[Stability Testing related News – vol.17]

◆ EU Commission issues two final Guidelines: GMP for Excipients and GDP for APIs (25-Mar-15 ECA)

  After nearly two years of consultation, the European Commission has published two important and long-awaited guidelines in the official journal of the European Union, edition 21st March 2015:

• The “guidelines on the principles of good distribution practice for active substances of medicinal products for human use” and 
• The “formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use”

Both guidelines were already published as draft documents on 6th February 2013 on the News page of the European Commission (Pharmaceutical Archives – 2012), and they were open for comments until 30th April 2013.

Both guidelines are considerably more detailed in their present form and contain more stringent requirements than the respective drafts. For instance, as part of the risk assessment for pharmaceutical excipients the supply chain including cold chain management, the stability of the excipient and the suitability of the packaging have to be evaluated.

The requirements with regard to the quality assurance system of distributors for APIs are also much more detailed and demand the tracking and documentation of deviations and a CAPA system.

The guidelines on GDP for APIs are also relevant for the national authorities as they are a further specification of the provisions laid down in part II of the EC GMP Guide.

A more detailed analysis of the two documents will be issued in the next newsletters.

 

◆ New EU GMP Annex 15 Revision published – Valid as of 1 October 2015 (02-Apr-15 ECA)

  In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 “Revision of the EU GMP Annex 15 for Qualification and Validation published”). Compared with the currently valid version the changes were significant in some parts. Now the draft was published as final document and will be valid as of 1 October 2015.

Life cycles build the centre of the new Annex 15, whether with regard to the product or to the process, whether with regard to equipment and the process validation itself. A special emphasis is on risk management which is mentioned in several sections in the guideline instead of being mentioned in one section only on risk assessment.

The revision is influenced from the ICH Guides ICH Q8, Q9 and Q10 can be clearly noticed. This makes the document more modern, and it is more adapted to the current state of science and technology. The addressing of API manufacturer is somewhat irritating. Although the new Annex 15 comprises clear changes it is not supposed to cause new requirements in the area of APIs.

Altogether there are plenty of new requirements which, however, partly only show the state of technology. Due to the (necessary) integration of ICH Q8-Q11 and the life cycle approach the new Annex 15 is now more comprehensive, but unfortunately also more vague. A close coordination with the FDA Guideline on process validation would have been desirable.

 

◆ GDP: Is Temperature Control required for each Transport? (22-Apr-15 ECA)

  The EU Good Distribution Practice (GDP) Guidelines (2013/C 343/01) revised in 2013 reflect the requirements and expectations of the authorities during the transport and distribution of medicinal products in a very detailed way. Nevertheless, there are still questions and insecurities.

Here, it is stated that a temperature control is not required for each transport:

“If no constant monitoring of temperature is carried out during the transport of medicinal products a risk assessment must be made of the transportation routes. This includes especially the travel duration including special aspects of the route, the time of year and day, including the weather forecast, the vehicles used and their equipment. The results of this risk assessment have to be part of the transportation planning.”

But at the same time this means that monitoring has to be done if no risk assessment was carried out or if the risk assessment led to the result that a temperature control is necessary.

According to the German ZLG (Central Authority of the German Federal Länder for Health Protection Regarding Medicinal Products and Medical Devices) document a lot of things have to be considered when carrying out the risk assessment:

• The mean kinetic temperature (MKT) cannot be used. The reason is that it does not take into consideration effects “that may lead to irreversible quality defects even when certain temperature limits that are established during stability studies in connection with the marketing authorisation are exceeded only for a short time. And it does not take into consideration the possible formation of fissures in the glass of ampoules and injection bottles at temperatures around the freezing point. Furthermore, calculation of the MKT requires that the temperature profiles of all transports are known that have been carried out previously. But usually this data is not available ….”
• In order to assess deviations “appropriate procedures” must be established.
• Storage conditions must generally be respected also during transportation. “Only in cases that according to the packaging or the confirmed written information given by the manufacturer, the pharmaceutical entrepreneur or the marketing authorisation holder. a transport within the aforementioned temperature range will not reduce the quality” this temperature range can be handled more generously. It has been demonstrated for example “in connection with the marketing authorisation of medicinal products on the labelling of which only storage between +2 and +8 °C is indicated that they remain sufficiently stable even if the temperature rises up to +25 °C for a short time.”

◆ New USP Chapter on the Integrity of Pharmaceutical Packaginge (27-May-15 ECA)

  The Pharmacopoeial Forum (PF) 40(5) from September / October 2014 comprised new proposals of the USP with regard to the in-process revision of the General Chapter on the Integrity of Pharmaceutical Packaging Materials.

In the same issue there is also an explanatory “stimuli article” about the history of the requirements with regard to the integrity of packaging. This article is supposed to facilitate the understanding of the changes planned by the USP.

So far, there is the General Chapter <1207> on the evaluation of the integrity of packaging materials for sterile products. In the future, the following 4 General Chapters are planned:

• Sterile product packaging – integrity evaluation <1207>
• Package integrity and test method selection <1207.1>
• Package Integrity leak testing technologies <1207.2>
• Package seal quality test methods <1207.3>

The Chapter <1207> is supposed to provide an outline, the other 3 chapter are planned to cover specific topics in detail.

Depending on the incoming feedback on these proposals a further revision of these General Chapters will be considered.