GMP Annex 1 and Lyophilization

The production of pharmaceutical products is subject to a set of rules and guidelines, notably the EU -Guidelines to Good Manufacturing Practice (GMP).  The purpose of GMP is to control the quality of products manufactured by holders of a Marketing Authorization (MA).

La Vague 76 A3p Bpf Annexe 1 Et Lyophilisation 1

GMP Annex 1 Lyophilization

Since they first appeared in the 1960s / 1970s, the GMP guidelines have changed regularly to take account of technological advances, as well as to guarantee improved drug quality. In addition to the quality requirements inherent in the drug, sterile drugs must meet specific criteria that guarantee their sterility.

A first draft was proposed for comments in December 2017 then a second draft in February 2020. Almost 10 years elapsed between the last revision of 2008 and the first draft. This represents a very long time in view of the technological and regulatory advances in the pharmaceutical world during this time period.

Note that this is the fourth revision of Annex 1 after those of 1996, 2003 and 2008.

 

1. Specific features relating to the production of clean, sterile lyophilized products.

 

Lyophilization is a complex process characterized by a time frame that is generally very long, and which takes place at a pressure below atmospheric pressure (under vacuum). Lyophilization requires the use of a lyophilizer which is also particularly complex and calls on very specific technologies and skills.

Moreover, for the production of clean, sterile products, other associated processes must be implemented, some associated with the lyophilizer; others associated with the product.

– Associated with the lyophilizer: cleaning, sterilization, gas filter integrity testing  and integrity tests (leak tests) of the whole of that part of the installation that is subjected to a vacuum during the process.

– Associated with the product: transfer, loading operations of partially stoppered units (from the filling line to the lyophilizer), then the unloading and transfer of stoppered units up to crimping.

In summary, the multiple operations involved in lyophilization, extended duration of exposure of unsealed containers in the environment, conditions of use of the lyophilizer with significant thermal and mechanical constraints, and related processes will necessarily generate increased risk of contamination (microbiological, particulate and cross) for the  product.

A comparative analysis of the contamination risks in aseptic filling processes of liquid and lyophilized forms demonstrates the increased contamination risk.

Over time, equipment manufacturers have developed installations to reduce contamination risks. Illustration 1 shows the main technical advances made in recent decades.

 

2. Annex 1 and Lyophilization

 

This aspect of contamination control for the production of lyophilized forms is one of the new points of the new GMP Annex 1.

The version of Annex 1 in force (2008) makes no specific mention of lyophilization, except on two subjects:

– Transfer conditions before and after lyophilization.

– Test for maintenance of vacuum in the case of vacuum sealing.

Now, in the new version, there is a set of paragraphs dedicated to lyophilization mainly within the “Production and Specific Technologies” chapter, but it is also mentioned in other paragraphs.

The tables below compare and present the 2008 and  2022 versions and all paragraphs which relate to lyophilization or lyophilizers.

 

 

Conclusion

In the new EU GMP Annex 1, all aspects of sterility assurance including the “Contamination Control Strategy” approach are addressed. The level of the new requirements will generate the need to implement all the latest technological developments, such as automatic or semi-automatic loading / unloading systems associated with barrier technologies.

A revolution in the processes that surround lyophilization will therefore begin, whether with respect to equipment, processes or methods with various impacts on organization and production capacities!

Come to Lyon on 4 & 5 April for days dedicated to aspects of contamination control for the production of lyophilized forms. All the info on www.a3p.org!

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La Vague A3p Sandrine Favre

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La Vague A3p Dominique Sierakowski

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