5/6 October 2023
The previous year 2015 was another eventful year. Again there were new developments in the GMP environment as well as announcements of changes that preoccupied the pharmaceutical industry. 2016 won't be less exciting, also because now many of the new requirements must be implemented.
Hereinafter a few highlights:
The main changes in the new chapter 3 EU Guidelines to Good Manufacturing Practice "Premises and Equipment" concern the sections on measures to prevent cross-contamination. The changes are closely associated with the revision of chapter 5 (Production) and with the new EMA-Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012). The new text provides for a risk-based assessment of the topic on the basis of toxicological data. This means that dedicated facilities are only required if the identified risks cannot be controlled using adequate technical or organisational measures.
This is also supported by EMAs Toxicological Guideline, mentioned above. It is valid since 1 June 2015 and describes a risk assessment based on the toxicological evaluation of the products manufactured in the shared facilities/production areas.
The new chapter 5 "Production" of the EU Guidelines to Good Manufacturing Practice is in operation since 1 March 2015. This chapter contains much more changes:
Annex 15 of the EU Guidelines to Good Manufacturing Practice "Qualification and Validation" also entered in force in its revised version (1 October 2015). It adopts principles from the ICH Guidelines Q8, Q9, Q10 and Q11 with reference to the application of quality risk management (QRM), process analytical technology (PAT), quality by design (QbD) and real-time release testing (RTRT).
It was coordinated with the EMA "Guideline on process validation for finished products - information and data to be provided in regulatory submissions" (in operation as of 24 August 2014).
The new Annex 15 lays down extended requirements on the validation master plan and the documentation. New is a general requirement for user requirement specifications (URS), factory acceptance test und site acceptance test (FTA/SAT). There were only few changes concerning IQ/OQ/PQ (they may be combined in justified cases). The most important changes concern process validation itself (consistent with the EMA Guideline mentioned above). A so-called retrospective validation now is obsolete and there is only a prospective validation. Two principal approaches are possible to process validation; the "traditional" one with three consecutive validation batches and a "continuous process verification" with reference to QbD. They can also be mixed (hybrid approach).
The requirements concerning the cleaning validation are described in more detail and go hand in hand with the requirements in Chapter 3 and with the "Toxicological Guideline".
The chapter on transport verification in Annex 15 is completely new. The chapter recognises that it is difficult to validate transports. It is recommended to also monitor other critical parameters besides temperature such as vibration, humidity etc.
By the way, FDAs "new" Guidance on Process Validation is valid since January 2011. There is a (satisfyingly) high level of agreement between the FDA Guidance on Process Validation and the revised Annex 15. But there are also differences that companies wishing to serve the US market as well as the European market must be well aware of.
The long awaited Annex 16 "Certification by a Qualified Person and Batch Release" was finally published in October 2015.
It is pointed out in a central position that the principal task of a Qualified Person (QP) is to certify batches for their release. In this context the QP must verify personally that the responsibilities listed in chapter 1.6 are fulfilled. Chapter 1.7 lists quite a few other responsibilities of the QP. But the related activities may be delegated and in doing so the QP can rely on the respective quality management systems. But the QP should make sure continuously that this confidence is justified.
It is the first time that the GMP expectations concerning excipients are described in a Guideline. The "Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use" were published in March 2015. Central topic is that the manufacturing authorisation holder is required to ensure that the excipients are suitable for use in medicinal products. For this he shall ascertain the appropriate good manufacturing practice he expects on the basis of a formalised risk assessment. This means that Part II EU GMP Guideline was not extended to include excipients.
The ICH Q3D Guideline for Elemental Impurities was published at the end of 2014. EMA published the relevant recommendations (EMA Elemental impurities in marketed products - Recommendations for implementation) on 26 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.
What will happen in the future?
A new Annex is planned for the EU Guidelines to Good Manufacturing Practice: Annex 21 for Importers of Medicinal Products. The concept paper was published on 13 May 2015. The consultation process ended in August 2015. The paper did not provide much information and the first draft of the new annex is expected soon for public consultation.
There also was a concept paper on Annex 1 of the EU Guidelines to Good Manufacturing Practice (Manufacture of Sterile Medicinal Products) (published on 2 February 2015). First public consultation ended in March 2015. A first draft of the revised annex is expected soon for public consultation. The revision is not supposed to create new expectations, but it will contain some adjustments.
Annex 17 of the EU Guidelines to Good Manufacturing Practice (Real Time Release Testing) is to be modified completely. The revised document was published on 15 September 2015, public consultation ended on 11 December 2015. The change of name alone signalises a complete reorientation. In the end, the actual annex 17 "Parametric Release" was 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.
There have also been new developments in the GDP area:
Good Distribution Practice for Active Ingredients: The Guidelines on Good Distribution Practice for Active Substances for Medicinal Products for Human Use which were published on 19 March 2015 are in force since 21 September 2015; irrespective of whether they are produced by the distributor himself, by someone else or whether they are imported. Distribution comprises all activities consisting of procuring, importing, holding, supplying or exporting active substances with the exception of brokering (nothing more than brokering). This determines the right of authorities to inspect distributors. Repackaging or relabeling are manufacturing activities and are regulated by GMP.
Distributors of active substances are to implement a quality system setting out responsibilities, processes and risk management principles. Analogously to the GMP Guidelines they have to be adequately resourced with competent personnel, for example, and they must have a person with defined authority and responsibility at each location where distribution activities are performed ("designated person").