As this is our opening edition of Excipients Insight for 2018, on behalf of the IPEC Europe Board, I’d like to wish all reading this a most successful and rewarding New Year. It will be a very busy one no doubt, as for sure the number of challenges we face as an ‘industry’ do not seem to be in decline!
Not surprisingly, the first weeks of January are heavily focussed on preparations for our forthcoming Annual Excipients Forum and Annual General Meeting in Bordeaux. We’ll be reporting on these events in full in February and the Forum programme is one of our feature articles in this issue. As always, we hope that the topics both inform and stimulate good debate. Our wish is that IPEC Europe helps to keep all attendees appraised of the latest developments related to excipients and through the presentations at the AGM for members, our work plans for the months ahead will be formalised. The Board and each committee will present on achievements in 2017 and proposals for objectives moving forward. We really do welcome active participation at these sessions. It provides the Board with direct and immediate feedback that we have the right focus, on the right issues not least with reference to what we learned at the Forum on the previous day. But of all that’s said and done in Bordeaux, it would be good to hear from all sides of the audience. Whether you’re from the user, producer, distributor or academic communities, we would value your input to ensure we maintain the all-important balance which makes IPEC Europe unique.
So please join us and feel free to ask about getting involved. We always need volunteers to contribute to our projects and fresh thoughts and ideas are always welcome. If you’d like to get involved, please either contact the Secretariat or - anticipating that many of you will be in Bordeaux - the Board value the opportunity to talk with you on how you could join a team or task force. Of course, we’re happy to discuss any other IPEC matter, too. I look forward to seeing you there where you can also catch up on our new look for IPEC Europe in this New Year!
IPEC Europe chair
On February 1, IPEC Europe will host its Annual Excipients Forum, a key date in the calendar for all involved in the supply, distribution and use of pharmaceutical excipients, Bordeaux.
We’re delighted to announce that the final version of the programme includes a presentation on the latest developments in China, and in particular a regulation on excipients – introduced briefly in the December 2017 edition of Excipients Insight – that introduces some fundamental changes to the way excipients are regulated. Mr Colin Li, Chair of IPEC China, has agreed to update delegates on these critical changes for companies operating in the Chinese pharma market.
That’s just the latest addition to what is a comprehensive and interesting programme for the annual seminar, picking up on some of the most pressing issues of the moment. There is still time for last-minute registrations if you would like to join us in Bordeaux, although the remaining seats are going fast so don't delay!
After opening comments from IPEC Europe chair Mr Frithjof Holtz, the first morning will feature a presentation from EDQM Director Dr Susanne Keitel on the draft General Monograph on Co-processed Excipients, along with other developments in the European Pharmacopoeia (Ph. Eur.) relevant to excipients, with the US perspective on co-processed excipients Mr Brian Carlin from IPEC-Americas.
After a break, Ms Catherin Sheehan of the US Pharmacopeia (USP) will cover the changes to the USP-NF excipient monographs and general chapters being carried out part as part of USP’s modernisation drive, as well as exploring harmonization opportunities between the compendium and its peers around the world – via the Pharmacopoeial Discussion Group (PDG). Dr
Dr Sabine Kopp of the World Health Organization will build on that topic with a talk on Good Pharmacopoeial Practices (GPP) as a facilitator for reduced duplication and greater convergence between pharmacopoeias.
Mr Li’s China presentation will kick off the session after lunch, and will be followed with a talk by Dr Yvonne Rosiaux of Gattefossé, who will examine how suppliers and users of excipients can work together on Quality by Design (QbD) projects – in theory and in practice – drawing on a specific case study. That will be followed by presentations by Ms Elham Blouet of Roquette Frères on excipient attributes required for parenteral formulations – a particularly timely presentation given recent developments on GMP for sterile drugs at the WHO and ICH – and Ms Kate Coleman on risk assessment for GMP excipients, another hot topic.
Finally, after what will be a full day, there’ll be time to relax at an historical vineyard on the outskirts of Bordeaux. The Cocktail Reception and Forum Dinner will take place in the distinguished Château Smith Haut Lafitte, nestled in a 78-hectare estate surrounded by wonderful scenery. You will have the unique opportunity to visit the impressive Château’s cellars, where more than 1000 wine barrels 'rest' as they slowly mature to perfection!
Looking forward to seeing you in the fine city of Bordeaux!
As 2017 drew to a close, the director of the European Medicines Agency (EMA) – Professor Guido Rasi – predicted that 2018 will a challenging year for the regulator and the industry it serves, not least because of Brexit and the resulting relocation of the EMA from London to Amsterdam.
The move and preparing for the UK’s withdrawal from the EU “will occupy the time of many staff members that we would rather spend on activities that make a difference to public health,” he said, adding that this will inevitably lead to refocusing of core tasks and adjournments for some initiatives. Questions still remain about the role of the UK Medicines and Healthcare products Regulatory Agency (MHRA) and impact on regulatory approvals. Notably, around 200 of EMA’s 900 staff in London have suggested they will not be staying with the agency after the transfer.
A recent article in Pharmaceutical Technology notes for example that the UK “not only has the EU’s second highest number of GMP and other medicinal manufacturing sites but the third highest number of batch certification sites. Replacement batch release sites in the EU/EEA will have to be set up with qualified personnel.”
Nevertheless, the day-to-day work of the EMA has continued, and 2017 saw a number of regulatory developments in the area of Good Manufacturing Practice (GMP) that will come to fruition in 2018 and beyond.
Towards the close of the year the EMA introduced major changes to Good Manufacturing Practice (GMP) for the manufacture of sterile drugs with revision to Annex 1 its GMP guide for these products with a number of changes including the introduction of Quality Risk Management principles, with the World Health Organization (WHO) and the Pharmaceutical Inspection Co-Operation Scheme (PIC/S) contributing to the update.
It seems that we have been talking about ICH Q3D Elemental Impurities for years – because we have – and as of 1 January this year a series of requirements and revisions to the guideline have come into effect, notably including General Chapter 5.20, the General Monographs on ‘pharmaceutical preparations’ (2619) and ‘substances for pharmaceutical use’ (2034) and general method 2.4.20 on ‘determination of elemental impurities’.
2017 also saw the introduction of a new and longer EU GMP guideline for investigational medicinal products (IMPs) and accompanying delegated regulation, taking into account new Good Clinical Practice (GCP) requirements in the 2014 Clinical Trials Regulation, and the removal of sections on IMPs from the current GMP directive 2003/94/EG which is being replaced by the new GMP Directive 2017/1572 that only covers commercial products.
The year also saw the publication of a GMP guideline for advanced therapy medicinal products (ATMPs) such as cell-based and gene therapies, which comes into effect on 22 May. These therapies offer ground-breaking new opportunities for the treatment of diseases and injuries and are particularly important for severe, untreatable or chronic diseases for which conventional approaches have proven to be inadequate.
There were other developments of note in the 2017. In November, a mutual recognition agreement that will allow regulators in Austria, Croatia, France, Italy, Malta, Spain, Sweden, the UK and the US to share inspections data came into effect. Other EU member states will be added as soon as their evaluation by the US FDA is complete, although the European Compliance Academy (ECA) notes there are some issues still to tackle, including differing approaches to the routine inspection of IMPs between the US and EU and in the issuing of GMP certificates.
Finally, it’s worth pointing out that 2017 was something of a landmark year in terms of new therapies making their way through development and regulatory review, which is being taken as a positive sign for the overall development and health of the industry.
The EMA approved 92 novel and generic drugs, while the FDA cleared a record 46 new molecular entities. The year saw the approval of the first chimeric antigen receptor T-cell (CAR-T) therapies for blood cancers as well as the US’s first gene therapy, leading analysts to predict rosy prospects for the biopharma sector – provided it can work out how to price them at a level healthcare systems can afford.
Over the course of 2017, IPEC Europe has taken a long look at our activities in the context of our Agenda 2020 objectives, our role in an increasingly diverse and complex environment for pharmaceutical excipients and the way we represent our members to the wider world. The results of those deliberations are broad, and will be discussed in more detail at the 2018 Annual Excipients Forum in Bordeaux on 1 February and the following day at IPEC Europe's Annual General Meeting.
One outcome of those months of deliberation is that we have decided our association would benefit from a new 'look', and a project was launched to identify a new visual identity that reflects the qualities and characteristics of IPEC Europe and the inclusive, dialogue-driven way we do business. Those of you attending the Bordeaux event will be the first to view the results of that effort, and we look forward to discussing the changes - and the thinking behind them - with you there!
Towards the end of 2017, the European Commission published a draft revision to its Good Manufacturing Practice (GMP) guidelines on the production of sterile drugs.
The EC has drawn up a new draft of Annex 1 ‘Manufacture of Sterile Medicinal Products’ - the first revision to the document since 2008 – and has published a consultation document that is open for comments until 20 March 2018.
The purpose of the revision is to add clarity to the Annex, introduce the principles of quality risk management (QRM), cover new technologies and processes, and change the document structure to a more logical flow.
Some of the changes include changes to the recommendations on clean rooms - taking revisions to ISO 14644 standards into account – as well as single-use systems. It also includes dedicated sections on utilities (water, sterilization, filtration and cooling systems used in the production of sterile drugs) as well as environmental and process monitoring.
According to the newly added scope section, the Annex "provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of quality risk management, to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented."
The EC also notes that the recommendations can be applied to the manufacture of some non-sterile products, such as creams, ointments or low bioburden biological intermediates where controlling contamination is important.
The new revision has been prepared in collaboration with the World Health Organization and PIC/S, who will have a say in the finalised version.
The European Commission has launched a public consultation on the potential risks of pharmaceuticals on the environment, an important consideration for all of us working within and supplying the industry.
The consultation – which started in November and comes to a close on 21 February – presents 30 possible policy options to achieve a “more environmentally sustainable use of pharmaceuticals” and to minimise the risk that pharma’s environmental footprint will affect fish populations, for example, or human health.
The EC has come up with 10 main action areas around the pharmaceutical product lifecycle that could help, including:
“Pharmaceuticals can enter the environment during their production, use and disposal,” says the EC. “The need for a strategic approach has been prompted by concern about risks to the environment itself, and possibly to human health via the environment.”
It continues: “Any actions to address those risks must also ensure that humans and animals can continue to benefit from the appropriate use of pharmaceuticals and that the competitiveness of EU healthcare systems is maintained.”
This is a consultation with potentially far-reaching implications on how pharmaceuticals are manufactured, used and disposed of, so don’t hesitate to let your thoughts be known at: https://ec.europa.eu/eusurvey/runner/PharmaInEnvConsultation2017
In December, the International Council for Harmonisation (ICH) began a 12-month public consultation on its draft Q12 guideline, which aims to provide a framework for pharmaceutical lifecycle management for manufacturing changes to already approved drugs.
The draft guideline – which is at step2b in the ICH process – “provides … a framework to facilitate the management of post-approval chemistry, manufacturing and controls (CMC) changes in a more predictable and efficient manner across the product lifecycle,” according to the document.
ICH Q12 is intended to complement ICH’s quality guidelines (Q8 to Q11) and according to the organization will enhance the management of post-approval changes, and transparency between industry and regulatory authorities.
The document points put that in certain ICH regions, the current version of the ICH Q12 guideline is “not fully compatible with the established legal framework with regard to the use of explicit Established Conditions ('EC') referred to in Chapter 3 and with the Product Lifecycle Management ('PLCM') referred to in Chapter 5 as outlined in this guideline.”
The EMA said the draft "strives to promote, for regulators (assessors and inspectors), an improved understanding of the applicants’ pharmaceutical quality systems (PQSs) for management of post-approval CMC changes." It is accompanied by three annexes that provide examples of ECs, PLCMs and post-approval CMC changes.
Modified-release formulations of paracetamol are to be suspended from the EU market because the advantages of the products do not outweigh the complications of managing an overdose of the medicine.
The Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) – a regulatory group representing the EU, Iceland, Liechtenstein and Norway – says the suspension is needed since the treatment procedures for immediate-release products are not appropriate for modified-release paracetamol.
The medicines will remain suspended unless the companies that hold the marketing authorisations can provide evidence of appropriate and practical EU-wide measures to help prevent overdose with these products and adequately reduce its risks. Immediate-release paracetamol products, which are not affected by this review, will continue to be available as before.
FDA and MHRA most recent inspection observations
Part of a comprehensive GMP Intelligence program is the monitoring of enforcement actions, including FDA 483s, warning letters, recalls, import alerts, consent decree agreements, and EU reports of GMDP noncompliance. This article presents the most recent GMP inspection data from CDER and MHRA. The CDER data are from inspections conducted in FY2016 and the MHRA data come from inspections conducted in 2015.
Aqueous solubility-enhancing excipient technologies: a review of recent developments
At least some degree of solubility in water is necessary for active ingredients in pharmaceutical products to be effective in vivo. However, as efforts to discover and synthesise new active ingredients are pursued by industrial and academic medicinal chemists, achieving sufficient aqueous solubility can often be a significant limitation to clinical and commercial success…
Medications should be labeled 'gluten free,' says FDA
For people living with celiac disease, everything that goes into the body has to be assessed for gluten. Even tiny amounts (trace amounts) of gluten can cause illness in some people with celiac disease. In order to do that, people need to know what they are putting into their bodies.
APDN teams up with Colorcon for pharma authentication
Applied DNA Sciences has formed an alliance with excipient and coating specialist Colorcon for the commercialization of DNA-based taggants used to authenticate products. The project will combine APDN’s molecular taggant and authentication markers with Colorcon’s portfolio of film coating systems, inks and colour dispersions for use in solid oral dosage forms.
Continuing the trend
Continuous processing is being adopted in pharma and biopharma. Could continuous cell therapies be next?
Here is a round-up of forthcoming events of interest to suppliers and users of excipients. Please let the IPEC Europe Secretariat know if we've missed one.
2018 IPEC Europe Annual Excipients Forum
Bordeaux, France - 1 February 2018
More information here.
11th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology
Granada, Spain - 19-22 March, 2018
More information here.