◆  EMA: Work on Annex 1 (Manufacture of sterile medicinal products) and Annex 21 (Guidance for importers of medicinal products) will continue (17-Oct-18 ECA)

The European Medicines Agency (EMA) has to face challenges like the relocation to Amsterdam and the loss of personnel. Because of this, EMA needs to temporarily scale back or suspend additional activities. EMA has now published a press release and announced the next phase of its Brexit preparedness business continuity plan (BCP), which entered into its third phase. The BCP will help to define core activities related to the evaluation and supervision of medicines.

"EMA will now temporarily suspend or scale back additional activities to ensure that resources can be redeployed so that its core activities can continue without interruption and to the same quality," commented Noël Wathion, EMA's Deputy Executive Director. "Over the next few months, EMA will continue to carefully monitor staff intentions to relocate and the anticipated impact on its activities whilst planning for the critical time period when the Agency will be moving to its new premises in Amsterdam."

Despite the necessary temporary suspension/ scaling back of activities, EMA has defined seven guidelines, which will exceptionally continue during BCP phase 3:

  • Revision of Annex 1 of the EU GMP Guide (H/V) - Manufacture of sterile medicinal products.
  • New Annex 21 of the EU GMP Guide (H/V) - Guidance for importers of medicinal products.
  • Reflection Paper of Good Manufacturing Practice and Marketing Authorisation Holders.
  • Guideline on quality requirements of medicinal products containing a device component for delivery or use of the medicinal product.
  • Good Pharmacovigilance Practice: Pregnancy and Breast Feeding.
  • Revision 6 of Note for Guidance on the evaluation of anticancer medicinal products in man.
  • Guideline on the use of minimal residual disease as a clinical endpoint in Multiple Myeloma trials.

Furthermore, meetings of product-related working parties will continue as scheduled; but all meetings of non-product related working parties have been temporarily put on hold.


◆  Current Questions on Validation of Blend Uniformity - Stratified Sampling (07-Nov-18 ECA)

Validating blend uniformity is a decisive factor for the validation of solid dosage forms. In Europe, there are no regulatory provisions for this. This is different in the USA: according to 21 Code of Federal Regulation (CFR) 211.110, the adequacy of mixing has to be regularly assessed. Until 2013, there was a FDA Draft Guidance which described how to realise this assessment. The FDA withdrew it in 2013 though.

Now, what is today's state of the art with regard to the validation of blend uniformity? To provide guidance on that topic, the ISPE started a Blend Uniformity and Content Uniformity (BUCU) initiative. This initiative was the topic of a webinar organised last year. In the following, please find a few questions and the answers provided by the speaker Dr Gerrit Hauck, today at Basilea Pharmaceutica International AG.

Question 1
In our process of validation, the tolerated standard deviation is derived as acceptance criterion depending on the sample size and mean in accordance with the label claim from the ASTM. Is this procedure acceptable?

Answer 1
As long as you refer to the tables laid down in ASTME2810, this procedure is - as far as I am concerned - correct, however only insofar as you consider a pure random sample.  Stratified Samples require other statistics.

Question 2
Does the approach of validation of mixing remain the same for more than one API?

Answer 2
Usually yes, unless one of the drug substances would be present in very high concentration so that one could argue that a determination of the mixing homogeneity shouldn't be required.

Question 3
Do you apply sampling already in the routine? How will you ensure in practice that samples are taken at 30 sampling locations? Will the samples be combined and should I take more in case that a pill falls off?

Answer 3
Yes, sampling at 20 or 40 sampling locations has to be exactly planned. We usually set the sampling times on the basis of significant events and then distribute the remaining samples according to the period between e.g. the beginning of the batch, change of template and batch end. It is quite not unusual to take more than e.g. 3 samples per locations so that for example a pill that fell off can be replaced. We usually take reserve samples.

Question 4
Will the ISPE recommendation be soon implemented in a guideline?

Answer 4
To my knowledge, the implementation in a guideline is not being planned. Through the publication of the ISPE recommendation, a method aligned with the state of the art is now available so that there is no actually need for a FDA Guideline.

Question 5
Why is the USP provision far less strict than the expectations of the FDA & Co?

Answer 5
In my opinion, many tests traditionally used in the pharmaceutical industry are not particularly demanding. Especially considerations about the risks for consumers are often excluded from the test criteria. Especially in the USA, the scientific debate is moving to more demanding tests.


◆  Classification of GMP Deficiencies - A new Guideline of the PIC/S (27-Nov-18 ECA)

Following the PIC/S Committee Meeting in Chicago (USA) at the end of September 2018, the PIC/S announced that the PIC/S working group had elaborated a new guideline on the classification of GMP deficiencies which is going to be adopted. The work on this paper had already begun in 2012 after the topic "classification of GMP deficiencies" had been discussed during the PIC/S meeting in 2011 in South Africa.

The aim of the new document is to provide harmonisation of GMP deficiencies in GMP inspections across the different inspectorates. Indeed, consistency should be ensured throughout the different inspectorates of countries to define when a deficiency is a critical one and when it is a major one.

The paper is to be seen as a tool which facilitates the risk-based classification of GMP observations. On the one hand, it should support  inspectors in their work and on the other hand it should serve as information for the industry on how deficiencies are classified. To that end, the guideline should include examples and be non-binding so that the responsibility for the extent of a deficiency discovered still remains in the hands of the manufacturer inspected.

Moreover, reflection is ongoing on also taking into consideration GDP deficiencies (i.e. inspection findings from Good Distribution Practice inspections) in the guideline.

The new guideline "Classification of GMP-Deficiencies" - which will carry the number PI 040-01.