Our annual GMP conference ("GMP-BERATER Tage") took place in Freiburg i. Br., Germany, on 28 and 29 October 2015. It was held in the form of interactive GMP dialogues. This year, once again, participants took full advantage of the opportunity to engage in intense discussions with authors, inspectors and colleagues.
One of the six GMP dialogues focused on the question: How do you transport and store medicinal products? As experts leading the discussion, GMP Inspector Dr. Petra Rempe (District Government of Muenster, Germany), Dr. Nicola Spiggelkoetter (Knowledge & Support) and Simone Dietz (Grieshaber Logistics Group AG) discussed with the participants the practical implementation of the requirements set forth by the GDP Guidelines.
“After the production of medicinal products, transport and storage are the steps that determine quality”, said Petra Rempe in her brief introduction to this exciting topic. She continued, “Transport is the mobile form of storage, meaning that both activities are basically subject to the same requirements”. The important thing is that transport is a process. The suitability of the process must be demonstrated through verification.
GMP inspector Rempe advised wholesalers to ask themselves the following questions:
Perhaps your answer is a simple “Yes!” In any event, however, the answers to these questions should be based on documented knowledge. Proof should be provided on the basis of the available data.
The three experts agreed that risk assessment is crucial to transport verification. “The wholesaler must know his product portfolio and openly pinpoint the risks”, emphasized Petra Rempe. Concerning the methodology of risk assessment the experts concurred that in most cases an FMEA (Failure Mode and Effects Analysis) is not necessary. Nicola Spiggelkoetter commented, “If the risks can be accurately assessed no FMEA must be conducted”. Petra Rempe added, “The fishbone diagram is also very well suited for direct practical application by employees”.
Simone Dietz stressed the advantages of risk assessments that permit different modes of implementation for different products. She advised wholesalers to trust the results of the analyses and not, for instance, to add a data logger to every shipment anyway “as an added precaution”.
Product knowledge and stability data are essential for verification of normal-temperature transports. What specifically has to be done if the temperature exceeds or falls short of the limits? According to Petra Rempe, “The wholesaler must define methods of dealing with such cases”. Each case must be assessed in relation to the specific product. For example, excessively high temperatures in ointments are generally more critical than with tablets.
“You should not in any circumstances use the mean kinetic temperature (MKT)”, warned the GMP inspector, “since you are not familiar with the temperature curves of all previous transports!” This is also the recommendation of the official Q & A paper by the Central Authority of the Länder for Health Protection (Zentralstelle der Länder für Gesundheitsschutz) (ZLG)1on operating a wholesale dealership in medicinal products.
Simone Dietz reported that in most cases, if the limit temperature is exceeded, in case of doubt the medicinal products are destroyed.
Older medicinal product approvals generally contain no data on stability at 40°C, with the result that the effects of exceeding the normal temperature cannot be evaluated. “Collecting additional stability data here is precisely the correct way. The data form the scientific basis for dealing with deviations”, confirmed Petra Rempe.
How can the wholesaler demonstrate physical sturdiness in transport verification? “The wholesaler must take a closer look at his portfolio from the perspective of risk”, advised Petra Rempe. “For example, am I selling tablets in blister foil, individually packaged effervescent tablets or powder mixtures (that could separate)?” Simone Dietz added, “Verification must always have a prospective orientation. This can be supported by historic data”.
The participants reported on their experiences with transport service providers, particularly regarding temperature-controlled transports. The important thing is that the contract giver stipulates the requirements for the transport. The possible temperature range should be set forth by contract.
It is also advisable to broach the subject of individual agreements with the transport service provider. For example, transport routes and pickup and delivery times that deviate from the usual standards could be specified.
Package delivery services are often reluctant to enter into contract. In such cases it is possible to put data loggers into the shipments. As an alternative, Petra Rempe mentioned qualified transport containers.
How often should a re-verification of the transports take place? How is this done and within what scope? The participants discussed these questions with the experts at the close of the dialogue.
“The frequency depends on the available data”, Nicola Spiggelkoetter indicated. Simone Dietz explained, “You should specify a cycle based on risk. Here you should look into whether a re-verification is at all necessary. The topic is also taken into consideration within the framework of Management Review. There is also a connection to Change Management”.
GMP inspector Petra Rempe pointed out that “in some cases the re-verification must be carried out at shorter intervals, for instance at the very beginning or when changes are made in the process.” She concluded, “In the case of continuous monitoring with loggers in temperature-controlled transports, re-verification may not be necessary, or if so, then only after a certain number of changes. The important thing is to have data, to evaluate the data and to detect trends”.
1. Q&A paper on operating a wholesale dealership with medicinal products, EFG 09 “Großhandel / Arzneimittelvertrieb”, Central Authority of the Länder for Health Protection with regard to Medicinal Products and Medical Devices (Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten)
Dr. Sabine Paris, Editor
Maas & Peither AG – GMP-Verlag, Schopfheim, Germany