Last Mile Shipping Conditions and Temperature Excursion Handling for Room Temperature Pharma Products in Europe

• Eli Lilly and Company
• MSD

Summary

Last mile distribution of pharmaceutical products at room temperature^A is challenging due to the shipping conditions and environmental weather conditions. Especially the management of multiple product temperature shipping ranges and handling of temperature excursions require special attention by the wholesalers, Marketing Authorization Holders (MAHs), logistic service providers (LSPs) and points of dispensing (e.g. pharmacy, hospital, clinic, dispensing doctor etc.). In order to improve last mile distribution practices in Europe, a Last Mile Temperature (LMT) model is proposed that provides clear guidance for last mile temperature management for the supply chain partners including but not limited to wholesalers, MAHs, LSPs and points of dispensing. Application of this LMT model will reduce false positive temperature excursions,^B prevent product shortages and elevate temperature control focus on strict 15- 25°C products.

Keywords

Last mile, distribution, shipping conditions, room temperature, phar- maceutical products, finished goods, temperature excursion handling, wholesaler, point(s) of dispensing and transport temperature.

Introduction

Last mile distribution from the wholesaler to the points of dispensing (e.g. pharmacy, hospital, clinic, dispensing doctor etc.) is the final critical shipment in the pharmaceutical supply chain to deliver on time, high quality, effective and safe pharmaceutical products. As in any step in the pharmaceutical supply chain, a temperature excursion during this shipment may impact product quality and/or delivery to the patient.^1-3 Therefore, it is of vital importance that all involved parties understand the shipping conditions and requirements, and how to handle and to avoid possible temperature excursions.

In collaboration with members of PCCIG, GIRP and EFPIA,^C the authors collected best industry practices and a set of requirements for operational temperature excursion handling of pharmaceutical products. In scope are only last mile temperature-controlled shipments using road vehicles from the wholesaler to the points of dispensing (e.g. pharmacy, hospital, clinic, etc.) in Europe for all pharmaceutical finished products with room temperature storage and transport conditions. Active pharmaceutical ingredients, excipients, bulk, intermediates, diagnostics, medical devices, qualification of active/passive shipping solutions, mail deliveries, other modes of transport, special supply chains for limited products including specialties and cold chain conditions (e.g. 2-8°C, < -20°C) are out of scope for this paper. Humidity is out of scope as well as the primary packaging of finished goods is selected to protect product from ambient humidity in the climatic zone where the product is marketed. In this article two main questions will be addressed:

1. Which temperature limits should be applied to maintain product quality in the last mile?
2. What is the best approach to handle and reduce temperature excursions in the last mile for pharmaceutical finished goods?

Before these questions are answered, one should first understand the last mile shipping conditions and storage statements on packages of finished goods, which will be addressed first.

Last Mile Shipping Conditions

The shipment duration of pharmaceutical products from the wholesaler to the points of dispensing depends on the local environment (e.g. number of in-country warehouses, size of the country, period of the year, etc.) and the applied business distribution model (e.g. number of stops, type of vehicles, etc.). For example, in Sweden, market practice for maximum delivery time throughout the country is 24 hours, while in other countries, such as Germany, typical transportation times range on average between 0.5 to 2 hours. Across Europe the average last mile shipment takes 4.6 hours.⁴ Other last mile shipping characteristics include:

• Use of vans owned or rented by wholesalers/2PL/3PL service providers.
• Missing flexible ramps or docking stations to allow weather protection of products during unloading (e.g. open air between road vehicle and receiver building).
• Mixed products in one plastic box/totes with lid delivered at point of dispense.
• Multiple drop off points (up to 50, the so-called milk-run) per vehicle resulting in many openings/closings of vehicle doors.
• Multiple deliveries per day to point of dispensing (e.g. 3 to 4 times per day on average in Germany).
• Large wholesaler portfolio of pharmaceutical products (typically >10,000) from multiple manufacturers (typically >100, on average 18.8 different manufacturers per delivery).⁴
• Multiple batches per drop off point.
• Small quantities per batch per delivery (very often single packages).
• Mixed products in one delivery (on average 35 products per delivery in Europe).⁴
• Short time between delivery at point of dispensing and product pick-up time by patient (possibly within hours).
• >60 different storage statements for room temperature products (e.g. store below 25°C, store below 30°C, do not freeze, no labelled storage condition, store at 2-25°C, etc.).⁵
• Variable ambient temperature conditions (see next paragraph).
• Vehicles may have no active temperature control in the last mile.
• Sometimes night deliveries at point of dispensing.

Thus, the last mile shipping conditions can be summarized as shipments of many different kinds of products, from various sources, to multiple customers, in a short timeframe (< 24 hours) under variable conditions.

Temperature is one of the variable conditions. Across Europe the outside temperature varies per hour, per day/night, and during the year from about -35°C in Scandinavia in the winter season up to about +45°C in Southern Europe during summertime. Applying strict, narrow temperature limits (e.g. 15-25°C) during these extreme conditions challenge the logistic environment (e.g. door opening of active systems, qualification of passive solutions, etc.) and leads often to short-term temperature excursions.

Can room temperature pharmaceutical products withstand short-term temperature excursions (measured in hours to days) to 30°C or 40°C or to 2°C without impacting product quality, efficacy, safety and shelf life? The short answer is -“it depends on the product”, as some products have low or high thermal stability. However, are there scientific based arguments to assume that short-term tem- perature excursions will not impact the product quality until the date of expiry? For this we need to consider and to understand how product labelled storage conditions and shelf lifes are determined.

Labelled Storage Conditions on Packages

Schumacher, Grimm, WHO and ICH played an important role from 1972 to 2009 to set the current and expected regulatory requirements for stability testing and labelled storage conditions for (new) pharmaceutical products in combination with product expiry.^6-10 Using average temperatures and mean kinetic temperature (MKT) calculations, the world has been divided in four climate zones by Grimm, WHO, and ICH. All European countries, US, Canada and Australia were assigned to climate zones I or II, while most countries in Africa, Asia and Latin America were assigned to climate zones III or IV. Based on these zones, temperature and humidity conditions were developed for stability testing and storage labelling statements. These zones and temperature conditions are summarized in Table 1. For clarity purposes the humidity is omitted from in this table.

For room temperature products, the ICH Q1A(R2) guideline⁹ clearly indicates for data filing submis- sion that it is up to the applicant to decide whether long term stability studies are performed at 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH for a minimum of 12 months. If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition at 30°C ± 2°C/65% RH ± 5% RH with data up to six months required upon data filling submission. In addition, the applicant should also submit accelerated stability data up to six months at 40°C ± 2°C/75% RH ± 5% RH. If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” (see Reference10 for definition of significant changes) occurs at any time during six months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. Based on these conditions and stability testing results, the labelled storage condition and product expiry are determined and submitted with the product filing. The labelled storage condition terminology as stated by EMA11 is also listed in Table 1, which shows the relation with the stability testing conditions and climate zones.

As indicated in Table 1, the labelled storage conditions and stability testing conditions are based on average temperatures and MKT calculations by Grimm using open air and storage room data over long periods (months to years). Table 1 shows that if a product has a storage statement “Store below 25°C” or “Store below 30°C” on the package, a significant change in stability may happen within six months at 40°C. However, the patient does not know when this change will occur as the manufacturer does not normally disclose this information in the leaflet. Interestingly, there are companies that list a "Store below 30°C" label even with compliant 40°C data (showing no significant change within six months at 40°C).

In addition, Table 1 shows that temperatures to 27°C are allowed during stability testing for products with a storage statement of “Store below 25°C” as the allowable temperature variation within a climate chamber is 25°C ± 2°C. Products with a storage statement of “Store below 30°C” have allowable temperatures to 32°C during stability testing as the climate chamber is at 30°C ± 2°C. Such practice is already widely applied and accepted for cold chain products with labelled storage condition of 2-8°C and testing after stability storage at 5°C ± 3°C.11

It should be noted that EMA guidance on storage conditions does not include "Store between 15°C and 25°C" as a recommended label text and specifically states that "room temperature" is not acceptable as a labelling term. EMA also recommends¹¹ that "storage at a continuous temperature of 25°C during real time stability studies covers the actual temperature exposure likely to be encountered under ambient conditions throughout Europe, including real time excursions from 25°C." This clearly implies an expectation that a product labelled "Store below 25°C" or "Store below 30°C" may be kept at ambient (uncontrolled) conditions in Europe for the duration of its shelf life.

Secure Temperature Control

To secure temperature control during the shipment of pharma- ceutical products, five basic principles should be applied by the shipper (e.g. wholesaler):

1. Temperature specifications are set for products, processes and systems.
2. Temperature is controlled in an environment within the intended range using qualified active and/or passive system(s).
3. Temperature is measured by calibrated sensors at hot/cold spot location(s) based on temperature mapping studies.
4. Temperature data is collected and securely stored in readable and retrievable electronic and/or paper format¹² according to data integrity ALCOAD principles.
5. Temperature excursions are investigated and product dispositions are executed according to current Good Distribution Practices (GDP)^2-3 and Good Pharmacy Practices (GPP).¹³

It is the responsibility of the wholesale distributor to ensure that vehicles and equipment used to distribute, store or handle medicinal products are suitable for their use and appropriately equipped to prevent exposure of the products to conditions that could affect their quality and packaging integrity as defined in the EU GDP.² Under certain circumstances, the shipper may decide not to use an active/passive shipping solution for temperature control (e.g. temperature-controlled vans, thermal pack outs, etc.) and/or temperature monitoring based on quality risk assessments. Here aspects as shipping lane temperature conditions, transport duration, mode of transport, transport process handling, product labelled storage condition and stability should be considered. The assessments should be data driven and may result in new requirements, for example execution of qualification studies of vans. How such assessments should be executed will not be discussed onwards.

As indicated in the EU GDP it is the wholesaler’s responsibility to ensure that the product quality is maintained during transportation. When temperature monitoring is applied, and a temperature excursion is happening during transportation, then the wholesaler, LSP and receiver should be fully aware how to act towards the product(s). The receiver is recommended to follow the next basic steps upon receipt of pharmaceutical products with a temperature monitor:

1. Check temperature monitor for alarms. If no alarm(s), product(s) can be dispensed.
2. Quarantine product(s) in case of temperature alarm.
3. Follow written procedures on how to handle and to investigate temperature excursions.
4. Dispense, discard or return the product(s) depending on the outcome of the investigation.

In case the product is deemed “out of range” upon receipt, and it is returned to the wholesaler, then the pack should be marked by the wholesaler following the rules by National Medicine Verification Systems (NMVS) in the EU¹⁴ starting in February 2019 (e.g. “Mark pack as Intended for Destruction” in case of not allowable temperature excursion during transportation/storage, or in case the excursion has to be further investigated “Mark pack as Locked”).

Which Temperature Limits Should be Applied to Maintain Product Quality in the Last Mile?

Analysis of a wholesaler product portfolio in Europe revealed more than 60 different temperature ranges for room temperature pharmaceutical finished products in one country (e.g. 2-25°C, 15-25°C, 8-30°C, 0-30°C, etc.).⁵ Under these circumstances it is not feasible for wholesalers, logistic service providers and receivers to apply multiple temperature limits during the last mile for the entire product portfolio. At the same time, applying a single strict temperature range of 15-25°C would result in an unnecessarily high number of temperature excursions due to the last mile shipping conditions. In many cases, this would produce false positive temperature alarms as supporting stability data are available at the manufacturer. In order to reduce the high administrative burden of many false positive temperature alarms, a risk-based approach should be applied to set temperature limits during the last mile for room temperature products.

Regulatory agencies expect that each stakeholder in the pharmaceutical supply chain follows the storage conditions during transportation within the defined limits as described by the manufacturers or on the outer packaging.² The storage conditions on the outer packaging are intended for the use by the patients and manufacturers do not normally disclose separate transport conditions to wholesalers. As a result, the EU GDP regulations mean that unless specified otherwise wholesalers should follow strictly the labelled storage conditions on the outer packaging.

Which temperature limits should be applied during the transport of 200+ room temperature products in one vehicle (e.g. van) to pharmacies in a region in summertime knowing that door openings result in short term excursions between 25 and 30°C? What would be the impact to all supplied products, to all points of dispensing and to all patients? For example, medicine shortages, long waiting times for product dispositions and no medication to patients.

Some EU Health Authorities have developed a pragmatic approach. In Austria, for example, short-term deviations (up to 12 hours) in a temperature range of 2 – 30°C are deemed acceptable for goods that have to be stored at room temperature as defined in the Austrian Transport Code.¹⁵ This example could be adopted more widely as a best practice and should be supported by at least one of the following: temperature monitoring of each delivery, transport temperature validation studies and/or data driven transport lane risk assessments. The risk assessment(s) should determine if temperature control and monitoring is necessary. Transport without control and monitoring should be acceptable if the necessary quality risk assessment has been performed.

In the broad wholesaler product portfolio, there are exceptions in relation to product stability for room temperature products. Some products will deteriorate above 25°C and others may for example physically degrade (e.g. phase separation) below a certain temperature over time. However, the majority of products have supporting stability data between 2 to 32°C for at least 24 hours as refrigeration is generally allowed and long term or intermediate stability data at 30°C±2°C or accelerated stability data at 40°C±2°C are available in the filing.^9,11

To improve temperature control for room temperature products in the last mile in Europe, it is important to define a model that is acceptable by all supply chain stakeholders including manufacturers, regulatory bodies, MAHs, wholesalers, and receivers. Furthermore, it should simplify and clarify the current complex situation. Therefore, this article proposes a Last Mile Temperature (LMT) model which fulfills those requirements and consists of three basic requirements:

1. Temperature in the last mile product vehicle is designed to remain at 15-25°C.
2. Product temperature excursions to 2°C and 32°C within 24 hours are allowed without product impact as supported by stability data.
3. Products that do not meet requirement 2 should be listed on a strict 15-25°C product list OR should be marked with a visual indicator (see further discussions below).

By applying this approach, temperature excursions in the last mile for pharmaceutical finished goods are reduced, product quality is ensured and unnecessary delays in providing medicines to patients are avoided. In total this brings the entire pharmaceutical supply chain to an elevated temperature control level.

Discussion

The proposed Last Mile Temperature (LMT) model for shipping room temperature products from the wholesaler to the points of dispensing provides multiple advantages to the last mile supply chain:

1. Clear guidance in last mile temperature management for wholesalers, logistic service providers and receivers.
2. Reduction of false positive temperature excursions.
3. Prevention of product shortages due to waste linked to temperature.
4. Elevated temperature control focus on strict 15-25°C products (like already in place for cold chain products).

On the other hand, the creation of a strict 15-25°C product list has challenges to solve. Who is the owner and should manage such a list? Who has access to this list? Which information should be captured in the list? Are there current tools available and/or organizations present that could take the lead? These questions and many more need to be answered in order to create a strict 15-25°C product list that provides the model’s applicability and viability.

One of the challenges could be solved by using the EMA SPOR database.^16,17 The interesting part of this topic is that the SPOR data model also includes package data for the medicinal products. It would be interesting to extend this database with LMT model data. Ideally, there should be a standardized and existing database which is available to all supply chain stakeholders and which is managed by a central organization.

There may be an alternative to the strict 15-25°C product list. From a practical point of view, a visual indicator or written last mile transport condition on the outer package would be a time saver and efficient solution for wholesalers, logistic service providers and receivers to distinguish between products with allowable last mile temperature ranges between 2 and 32°C for 24 hours and the products with strict 15-25°C limitations. A simple visual indicator would be preferred as it can serve as an universal reference for all citizens. A visual marking is independent of the national languages and it is an ultimate reference tool easier to understand than text. For example, a visual indicator could be a red triangle on the outer package for the products with strict temperature limitations between 15-25°C. Alternatively, a visual indicator for products with supporting stability data between 2 and 32°C for a maximum of 24 hours could be considered. Format, size and color of a visual indicator will not be further discussed as it is out of scope in this article. Whatever is unanimously chosen, a visual indicator would ideally require regulatory enforcement, political agreement and probably 5-8 years for implementation in Europe. Therefore, if the pharmaceutical supply chain would support the LMT model and a visual indicator, it should be the pharmaceutical industry itself to take the lead to accelerate implementation.

The strict 15-25°C temperature range products are harder to manage by wholesalers, logistic service providers, receivers, and manufacturers due to the management of the temperature excursions and product dispositions based on individual product/batch stability assessments. Therefore, it is up to the pharmaceutical industry to take its responsibility to re-evaluate all available stability data in order to remove as many products as possible from the strict 15-25°C product list. Why? Because it is from a commercial and quality point of view a competi- tive advantage not to have products on the strict 15-25°C product list. The broader allowable 2-32°C shipping conditions would result in less temperature excursion handling activities, discards and prevention of product shortages.

Further Considerations

The upper temperature limit of 25°C for storage conditions of strict 15- 25°C products is based on stability testing at 25°C±2°C.⁹ During stability testing in climate chambers, temperature excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effects assessed.10 In other words, if the temperature remains for 24 hours or more above 27°C, product impact may be expected. Thus, the question is why a storage limit of maximum 25°C should be used for last mile shipments if shipments are executed within 24 hours. Based on stability testing guidance, a limit of maximum 27°C would be allowable for the strict 15-25°C products in the last mile.

The lower limit of 15°C is based on the definition of room temperature in European Pharmacopoeia as testing of pharmaceuticals should be executed at 15-25°C.18 The basic idea behind this requirement is that testing should be standardized and reproducible by eliminating test variability like temperature as much as possible. For example, water density is sensitive for temperature changes impacting the volume by temperature. In the European Medicines Agency (EMA) “Guideline on Declaration of Storage Conditions,”¹¹ storage statements are proposed and can be combined. For example, “Store below 25°C” and “Do not refrigerate” would mean store at 9-25°C as refrigeration is at 2-8°C. Would it be an option to change the strict 15-25°C condition for product last mile shipments to 9-27°C < 24 hours? If yes, this would reduce the number of temperature excursions and its handling even further for this category of products.

To avoid temperature extremes and excursions, the weather forecast can be used. In summertime deliveries should be preferably executed in the morning/evening/night to avoid heat, while in the winter season the extreme cold can be avoided by delivering products in the afternoon. This approach can be a risk mitigation solution after the execution of a transport lane risk assessment. Another risk mitigation solution is to apply real-time temperature monitoring using a control tower. These new technologies allow pro-active temperature risk control versus re-active temperature logger observations after delivery at the receiver. The location of the temperature sensors should be based on vehicle temperature mapping to identify hot and cold spots (e.g. biggest risk areas).

One of the most important challenges is the qualification of transportation routes or so-called shipping lanes. Best practices used for standard 13.6 meters long ATP FRC certified temperature-controlled trailers¹⁹ are hard to apply for vehicles like vans due to the air gaps between the van and points of dispensing during unloading as no docking station is present. In addition, the door size and the small volume of the van directly leads to (extreme) temperature excursions when temperature differences are large (>10°C) between inside and outside of the van. Today’s temperature data loggers are highly sensitive towards temperature variations resulting in excursions upon opening of the van’s door, which can be solved by proper handling instructions and applying the correct rounded rules to whole numbers as defined in the regulations.^11,18 Another solution to reduce temperature excursions is to qualify transported medicinal products within used boxes or so-called totes. These boxes are always closed systems – short term temperature changes due to open doors will not impact the inside temperature directly. To improve the temperature monitoring of the product during transportation it is recommended to place the temperature sensor inside the box. This approach has the advantages that the temperature changes upon door opening are minimal inside the box and false positive temperature excursions are not recorded. This industry best practice has another advantage: The closed box with lid is protecting medicinal products against direct sun and rain impact.

Conclusions

Last mile shipping conditions can be summarized as shipments of many different kind of products from various sources to multiple customers in a short timeframe (< 24 hours) under variable conditions including temperature. During the last mile distribution of pharmaceutical products with room temperatures as labelled storage condition from the wholesaler to the points of dispensing, vehicles often encounter many door openings and air gaps between the vehicle and points of dispensing. As a result, temperature excursions are happening outside the typical room temperature range of 15-25°C, because the ambient temperature outside the vehicle in Europe varies between -35°C and +45°C during the year. To reduce the burden of temperature excursions in the last mile, the Last Mile Temperature (LMT) model proposes the following approach:

1. Temperature in the last mile product vehicle is designed to stay at 15-25°C.
2. Product temperature excursions to 2°C and 32°C within 24 hours are allowed without product impact as supported by stability data.
3. Products that do not meet requirement 2 should be listed on a strict 15-25°C product list OR should be marked with a visual indicator (for example a red triangle).

This approach brings the entire pharmaceutical supply chain to an elevated temperature control level in the last mile including clear guidance for wholesalers, logistic service providers and receivers, reduction of false positive temperature excursions, prevention of product shortages and elevated temperature control focus on strict 15- 25°C products. In addition, if product temperature monitoring is applied during transportation, it is recommended to place the temperature sensor inside box/totes with a closed lid. This would further reduce the number of rejections and false positive temperature excursions.

Disclaimer

This paper was put together by a voluntary pharmaceutical industry working group. The content and the view expressed in this document are the result of a consensus achieved by the authors and are not necessarily views of the organizations they present or represented.

The mention of a product or service provider does not mean it is the sole product or service that is available for use.

Acknowledgements

The authors would like to thank Monika Derecque-Pois (GIRP), Judith Kalina (GIRP), Simon White (Pfizer), Alexandre Poissonnet (McKesson Europe), Gino Vleugels (Johnson & Johnson), Joseph Zelhof (Bristol- Myers Squibb), Ruud van der Geer (MSD), Olivier Simonnot (Sensitech), Esther Destratis (Takeda Pharmaceuticals International AG) and Eric Stener (Sanofi Pasteur) for their review and comments while preparing the manuscript of this article.

Explanation Notes

1. Room temperature is defined as 15-25°C in the European Pharmacopoeia.18 Here any medicinal product that can be stored and transported at this temperature range and/or wider is considered as a room temperature pharma product.
2. False positive temperature excursion is any temperature alarm that has no impact to the product quality as supported by stability data. For example this can happen if temperature specifications of temperature monitoring systems are set narrower than the product temperature specifications.
3. PCCIG = Pharmaceutical Cold Chain Interest Group of the Parenteral Drug Association (PDA); GIRP = European Healthcare Distribution Association, the umbrella organization for pharmaceutical full-line wholesalers and distributors of healthcare products and services in Europe; EFPIA = European Federation of Pharmaceutical Industries and Associations.
4. Data should comply to Data Integrity ALCOA principles: Attributable to the person generating the data, Legible and permanent, Contemporaneous, Original record or true copy, and Accurate.

References

1. E.J. van Asselt and R.H. Bishara, "Establishing and Managing the Drug Product Stability Budget," Journal of Pharmaceutical Outsourcing, vol. 16, no. 4, July/ August, pp. 20-27, 2015.
2. European Commission, "Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01)," Official Journal of the European Union, 2013.
3. PDA Technical Report 58, "Risk Management for Temperature-Controlled Distribution," 2012.
4. Institute for Pharmaeconomic Research (IPF), "Distribution profile and efficiency of the European pharmaceutical full-line wholesaling sector (Commissioned by European Healthcare Distribution Association, GIRP)," 2017. [Online]. Available: http://www.girp.eu/files/GIRP-IPF%20Study%20 2016.pdf. [Accessed 18 Jun 2018].
5. L. Schütte, "Challenges of last mile distribution for ambient products," in PDA Pharmaceutical Cold & Supply Chain Conference, Amsterdam, 2015.
6. P. Schumacher, "Über eine für die Haltbarkeit von Arzneimitteln maßgebliche Klimaeinteilung [The impact of climate classification on the stability of medicines]," Die Pharmazeutische Industrie, vol. 34, p. 481–483, 1972.
7. W. Grimm, "Storage conditions for stability testing in the EC, Japan and USA; the most important market for drug products," Drug development and industrial pharmacy, vol. 19, pp. 2795-2830, 1993.
8. World Health Organization (WHO) Expert Committee on Specifications for Pharmaceutical Preparations, "WHO Technical Report Series, No. 863 - Thirty- fourth Report," 1996.
9. International Conference on Harmonization ICH Q1A(R2), "ICH Harmonised Tripartite Guideline Stability Testing of New Drug Substances and Products," Current Step 4 version, dated 6 February 2003.
10. World Health Organization (WHO), "Stability testing of active pharmaceutical ingredients and finished pharmaceutical products," 2009.
11. European Medicine Agency (EMA) CPMP/QWP/609/96/Rev 2, "Guideline on Declaration of Storage Conditions," 2007.
12. EudraLex, "Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems," vol. 4.
13. World Health Organization (WHO), "Good Pharmacy Practices. Annex 8. Joint FIP/WHO Guidelines on GPP. Standards for quality of pharmacy services," WHO Technical Report Series, No. 961, pp. 310-323, 2011.
14. EU, "Delegated Regulation (EU) 2016/161 of 2 October 2015, supplementing Directive 2001/83/EC of the European Parliament and of the Council by laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use".
15. Austrian Code, "Code of Conduct for the Transportation of Medicinal Products in Austria," 2014.
16. European Medicine Agency EMA/732656/2015, "Introduction to ISO Identification of Medicinal Products, SPOR programme," 2016.
17. European Medicine Agency (EMA), "http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/general/general_content_000645.jsp," [Online]. [Accessed 24 May 2018].
18. Pharm. Eur., European Pharmacopoeia, edition 9.0, vol. I, 2017.
19. E.J. van Asselt, et. al., "Pharma requirements for temperature controlled trailers," Journal of Pharmaceutical Outsourcing, vol. 18, no. 4, Jul/Aug, pp. 12-19, 2017.