News

Dear readers,

Already at the end of this year’s second month, we have a packed edition of our newsletter for you which features several reports of our recent events in Bordeaux, France. Hopefully, for those who weren’t able to attend it will provide some great information - and for those who were there perhaps some nice reminders which you can share with colleagues. As the year progresses, we will look more in depth at some of the subjects which were part of the Forum agenda and also review how participants viewed it. We had good attendance from across the range of our membership and the highest number of non-members registered in our history. Hopefully, this is a good validation of the programme, that it is hitting the right spots in terms of current and future challenges.

So far, I think we can judge the event as a great success, not least because of your contributions to make all sessions very interactive which provided valuable insights into the topics under discussion. There is great value in being able to have direct face-to-face discussions and, while we must leverage all modern technologies to communicate with the excipient community, we will always try to hold ‘live’ events like our Forum. I hope you agree and that next year we will see you all again and of course, new delegates, too. Organising these events is very demanding and as always, huge thanks to our Secretariat who I believe work wonders to pull off these events in such a professional manner. Carole, Ilias, and Joanne, thank you very much and of course, this extends to the all of the members of the Event Committee without whom none of this would be possible.

This edition also includes overviews of the activities of several of our committees, setting out their objectives for the coming year to help us move towards our Agenda 2020 vision. These complement the Board’s plans for 2018 which I presented at the AGM and to serve as a reminder of our strategy for this year, will be highlighted in the Excipients Insight to be published in March. Meanwhile, your comments on what we are doing and what you think we should be doing are always welcome at info@ipec-europe.org, as are volunteers to join the various committees and task forces.

Until next time, enjoy reading the articles in this issue.

 

Frithjof Holtz

IPEC Europe chair

IPEC Europe's annual Excipient Forum took place on 1 February in Bordeaux, providing the usual high-quality insights into the commercial, regulatory and scientific issues affecting both suppliers and users of pharmaceutical excipients.

Kicking off proceedings, Dr Susanne Keitel, director of the European Directorate for the Quality of Medicines and Healthcare (EDQM), updated delegates on the draft general monograph on co-processed excipients as well as other European Pharmacopoeia (Ph. Eur.) developments. These included the modernisation programme for general methods in the compendium and the implementation of ICH Q3D on elemental impurities.

Co-processed excipients or CPEs – which have improved functionalities compared to ‘simple’ blends – have been used in marketed products for a number of years but the term has not been clearly defined in the EU. The decision was taken at EDQM to develop a general monograph as CPEs may require different quality controls to excipient mixtures, and a first draft was prepared in 2015 with a second revision published last year. EDQM’s Excipients Working Party will review feedback on the latest draft at a meeting in March, after which it will be either sent to the Ph. Eur. Commission for adoption or put through another round of discussions.

Keitel also reviewed the progress with revisions to the general chapters, texts and monographs which need updating as there are inconsistencies between them in some cases. Also, new technologies and regulatory developments – such as the REACH toxicity legislation – have to be accommodated. So far eleven General Methods have been revised, with more on the way including chromatographic separation techniques (2.2.46), IR absorption spectrophotometry (2.2.24), and absorption spectrophotometry, ultraviolet and visible (2.2.25), amongst others. General texts up for revision include those covering residual solvents (5.4), chemometric methods applied to analytical data (5.21) and chemical imaging (5.24).

Prof Brian Carlin, immediate past chair of IPEC-Americas QbD Committee, picked up the baton on co-processed excipients and discussed how these can be used to overcome the lack of new chemical entity (NCE) excipients being introduced onto the market, with only three novel excipients launched in the last 20 years. CPEs can provide improved functional characteristics and enhanced properties that are simply not achievable through simple blending, but minimise the safety data burden as they are typically composed of substances already evaluated for safety.

From a regulatory perspective, they should be assessed on the CPE as a whole and not as a simple blend, and risk assessment should be scientifically based and evaluated on a case-by-case basis. He told the meeting that IPEC-Americas new Excipient Safety Evaluation Procedure could be used to reduce CPE regulatory uncertainty, while the recently-published IPEC CPE guide provides an invaluable framework for the manufacturers and users of these excipients.

Covering the topic of monographs from a US perspective, Catherine Sheehan of the US Pharmacopeia Convention (USP) noted that excipients are a hot topic at the moment for a number of reasons. These include the emergence of CPEs and dual active/atypical active excipients, and a recognition that there is a lack of new excipients being developed. USP’s excipients Expert Committee is continually working to revise excipient monographs to take into account changes in industry practice. At current estimates, 172 National Formulary (NF) monographs need to be updated because changes need to be made to identification, assay, impurity and specific test sections.

Sheehan also covered CPEs, noting that USP has a guideline in place for introducing these excipients into the NF but is up for revision and is in the fiscal year 2019 work plan, as well as novel excipients. As new excipients are only evaluated as part of the New Drug Application (NDA) procedure there is an immediate disincentive to using them, and USP has agreed with FDA to carry out a quantitative survey to examine how it may be possible to develop ways to encourage their development and use.

Staying on a pharmacopoeial topic, Dr Sabine Kopp – group lead, medicines quality assurance at the World Health Organization (WHO) – updated delegates on the agency’s work in developing a Good Pharmacopoeial Practices guide (GPhP), and discussed the role it can play in encouraging convergence among international compendia and supporting regulatory authorities in overseeing the quality of pharmaceutical ingredients and their finished products.

The main GPhP text on pharmaceutical substances and finished pharmaceutical products was adopted in 2016. Two additional chapters in the GPhP covering compounding and herbal medicines are still subject to a final round of consultation by participating world pharmacopoeias but look like they will be included in the next report.

Tackling the continually evolving regulatory requirements for excipients in China, IPEC China chair Colin Li introduced the changes introduced towards the end of last year (CFDA No. 146) and explained that while the new regulation is a clear improvement over the earlier ‘bundling’ approach to excipients, there are still some important differences with the EU and US regulatory systems.

As of 30 November 2017, China has effectively introduced a drug master file (DMF) system for excipients, including a registration scheme and excipients database. This means that excipient companies can submit dossiers for excipients themselves, although they will be reviewed alongside a drug product application in common with active ingredients and packaging. Excipients used in imported finished drugs are also covered by the new regulation, and a letter of authorization (LOA) between the drug manufacturer and excipient supplier must be included in the application.

There are also revised procedures for change notifications and annual reporting currently out for public comment, and some of the feedback received focuses on a proposed transition period for registration of excipients used in imports and classification of the dossier requirements for different types of excipients. Li said that the introduction of a DMF system is the culmination of eight years of effort by IPEC China and other stakeholders.

With formalised risk-assessment for assessing the appropriate GMP for excipients now an EU requirement, Kate Coleman of consultancy PharmaLex described a new tool the company has developed that can be used to standardise and simplify how an excipient risk assessment is conducted and incorporated into a quality management system.

The Microsoft Excel-based software tool – called RATE – can be used to create a risk profile for an excipient, determine the appropriate GMP that should be applied to its manufacture, determine the approach that will be taken to assess the excipient manufacturers’ compliance with the required GMP as well as the manufacturer’s overall risk profile. RATE is currently being trialled at a facility in Ireland where around 80 excipients are being used in multiple formulations, she said.

Prof Carlin returned to the podium later in the day alongside Dr Yvonne Rosiaux of Gattefosse to tackle the topic of quality by design (QbD), and specifically a case study that reveals the benefits of excipient suppliers and users working together in applying the concept. Suppliers can support QbD projects by generating knowledge for the user on excipient variability, process capabilities such as predicting out-of-specification risk and using case studies to identify potential critical material attributes that could affect the drug product, said Rosiaux.

From the perspective of excipient users, Carlin noted that QbD requires that the impact of excipient variability on finished product quality is understood and controlled, particularly as excipients are not uncommonly the reason for special cause variation (SCV) – new unanticipated emergent behaviours in the manufacturing system. There is no such thing as a non-critical excipient, he remarked, and explained how Kano analyses can be applied to provide a more structured approach to excipient incorporation in formulation design.

Don’t just rely on compliance testing, he advised, adding that keeping communication channels open with suppliers can help remove uncertainty and improve understanding of complexities and criticalities to hopefully avoid SCV.

Rounding off the day’s programme, Elham Blouet, global market manager at Roquette, discussed the excipient attributes required for parenteral preparations, providing a comprehensive rundown of the different types used in injectables and their functional properties.

The attributes of excipients – i.e. their physical or chemical or biological properties – should be evaluated in the context of the specific formulation to determine the critical material attributes (CMAs) and to ensure the critical quality attributes (CQAs) of the final parenteral preparation, she concluded.

Please contact the IPEC Europe Secretariat for any questions related to the IPEC Europe Forum 2018.

The leadership baton at the IPEC Federation formally changed hands at its meeting in January in Bordeaux, with Patricia Rafidison standing down as president after a two-year term, to be replaced by former vice president Priscilla Zawislak, who is currently also chair of IPEC-Americas. The vice chair of IPEC Europe – Frank Milek – has taken over the same role at the Federation.

In her last official role before passing over the chair of the IPEC Federation Patricia Rafidison gave a review of the last year’s activities during the IPEC Europe annual general meeting in Bordeaux on 1 February, and the progress made in the pursuit of its main objectives: managing global regulatory expectations, harmonisation of standards and promoting supply chain security.

Over the course of 2017, the Federation participated in the ICH assembly as an observer (with particular attention given to ICH Q3D on elemental impurities), continued collaboration with the Pharmacopoeial Discussion Group (PDG) on cellulosics, pre-gelatinized starch and silicon dioxide, and engaged with a series of conferences in China to spread the word of harmonization in the evolving regulatory landscape for excipients in that market.

Other highlights included a collaboration with the Parenteral Drug Association that will focus initially on the development of a technical report on risk assessment for excipient GMP, contributing to the revision of the IPEC GMP, GDP and Quality Agreement guides as well as two bilateral guides on risk assessment and co-processed excipients.

Looking to 2018 and beyond, new president Zawislak told the AGM that the priorities include completing no fewer than six Federation position papers on data integrity, atypical actives, co-processed excipients, supply chain security, gluten labelling, excipient stability during transport, continuing the project with PDA and looking into new collaborations in Mexico and Canada.

Along with the continuing role as an ICH observer and monitoring the regulatory environment in China and other countries, the Federation also intends to build on the latest revisions to the GMP and GDP guides with new ‘how to’ documents, as well as contribute to the ongoing work to align the GMP guide with ISO 9001/2015 and revise the Excipient Information Package. To make it a global document. Also in the planning stages is an inaugural global IPEC Federation conference, hopefully to take place in 2019 - watch this space!

The IPEC Federation is an umbrella organization representing regional IPECs from the Europe, the Americas, Japan, China and India.

The Quality & Regulatory Affairs Committee covered a lot of ground in 2017, completing and publishing the new version of the IPEC Quality Agreement guide, forming task forces on continuous verification, China’s bundling process for excipients (now defunct) and newer regulatory developments, and requirements for primary packaging materials. It also contributed to the revisions of the IPEC-Americas phase 1 risk assessment guide as well as its work on the FDA’s Critical Path Initiative.

Speaking at the IPEC Europe annual general meeting in Bordeaux, Committee chair Johanna Eisele (pictured) also highlighted the work done in preparing and submitting comments to the European Pharmacopoeia (Ph. Eur.) on the draft monograph on co-processed excipients, working with IPEC-Americas in a coalition on atypical actives and monitoring the new requirements for elemental impurity testing.

2018 is also shaping up to be a busy year as the work on primary packaging materials and the continuous verification guide continues along with new projects – including revisiting the objective of an excipient master file (EMF) in Europe, the revision of the Excipient Information Package guide, a project with IPEC-Americas to develop a ‘how to’ document to accompany the revised IPEC PQG GMP guide. The Committee also intends to keep a close eye on regulatory developments including the new EFSA draft guidance on risk assessment on nanoparticles in food (see our article here).

2017 was a big year for the GDP Committee, with a key achievement the publication of the revised IPEC GDP Guide as an IPEC Federation document that is aligned with the World Health Organization’s Good Trade and Distribution Practices (GTDP) document.

Presenting on behalf of the Committee at IPEC Europe’s Annual General Meeting (AGM) in Bordeaux earlier this month, current chair Frank Milek (pictured) highlighted other initiatives in the year, including the presentation of a webinar to introduce the guide run by Committee member Allan Whiston, the drafting of a position paper on supply chain security, and the revision of the GDP audit guide to align with the 2017 GDP Guide and the EXCiPACT standards.

Another emerging project focused on the impact of transport conditions on excipient quality, and a decision on the future direction of that initiative will be taken in due course.

Looking ahead to 2018, the revision of the GDP audit guide will continue in collaboration with IPEC-Americas with the aim of developing a single Federation document. At the same time, work will start on the development of a ‘how to’ document to provide practical examples in adhering to the GDP guide, and the supply chain security position paper will be finalised. The Committee will of course also continue its efforts to represent IPEC Europe on supply chain topics and evaluate new developments that affect the distribution of excipients.

2017 proved to be a transitional year for the Pharmacopoeial Review & Harmonisation Committee, following the departure of the chair and vice-chair in 2016. While some activities took place – including a face-to-face Committee meeting and representation at meetings with the Chinese Pharmacopeia and IPEC Federation/Pharmacopoeial Discussion Group (PDG) – the primary task is now to re-design and revitalise the group.

Committee member Tim McArragher said the immediate goal is for the IPEC Europe secretariat to conduct a survey of members to try to understand their needs with regards to harmonization and pharmacopoeial review, and to develop objectives that are aligned with the requirements of members and the European Pharmacopoeia (Ph. Eur.).

The survey will be sent out shortly by the IPEC Europe Secretariat. Please let us know your thoughts when received – and be sure to forward it to other representatives in your company if appropriate – so we can ensure the new Committee gets off to a flying start! And of course don’t hesitate to put yourself forward if you would like to claim a position on the Committee in 2018.

IPEC Europe’s taskforce on primary packaging materials (PPMs), which was set up last June, is now well advanced in the process of preparing a position paper on the topic which is scheduled for publication in the coming months.

The task force was set because excipient suppliers are increasingly being asked by customers whether PPMs for excipients meet pharma and other industry requirements in the context of the potential composition and migration of substances from contact packaging.

Task force leader Armand Janssen told attendees at the IPEC Europe annual general meeting in Bordeaux earlier this month that the aim is to develop a document that highlights the issues for consideration by excipient users. A knowledge-gathering exercise has been carried out – looking at food contact packaging legislation in Europe and making comparisons between food and pharma approaches – to provide backdrop for the development of the position paper.

EXCiPACT saw a significant growth in new certifications last year, rising 56% from 43 in 2016 to 67, including 10 re-certifications, according the organization’s president Kevin McGlue.

“Many more certifications are known to be in the pipeline in Europe, China, India and North America, says McGlue, who notes that 2017 also saw the registration of a seventh certifying body – Italy’s Certiquality – and the approval of three new auditors in Japan (SGS), Switzerland (SGS) and Spain (AENOR). One of the most important achievements in the year was the launch of the revised EXCiPACT standard in November.

A number of new projects will come to fruition in 2018, including a new auditor training course that is being developed by Alain Becart, EXCiPACT’s recently appointed quality manager, and a general awareness course aimed at people who want to learn about the EXCiPACT standard, such as companies just starting out on the certification journey.

New IPEC Federation president Priscilla Zawislak has been interviewed for a feature article in Pharmaceutical Technology magazine - entitled Managing Risk in a Complex Excipient Supply Chain - which focuses on ensuring excipient safety by specifying risk assessments and shared responsibility.

In the piece – which looks at regulations and industry guidelines – Zawislak and others highlight the need for open communication channels between pharma manufacturers and excipient suppliers, and the benefit of using the IPEC Quality Agreement Guide published last year as well as the IPEC GMP and GDP guides.

“Patient safety is the ultimate goal and often requires development of regulations and standards to achieve that goal in an ever-changing world,” says Zawislak in the article.

The fast-growing Making Pharma conference will make its first appearance outside the UK next month, opening its doors in Brussels on 13-14 March, and IPEC Europe will be prominent at the event.

We will have a stand (Number 118) on the exhibition floor and will be represented by IPEC Europe board member Liz Meehan, senior advisor Adrian Bone, executive manager Carole Capitaine, and communication assistant Ilias Grampas. Furthermore, on the second day of the conference IPEC Europe will host three presentations on: new IPEC Guidelines (Astrid Stockrahm-Uhling); excipient functionality related characteristics (Liz Meehan), and novel excipients (Christian Becker). More information on the event can be found here.

Group	Q1/2 2019
IPEC Europe Board	16 March
Good Distribution Practices Committee	31 January, Bordeaux, France
Pharmacopoeial Review & Harmonisation Committee	NA
Quality & Regulatory Affairs Committee	31 January, Bordeaux, France

The European Food Safety Agency (EFSA) has published draft guidance on nanotechnology which will have a significant impact on the types of evaluations that have to be carried out on food and colour additives with nanoparticles present and could potentially also affect pharmaceutical excipients.

The extensive and wide-ranging guidance runs to around 100 pages and provides an overview on information requirements and how to perform risk assessment of nanomaterials in food and feed. It is notable that the scope of the guidance covers extends to substances not engineered as nanomaterial but which contain a fraction of nanoparticles, less than 50% in the number-size distribution, with one or more external dimensions in the size range of 1-100nm.

It is possible that the premises laid out in this document may have an impact on discussions around nanotechnology as it relates to excipients, so we would encourage IPEC Federation members to take a look at the document and if appropriate comment during the consultation period, which comes to an end on 4 March. The guidance may have an impact on the studies that are currently going on within various consortia on Titanium Dioxide (E171) and Iron Oxide (E172).

The US FDA recently published a guidance on nanotech which IPEC-Americas is just starting to review, and there may be advantages to combining efforts at the Federation level so that the US and EU guidance can be considered in tandem.

The European Medicines Agency has published a draft guideline on quality aspects included in the product information for vaccines and is asking for comments before 31 July.

The aim of the document is to “provide applicants and regulators with harmonised guidance on the quality aspects to be considered in the Summary of Product Characteristics (SmPC), Package Leaflet (PL) and labelling for vaccines for human use.”

The guidance covers the qualitative and quantitative composition of vaccines and includes a section (6.1) on the listing requirements for excipients, including excipients with known effect, as well as information on outer packaging labelling.

Towards the end of 2017, Argentina’s health authority ANMAT has published a new document – Good Manufacturing Practices of Pharmacopeial Products – which included sections on quality systems, good quality control practices, self-inspection and auditing and raw materials, amongst others.

An English translation is available – you can contact the IPEC Europe Secretariat for a copy – and we encourage IPEC Federation members, EXCiPACT and other interested parties to take a look and examine whether the guidance is in line with IPEC, EXCiPACT and ANSI 363 excipient GMP guidelines. IPEC has also reached out to Argentinian trade association SAFYBI for feedback on the new document.

Eye on Excipients: Effect of HPC molecular weight on granules and tablets prepared by two wet granulation methods

The authors studied six different grades of HPC to determine how they performed in high-shear and fluid-bed granulation.

Tablets & Capsules (Free registration required)

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EC publishes new safety features Q&A document

The European Commission has published the latest iteration of its questions & answers document on safety features for medicines.

SecuringIndustry.com

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US FDA’s co-crystal final guidance to reduce cGMP burden

In response to stakeholder feedback, the US FDA has issued a final guidance detailing changes to the regulatory classification of co-crystals, from intermediate to API.

in-PharmaTechnologist.com

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EU penalties for falsified medicines 'varied'

26 EU member states have introduced changes to their legislation in relation to penalties for the falsification of medicines, active substances and excipients.

SecuringIndustry.com

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Formulation and functional considerations for delivering biologics in prefilled syringes

Prefilled syringes represent a win–win scenario for both end-users and manufacturers. This drug-delivery system is widely used across a range of therapeutic areas because of its broad acceptance among healthcare workers, patients, and caregivers. As a result, there is a lot interest in the development of biologic drug products in prefilled syringes within the bio/pharmaceutical industry. Graham Reynolds, vice-president and general manager, Global Biologics at West Pharmaceutical Services, Inc., shares with Pharmaceutical Technology the various aspects that have to be taken into account when developing a biologic drug product in a prefilled syringe.

PharmTech.com

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.

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Making Pharmaceuticals Europe
Brussels, Belgium - 13-14 March, 2018
More information here.

11th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology
Granada, Spain - 19-22 March, 2018
More information here.

Making Pharmaceuticals
Coventry, UK - 24-25 April, 2018
More information here.

ExcipientFest Americas
San Juan, Puerto Rico - 1-2 May, 2018
More information here.

ExcipientFest Asia
Beijing, China - 19-20 July, 2018
More information here.

CPhI Worldwide
Madrid, Spain - 9-11 October, 2018
More information here.