The transport of pharmaceuticals is subject to strict requirements. This reality has long since arrived in logistics. Transparency, reliability and compliance with rules are therefore part of the daily business of a pharmaceutical logistics company. Where are the current challenges? Does DIN SPEC 91323 offer answers when it comes to standards for the vehicles used? What must be considered if a manufacturer is also wholesaler? Which problems arise from the different definitions of the term "wholesale" in Germany and the EU? These and other questions were discussed at our GMP conference, the GMP-BERATER Tage 2018 with the experts GMP inspector Dr Daniel Müller and Axel Radke, expert for storage and transport damage at TRUST-Expertenservice.
First of all, the question of "who" is clarified: the responsibility for transport matters lies in Germany with the authorities of the federal states. Each federal state is responsible for the operating sites located within its borders and is therefore responsible for their activities. To this end, the competent authority shall carry out an inspection of storage service providers. However, only the wholesaler receives an activity-related permit. The mere storage of medicinal products is not subject to authorisation in Germany, but must be notified in accordance with § 67 German Drug Law. If drugs are purchased and resold, a wholesale permit is required. The views of the various federal states differ on this point. There is the possibility, following the European model, of including a warehouse in the manufacturing authorisation of the pharmaceutical manufacturing company, which also grants the release for the stored medicinal products. This can be done, for example, in the form of an attachment to the authorisation. Inspection of the warehouse is ultimately the responsibility of the authority on whose 'territory' the warehouse is located.
A manufacturer with a manufacturing authorisation is usually inspected every two years. For wholesalers and warehouse service providers who store and retrieve goods, the acceptance period for an inspection is between four and five years, as the certificates are recognised for such a long time. Some federal states include these bearings in the manufacturing permit of the pharmaceutical manufacturer, others do not. If the warehouse of a Mannheim-based company (Baden-Württemberg) is located in Ludwigshafen (Rhineland-Palatinate), the inspector from Baden-Württemberg will contact his colleague from Rhineland-Palatinate in order to obtain information and is able, but not obliged, to include this in his manufacturing authorisation for the Mannheim-based pharmaceutical company. This optional possibility sometimes leads to misunderstandings.
But how far does the authority go? Up to what point is testing or inspection carried out? There are clear rules on this:
For transports in general and especially worldwide via many stations it is essential to make individual agreements in the form of contracts, logistic services, etc. agreements and limitation agreements. This binds the logistics service provider and the shipper to certain processes and clearly defines responsibilities. As a forwarder, it is at the same time his task to point out possibilities for the correct bridging of waiting times and also to inform about the additional costs. Conversely, this also means that the client can assess the transport chain from door to door and develop an awareness of possible problematic areas. Good cooperation between the two parties is indispensable, because the forwarder is often also the interface to the air carrier, for example, and can only pass on information that he also receives from his client. Since agreements of this kind usually involve long-term cooperation, it is always necessary to carry out an audit of the logistician in order to inspect the processes directly on site, coordinate interfaces and discuss problem areas. Contractual agreements can thus be made more precise. The transport of medicines is not a "package tour", but always requires individual planning and risk assessment. As a good partner, it is also the forwarder who should draw attention to the fact that, for example, an aircraft generally does not have a pre-tempered, monitored cooling chamber, but only zones with approximate ambient temperatures and that loading on the tarmac can also involve periods without safe temperature control. In return, however, the freight forwarder is also dependent on exact information about the product and the risks in order to be able to give correct advice. If the entire supply chain is well discussed, this results in a solid concept for safe transport.
First of all, it is important to clarify the terms "import" and "wholesale" once again. From a legal point of view, imports always take place when goods come from outside the European Union. In contrast, wholesale trade always takes place within the EU. According to the German Drug Law, an import from France is therefore not an import, but an introduction into the scope of the Drug Law. On the other hand, the official hurdles are much lower. For an "import", a production/import permit is required. The quality of the goods must be checked and certified again in the EU, even if this step has already been taken outside the EU. Even retention samples must then always be stored within the EU.
In principle, the filling process mentioned in the example from a large container into smaller bottles is legally seen as a manufacturing step and must therefore also be certified. A manufacturing permit is usually required. The degree of pharmaceutical production is extremely narrow at this point and there is no officially accepted example known where a wholesaler was authorised to carry out such a filling process. In most cases, these are the pharmaceutical companies themselves, which are also wholesalers and have the appropriate premises at their disposal.
First of all, reference is made to DIN SPEC 91323 to clarify this question, even if it is not legally binding. It distinguishes, for example, between vehicle sizes and describes a possible sequence of certain procedures for qualification and validation. It can be used as a good aid. During official inspections, the client will be questioned on the subject of transport validation and should ideally be able to present a conclusive concept. This also includes an audit at the forwarding agent and not just a self-disclosure questionnaire. In Annex 15 of the EU GMP Guide, Chapter 6 Transport Verification, various requirements are formulated, albeit not in detail. Key equipment must be qualified and key processes validated.
If the selection falls on the standard parcel services for daily postal and parcel shipments without temperature-controlled services, validation is hardly possible. Here, one should also be aware of the handling forms and handling of parcels on roller conveyors and in automatic sorting systems.
In accordance with § 52 German Drug Law on wholesale permits, this delivery to pharmacies is covered by the manufacturing authorisation, so that no separate wholesale authorisation is required. However, this permit explicitly refers to the products listed in the manufacturing authorisation. Their content is known to the competent authorities but not, for example, to the customer in France. This will rather refer to the EU GDP Guidelines and expect a GDP certificate. If, however, the manufacturer only resolds, what he also produced himself, there is no necessity for a GDP certificate according to German law, also not for a sale to France. This can lead to irritations in the international trade of goods.
From the point of view of the authorities, this is referred to as a "deviation", which requires a determination of the cause of the error (CAPA). One possibility would be to carry out another quality control within the framework of the dossier data. If there are no other data of a temperature recording available about the means of transport, then one can only orientate oneself by means of an auxiliary catalogue of facts, e.g.
Ultimately, however, the risk-based decision remains with the qualified person to what extent a safe and comprehensible release is possible for the authority. However, if the goods are on their way to Africa, for example, it is far more complex to make a risk-based decision than with transports in Europe or at home. Since the data situation is then rather unclear, the product is often classified as no longer usable.
Drug distributors must be registered. Whether storage is already assessed as "trade" is not harmonised throughout Europe. In the German Drug Law § 67 „General duty of notification“, active substances and excipients are listed in addition to drugs. The service provider must therefore notify the local competent authority of the storage of the active substance. This can be done informally. It is not necessary to display every single active ingredient, but only general information, e.g. in the form of a list containing everything that is stored.
Put simply, the devil is here in the detail of the German formulation "for the purpose of trading". In Europe and also in Directive 2001/83/EC, the term "wholesale" is used. In principle, this includes the transport and storage of pharmaceuticals, for which a Wholesale Distribution Authorisation (WDA) is required in Europe. This also applies, for example, to a pure storage service provider, which is thus supervised by the relevant supervisory authorities. Information on the WDAs can be found in the EUDRA GMDP database.
In German legislation, the English "wholesale" is translated as "for the purpose of trading". This always leads to misunderstandings. From a legal point of view, this formulation includes the circumstance of buying and selling and not just storage. For the pure storage in Germany no WDA is necessary, however in all other European countries it is necessary. This problem is also repeatedly brought to the attention of the authorities. A uniform regulation would certainly be advocated here, but is currently not in sight.
The crucial difference is that quarantine goods are not yet released by the manufacturer and therefore they are not yet in the legal trade and supply chain. Quarantine goods must therefore be handled under a manufacturing authorisation. Thus the responsibility lies with the client, who could set up an external office for the quarantine goods, e.g. at the logistics company. This of course involves a certain amount of effort for the pharmaceutical manufacturer, because this site must be clearly and comprehensively delimited, from the personnel to the security of the premises. A direct connection to the own IT-system is also required, as long as no readable status labels are attached to the goods. If the logistics service provider has its own manufacturing authorisation, it would also be conceivable that the logistics service provider would release the order after examination and that its qualified person would assume responsibility (for release and storage). This variant is less common, however, as it is not the core business of logistics providers.
German Drug Law
EU GDP Guidelines for medicinal products for human use
EU GDP Guidelines for active substances
EMA, Q&A in the area of GDP
DIN SPEC 91323 for the technical qualification of air-conditioned commercial vehicles (available for purchase from Beuth Verlag)
Maas & Peither AG - GMP Publishing