GMP Compliance Adviser Update No. 7/2019

With this GMP Compliance Adviser UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

General Information


GMP in Practice

Chapter 24 becomes
Chapter 16

16.M Risk management in transportation
16.N Qualification of large-scale active systems (trailers)
16.O Qualification of passive insulation boxes
16.P Logistics service providers
16.Q Transport validation
16.S GDP inspections: Frequent deficiencies in the qualification of logistics service providers and how to avoid them (NEW)

GMP Regulations

Chapter C

C.8.2.1 Safety features for medicinal products for human use Questions and Answers – Version 16
C.10.1 Regulation (EU) 2017/745 of the European Parliament and of the Council (EU MDR)
C.10.2 Regulation (EU) 2017/746 of the European Parliament and of the Council (EU IVDR)

Chapter E

E.3.C ICH Q3C(R6): Impurities: Guideline for Residual Solvents

GMP in Practice

Chapter 24 Storage and transportation becomes Chapter 16

All chapters dealing with transportation have been reviewed and updated to reflect current regulatory requirements as well as the state-of-the-art in the GDP area (Update 5 and Update 7).

16.M Risk management in transportation

As processes become farther removed from the pharmaceutical manufacturer, that entity’s influence on the quality of the processes diminishes while at the same time work is being delegated to service providers from areas that are not experienced in GMP. The pharmaceutical contract giver of logistic services then assumes more of a controlling function. Methods of risk management can be beneficially employed to identify, assess and control risks. The immense volume of details associated with a transport can only be represented using a finely structured segregation of elements of the transport chain. It then becomes clear that potential risks change from one transport segment to the next. The results of a risk analysis can serve as the basis for the qualification of transport vehicles and transport packaging; they can provide important starting points for the qualification of transport service providers or they can form the foundation of a monitoring concept. (Nicola Spiggelkötter, PhD)

16.N Qualification of large-scale active systems (trailers)

The first step in the qualification of large-scale active systems is to define the requirements profile. Proceeding from there, a qualification plan is set up that includes operational and performance qualification.

Operational qualification is done in the unloaded state. The critical points here are selecting a suitable temperature profile that comes as closely as possible to the later real conditions and specifying the testing period. For this purpose, it is quite possible to simulate different scenarios. DIN Spec 91323 provides an approach for a unified qualification of trucks for use within Germany.

In the subsequent performance qualification in real operation, the loading state is added as another influencing factor. Test drives should take place under representative conditions on the one hand, but on the other they should also cover extreme situations, for which reason a broad data base must be created.

Qualification of a 2-temp-vehicle leads to farther-reaching demands, since different temperature ranges must be qualified.

In general, it would be preferable in terms of comparability if standardised testing scenarios, particularly temperature profiles, were established. (Nicola Spiggelkötter, PhD)

16.O Qualification of passive insulated boxes

Qualifying insulated thermal shipment packaging includes design qualification, in which the fundamental requirements are defined, followed by operational and performance qualification, in which the performance data of the packaging are gathered.

When appropriate insulated shipment packaging is being selected, evaluation and performance criteria must be considered, such as the insulation material used, the position of the cooling elements and the usable net volume, including aspects such as the unit price, reusability or dimensions (inner and outer).

A suitable temperature profile must be selected for the operational qualification, which is performed with empty packaging. A basic distinction is made here between profiles with constant outside temperature and those with fluctuating, cycling temperatures. In performance qualification the temperature-maintaining capacity of the loaded box is tested under real conditions. (Nicola Spiggelkötter, PhD)

16.P Logistics service providers

Logistics service providers are assuming ever more extensive responsibilities in the distribution chain. In addition to the central tasks of logistics – dispatching, forwarding, transferring, storing and providing information – growing numbers of special and complementary functions are being added, which can provide the competitive edge particularly in transports of medicinal products.

The requirements profile of the logistics service provider should include the definition of interfaces, the existence of a QM system, regular employee training, managing subcontractors and providing reliable information management.

The particular distribution procedure envisaged also plays an important role in the selection and qualification of a logistics service provider. Taking a refrigerated transport as an example, critical aspects of overland carriage by truck, distribution logistics and courier service are explained.

The qualification of logistics service providers is described using a carrier as an example. Possible questions for an initial audit are compiled in a questionnaire. (Christoph Frick, PhD, Nicola Spiggelkötter, PhD)

16.Q Transport verification

A transport process comprises many single steps. To ensure the validity of the transport chain, first of all, all individual steps must be qualified and/or verified. The suitability for verification of different types of transport is illustrated with the example of a refrigerated transport. Whereas in an actively cooled vehicle it is possible to maintain the required temperature range during transport independently of the outside temperature, transport in passively temperature-controlled packages offers adequate protection only at moderate outside temperatures, in spite of different packing schemes.

The verification of a global transport chain from the manufacturer to the end consumer presents a great challenge due to the numerous steps, the large number of people involved and the possible influencing factors. It can be helpful here to contractually bind logistics service providers and/or distribution centres, which in turn have an appropriate QA system. (Christoph Frick, PhD, Nicola Spiggelkötter, PhD)

16.S GDP inspections: Frequent deficiencies in the qualification of logistics service providers and how to avoid them

This new chapter sets out the 10 most frequent deficiencies found in the qualification of logistics service providers within the framework of GDP inspections carried out by the competent supervisory authority. For example, an underdeveloped quality risk management system for the qualification of logistics service providers has been found very frequently. If the quality risk management system is not fully developed, this can have serious consequences: for example, if a logistics service provider is not adequately qualified and deficiencies at the logistics service provider are overlooked during the qualification process.

Behind the formulation of deficiencies, there is often a lack of transparency with respect to the actual thought processes, such as they are, of the inspected company. It is difficult to find an inspection report that does not state at some point “it was unclear why...” or “it was not clear (documented) that...”. But the problem is not only with transparency. This chapter also shows, for example, why the efforts of wholesale distributors to reduce the scope of qualification on the basis of a so-called GDP certificate often fail. Or the problems entailed with the involvement of commissioned third parties.

For the most frequent deficiencies in the qualification of logistics service providers, strategies to avoid the deficiencies are identified. For each deficiency, you will find clear guidance for action in the form of a small table.

You will also find concrete assistance with work practices, for example on the approach to creating the SOPs required, or step-by-step instructions on reviewing the qualification of a transportation provider by the logistics service provider. (Lea Joos)

GMP Regulations

Chapter C EU Directives and Guidelines

C.8.2.1 Safety features for medicinal products for human use Questions and Answers – Version16

On 25 September 2019, the European Commission published Version 16 of the document on safety features for medicinal products for human use.

New questions:

  • Q&A 2.23 which explains the requirements for the characters used in batch and serial numbers.
  • Q&A 7.20 clarifies what is meant by "investigation" of all potential incidents of falsification in Article 37(d) of Commission Delegated Regulation (EU) 2016/161.

Additions were made to the following questions:

  • Q&A 2.3 addresses the fact that barcodes on packaging should not be in proximity to each other in order to avoid errors in scanning by the end-user.
  • Q&A 2.12 clarifies that a QR code with safety features should also not be placed in proximity of a data matrix.
  • Q&A 4.5 states that when uploading to the repository system, manufacturers and marketing authorisation holders should work together to ensure the consistency and correctness of the information encoded in the unique identifier.
  • Q&A 7.17 outlines that the NMVO should ensure that the national competent authorities, the EMA and the EU Commission are informed of falsifications. Two footnotes therefore refer to the e-mail addresses of the EMA and the European Commission.

C.10.1 Regulation (EU) 2017/745 of the European Parliament and of the Council (EU MDR)

The Regulation now includes Corrigendum 15409/1/18 REV 1 published by the Council of the European Union on 13 March 2019.

C.10.2 Regulation (EU) 2017/746 of the European Parliament and of the Council (EU IVDR)

This Regulation now includes Corrigendum 15418/1/18 REV 1, published by the Council of the European Union on 13 March 2019. The two EU Directives have been in force since 25 March 2019. The MDR will be fully applicable in May 2020, while the full implementation of the IVDR is scheduled for May 2022.

Chapter E ICH Guidelines

E.3.C ICH Q3C(R6): Impurities: Guideline for Residual Solvents

The PDE value for ethylene glycol was reinstated to its previous PDE value of 6.2mg/day and a concentration limit of 620 ppm. It was changed in October 2018 with the ICH Q3C(R7) version to a PDE of 3.1 mg/day and a concentration limit of 310 ppm.

In 2019 the ICH received a request to suspend the error correction for ethylene glycol. Based on archive documents and in-depth literature research, the 2018 decision was reversed by the Expert Working Group. As a consequence, the Q3C(R6) version has now been reinstituted.

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