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Anyone who believes that the biggest changes and upheavals in the GMP environment are through may be mistaken. Not only due to the current political impassabilites, such as the Brexit, things are in motion. This also became clear in a live Webinar, presented by Dr. Bernd Renger on 5 December 2018. He also deserves our thanks for most of the information in this article.

Revision of Annex 1 to the EU-GMP Guidelines (Sterile Medicinal Products)

On 20 December 2017, the long-awaited draft of Annex 1 was published (Annex 1 "Manufacture of Sterile Medicinal Products; Targeted stakeholders consultation"). The GMP Journal has already provided comprehensive information on the planned changes, so that they will not be discussed here again. The final version is still pending and there may be some adjustments. The comment period ended on 20 March 2018 and more than 6,000 comments were received. One of the most comprehensive feedbacks came from the ECA Task Force (31 pages). In addition to some ambiguities in some details, there is also a general need for improvement. The adaptation to other chapters of the EU-GMP Guidelines Part 1 has not always been successful and there are many unnecessary repetitions. Also, the glossary from the FDA Aseptic Guide was simply adopted, which in in some instances leads to unclear and contradictory terminology; several important terms are not described in the glossary and there are terms in the glossary that do not appear in the text.

Other Annexes to the EU-GMP Guidelines

The European Commission has published a revised version of Annex 2 "Manufacture of Biological active substances and Medicinal Products for Human Use" with the entry into force of the new Guidance Document on GMP for ATMPs. With this entry, a revision of Annex 2 had become necessary in order to remove or adapt the ATMP-relevant parts. On this occasion, several minor changes were also made. On 26 June 2018, the new Annex 2 entered into force.

Annex 17 ("Real Time Release Testing and Parametric Release") was published in its final version on 26 June 2018 and came into force on 26 December 2018.

The approaches described in the new Annex go far beyond what was included in the previous version ("Parametric Release"). The new Annex outlines the requirements for the application of the Real Time Release Testing (RTRT) approach as an alternative to routine end product testing and applies to finished drugs, active ingredients and intermediates.

It is important that the RTRT approach is anchored in the marketing authorisation and is based on an RTRT strategy, including a risk assessment of the entire process and identification of critical process parameters (CPPs) and critical quality parameters (CQA). Certification by the QP is then based on compliance with relevant properties of starting materials and compliance, monitoring and control of the defined critical process parameters as a substitute for final product testing. The real-time release approach must include an emergency plan in case sensors or measuring devices fail. The performance of end product testing is not accepted if the RTR Test Approach has delivered undesirable or noncompliant results. However, end product testing can be accepted under certain circumstances, e.g. if important sensors and devices fail. It is also important that the approach is regularly subjected to a new risk assessment ("continued assurance of product quality").

However, the "Parametric Release" has not completely disappeared. One section describes the application of parametric criteria for the routine release of terminally sterilized products by steam, dry heat or ionizing radiation. Prerequisites are a robust "Sterility Assurance Program" and an acceptable GMP compliance history including a bioburden test as in-process control for each ba

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The completely new Annex 21 ("Importers of Medicinal Products") has not yet been published. The "Concept Paper" was already published on 13 May 2015 (EMA/238299/2015) and the consultation phase ended in August 2015. This Annex will primarily be addressed to importers. It is intended to clarify the location of the physical import of the testing and/or releasing site and to regulate import activities not previously covered by other GMP regulations.


In December 2017, ICH published the Q12 draft document for comments. In February 2018, the EMA published the corresponding draft of the "Guideline on technical and regulatory considerations for pharmaceutical product lifecycle management" and its annexes for comments. The deadline for comments was 18 December 2018.

The new guideline is intended to supplement the existing ICH Q8 to Q11 guidelines and lead to more flexibility in the event of changes in the product life cycle. It is applicable to Active Pharmaceutical Ingredients (APIs) and medicinal products, including biotechnological/ biological products. It also applies to Drug-Device Combination Products ("Drug-delivery products") which meet the definition of a pharmaceutical or biotechnological / biological product.

Investigational Medicinal Products

As early as May 2014, it was decided to reorganize the requirements for clinical trials in the EU. Comprehensive reports have already been submitted on this.

However, I would like to draw your attention once again to the detailed guidelines "... on Good Manufacturing Practice for Investigational Medicinal Products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014", the core document for GMP aspects, which is to replace Annex 13 of the EUGMP Guidelines ("Manufacture of Investigational Medicinal Products"). This 16-page document was published on 8 December 2017.

The reference to other relevant chapters of the EU-GMP guidelines has been successful, which prevents duplication and possible contradictions. The content is structured analogously to the EU-GMP Guidelines, Part I:
1. Scope
2. Pharmaceutical Quality System
3. Personnel
4. Premises & Equipment
5. Documentation
6. Production
7. Quality Control
8. Release of Batches
9. Outsourced Operations
10. Complaints
11. Recalls & Returns
Among other things, the new document defines the responsibilities of the Qualified Person (QP) in relation to the release of investigational medicinal products (IMPs). According to Chapter 8, a QP must certify according to Regulation (EU) No 536/2014 (Clinical Trials Regulation = CTR) and Annex 16 of the EU-GMP Guidelines:
The release of IMPs can only take place after the QP has examined whether the requirements of Article 63(1) and (3) of the CTR and those of Article 12 of the Commission Delegate Regulation (EU) 2017/1569 have been met in accordance with Article 62(1) of the CTR. The testing of each batch and certification by the QP prior to release shall be carried out according to the principles described in Annex 16.

Investigational medicinal products may not be used in clinical trials until the completion of a two-step release procedure (QP and sponsor as described in the Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice).

The current Annex 13 contains detailed requirements for the labelling of IMPs, including a summary of the labelling details in a table. This table is not included in the Detailed Commission Guideline and the labelling requirements have been moved from GMP to GCP and are now part of the CTR. The new guidelines for IMPs also include new or revised rules in the following areas:

  • Application of CAPA principles
  • Greater attention to change control for better traceability of changes in specifications and manufacturing
  • Cross-contamination prevention systems
  • Specifications on the scope and content of the Product Specification File (PSF)
  • Better documentation of development steps
  • Requirements for blinding, packaging and labelling

However, the existing Annex 13 is still valid. The Detailed Commission Guidelines on GMP for human clinical trial samples do not need to be applied until the CTR becomes valid.

Development of the MRA

The Mutual Recognition Agreement (MRA) with the USA was extended in 2018 to include other countries: Czech Republic, Greece, Hungary, Romania, Ireland, Lithuania, Portugal, Belgium, Denmark, Estonia, Finland, Latvia. By July 15, 2019, all authorities and countries should have been inspected and approved.

No more inspections?

What sounds simple is not always so. For example, the FDA does not carry out routine inspections of manufacturers of investigational medicinal products (IMPs). After the implementation of the Delegate Regulation 2017/1569, the manufacturing of IMPs in third countries will in future always have to be inspected by the national EU authorities. It is not yet clear whether and to what extent the EU authorities will inspect manufacturers of IMPs despite the MRA in the USA (the Delegated Regulation does not currently apply).

In exceptional cases, the FDA will also continue to visit the EU for inspections, e.g. within the framework of approval procedures (so-called pre-approval inspections). This also became clear at an ECA conference in November 2018, where participants from Spain, Austria and Denmark reported on announced inspections in 2018 and 2019.

What about audits by the manufacturer?

The holder of the manufacturing authorisation is responsible for an appropriate supplier qualification. Audits will therefore continue to be an essential part of this process. Another essential part of supplier qualification is the verification of the available GMP certificates. Here an EU Qualified Person (QP) must check what will be available in the future. For example, the FDA plans to issue "cGMP Declarations" if a EU authority does not accept a valid certificate of pharmaceutical product (CPP) and wants additional assurance of a facility's cGMP status.

Additional advantages

If the agreement is in force, the additional full analysis of a drug imported from the USA will not be necessary. An EU QP certifying the "Quality Metrics Feedback Program" and the "Quality Metrics Site Visit Program", taking into account the feedback received:

In the Quality Metrics Feedback Program, companies can now describe in detail their currently used (internal) quality metrics programmes in meetings at FDA. These programmes should include the routine review of the quality culture and its control by management.

The Site Visit Program goes even further and the FDA will visit local facilities. The purpose is to give FDA employees hands-on learning opportunities and companies the opportunity to explain their systems.

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Will there be a global approach to classifying GMP deficiencies?

Most inspectors classify the observations made in inspections. In the EU, for example, a harmonised system for the categorisation of deficiencies is used and is well known to all pharmaceutical companies. The following categories are described:

  • Critical deficiency
  • Major deficiency
  • Other deficiency

However, other regulatory agencies - such as the US FDA - do not use such a classification system.

In November 2018, the PIC/S Committee issued a new Guidance on "Classification of GMP Deficiencies" (PI 040-1). This was developed by the PIC/S Working Group on the Classification of Deficiencies, chaired by Australia. Once implemented, this Guidance will provide a document to support the riskbased classification of GMP deficiencies from inspections, which will also ensure greater consistency among authorities. The idea is to be able to distinguish a "critical" from a "major" deficiency. The guidance will come into force on 1 January 2019.

The US FDA is also a member of the PIC/S and it remains interesting to see if it will adopt this procedure. In any case, there is no obligation.


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.

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