26.06.2013 |

LOGFILE No. 04/2012 - GMP Guidelines 2012

GMP-Guidelines: What can we expect in 2012?

Author: Anita Maas, Maas & Peither AG

Here it is – the year 2012 blessed with plenty of predictions has begun. It remains to be seen whether and in which areas the signalized changes will occur. One thing is for sure: There will be further development in the field of GMP. What has to be expected this year was summarized by Dr. Wanninger, GMP inspector, at the 17th GMP-Conference in November 2011 in Mainz, Germany.




EC-GMP-Guidelines Part I

After an update of Chapter 4 - Documentation along with Annex 11-Computer-Validation, the year 2012 will proceed with a series of topics.

Chapter 1: Quality Management

The current draft was revised once more after consultation. The background of this revision is the implementation of ICH Q10, which will mainly include guidelines, regarding the structure of a QM-system and the regulation of responsibilities within an organisation. Furthermore and long overdue, the subject CAPA (Corrective Action Preventive Action) will be incorporated. As indicated for a while now, the supply chain will be examined more closely. In times of intensified outsourcing the relations to contractors and suppliers of raw materials (this includes not only active substances but also excipience and packing material!) become more important.

More attention should be directed towards an ongoing observation of production processes in terms of Product Quality Monitoring Systems.

Chapter 2: Personnel

The draft is already in consultation phase. The amendments relate to the contact with consultants, an appropriate use of personal as well as the responsibility of senior managements.

Chapter 3: Premises and Equipment

This is about the toxicological risk assessment of active substances and how to minimize risks, e.g. by using separated areas or containment. At present a Safety Working Party of the EMA is dealing with it.

Chapter 5: Production

In the course of revising this chapter the qualification of the supply chain as well as the traceability of raw materials will be addressed.

Chapter 6: Quality Control

The current draft contains supplementary requirements relating to reagents and reference standards as well as a new paragraph to method transfer.

Chapter 7: Contract Manufacture

The draft has already been approved and the publication can be expected in the near future.

This chapter is applicable to all „outsourced activities“ from software manufacturers up to common carriers. Therefore –following a risk analysis - all business relations have to be evaluated and audited prior to any commencement of work. The contract giver is also responsible for continuous monitoring and review after awarding contracts.

GMP-Guidelines Part III

In December 2010 a part III has already been introduced, which is conceived as „Collection of GMP-Related Documents“ and serves as a source of information for “best practice” and represents the regulatory expectations. After shifting Annex 20 Quality Risk Management (ICH Q9) here, ICH Q10 Pharmaceutical Quality System is to be found here, too. In addition the PIC/S annotations regarding the Site Master File are also included in Part III.

The Internationally Harmonized Requirements for Batch Certification have been newly added in June 2011. Again, reference is made to exactly specify the supply chain. All manufacturing and testing sites have to indicate the GMP-certificate in addition to the authorization code.

EC-GMP-Guidelines Annex 2
Biological Medicinal Products

The finalised version was already submitted to the Commission, and publication is expected in due time.

New manufacturing technologies and the further increase of biological products required this revision. It also includes ATMPs (Advanced Therapy Medicinal Products). In Part A general requirements are described. Part B deals with the various product types (from vaccines to recombinant up to transgenic products). Particular focus is directed on which guidelines apply to which manufacturing steps.

EC-GMP-Guidelines Annex 14 
Human Blood or Plasma

The revised Annex 14 has already come into force by the end of November 2011.

EC-GMP-Guidelines Annex 15 
Qualification and Validation

A revision is planned along with the EC-Guideline on process validation. The background is an implementation of ICH Q9 and 10. A flexibilisation by various methods of solution is intended. The revised Chapters 3 and 5 of the EC-Guideline should be taken into account. At present no draft for the revision of the Guideline of Process Validation has been published.

EC-GMP-Guidelines Annex 16
Certification by a Qualified Person and Batch Release

The consultation period for the present concept paper expired on 31 January 2012. The first draft is scheduled for May 2012.
A comprehensive clarification of questions that emerged in practice with QPs can be expected. Due to the complex production in various permanent establishments, QP cannot be located at every place of quality control and production. Also it has to be clearly regulated, which position the QP is taking within an organisation, how things stand regarding their independence and which role the QP is playing in case of quality shortcomings.

„QP Declaration Template“

Within this document QP should confirm the verification of the supply chain, as well as GMP-compliance. A draft for consultation is available, the deadline is set for 30 September 2011.

Once again the focus is on complete acquisition and control of the supply chain including broker and re-packager and their compliance with the marketing authorisation. Proof has to be provided, that every batch of active substance used for the production of drugs, originates from this certain supply chain. This declaration has to be made within the scope of applications for approvals or changes and prolongations therein.

The basis for a declaration is an audit of the manufacturer of medicinal products, by or on behalf of the manufacturer. The GMP-Certificates of the supervisory authority cannot supersede those declarations.

EC-GDP Guidelines

A revision of the Commission Guidelines on Good Distribution Practice of Medicinal Products for Human Use is being developed. The consultation period ended on 31 December 2012.

The current draft includes, among other things, the following topics:

  • Suitability and competence of contractors
  • Monitoring: Evaluation of particular indicators as complaints, variations, CAPA, changes, audits
  • Assessment of quality risks
  • Supervision of temperature und humidity (mapping with calibrated measurement devices)
  • Qualified equipment, including computer systems
  • Periodic monitoring of recipients
  • Receipt of goods: handling of products suspected of being counterfeit
  • FEFO First expired – first out
  • Written agreement between contractor and customer for responsibility demarcation
  • Recording of all transactions

A passage that remains contentious above all is that an interim storage as part of a transport > 24 h is defined as storage and, therefore, requires a wholesale permit for common carriers. A format for such a permit is currently in testing.


In 2012 significant amendments in GMP-Regulations are to be expected. One basic idea is present throughout the diversity of drafts: Production no longer relates to one site only. All production sites involved must be made transparent and their suitability has to be proven.

Furthermore, GMP is not only limited to the sheer production of a product. On the contrary all fields prior to production (production of pharmaceuticals) and after production (transport) require a more closer look at. Anyhow, the authorities substantiate their expectations in these areas. To get to grips with the jumble related to verifications by audits and a continuous monitoring, applied risk management plays a key role. How good that most companies have dealt with Quality Risk Management intensively.

The inspection pressure on all contracts on behalf and the whole supply chain worldwide will strongly increase. Therefore, companies will have to be concerned about alliances and qualified third-party-audits.


Draft revisions of EC-GMP-Guidelines:

Draft of EC-GDP-Guideline:


Anita Maas
Maas & Peither AG GMP Publishing