894.02_SA_Guide_to_GWP_v2_Nov15.pdf. tions and during temperature excursions. Eur J Pharm Biopharm. 2018;125:
56. https://ista.org/thermal_standards.php. 76-84.
57. https://ista.org/docs/7Eoverview.pdf. 72. Ammann C. A mathematical approach to assessing temperature excursions in
58. Technical Report No. 39. Cold Chain Guidance for Medicinal Products: Maintaining temperature-controlled chains. Eur J Parenter Pharm Sci. 2008;13(2):57-59.
the Quality of Temperature Sensitive Medicinal Products Through the Trans- 73. Ammann C. Handling temperature excursions and the role of stability data.
portation Environment. Parenteral Drug Association; 2005. Pharm Outsourcing. 2013;14(5):34-40.
59. https://www.iata.org/publications/store/Pages/time-temperature-labels.aspx. 74. Wang W, Roberts CJ. Non-Arrhenius protein aggregation. AAPS J. 2013;15(3):
60. https://www.iata.org/whatwedo/cargo/pharma/Documents/tt-checklist-notice. 840-851.
pdf. 75. Kayser V, Chennamsetty N, Voynov V, Helk B, Forrer K, Trout BL. Evaluation of a
61. http://www.coolpack.com/clpk/wp-content/uploads/2013/03/IATA_time-and- non-Arrhenius model for therapeutic monoclonal antibody aggregation.
temperature-label-faq.pdf. J Pharm Sci. 2011;100(7):2526-2542.
62. Dill S, Brees K, Stahly A, Cheng E, Carpenter J, Caplan L. Mechanical shock 76. Kayser V, Chennamsetty N, Voynov V, Helk B, Trout BL. Conformational stability
during shipping of medications: the roles of packaging and transportation and aggregation of therapeutic monoclonal antibodies studied with ANS and
vendors. J Pharm Sci. 2020;109(1):670-676. Thioflavin T binding. mAbs. 2011;3(4):408-411.
63. Conny A. Temperature monitoring during shipment and storage. In: Kim H-B, 77. Weiss WFt, Young TM, Roberts CJ. Principles, approaches, and challenges for
ed. Pharmaceutical Stability Testing to Support Global Markets. first ed. New predicting protein aggregation rates and shelf life. J Pharm Sci. 2009;98(4):
York: Springer-Verlag; 2010:161-167. 1246-1277.
64. ISPE Good practice guide: cold chain management. https://ispe.org/ 78. http://portal.anvisa.gov.br/legislacao/?inheritRedirect¼true#/visualizar/28738.
publications/guidance-documents/good-practice-guide-cold-chain-management. 79. ASEAN Guideline on Stability Study of Drug Product. R1. 25th ACCSQ-PPWG.
65. https://www.google.com/url?sa¼t&rct¼j&q¼&esrc¼s&source¼web&cd¼5&cad https://asean.org/wp-content/uploads/2018/01/25PPWG-ANNEX-7-iv-Final-
¼rja&uact¼8&ved¼2ahUKEwiQ5uTvhdvkAhWRecAKHS_MBHMQFjAEegQIAhAC ASEAN-Guideline-on-Stability-Study-Drug-Product-R2.pdf.
&url¼https%3A%2F%2Feipg.eu%2Fwp-content%2Fuploads%2F2013%2F07%2Fse 80. Central Drugs Standard Control Organization, Ministry of Health and Family
minar-armin-presentation-eipg-madrid.pdf&usg¼AOvVaw1ddVn3FKzwD5ONz Welfare, Government of India. Guidelines on Good Distribution Practices for
7aQgoxX. Biological Products (CDSCO/GDP.BP Ver:00); 2012. https://www.google.com/url?
66. Geigert J. Designing the stability program. In: Geigert J, ed. The Challenge of CMC sa¼t&rct¼j&q¼&esrc¼s&source¼web&cd¼2&cad¼rja&uact¼8&ved¼2ahUKE
Regulatory Compliance for Biopharmaceuticals. Cham: Springer International wiausX_q-zkAhXbQkEAHTN-A48QFjABegQIABAC&url¼http%3A%2F%2Fwww.
Publishing; 2019:331-354. msk.nclinnovations.org%2Fmedregulations%2Fv1%2Fhtml%2FGuidance%2F
67. Siska C, Harber P, Kerwin BA. Shocking data on parcel shipments of protein Guidelines%2520on%2520GDP%2520for%2520Biological%2520Products.pdf&
solutions. J Pharm Sci. 2020;109(1):690-695. usg¼AOvVaw2s47x-T3ccS84jFrApbNrx.