STIMULI TO THE REVISION PROCESS

Stimuli articles do not necessarily reflect the policies of the USPC or the USP Council of Experts

The Use of Mean Kinetic Temperature and the Need of Allowable

Excursion Limits for Climatic Zone IVb
Glaucia K. Bragas,.Q, Luciana S. Takara.£, Chris J. Andersons,f!, Robert H. Seeverss ,g, S0ren Kare Nielsens,f,
Desmond G. Hunt.£
Correspondence should be addressed to: Desmond G. Hunt, Senior Principal Scientist, US Pharmacopeia,
12601 Twinbrook Parkway, Rockville, MD 20852-1790; email: g_g�i:2.or9..

ABSTRACT
There is a growing concern about the proper storage and transportation of finished drug products, because
storing and transporting products outside of their storage specification can potentially impact product quality,
efficacy, and safety. However, although every effort should be made to keep the drug product within the
temperature range indicated on the packaging, temperature excursions can occur. Once it occurs, the impact
should be assessed. Mean kinetic temperature (MKT) is a single calculated temperature at which the total
amount of degradation during a given period is equal to the sum of the individual degradations that would
occur at various temperatures. However, MKT alone is not enough to assess the impact of a temperature
excursion. It is necessary, in addition to MKT, to know the following: the time period of the temperature
excursion, the actual excursion temperature(s), if there was a temperature excursion above 40 ° , and the time
frame used to calculate MKT. Allowable excursion limits are essential to answering those questions and
assessing the severity of excursions in a risk-based approach. MKT temperature excursion limits in Mean
Kinetic Tem12.erature in the Evaluation of Tem12.erature Excursions During Storage and Trans12.ortation of Drug_
Products (1079.2}_ are specific for products stored at controlled room temperature (20 ° -25 ° ) and at controlled
cool temperature (2 ° -8 ° ). As currently written, the chapter does not consider product storage between 15 °
and 30 ° , which is generally the storage and transportation range for drug products in climatic zone IVb
countries. Establishing allowable temperature excursion limits for climatic zone IVb is particularly important at
this moment not only to assess the impact of an excursion to the product during distribution, but also to
establish an acceptance criteria for lane temperature profiling studies (lane temperature mapping). Setting
MKT excursion limits for the storage and transportation of drug products in climatic zone IVb will be an
important resource globally, so the aim of this Stimuli article is to present the case for updating .(1079.2}. to
address MKT for climatic zone IVb.

INTRODUCTION
In March 2022, the US Pharmacopeia (USP) Latin America (LATAM), in partnership with Sindusfarma
(Pharmaceutical Products Industry Companies Union) and the Brazilian Academy of Pharmaceutical Sciences­
two important stakeholders in Brazil, organized a workshop on good distribution practices of finished drug
products (GDP). This event was an opportunity to share more about USP's resources related to GDP, including
general chapter Risks and Mitigation Strategies for the Storage and Trans12.ortation of Finished Drug Products
!10791 and Mean Kinetic Temperature in the Evaluation of Temperature Excursions During Storage and
Trans12.ortation of Drug_ Products (1079.2}_. The program also included presentations on the GDP regulatory
framework in Brazil (ANVISA Resolution, RDC No. 430/2020), utilization of mean kinetic temperature (MKT)
to evaluate temperature excursions in different regions of Brazil and the methodology and results of a lane
qualification pilot study executed to be in compliance with ANVISA GDP regulation.
 There were over 800 workshop participants, including regulators, Brazilian trade associations (drug
manufacturers, distributors, and transporters), and regulatory affairs professionals. Active discussion during
the question-and-answer session led to insightful questions being posed as well as USP LATAM identifying
gaps in MKT knowledge within Brazil and within USP's MKT standard. Some of the discrepancies identified
included how temperature excursions are handled in Brazil, confusion around MKT use, how USP MKT
excursion limits apply to the storage and transportation of drug product in climatic zone IVb, and the potential
for updating the USP MKT standard to accommodate storage and transportation of drug products in climatic
zone IVb.
In general chapters Packaging and Storage Reguirements (659). and .(1079.2)., MKT temperature excursion
limits are specific for products stored at controlled room temperature (CRT, 20 ° -25 ° ) and at controlled cool
temperature (2 ° -8 ° ). As currently written, the chapters do not consider product storage between 15 ° and
30 ° , which is generally the storage and transportation range for drug products in climatic zone IVb countries.
In parallel, USP internal research identified the topic of temperature excursions and climatic zone IVb as an
area where further USP guidance may be necessary and supported the Packaging and Distribution Expert
Committee to look further into the topic. Because setting MKT excursion limits for the storage and
transportation of drug products in climatic zone !Vb will be an important resource globally, the aim of this
Stimuli article is to outline the rationale for updating .(1079.2). to address the use of MKT for climatic zone IVb
and proposing excursion limits.

PHARMACEUTICAL SUPPLY CHAIN AND THE RISK OF TEMPERATURE EXCURSIONS

A holistic view of the pharmaceutical supply chain should be done to understand the risks related to
temperature excursions, considering factors such as (Figure 1):

• The complexity of the supply chain with multiple supply chain partners
• Two key activities common to all supply chain partners: storage and transport
• The use of different modes of transport that allow the movement of product along the supply chain,
from manufacturer to customer
• Global supply chains can have different local regulations and different climatic zones serving as
complicating factors
• All supply chain partners have joint responsibility

FORWARD

Brokers Hea lthc:af e _________ ,

Supplier } Providers ]

Whel'esale 1
Suppll:er Manufactiurer and/or ------ Pharmades Patient
�trlbuto:r

- -- - - - - - •
J
Hospitals j
Go,vernmentt Destru ctlon companies

BACKWARD

Click image to enlarge

 Figure 1. Pharmaceutical supply chain.
To maintain the original quality of the product, every party involved in the storage and transportation of a
finished product should have an in-depth understanding of the storage and transportation risks and have the
appropriate mitigation strategies in place to control these risks.
Organizations should devote effort and resources to the transport, handling, and storage of drug products in
such a way that reduces the risk of exposure to temperatures outside the labeled storage conditions, also
known as temperature excursions. Although every effort should be made to keep the drug product within the
temperature range indicated on the packaging, temperature excursions can occur. In climatic zone IVb, drug
products whose stability studies were conducted to provide storage from 15 ° to 30 ° are often transported in
nontemperature-controlled vehicles that can go through various temperature extremes during a journey or
are stored and in-transit storage facilities that do not have thermostatic control of temperature. Even in
stability chambers, where drug products stability studies are conducted with varying temperature and relative
humidity, temperature excursions can occur. Not addressing stability chamber excursions is a frequent audit
finding, as is evidenced by a sampling of Warning Letters from the FDA, as mentioned by Huynh-Ba and Latoz
(2021).
Temperature excursions are a risk in today's pharmaceutical supply chain and when observed should be
assessed, reduced, and communicated. The effect of an excursion can be a loss of assay, the increase of
impurities, precipitation of drug, change in dissolution pattern, phase changes, etc. (Nirmal and Ajey a, 2017).
These effects depend on product stability and the temperature and the duration of the excursion.
Without risk assessment, temperature excursions often result in considerable losses for public health
programs operating in countries with limited resources. In order to assess the impact of a temperature
excursion, consulting the manufacturer is the preferred approach. However, this can be challenging depending
on data availability and the responsiveness of the drug product manufacturer (Jenkins et al., 2022). Thus,
MKT can be a useful tool when stability data is not known by a downstream supply chain partner.
Chapter {1079.2). defines MKT as the single calculated temperature at which the total amount of
degradation during a given period is equal to the sum of the individual degradations that would occur at
various temperatures. It is a way of summarizing the exposure time history of a product with a single
"effective" or "virtual" temperature. Thus, MKT integrates the time-temperature history by making
assumptions about the kinetics of the chemical degradation of a product.
Basically, the Arrhenius equation demonstrates that a rate of reaction will increase exponentially with
temperature, rather than linearly. Correspondingly, MKT is important to understand because it provides the
effective isothermal temperature experienced by the product that accounts for the Arrhenius-based effect of
temperature excursions during storage (Jenkins et al., 2022).
Although MKT is a valuable tool in helping to access a temperature excursion, it may not be appropriate in
some situations. For example, in cases where a product is subject to phase change (suppositories, liquids,
suspensions, emulsion, creams, etc.) and/or where clinical data indicate that temperature excursions can
impact product quality and safety. Health Canada (2020) also noted biologics as a category of products for
which MKT may not be suitable. If MKT cannot be used, stability and stress studies and freeze and thaw and
high temperature cycling studies can be used to analyze the risk and justify the decision-making process to
sell or dispose the product. Thus, when MKT is not appropriate for assessing a temperature excursion, this
point should be communicated to supply chain partners.
In using MKT to evaluate a temperature excursion, it should not be abused. MKT alone is not enough to
assess the impact of a temperature excursion and it is necessary to also know the following:

• How long was the temperature excursion?

• What were the excursion temperature(s)?
• Was there a temperature excursion above 40 ° ?
 • What time frame was used to calculate MKT?

SUGGESTION FOR ALLOWABLE EXCURSION LIMITS FOR NONCONTROLLED ROOM TEMPERATURE IN CLIMATE ZONE
IVB BY ANALOGY TO CRT
The rationale and foundation for the potential excursion limits for climatic zone !Vb was based on the
current excursion limits for CRT. The current limits for CRT and suggested limits for storage from 15 ° to 30 °
(RT in climatic zone !Vb) is shown in Table 1.

Table 1

Maximum
Time Period of Acceptable Maximum Excursion
Storage MKT MKT Excursion Temperature Time
Range (NMT) Calculation Range (NMT) (h )
30 days or the
time a product
remains in the 15 ° -20 °
organization's and Transient
CRT 20 -25
° °
25 °
possession 25 -30
° °
spikes 40 ° 24 h
30 days or the
RT2in time a product
Climatic remains in the
Zone organization's
IVb 15 -30
° °
30 °
possession 30 ° -40 ° .Q 40 ° 24 h

a RT, room temperature.

b At room temperature in climatic zone IVb any excursion below 15 ° , even with MKT NMT 30 ° should be evaluated case by case.

The MKT limit for room temperature in climatic zone IVb should not be more than 30 ° , as this is the
isothermal where the long term stability for this condition was established.
The time period used in calculating MKT should be for 30 days or the time a product remains in the
organization's possession, as established in .(1079.2}.. Because MKT is a calculation, the use of an extended
period of time would bias the calculation by including a majority of temperature data points outside the
excursion, thus presenting an inaccurate picture of the MKT and, consequently, the real impact of the
excursion.
The maximum temperature excursion should be NMT 40 ° , as 40 ° is the standard ICH accelerated condition
for room temperature drug products. If satisfactory stability data is available, temperature excursions beyond
40 ° could be accepted. Temperatures higher than 40 ° increase the likelihood for product degradation. The
adverse impact of lower excursion temperatures has also been demonstrated, which can lead to loss of
therapeutic effect or poor product quality. Precipitation of the drug product or the dislocation of the lattice
positions are some examples of the adverse effects of low temperature excursion in some products (Nirmal
and Ajeya, 2017). For this reason, temperature excursions below 15 ° should also be evaluated for impact,
because the classical stability studies do not challenge products for low temperature exposure when
developing product storage requirements at 15 ° -30 ° . Temperatures from 2 ° to 15 ° present a risk only for
precipitation of very concentrated solutions. For all other drug products, such temperatures just slow down
any degradation processes.
It is the assumption that a 24-h excursion within the acceptable excursion range would have negligible
impact on the product. However, as stated previously, there are certain products that might have a narrow
tolerance for temperature excursions and in this situation, MKT should not be used to evaluate an excursion.
The idea of a 24-h excursion range is supported by the following:

• ICH (2003) established that excursions in storage facilities for formal stability studies that exceed the
defined tolerances for more than 24 h should be described in the study report and their effect assessed.
• The study of Jenkins et al. (2022) showed a shelf-life loss of 2 weeks for a solid dosage form that had a
24-month self life. The maximum storage temperature for the product was 30 ° and with a temperature
excursion at 40 ° of 6 days, the impact was minimal.
The frequency of temperature excursions should be evaluated periodically by quality professionals. For
cases where there are recurring observations of excursions from a particular facility or lane, a decision should
be made (Nirmal and Ajeya, 2017) and a CAPA (corrective action and preventive action) opened to determine
the process and measures to be taken, if any. A common problem that should be ruled out is failure by
receiving staff to turn off temperature monitoring devices once a product has been stored and the device
removed.
Establishing temperature excursion limits for climatic zone IVb is of particular importance at this moment,
not only to assess excursions during distribution, but also to establish acceptance criterion for lane
temperature profiling studies (lane temperature mapping) to select lanes and then perform the necessary
qualifications.

CONCLUSION
The storage, handling, and transportation of a drug product must be kept under recommended storage
conditions to maintain its quality, safety, and efficacy.
MKT cannot be used to normalize storage conditions situations that are out of control but can be a valuable
tool to evaluate a temperature excursion. Thus, the use of MKT in evaluating a short term excursion (as
defined in _(1079.2).) and the time frame used to calculate MKT as recommended by USP can allow for
responsible management of excursion risk.
The temperature excursion limits for climatic zone IVb in this article that were suggested for updating
.(1079.2). can help supply chain stakeholders in the decision-making process as to whether to keep or discard
a product after excursion. Products from public health programs operating in countries with limited resources
will not be lost due to a lack of a standard to help evaluate the risk and the impact of a temperature
excursion. Therefore, those limits will allow the stakeholders when performing lane temperature profiling
studies to decide for which lanes the product should have a qualified passive or active protection. Therefore,
these limits can also be applied for products distributed in climatic zones III and IVa, if the products were
tested during long term stability at 30 ° and are stored at a room temperature of 15 ° -30 ° .

ADDITIONAL SOURCES OF INFORMATION

• Anderson C, Seevers R, Hunt D. The use of mean kinetic temperature to aid evaluation of temperature
excursions: proper and improper application. In: Pharm Forum. 2018;44(4).
• Anderson C, Seevers R, Hunt D. The use of mean kinetic temperature to aid evaluation of temperature
excursions for controlled cold tem12.erature drugs: 12.ro12.er and im12.ro12.er a12.12.lication. Pharm. Forum. 2019.
• Jenkins D, Cancel A, Layloff T. Mean kinetic temperature evaluations through simulated temperature
excursions and risk assessment with oral dosage usage for health programs. BMC Public Health.
2022;22(1):300. doi: 10.1186/s12889-022-12660-9.
• Health Canada. Guidelines for environmental control of drugs during storage and transportation. GUl-
0069. 2020.
• Huynh-Ba K, Latoz C. How to investigate temperature and humidity excursions of stability chambers.
Am. Pharm. Rev. 2021.
 • International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals
For Human Use. ICH harmonised tripartite guideline. Stability testing of new drug substances and
products Q1A(R2). 2003.
• Nirmal K, Ajeya J. Temperature excursion management: a novel approach of quality system in
pharmaceutical industry. Saudi Pharm. J. 2017;25(2)176-183.

a USP Packaging & Distribution Expert Committee.

b QUALITASPHARMA.

c USP staff.

d Cardinal Health.

e Pearl Pathway.

f Novo Nordisk.

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