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"The GMP world seems to turn faster and faster." Lately, articles on the actual changes in the area of GMP frequently started with these words. It turned less fast during the last year, but the developments haven't been less interesting. This also became evident during a live Webinar, presented by Dr. Bernd Renger on 14 December1. He ought to take credit for most of the information in this article.

Directive 2011/62/EU, the so-called Falsified Medicines Directive and the resulting changes and adjustments in other areas are still widely felt.

The deadline is approaching: As of 2018 safety features will have to be affixed on the packaging of all medicinal products subject to prescription but also to critical non-prescription medicinal products in order to permit the identification and unambiguous tracing. The outer packaging, or if it doesn't exist, the primary packaging of each medicinal product must present safety features that allow for the verification of the authenticity of the medicinal product and for the identification of individual packs. Furthermore, a device is required allowing the verification of whether the outer packaging has been tampered with. When certifying a batch the Qualified Person shall be obliged to verify that the safety features have been affixed on the packaging in the correct way.

The safety features will be implemented by means of a 2D barcode that should be readable by common scanners (it is recommended to use barcodes conforming to the requirements of the International Organization for Standardisation/International Electrotechnical Commission (ISO/ IEC) 16022:2006). The technical and organisational details have been defined in the Commission Delegated Regulation (EU) 2016/161, issued on 9 February 2016. The requirements have to be finally implemented until 9 February 2019. A transitional period is granted to countries which already have similar systems in place and have to adapt these to the new requirements.

In the end it's an end-to-end verification system. Depending on the type of supply, possible verifications (and deactivations) at wholesale level are also discussed, however.

Ultimately this means that the European pharmaceutical supply chain for medicinal products (subject to prescription) will be fully digitalised! As this will produce a large amount of data the question arises where all these data will be stored. The required repository systems shall be set up, made available and managed by a "non-profit legal entity" or "non-profit legal entities" established in the Union by manufacturers and marketing authorisation holders. This will be interesting.

The resulting code shall have less than 50 characters and be globally unique which certainly can be challenging. This requires a considerable effort during the complete period of introduction and implementation and some companies will have to speed up to comply with the time limits.

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30 June / 1 July 2021

Live Online Training: Qualified Person Education Course - Module B

Annex 1 EU Guidelines to Good Manufacturing Practice: (Manufacture of Sterile Medicinal Products)

A concept paper on Annex 1 EU Guidelines to Good Manufacturing Practice (Manufacture of Sterile Medicinal Products) was already published in 2015 (the consultation phase ended in March 2015). But the first draft of the revised Annex was not issued so far for public consultation and there have already been rumours that it would never be published. The development hasn't been as dramatic, though. The main reason for the delay has been a change in the relevant ISO standard, and the EMA is already discussing the draft internally.

The revision basically involves the following changes and amendments:

  • applicability to non sterile products (clean room classes) and to earlystage products
  • extended use of quality risk management principles (design and implementation of facilities, equipment and processes)
  • taking into account the new Pharm. Eur. Monograph for WFI (manufacture by means of reverse osmosis coupled with other technologies)
  • alignment to other international regulations (FDA Aseptic Guide)
  • alignment to revisions in other chapters of the EU Guidelines to Good Manufacturing Practice
  • clarification of controversial or ambiguous requirements (it remains to be hoped at least)
  • harmonisation with the revised EN ISO 14644-1 as concerns the classification of clean rooms

Revision of ISO 14644-1

The new EN ISO 14644-1:2015 Cleanrooms and Associated Environments - (Part 1: Classification of air cleanliness by particle concentration) was published on 1 November 2015 and has been effective since 1 January 2016. Annex 1 of the EU Guidelines to Good Manufacturing Practice takes the standard into consideration (see above) which is considered to be state-of-the-art when it comes to the performance of particle measurements in the cleanroom and the way they are carried out during qualification and in the context of regularly recurring measurements.

A transitional period for implementing the changes such as the definition of sample locations isn't mentioned. In case of doubt it might be helpful to talk with the competent authority.

The new version comprises the following main changes:

  • The number of sample locations is no longer calculated as the square root of the surface but given in a table.
  • No more statistical UCL calculation: there is no need to perform an observation of all sample locations in the room any longer. Each single sample location is considered individually and has to meet the limit value.
  • The actual limit of 29 particles for 5.0?m particles in class ISO 5 (100,000) are dropped as it is not sensible from a metrological point of view. In ISO classes 1-3 particle sizes characterised by low concentrations will also be eliminated. Low particle concentrations require (too) high quantities of samples for statistically reliable statements. This, in turn, requires an adaptation in Annex 1 where these limits still are defined.

The requirements are relatively clear. It will be interesting to what extent a risk-based approach for the definition of the number of sample locations will still be possible in the revised Annex 1.

Annex 17 EU Guidelines to Good Manufacturing Practice (Real Time Release Testing)

Annex 17 EU Guidelines to Good Manufacturing Practice (Real Time Release Testing) is supposed to be modified completely. The revised document was published on 15 September 2015, the public consultation ended on 11 December 2015. Responses to the public consultation were published in July 2016 - with some interesting comments.

The change of name alone indicates a complete reorientation. In the end, the current Annex 17 "Parametric Release" is restricted to be used for the routine release of products sterilised in the final container without sterility tests on the basis of sterilisation parameters. Now the revision shall also implement the principles of the concepts of ICH Q8, Q9 and Q10. A real time release approach will be part of the marketing authorisation in future. Then certification and release of a batch can be based on monitoring and control of critical process parameters and relevant material attributes, sufficient product knowledge and process understanding and a combination of in-process-monitoring and controls that provide sufficient data. This would justify a batch release without any further testing of samples of the finished product.

The certification carried out by the Qualified Person (QP) will then be based on the results of monitoring and control of critical process parameters and relevant material attributes. Then data from a final analytical quality control won't be needed anymore. This is an paradigm shift that will be difficult for many. And experiences are still scarce. Hence, there is considerable interest in relevant case studies. Should the well-disposed reader have something in his possession the author of this article would welcome a corresponding response.

New Annex 21 - Importers of Medicinal Products

There also were rumours concerning the publication of the completely new Annex 21 on the import of medicinal products - that it would simply disappear into oblivion. The concept paper was already published on 13 May 2015 (EMA/238299/2015) and the consultation phase ended in August 2015. But the Annex is still alive! The actual problem is the discussion on how to react in the case of a merely financial change of ownership ("financial import and export") where the goods remain in the EU but the change of ownership takes place in a third country (such as Switzerland).

ICH Q3D Guideline on Elemental Impurities

The ICH Q3D Guideline on Elemental Impurities and the relevant papers of other authorities have accompanied us for quite a while now. The EMA published the Guideline "Elemental impurities in marketed products. Recommendations for implementation" (EMA/CHMP/QWP/ 109127/2015) already in February 2015. These recommendations are addressed to manufacturers of medicinal products and to the national regulatory authorities. The latter should comply with the recommendations when carrying out their activities in order to ensure a consistent approach. This should also reduce the workload concerning the handling of variations that are assessed according to the same criteria.

Now the EMA Guideline "ICH Q3D on Elemental Impurities "(EMA/ CHMP/ICH/353369/2013) was published on 25 July 2016 (as step 4 document already in December 2014). For new marketing authorisations the Guideline comes into effect immediately and in December 2017 for medicinal products for human use with existing authorisation. In this case no change notice is necessary if a risk assessment shows that neither further controls, nor a replacement or a change of quality of materials used or a change of the manufacturing process are needed.

The risk assessment serves also as the basis for the development of a control strategy that is able to ensure compliance with the Permitted Daily Exposures (PDEs).

This risk assessment is rather difficult to perform as it must be substantiated with a lot of analytical data. And unfortunately the efforts made by the companies are very high or rather too high. To quote a representative of an authority whose name will not be mentioned and who put it in a nutshell when he stated at an event last year (2016): "We created a monster".

What are potential sources for all these impurities? In excipients impurities occur mainly because of mining (e.g. talc or salt). But they also occur in the synthesis using metal catalysts (e.g. mannitol), in the synthesis without metal catalysts (e.g. colloidal SiO2), in the case of excipients of plant origin (e.g. cellulose derivatives) or of animal origin (e.g. lactose and gelatine). In the case of active pharmaceutical ingredients catalysts are regarded as one of the most important sources of elemental impurities, but not as the only one.

For this reason the EMA published another draft for a guideline on this topic: Draft EMA Guideline "Implementation strategy of ICH Q3D" (EMA/404489/2016). Scope of this document is to support the implementation of ICH Q3D in the European context. So far and since September 2008 the CHMP Guideline "on the Specification Limits for Residues of Metal Catalysts or Metal Reagents" has been valid. Now European authorities have to coordinate this change and to harmonize the regulatory expectations.

Draft FDA Guide - Request for Quality Metrics

The US Food and Drug Administration (FDA) has started an initiative for the use of so-called quality metrics for the planning of its risk-based inspections already in 2015. A first draft of a guideline was published in July 2015 for comments by associations and industry. After coming into force the FDA wants the manufacturers to communicate defined quality metrics to US FDA via an electronic portal. The FDA will then calculate specific statistics which are supposed to allow a risk-based control and planning of the FDA inspections.

A first revision of the draft was published in November 2016. What is new in the revised draft?

  • The program starts with a voluntary reporting phase which will last until 2018. The program will become binding after this relatively short period.
  • The scope will be reduced to three different key matrices which is supposed to result in more flexibility and a reduction of the reporting effort: Lot Acceptance Rate (LAR), Product Quality Complaint Rate (PQCR) and Invalidated Out-of-Specification Rate (IOOSR) plus three optional metrics.
  • The reports can be product-specific as well as site-specific.

The revised document includes various illustrating examples.

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29 June - 1 July 2021

Live Online Training: Qualified Person pre-course Session Interpersonal and Soft Skills PLUS Education Course Module B

The FDA Quality Metrics Technical Conformance Guide already was published in June 2016. It specifies data structure and content of the data to be reported. For this technical specifications and areas are defined. In principle, the data standards already established in other areas are taken as orientation by the FDA. FDA's so-called Study Data Technical Conformance Guide serves as basis. XML will be the format used for the exchange of data, a standard which is already widely used by industry, e.g. for the transmission of data concerning authorisations such as eCTD.

What other changes are forthcoming in the year 2017 will be subject of part II of this article - in the next issue of the GMP Journal.


Wolfgang Schmitt
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA, GMP and GDP.

1 A recording of this and further webinars is available at

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