14.08.2015 |

LOGFILE No. 01/2016 – 2016 - GMP in Production

2016 – GMP in Production

by Thomas Peither

We used the transition from the old year to the new to polish our crystal ball and take a bold look into the future of Good Manufacturing Practice (GMP). Many of the GMP topics for 2016 have their roots in the production of medicinal products and test preparations. But technical infrastructure and quality management also play a part. An outline of the topics that are already emerging for 2016 is presented below.

New: Production of Sterile Medicinal Products

In 2016 we are expecting a revision of Annex 1 to the EU GMP Guide. The draft will be prepared by the European Medicines Agency (EMA) in conjunction with the Pharmaceutical Co-operation Scheme (PIC/S). Perhaps the amendment of DIN EN ISO 14644 will also be taken into account there (see below). It is not yet possible to judge how extensive the changes will be.

New: Production of Investigational Medicinal Products (IMPs)

We are also expecting a new draft of Annex 13. It will be prepared jointly with the CAT (Committee for Advanced Therapies).

IMPs will also be affected by the “Viertes Gesetz zur Änderung arzneimittelrechtlicher und anderer Vorschriften“ (fourth law to amend pharmaceutical and other regulations). The draft legislation was published on 25 November 2015. We expect the law to be passed before the summer break of 2016.

The amendments relate primarily to regulations for clinical trials pursuant to EU Regulation 536/2014, which directly applies in the EU Member States:

In the future, the German AMWHV (ordinance on the production of pharmaceuticals and active pharmaceutical ingredients) will no longer be applicable to IMPs for human use, for the previously valid Directive 2001/20/EC concerning clinical trials with medicinal products for human use will be voided by the EU regulation.

The presently valid Directive 2003/94/EC, which sets forth principles and guidelines on Good Manufacturing Practice for medicinal products for human use and for IMPs for human use, is to be replaced with the future delegated act of the Commission.

However, the AMWHV will continue to apply to investigational medicinal products that are not subject to Directive 2001/83/EC, such as blood preparations and tissue preparations, but that are to be classified as medicinal products under the German Pharmaceutical Act (AMG).

New: Parametric Release

Annex 17 Parametric Release is also slated for revision. According to the recently published Annex 16 Certification by a Qualified Person and Batch Release, release based on production data should also be revised. We expect to see publication of the first draft in 2016.

Development: Qualification & Process Validation

Revised Annexes 15 and 16 were already published in 2015. Annex 15 Qualification and Validation has been in effect since 01 October 2015; Annex 16 Certification by a Qualified Person and Batch Release will go into effect on 15 April 2016.

Thus, the world of GMP will be dealing with implementation for years to come. Topical issues for 2016 will certainly include:

  • further development of process validation
  • determining PDE values as the basis for cleaning validation

Production, Facilities and Equipment

The implementation of Chapter 3 Facilities and Equipment and Chapter 5 Production of the GMP Guide has remained a topic of interest ever since they went into effect on 1 March 2015. The main keywords are mentioned below:

  • avoiding cross-contamination
  • dedicated facilities
  • calculating limit values

The PIC/S Working Group (WG) on Controlling Cross-Contamination in Shared Facilities also deals with this topic. This Working Group is planning an Aide-Mémoire, which should be submitted as a draft in 2016.

Liquid Oxygen, Official Batch Release and Counterfeits

Before the end of the first half of the year we expect enactment of the fourth law to amend pharmaceutical and other regulations (Viertes Gesetz zur Änderung arzneimittelrechtlicher und anderer Vorschriften) (draft legislation dated 25 November 2015).

The German AMG and the German AMWHV will be amended as a result (see above). Minor changes in the AMG that relate to the GMP sector are:

Wholesalers no longer need a manufacturing authorisation for refilling and labelling liquid oxygen. The amendment will include adaptation of the prerequisites for the following cases:

  • wholesalers in hospitals filling a container with liquid oxygen for patients on an outpatient basis and
  • suppliers performing the same task directly at the patient‘s location.

In the future, the higher federal authorities must publish the official batch release (for sera, vaccines or allergens). In this way, in the event of supply shortages the public can be properly informed about available batches that have been released in Germany.

The authorities would like to improve prevention of counterfeits. Corresponding measures will be facilitated. The responsible authorities should be in a position to more easily prevent marketing and dealing with counterfeit medicines, for instance through recalls. This is true regardless of whether or not there is reason to suspect that quality has been compromised or that the medicinal product is harmful.

Production of Finished Medicinal Products

In 2015 the EMA already published a draft on the topic of Manufacture of the finished dosage form. The consultation period ended on 09 January 2016. With this production topic as well we may expect the final version to appear in 2016.

Quality Characteristics for the US FDA

The US Food and Drug Administration (FDA) have already issued a much noticed and widely discussed draft, Request for Quality Metrics, which was published last year.

Quality characteristics are currently a very prominent topic of discourse. It will be most interesting to see the enacted guideline.


In 2015 the FDA published three final Guidances on Biosimilars, which have yet to be implemented. Expectations for biosimilars are high and much has changed.

The first guidance, a Q&A document, provides answers to frequently asked questions concerning matters such as exchangeability, exclusivity or the requirements that must be met in setting up a biosimilar.

The second document deals with providing proof of whether a biosimilar and the corresponding reference product are highly similar. Analytical methods are required for this that are sensitive and specific enough to enable differences to be recognised and characterised.

The third guidance concerns determining biosimilarity on the basis of scientific criteria and data.

New: Water for Pharmaceutical Purposes

Before 2015 ended, the United States Pharmacopoeia (USP) published a draft of Chapter <1231> Water for Pharmaceutical Purposes. We also expect the final version of this document to appear in 2016.

New: DIN EN ISO 14644:2015

The US IEST published the new version of ISO 14644-1:2015 Classification of air cleanliness by particle concentration in 2015. The final version will probably become available in Germany and thus go into effect in 2016. Since publication of the latest draft dates back to 2014, there will be no transition period.

Global Activities

The World Health Organisation (WHO) already published two drafts in 2015, which will perhaps become final in 2016:

The draft guidance on Good Data and Record Management Practices should be viewed from the perspective of electronic documentation. The WHO’s special objective is global harmonisation. Thus, electronic documentation that can be used virtually anywhere will now be regulated by the WHO.

The draft of HVAC Systems for Non-Sterile Pharmaceuticals has an important part to play internationally. Many regulations exist for sterile production, but not for the non-sterile area. These voluminous, diverse applications are precisely what the WHO could properly regulate.

The Chinese Food and Drug Administration (CFDA) published four guidelines in 2015 relating to on-site inspections. It will be interesting to see how the CFDA implements these guidelines and whether the CFDA can close the gaps in monitoring practice.

The Pharmaceutical Co-operation Scheme (PIC/S) is planning a guidance on data integrity. Since the topic of data integrity was already one of the most frequent GMP shortcomings in 2015, it makes sense to outline the official opinion in a guidance. One should be developed not only for industry, but also for the authorities. This would allow the industry to implement standards and the authorities to better identify violations of data integrity.

The new Croatian supervisory authority HALMED was admitted to the PIC/S as the 48th member effective 01 January 2016. Nine additional countries have submitted applications for admission. China plans to apply in 2016. Thus, the PIC/S continues to develop into the most important organisation for the global harmonisation of GMP regulations and inspections.

The International Conference on Harmonisation (ICH) is working together with the PIC/S on a draft for the ICH Q12 Guidance Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. A concept paper was developed as early as 2015 and the draft is expected in the second quarter of 2016.

A Q&A document will be compiled to answer questions about the ICH Q11 Guidance.

A Look Ahead

2016 will be a year replete with challenges for everyday GMP. However, none of these topics will give reason to doubt that the key elements of GMP practice will retain their validity:

  • setting up working instructions in such a way that they help the product, the employee and the company in manufacturing the best medicinal product;
  • always executing and documenting work steps and quality processes in conformity with GMP and with instructions, in both digital and analogue form;
  • validating and qualifying production processes, quality processes, infrastructure and equipment in such a way that only a tolerable residual risk remains.

These elements can only become reality if all employees in a company strive to achieve GMP conformity as a common goal. Communication and conduct towards one another are important factors here. This is true not only within the company, but also in international harmonisation.

Perhaps in 2016, within the framework of the TTIP (Transatlantic Trade and Investment Partnership), we may experience a decisive international step towards mutual acceptance of GMP inspections between Europe and the USA. Many people are at work to make this vision of more than a decade come true. If they succeed, 2016 would become a milestone in the history of GMP.

We of GMP Publishing are looking forward to the year ahead and shall continue in 2016 to keep you posted on upcoming developments – you can depend on this.


Draft legislation of the Bundesministerium für Gesundheit (German federal health ministry) on the draft of 25 November 2015 on a fourth law to amend pharmaceutical and other regulations (Viertes Gesetz zur Änderung arzneimittelrechtlicher und anderer Vorschriften)


Thomas Peither
Editor in Chief
Maas & Peither AG, Schopfheim, Germany
E-mail: thomas.peither@gmp-publishing.com