Dear All,

 In February 2005 the EMA published a Concept Paper on the topic of the need for ‘dedicated facilities’ for certain highly potent or sensitising drugs, to clarify the requirements given in Chapter 3, Section 6, of the EU GMP Guide.  The Concept Paper proposed revising Chapter 3, Section 6, together with Chapter 5, Section 19 (which deals with cross-contamination) to clarify when dedicated facilities are required.

In October 2011 the EMA CHMP published a new Concept Paper on this subject entitled “the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities” with comments being due by 31 January 2012.

The October 2011 Concept Paper problem paper states:-

“At present there is no defined approach in order to outline a method of deriving acceptable exposure limits for cross contamination between products manufactured using shared facilities.  The concern arises that in the absence of any guidance and with a plethora of toxicological tools being available a lack of harmonised interpretation could occur both in pharmaceutical industry and National Competent Authorities.  This may result in different production requirements with significant financial impact on manufacturers and potentially, in medicinal products of impaired quality which may adversely affect patients’ health”

It goes on to state:

“A more scientific approach based on current available pharmacological and toxicological information is required to establish threshold values to be used as part of the overall Quality Risk Management in shared facilities.”

“The Safety Working Party recommends drafting new guidance on toxicological assessment to be used in the risk identification stage of the Quality Risk Management process in determining whether a medicinal product should be manufactured in dedicated facilities. More specifically the agreed approach should be scientifically based and aim to limit variability in deriving acceptable exposure limits thereby ensuring consistency.”

The recommendation made by the October 2011 Concept Paper would appear to be in alignment with the ISPE ‘Baseline Guide’ on the subject of ‘Risk-Based Manufacture of Pharmaceutical Products (RISK-MaPP)’ that was published in September 2010.

The time table for progressing this issue is given in the Concept Paper as follows:

• Draft guidance to be published for a 3 month consultation in June 2012.

• Final guidance to be published in March 2013 with a 6 month implementation deadline.

Given that we had over six years of discussion and inaction following the publication of the 2005 concept paper, this timetable is probably a little ambitious but we will have to wait and see.

Best regards,

 Pete

Peter Gough, Partner

NSF-DBA Ltd.

On the 28 October the EMA GMDP Inspectors Working Group (GMP/GDP IWG) published a Concept Paper on revising Annex 16.  Anne Junttonen, a Senior Pharmaceutical Inspector with the Finnish National Agency for Medicines (FIMEA) and who serves on the EMA GDP/GMP IWG, is the leader of the group’s effort to revise this Annex.  The Concept Paper states that “new legislation and developments in science and technology have created new areas where further guidance is desired; both by the regulators and the industry”.

This Concept Paper recognises that there is currently a lack of harmonisation in requirements between Member States.  It lists several areas that are currently being interpreted differently across the EU:-

·        What is the minimum a Qualified Person (QP) must personally carry out when certifying a batch?

·        What are the prerequisites for relying on statements from persons other than fellow QPs?

·        How is the Control Strategy and the batch certification release process linked?

·         What are the expectations for QPs reviewing batch records manufactured by third parties in third countries?

·         What knowledge should a QP have about the site(s) involved in the manufacturing of a batch?

·        What actions are expected from the QP when a batch cannot be certified and therefore released?

·        Sampling and testing of batches produced outside the EU/EEA.

·        Dealing with minor deviations from marketing authorisations.

The Concept Paper states “The implications of the new legislation related to active pharmaceutical ingredients (APIs), excipients and finished product to the batch certification and release procedures should be explored, as well as ensuring that the guideline is up-to date concerning investigational medicinal products.”

The most contentious area that has to be addressed by the revision of Annex 16 is the QP’s discretion when dealing with minor deviations from the details described in the Marketing Authorisation, which was addressed in the Reflection Paper published by EMA in 2007 and updated in 2009.  The concept paper states “This reflection paper has been misinterpreted in some cases and there are many questions regarding its status.  Annex 16 would be an appropriate place to provide guidance on what is understood by certification of compliance with the Marketing Authorisation.”  It will be very interesting to see the wording that addresses this issue in the draft revision that should be published in mid-2012.

There are a number of additional areas where clarifying guidance regarding the QP is strongly desired; e.g.:

·        The QP’s position in an organisation's structure

·        The physical location of the QP

·        Independence of the QP from the Head of Production Manager and/or Quality Control

·        The QP’s role in product defects and related investigations

The concept paper states that as these questions are, not directly related to the batch certification activity itself, they are not in the scope of the current Annex 16.  They could be addressed in future revisions of applicable Chapters of the GMP Guide or in the Q&A’s section on EMA’s website.

The Concept Paper ends with the following timetable to lead to the revision of Annex 16:-

·        Release of Concept Paper for Public Consultation: October 2011

·        Deadline for comments on Concept Paper: January 2012

·        First draft of revised Annex 16 for discussion in IWG: May 2012

·        Agreement of Annex 16 draft guidance in IWG: October 2012

·        Release of Annex 16 draft guidance for Public Consultation: December 2012

·        Interested Parties meeting: February 2013

·        Deadline for comments on Annex 16 draft guidance: End February 2013

·        Final draft of revised Annex 16 for discussion in GMP/GDP IWG: September 2013

·        Adoption of revised Annex 16 guidance by European Commission November 2013

In July 2011 the EMA issued a revised version of The Compilation of Community Procedures on Inspections and Exchange of Information.  This document is a tool for facilitating co-operation and harmonisation between the GMP inspectorates of the EEA Member States.  Previously it had been issued as separate pdf files for each section.  This revised version has reverted to being a single document and includes a section on GDP inspections.

Best regards,

 Pete

Peter Gough, Partner

NSF-DBA Ltd.

On 11 October 2025 the European Commission adopted revised proposals, as a draft Regulation and Directive, on information on prescription-only medicines.  These revised proposals amend the original Commission proposals of 2008 and take into account the European Parliament's amendments to the original proposals for legislation on information to patients.

The revised proposals set out a clear framework whereby companies with marketing authorisation for a product may – and to some extent must – provide good quality and objective information on their prescription-only medicines to the general public.  As a result, the proposals should lead to better empowered patients, more rational use of medicines, whilst, at the same time, maintaining the ban on advertising prescription-only medicines. It also seeks to further strengthen the current pharmacovigilance system.

The proposals maintain the current advertising ban on the prescription-only medicines and foresee that:

·        Only certain information on prescription-only medicines would be allowed.  For example, information on the label and on the packaging leaflets; information on prices; on clinical trials; or on instructions for use.

·        Information on prescription-only medicines would only be allowed through limited channels of communication. For example, information on officially registered internet websites; or printed information made available when specifically requested by members of the public. A publication in general print media will not be permitted.

·        The information must fulfil recognised quality criteria. For example, it must be unbiased; it must meet the needs and expectations of patients; it must be evidence-based, factually correct and not misleading; and it must be understandable.

·        As a general principle, information which has not been approved before needs to be verified by competent authorities prior to its dissemination.

The revised proposals will now be debated by both the European Parliament and the Council of Ministers so it could be another year before we have final legislation on this topic.

Best regards,

Pete

Peter Gough, Partner

NSF-DBA Ltd.

Earlier this month the FDA issued final Guidance for industry on the “Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anti-counterfeiting”.  This guidance provides recommendations to pharmaceutical manufacturers on:

1.       Design considerations for incorporating PCIDS into Solid Oral Dosage Forms (SODFs),

2.       Supporting documentation to be submitted in new drug applications (NDAs) and abbreviated new drug applications (ANDAs) to address the proposed incorporation of PCIDs in SODFs,

3.       Supporting documentation to be submitted in post-approval submissions to report or request approval to incorporate PCIDs into SODFs, and

4.       Procedures for reporting or requesting approval to incorporate PCIDs into SODFs as a post-approval change.

The FDA recommends that the PCID ingredients be pharmacologically inactive so that they can be treated as excipients. To minimize toxicological risk, FDA recommends that manufacturers use permissible direct food additives, food substances that are generally recognized as safe (GRAS), or ingredients listed in the agency’s Inactive Ingredient Guide that have been used in solid oral dosage forms.  They also recommend that companies add a PCID to the product at the lowest level that will ensure the dosage unit’s identification. PCIDs that are relatively inert also can minimize the potential for adverse interactions.  In addition, FDA recommends that manufacturers examine the potential effect of a PCID on the product’s quality, performance and stability.

NOTE: So far, the use of PCIDs is not permitted within the EU and does not feature in the Falsified Medicines Directive 2011/62/EU.

Best regards,

Pete

Peter Gough, Partner

NSF-DBA Ltd.

Great feedback from a great group!

As you may be aware we are in the process of being assessed for certification by IRCA to enable our highly successful and popular auditor course to be certified to train auditors who can themselves apply for certification by IRCA as Pharmaceutical Quality Management System auditors, a new standard for the industry.

As part of this process we have now run 2 pilot courses as public and internal courses and have scheduled a further public and two internal courses for this year with a total take up of over 100 potential auditors for certification. In addition we have a group of 150 people who have been through the course in the past 5 years who may want to convert to the certification scheme with a top up course.

Interest is very high and includes the pharma industry, major multinationals as well as smaller virtual organisations and regulators inside and outside Europe. During the week of 3 to 7 October we ran a special course for invited delegates, our QP alumni group and some of our NSF-DBA auditing colleagues,  a tough audience to impress but impress we did with an overall course score of 4.71 and some comments like

·         An exceptional course led by exceptional tutors.  Thank you.

·         Amazing course to reconfirm my audit process awareness and help me regain confidence in leading audits. 

·         I found this course to be extremely beneficial, certainly one of the best courses I have attended.  The tutors were excellent, very passionate about the topics and more importantly very knowledgeable.  I will certainly be recommending the course throughout my company and would view it as a must for all auditors.  Having completed the course I am now highly motivated to put into practice all that I have learnt and take back with me certain elements which I believe can be improved upon within my company.  I have found it to be an excellent forum to build new relationships and learn from others’ experience. 

·         Fantastic course, part revision, lots of challenge.  One of the best courses I have attended.

·         Very well presented and material well laid out.  Tutors were very helpful and knowledgeable.  Very good group of people attending the course.  Very open and willing to share their experience.  Excellent course and would recommend others to attend.

I am delighted to report that we had 100% pass rate in the exams.

The group were very positive and gave some good thoughts for course evolution and tweaking so like every NSF-DBA course we are now in the process of continual improvement ready for next time.

The next course runs in Amsterdam from 14 November 2025 and we aim to keep the groups fairly low in size to improve the interaction so places will be limited.  If you are interested in holding a place or would like more information please contact Bev Willett, Course Administrator; [email protected].   Keep watching this space for news on the certification process, top up courses, conversion courses for ISO 9001 lead auditors to PQMS lead auditor and auditor CPD.

Regards

Mike

I was delighted to host and run another of our hugely successful GMP courses to a full house from 16 to 19 May in Manchester.

Overall the course feedback was a very reassuring average 4.5/5.

The delivery team were delighted by the many positive comments from delegates both in writing and verbally during the course and are also pleased to receive the constructive criticism for continual improvement. This is a large subject and the feedback ranged from those who wanted more detail to those who thought it was pretty complex with most happily somewhere in between. Although targeted to those in their first 5 years’ experience in the group ranged from those in their first month in the industry to some with up to 15 years’ experience!

The GMP quiz at the end of the course was good fun and had some great teamwork, and although very close there was a clear winning team with some special souvenir pens as prizes. In addition the challenge to come up with new definitions for “GMP” worked well and went with the theme of patient protection.

Several delegates asked at the end of the course what more they could do to continuing this training in the years ahead.  I would whole heartily recommend specialist training in skill areas to support auditing and self-inspections. (this GMP training is a useful entry to our auditor training courses) Auditing is a great area of focus for the future and is a great learning ground. In addition for those hungry for more detail then I would recommend the Qualified Person and Continual professional development training course whether or not you wish to become a QP, it can lead to Post Graduate qualifications in “Pharmaceutical Quality and GMP” at Certificate , Diploma or MSc level.

A couple of people did comment that the wish the course was run in Amsterdam, it is! And will run there again on 28 November. We are also planning to run it in Istanbul next year so watch the website for details of this and other courses.

Throughout the course the focus was on protecting the patient and protecting the company and to use knowledge of GMP and the legislation to ensure both these objectives are met.

Mike Halliday

NSF-DBA Partner

The MHRA has launched its new Notification Scheme for clinical trials today (1 April 2025) for medicinal products.

The Notification Scheme is available for trials involving medicinal products authorised in any EU Member State if:

•  they relate to the licensed range of indications, dosage and form
• or, they involve off-label use (such as in paediatrics and oncology, etc) if this off-label use is established practice and supported by sufficient published evidence and/or guidelines.

The Notification Scheme will be open to trials meeting the above criteria and may include randomisation of subjects to different marketed products or repackaging and/or relabelling of the marketed product(s). Placebo controlled trials will not be open to the notification scheme, nor will trials in which the marketed product has been modified, for example by over-encapsulation.

Following receipt of a valid notification submission, sponsors will receive an acknowledgement letter to say that the trial may go ahead after 14 days from receipt of the notification, if the MHRA has not raised any objections. This means that the acknowledgement letter will act as the authorisation.

 If the MHRA raises an objection to the notification, the submission is treated as a standard request for authorisation and an assessment is carried out in the usual way with a time line of 30 days from the receipt of the original notification.

A risk assessment based on the potential risks associated with the use of the investigational medicinal product (IMP) should be made by the sponsor. Background documentation on how to do this is provided on the web site in the new section on the Notification Scheme.

This is the first part of the Medical Research Council (MRC) / Department of Health (DH) / MHRA Joint Project on Risk Adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products.

The second part of the project will provide guidance on risk-proportionate approaches to the management and monitoring of clinical trials. This will be available following the completion of the currently on-going pilot phase.

Pete Gough, 

NSF-DBA Ltd.

There is a proposal for a new general chapter in the European Pharmacopoeia - Demonstration of Uniformity of Dosage Units (UDU) using large sample sizes (see attached).

 In order to take advantage of increased batch control offered by process analytical technology (PAT) tools, for example large sample sizes used for the control of uniformity of dosage units, a new Ph. Eur. general chapter 2.9.47 is proposed. Comments on the proposed general chapter should be submitted by 30 June 2011.

The document can be found at the following site:  http://www.edqm.eu/medias/fichiers/Enquiry_Demonstration_of_Uniformity_of_Dosage_Unit.pdf

Pete Gough

NSF-DBA Ltd.

"NSF-DBA's course on Human Error:Causes and Prevention helped us to reduce errors and repeat deviations by 51% in the 8 months after the course"

"NSF-DBA are the "go to" consultants for error reduction in the pharmacuetical industry"

"Error reduction is possible and NSF-DBA's course shows you how" 

These are just a sample of the comments from statisfied delegates who attended our course on 'Human Error:Causes and Prevention'. If you are interested in 

• Error proofing your proecesses
• Simplifying your systems to reduce errors
• Identifying and removing the 'root cause' of human error
• Reducing errors by improving decision making