Written procedures for storage and transport must be in place in compliance with GDP. Evidence of their suitability must be provided insofar as they have an impact on the quality of starting materials and intermediates for the production of medicinal products and finally on the finished pharmaceutical products themselves. This simply means taking relevant validation actions.
The EU GDP Guide expresses this requirement in Chapter 3.3.2. Qualification and Validation as follows: “Wholesale distributors should identify what key equipment qualification and/or key process validation is necessary to ensure correct installation and operation. The scope and extent of such qualification and/or validation activities (such as storage, pick and pack processes) should be determined using a documented risk assessment approach.”
This makes it imperative to validate transport routes if a risk analysis arrives at this conclusion. And this includes temperature-controlled shipments.
The most important point on this topic is to take the entire transport chain into consideration. The most diligent observance of the cold chain in manufacturing operations fails to achieve its objective if temperatures during the delivery exceed or fall below acceptable levels. The chain begins with storage in qualified cold-storage facilities and continues up to ready-to-dispatch packaging. Almost 90 percent of deliveries are carried out by truck, nowadays generally under controlled conditions, in qualified vehicles.
To achieve a validated process, first of all it is important to look at each transport step individually. All vehicles and cold-storage facilities used must be qualified. These qualifications must be repeated at regular intervals in order to maintain the qualified status. This involves regular calibration of any sensors that have been fixed in place and the inspection of alarm locations and intervals as well as a regular maintenance following a set schedule. In total this must result in a validated chain. An often cited, but important principle is: “A chain is only as strong as its weakest link.” The individual links of the chain are described in greater detail below.
As mentioned previously, there are two ways to ship refrigerated medicinal products: with active or passive cooling. Both procedures will be dealt with below and the limits of the passive cooling in terms of a validation will become apparent as a result.
The most common shipping means will be treated first: shipment by refrigerated truck/transport vehicle. Since this type of shipment is usually handled by an external service provider, it is imperative to conduct an initial audit to make certain that the service provider is suited for the job. Particularly in light of medicinal product safety, an audit prior to commencement of business relations is advisable. This should be followed by regular inspections and if necessary audits scheduled at short notice.
It is also important to conduct random temperature checks of individual deliveries. Another possibility here would be to add temperature loggers to selected shipments without the service provider’s knowledge, to enable these temperatures recorded by the loggers to be compared with those of the transport vehicle. Only a temperature logger that has been placed inside the package will give the actual temperature of the medicinal product and not the recorded air temperature in the freight compartment of the transport vehicle. Especially at the beginning of a business cooperation it is advisable to check shipments more often; if these checks indicate that a transport is secure, a transition to monitoring the temperature on a spot-check basis could be made.
It has proved useful to conduct the qualification of a transport vehicle analogously to that of a cold-storage facility. If possible this should be done in cooperation with the external service provider.
It is important to look at the transfer depots of the carrier as well, as they must also meet the requirements of proper storage.
Figure 48 shows the possible distribution of five calibrated temperature loggers in critical areas during the PQ, including, for instance, near the door, at the bottom close to the refrigerator unit or directly in front of the air-blowing area of the refrigerator unit.
Figure 48: Distribution of Temperature Loggers in the Qualification of a Refrigerated Transport Vehicle
To prevent direct influence of weather on the loaded freight when the doors are open, protective strip curtains of transparent plastic are often hung between the door and the freight compartment. As the USP monograph <1079> describes, it makes sense to provide summer and winter profiles under extreme conditions. A review of average external temperatures (“ambient conditions”) is also appropriate for comparative purposes. In addition, it is also feasible here to check the temperature curves in the vehicle both in the loaded and unloaded states as well as the impact of open doors. Various institutes offer large climatic chambers on a rental basis, in which an entire tractor-trailer rig can be accommodated for testing purposes. This makes it possible to conduct qualifications independently of natural weather conditions. After all, the result should be that a proper transport is guaranteed independently of the weather.
Moreover, refrigerated shipment is a process that takes place under high humidity. Therefore, there should be an investigation into whether moisture-sensitive preparations are being transported in which the transport and/or storage represents a risk and therefore should be tested separately. However, since most of the preparations to be handled at 2 C to 8 C are liquids or lyophilisates in glass containers (vials), scrutinizing moisture is probably of lesser relevance and more the exception than the rule.
A possible alarm system for generating alerts during transport is depicted in the diagram shown in Figure 49.
Figure 49: Alarm Scheme for a Refrigerated Transport
To simplify matters, only one measuring point of the temperature readings is indicated.
The specified temperature range for a refrigerated transport is 2 C to 8 C. A temperature measurement is made every five minutes. If at any one time the monitored temperature is below zero C or above 12 C (i.e., greater than/equal to 2 C or 4 C difference to the specified temperature range) an alert is generated immediately. If the temperature at four consecutive measuring points lies within the range of 2 C to zero C or 8 C to 12 C (i.e., <2 C or 4 C difference to the specified temperature range), an alert is also generated. An analogous system can be applied to the transport at ambient temperature, where it is likewise very useful. The tolerance ranges here are determined at the discretion of the pharmaceutical company.
The GMP Focus PDF Download Creating a Master Plan for Drug Warehousing, Transportation and Distribution walks you through the planning and implementation process, including the six key requirements included in the EU GDP Guidelines:
Dr. Christoph Frick
kohlpharma GmbH, Merzig
Dr. Nicola Spiggelkötter
Knowledge & Support, Bad Harzburg