Transport Risk Assessment and Verification – from Theory to Practice

Legal and regulatory requirements, including GMP and GDP guidelines, require consistently that medicinal products shall be stored and transported in a way that the product delivered maintain their quality and integrity and remain within the legal supply chain during storage and/or transportation. Storage and transport need to be described in the Pharmaceutical Quality System and the principles of quality risk management shall be used for designing and managing these activities.

While the respective requirements seem well implemented for storage facilities in the pharmaceuti­cal industry and the supply chain, observations in audits and inspections as well as frequent questions concerning imple­men­tation of transport requirements demonstrate that consultancy on this topic is highly valued.

The following discussion is based on the requirements described in the EU Guideline on Good Distribution Practice of medicinal products for human use, however, the GDP Guidelines for active substances, the GMP Guidelines and similar regulations contain comparable requirements for the respective areas within or outside of the EU.

Transport as “Mobile Storage”

Transport is nowadays jointly acknowledged as “mobile storage”. However, compared to the storage in warehouses, there are much more external factors that may affect product quality during transport, for example, but not limited to

• environmental factors (climatic zones, temperature, humidity, light, vibration…)
• mode of transport (air, sea, road)
• delivery routes
• transport duration
• number of transits
• holding times
• vehicles
• shipping containers
• transport temperature
• equipment to control environmental requirements (active, passive)
• equipment to measure environmental factors
• handling at airport
• handling at customs clearance
• security aspects (e.g. damage, contamination, adulteration, theft)

Chapter 9 of the EU GDP guideline points out that it must be finally possible to demonstrate that the medicinal products have not been exposed to conditions that may compromise their quality and integrity during transport. The GDP guideline requests explicitly a transport risk assessment focusing on the temperature during transport as critical factor for all medicinal products. The outcome of the risk assessment shall facilitate decision making where temperature controls have to be implemented. However, depending on the product, also other factors (e.g. moisture, light, vibration, air pressure) may be considered critical for a specific product and should then be included in the risk assessment and be controlled or monitored during transport.

Such a risk assessment of the delivery routes requires not only a profound knowledge of the product characteristics (product susceptibility, stability data and subsequently registered storage conditions) but also detailed knowledge on the planned or already existing delivery routes that shall be assessed. A collaboration with the concerned carrier is recommended to clearly understand details of the delivery route.

According to chapter 6 of the EU GMP Annex 15 on validation and qualification, the impact of variables in the transportation process other than those conditions which are continuously controlled or monitored, e.g. delays during transportation, failure of monitoring devices, topping up liquid nitrogen, product susceptibility and any other relevant factors should also be considered during risk analysis.

Transport Mapping

Thus, the first step to approach a risk assessment should be the development of an initial, high level transport mapping, describing the transport from the storage facility at start up to the storage facility of the final recipient. This initial mapping should already show intermediate storage facilities, modes of transport, transits, climatic zones and rough estimate of timelines. The information can e.g. be visualized as flow chart, shown in tabular form or alike.

At this step, a grouping of products with comparable product characteristics, stability and delivery routes and/or the determination of few worst-case scenarios may reduce the number and complexity of risk assessments to be performed. 

In further steps the transport mapping can be finetuned with additional information, e.g. on vehicle types, intermediate hubs, further transits, holding times, information on environmental factors, already established controls or monitoring of environmental factors, more detailed timelines et cetera (see list above).

Risk Assessment

Based on this more detailed transport mapping, a risk assessment can now be performed. A commonly used tool is the FMEA-analysis (failure mode and effect analysis). This method correlates the severity of potential failures with the probability of occurrence and the probability of detection. A quantifiable relative risk score can be derived. However, other risk assessment tools can be used alternatively (see e.g. ICH Guideline Q9).

In case of complex transport routes, it may be helpful to beak them down and analyze the respective parts step by step.

Risk Mitigation / Minimization Measures

After risk analysis and evaluation, risk mitigation or minimization measures should be derived, where appropriate. The most effective and save transport is usually the most direct and quickest one with the least number of transits. Questions to be considered for risk minimization could therefore be the following: Is it possible to reduce transport time and/or holding times? Can the number and duration of transits be reduced (e.g. change of transport mode, change of vehicles, interim storage, reloading)? Can the shipping containers be improved? Have additional temperature controls (or other controls) to be implemented? Thus, a risk assessment can also be used for transport optimization purpose.

When risk minimization comes to its limits, it has to be decided whether the remaining risks can be accepted (including the resulting consequences) or not. The risk assessment and its results will be documented and communicated. After a defined period, the effectiveness of the implemented measures should be controlled.

Transport Verification

It is obvious that it will be difficult to perform a transport validation for entire delivery routes based on the outcome of the risk assessment(s), as a validation requires exactly replicable flows and parameters. Too many variables are usually involved in transport. However, a feasible alternative approach is a transport verification that can be performed in a structured approach during the operational business.

As mentioned above, temperature is a significant risk factor able to affect product quality. Thus, with the focus on the temperature, a transport verification process shall confirm in a pre-defined scenario based on the outcome of the risk assessment that the products remain within a predefined temperature range during transport (e.g. by evaluating temperature records from accompanying data loggers, temperature indicators or similar while using qualified vehicles, transport equipment and calibrated temperature measuring systems). Additional controls of other relevant factors can be managed analogously, depending on the product characteristics and requirements.

The transport verification process is described in a pre-defined transport verification protocol and assessed and concluded in a respective report, confirming finally the suitability of the defined transport routes. Seasonal variations have to be taken into consideration; thus, a pre-defined winter and summer scenario should be evaluated. However, as stated in Annex 15, due to the variable conditions expected during transportation a successful transport verification does not replace continuous monitoring and recording of any critical environmental conditions to which the product may be subjected, unless otherwise justified.

Outsourcing of Transporting Activities

Transport activities for medicinal products are often outsourced to carriers as service provider. The requirements mentioned in chapter 7 of the EU GDP Guideline apply for outsourcing of such GDP activities. In Europe, carriers involved in transport of medicinal products neither hold a Wholesale Distribution Authorization or GDP certificate (despite they are also performing storage activities), nor are they controlled by the Competent Authorities. However, they have to comply with the requirements of the EU-GDP Guidelines. This should be taken into account for carrier qualification and re-qualification and subsequent carrier management. 

Conclusion

In conclusion, profound knowledge of the medicinal products concerned, and the delivery routes are basis for the execution of risk assessments on transport. The risk assessment is a powerful tool for the planning of new transport routes as well as for optimizing and controlling existing transport routes. It is also the basis for a subsequent transport verification.

References:

1. EU Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01)

(https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2013:343:0001:0014:EN:PDF)

1. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation (01 October 2015)

(https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-4/2015-10_annex15.pdf)

1. ICH guideline Q9 on quality risk management (January 2006)

(https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-3.pdf)