Stability Testing related News – Vol.6

◆  What are the current GMP Inspection Initiatives? (08-Feb-17 ECA)

The International Coalition of Medicines Regulatory Authorities (ICMRA) has published a very interesting overview about the current global GMP inspection initiatives by the competent authorities. It also shows the various initiatives between the EU and the US Food and Drug Administration (FDA):


This programme of the European Medicines Agency (EMA), the European Directorate of the Quality of Medicines and Healthcare (EDQM), the European National Supervisory Authorities, the US Food and Drug Administration (FDA), the Australian Therapeutic Goods Administration (TGA) and the World Health Organization (WHO) tries to foster the cooperation and mutual confidence between the participants through better communication and exchange of information on inspection planning. It covers joint inspections of API manufacturers located outside the participating regions but also the reliance on API inspections by other authorities.

EMA/FDA Mutual reliance Confidence building

The overall objective of this initiative is to allow some inspections on each others’ territories to be deferred or waived completely based on a number of considerations.

EMA/FDA Finished Products programme

This programme is closely related to the one above. Here, EMA and FDA are evaluating whether greater international collaboration can help to better distribute inspection capacity, allowing more sites to be monitored and reducing unnecessary duplication, limited to inspections of manufacturers of human medicinal (finished drug) products which come under the authority of FDA’s Center for Drug Evaluation and Research and the centralised marketing authorisation process in the EU.

PIC/S Pharmaceutical Inspection Co-operation Scheme

Inspectorates from various EU Member States and the FDA are member of PIC/S which tries to foster the international co-operation in the field of GMP by developing and promoting harmonised GMP standards and guidance documents, training GMP inspectors, assessing (and reassessing) GMP inspectorates and facilitating co-operation and networking and planning of inspection.

The International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level, strategic coordinating, advocacy and leadership entity of regulatory authorities that work together to

  • address current and emerging human medicine regulatory and safety challenges globally, strategically and in an ongoing, transparent, authoritative and institutional manner
  • provide direction for areas and activities common to many regulatory authorities’ missions
  • identify areas for potential synergies
  • wherever possible, leverage existing initiatives/enablers and resources

ICMRA wants to provide a global architecture to support enhanced communication, information sharing, crisis response and address regulatory science issues.

The overview is available as ICMRA – Mapping of GMP Inspection Initiatives


◆  USA and EU adopt Mutual Recognition Agreement – Does it mean the End of FDA Inspections in Europe? (08-Mar-17 ECA)

On 2nd March 2017, the US FDA and the EU (EMA) informed that they concluded a so-called MRA (Mutual Recognition Agreement). Such agreements are intended to mutually recognize GMP inspection systems. As a consequence, the GMP Compliance of a site is reviewed by the respective inspection authority. Afterwards, the FDA can use EU inspection results and vice-versa. FDA inspections in the EU or EU inspections in the USA should be only performed in exceptional cases.

The EU has already concluded MRAs with other countries like Australia, Canada, Japan, Switzerland and New Zealand. The MRA with the USA has already been under discussion since the nineties. In 1998, a contract was made but never put into practice, though, because of the two very different legal systems. The question of communicating detailed inspection results has been a recurring subject of discussions. Moreover, the FDA had doubts about the consistent quality of inspections in Europe. Equivalent systems had been recognised for some countries but it had also been noticed that some EU countries couldn’t show an inspection system comparable to that of the FDA. Yet, the EU has consistently made clear that the agreement could only be concluded with the EU and not with individual EU member states.

In the context of negotiations over the last years, progress has been made with regard to those points. Since 2014, cooperation has been intensified. Thereby, a Joint Audit Programme has been established. So far, the FDA has participated as an observer in 13 audits performed among EU countries. During the first audit of this kind, inspectors from England and Norway audited the Swedish GMP inspectorate under FDA supervision.

It will be interesting to see how the procedural rules are concretely applied in case of suspension of recognition of an authority – e.g. when the FDA refuses to recognise the inspection authority of an EU country and vice-versa. Article 13 specifies that. According to it, “Each Party has the right to suspend recognition of a recognized authority of the other Party. This right shall be exercised in an objective and reasoned manner and communicated in writing to the other Party and the recognized authority.” […] Furthermore: “Upon the suspension of an authority previously listed as a recognized authority, a Party is no longer obligated to accept official GMPs documents of the suspended authority.”

The agreement which has been made shall cover both medicinal products and APIs. Human blood, human plasma, human tissues and organs, and veterinary immunologicals are excluded from the scope of the agreement. The new agreement should come into force on 1st November 2017. Until then, the FDA wants to review the authorities of further EU countries. Similarly, the EU wants to check the regulatory authorities in the different US Federal States.


◆  API mixtures and CEP Procedure: What should be considered? (30-Mar-17 ECA)

In some cases, it is necessary to produce APIs not in pure form, but as a mixture. Among others, easier manageability or API stability can be a reason for that. Chlorhexidine digluconate in aqueous solution, a clavulanate potassium auxiliary mixture or simvastatin blended with an antioxidant are typical examples. In April 2016, the QWP of the EMA published a Q and A document entitled “Quality Working Party questions and answers on API mix” (EMA/CHMP/CVMP/QWP/152772/2016) on this issue. It clarifies how these API mixes are to be handled in an ASMF or CEP procedure during an authorisation.

In December 2016, the EDQM published a “Public Document” called “API-Mix (or mixtures) and CEPs” (PA/PH/CEP (16) 70). This document describes the procedure of applying for a CEP for API mixtures.

An application for a CEP for an API mix must contain at least the following information:

  • Information on the mixing process, on qualitative/quantitative composition and on the control strategy
  • Supporting data on the choice and amount of the excipient, unless already covered by the pharmacopoeial monograph itself
  • Supporting data on the choice and amount of the excipient, if these are allowed according to the monograph but not defined in any more detail (“…a suitable antioxidant may be added …”). Additional data (stability data e.g.) are required for changes in the content of the antioxidant and in the impurity profile of the mix. The EMA guideline provisions “Excipients in the dossier for application for marketing authorisation of a medicinal product” (EMEA/CHMP/QWP/396951/2006) must be observed.

A CEP for an API mix contains the following information (unless already contained in the pharmacopoeial monograph):

  • designation of the excipient(s) used and their amount
  • in case of antioxidant, a validated test method for its control (as an annex to the CEP)
  • information on the labelling of the mixture, if the monograph contains a paragraph on labelling

As of 1 December 2016, a CEP is generally granted for an API mix if the excipient used is listed in the “Definition” paragraph of the pharmacopoeia. If the mixture does not comply with the monograph regarding qualitative and/or quantitative composition, the application for a CEP will be refused.


Please feel free to ask us if you have any questions.

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