IPEC e-newsletter - Excipients Insight June/July 2017 - 10-07-17



Dear colleagues,

Welcome to my first editorial since I succeeded as chair of IPEC Europe in this double edition of Excipients Insight as we head in to the summer vacation period.

As always, many things are happening and it was fortunate that the IPEC Europe Board met in Brussels at the end of June as it was a great opportunity for us to take stock of where we are with our objectives and agree plans for the remainder of 2017.

We have achieved some significant goals in the first half of this year, including the official launch of two of our most significant guides (covering excipient GMP and GDP), three new members joined us, we held a webinar on GDP, and we presented and exhibited at two major industry symposia recently in Italy (AFI) and the UK (Making Pharmaceuticals). Of course, the greatest benefit of all of these events is that we are expanding our reach, spreading the word on excipients, their role and why specific guidance is needed, which is nicely aligned with our mission. As you can see from the calendar in this edition, this continues throughout the year. In September we’ll be attending PowTech 2017 on Powder and Bulk solids in Nuremberg and the APV/IPEC Europe Conference in Berlin. And as we have other guidance documents ready for release, such as the new CoProcessed Excipients Guide and the revised Quality Agreements guide, there’ll be a lot more information to share, so don’t hesitate to come and visit us if you’re there.

One recent development on which I’m very pleased to report is that IPEC Europe is now on the European Medicines Agency’s (EMA) list of eligible stakeholders. Again, this will help to establish a platform at the regulatory level in Europe for important excipient issues. We’ll share more details of how this process works as we learn more but, however this transpires, this is a great step forward for IPEC Europe. Equally, our increased engagement with other associations such as APIC and EFCG promotes good debate on thought-provoking issues of common interest and helps focus our agenda. Your ideas are always welcome and, as an example, members have again raised the subject of excipient master files in Europe. As China has now indicated that it agrees with this philosophy, maybe it’s time again to tackle this in IPEC Europe. What do you think? As ever, if you feel there are areas uncovered you like us to address, let us know.

Meanwhile, please enjoy this edition and here’s hoping you all make the most of the summer months ahead!


Frithjof Holtz

Chair of IPEC Europe



IPEC Europe represented at AFI symposium

IPEC Europe attended the annual Associazione Farmaceutici Industria (AFI) symposium in Italy in early June, with vice-chair Frank Milek delivering a presentation to delegates on the topic of "Activities for Excipients GMP Compliance" and IPEC Europe running a stand in the associated exhibition area.

The conference – attended by around 1,200 people who were mainly from Italy-based mid-sized drug product manufacturers – took place from 7 to 9 June in the Rimini congress centre and covered a broad range of topics including pharmaceutical quality, formulation, manufacturing, regulatory affairs, clinical development and supply chain .

Milek's presentation covered the regulatory environment for excipients and explained how IPEC Europe works help industry remain in compliance with those regulations, through the development of guidelines and tools and collaboration with sister IPECs around the world as well as other international trade associations and regulators.

Whilst at the show Milek had a fruitful discussion with the AFI president about the possibility of IPEC Europe running an event in Italy in 2018 – with AFI support – and this will be explored further in the coming months.



Q&RA committee update

The Quality & Regulatory Affairs Committee covered a large amount of ground at its latest meeting on 1 June, including progress with the revision of the IPEC Quality Agreement guide, which is being carried out by IPEC Europe in collaboration with IPEC-Americas. Comments on the draft are currently under review and – after they have been taken into account – the updated version will be sent to all IPEC Federation members for appraisal.

It's worth noting that the current guide – which was published in 2009 - covers the purchase via distributor but does not sufficiently address the relationship between distributor and manufacturer. The new version will cover this scenario with a manufacturer's quality statement.

There was also discussion on the requirements for selecting and qualifying primary packaging materials used for excipients, and a decision taken to draft a position paper on the topic - for review at the next Q&RA committee meeting in September – that will enhance what is covered in the GMP Guide on primary packaging materials.

Other topics on the Q&RA committee radar that were discussed at the meeting included: co-processed excipients;  elemental impurities; the revision of the EXCiPACT standard; drug master files for excipients; atypical actives; quality-by-design and the FDA Critical Path Initiative, specifically its potential as a model for excipient safety evaluations.



EXCiPACT looks back on successful start to 2017

As the first six months of 2017 draws to a close EXCiPACT can look back on a successful half with 14 new certifications completed year to date, bringing the total number issued to date at 55. It is notable that all but one of the suppliers certified in 2013 and early 2014 have been re-certified for another three years.

There has also been development among EXCiPACT's certification partners, with Certiquality Italy joining  AENOR, AJA Europe, Blue inspection body, BV China, DQS, and SGS  and becoming the association's seventh registered certifying body.

Meanwhile, the EXCiPACT Board has updated the 2012 version of its Quality Manual (and by-laws) to reflect changes to the organisation’s governance, structure and business relations, and is in the process of revising the EXCiPACT Standards. A significant number of comments have been received during the public consultation period on the standards revision, and a review meeting is planned to consider those responses. As it stands, the publication of the new standards is still expected well before the year end.

Looking to the latter half of the year, EXCiPACT will run a one-day seminar in Shanghai, China on 14 July featuring speakers from the China Food and Drug Administration (CFDA), excipient suppliers and users, IPEC-China, SGS Asia/Pacific and EXCiPACT vice-president Sarbari Roy.

It is also planning an auditor training course in Milan in September specifically for candidates from two of its certification bodies, and a webinar intended to raise the profile of EXCiPACT in the US is scheduled for October.



Rousselot joins IPEC Europe

IPEC Europe is delighted to welcome Rousselot, a specialist in gelatin and collagen peptides – as the latest new member of the association.

Rousselot's range of products includes gelatin, hydrolyzed gelatin, as well as gelatin solutions facilitating innovation. The company works in partnership with customers all over the world, enabling them to create world class pharmaceutical, food and nutritional products, and is a brand of Darling Ingredients Inc.

"Our membership in IPEC Europe will provide us fast information about upcoming regulations and quality standards for pharmaceutical excipients," said Tanja Vervust, global quality director at Rousselot. "As the global leader of gelatin and collagen peptides for the pharmaceutical, food and nutrition markets, it’s important to adapt our current processes continuously. Also networking and participation in committee work with other excipient producers and experts will be beneficial for us."

Joel D'Silva, Rousselot's director, global regulatory affairs, said: "Compliance and regulatory foresight is important for our operations. Having production and sales worldwide our regulatory team monitors both local and global regulatory environments. Through our membership in IPEC Europe, we see an opportunity to contribute and be kept informed on future regulation as well as increase our collaboration with the pharmaceutical excipient community."



IPEC Europe calendar

Group Q2/Q3 2017
IPEC Europe Board 26 September - Nuremberg
GDP Committee 13 August
Pharmacopoeial Review & Harmonisation TBC
Quality/Regulatory Affairs 28 September - Brussels



Europe delays decision on EMA's new home

The decision on which country will host the European Medicines Agency (EMA) once the UK leaves the EU has been postponed by one month.

A verdict on the new location for the agency when it moves from London will now be made in November, after a meeting of the heads of state or government from the 27 states that will make up the EU after March 29, 2019. The EU's November meeting will also see a decision on the post-Brexit location of the European Banking Authority (EBA), which must also leave London.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has voiced its concern about the delay, whilst acknowledging the complexity of the Brexit negotiations, saying that "medicines constitute a special case in term of securing swift agreement on both sides."

"It is imperative for the safeguarding of public health that we ensure future alignment between the UK and EU regulatory regimes in order to maintain capacity, processes and timeframes for the introduction of new medicines for patients, EFPIA added.

Meanwhile, the Association of the British Pharmaceutical Industry (ABPI) executive director of research, medicine and innovation, Dr Virginia Acha, said: "It will be critical to avoid divergence and duplication of regulatory regimes, so that patient safety is not put at risk."

At least 21 countries are thought to have proposed cities to host the EMA – including Copenhagen, Barcelona, Lisbon and Dublin – and any others that are interested have until July 31 to submit a formal offer.



Regulatory guidance for industry as UK negotiates withdrawal from EU

The European Medicines Agency (EMA) and the European Commission have published guidance to help pharma companies prepare for the UK's withdrawal from the EU.

A new questions-and–answers (Q&A) document concerns information related to the location of establishment of a company in the context of centralised procedures and certain activities, including the location of orphan designation holders, qualified persons for pharmacovigilance (QPPVs) and companies' manufacturing and batch release sites.

EMA said it is also preparing a series of further guidance documents which will be published on its dedicated Brexit webpage in due course.

This Q&A document follows the publication of a Commission/EMA notice to marketing authorisation holders of centrally authorised medicines for human and veterinary use. That notice emphasises – among other things – that EU law requires that marketing authorisation holders are established in the EU (or EEA), and some activities - pharmacovigilance, batch release etc - must be performed in the EU/EEA.



IPECs respond to EC excipient labelling guideline revisions

In May, IPEC Europe and IPEC-Americas submitted comments to the European Commission on its draft revision of the guidelines for excipients in labelling and package leaflets of medicinal products for human use.

Under EU regulations, all excipients must appear on the outer packaging of medicinal products or, where there is no outer packaging, on the immediate packaging if the medicinal product is an injectable or a topical or eye preparation. The package leaflet must also list the qualitative composition of active substances and excipients. The revised version updates the current version of the guideline, which was published in 2003.

"In general, IPEC is supportive of the proposed amendments to the guidelines and welcomes the clarifications offered on excipients labelling requirements of medicinal products for human use," said IPEC Europe and IPEC-Americas in its submission.

Some of the comments received by the IPEC membership during the review period related to the annex of the guideline which at this point remains unchanged, and these were included in the submission for reference.



FDA to meet with industry groups on novel excipients

The FDA's Office of Product Quality (OPQ) – part of the Centre for Drug Evaluation and Research (CDER) has agreed to meet with the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) and IPEC-Americas later this year to discuss the need for novel excipients as a gap in manufacturing innovation.

An update from the American Association of Pharmaceutical Sciences (AAPS) Excipients Focus Group (EFG) notes that after preliminary exchanges with the OPQ, it is clear the agency "supports the concept of novel excipient availability and use independent of specific drug products", and "is interested in discussing this concept further [to examine] how this effort can be advanced."

IQ Consortium's Novel Excipients Working Group defines a novel excipient as "a material or a composition that has not been previously used in an approved drug product in the US… or that has been previously used in an approved drug product" that can be used used to facilitate a new route or administration or elevated dosing, enhance pharmaceutical safety or efficacy or enable the formulation of low-solubility compounds, amongst other applications.

"FDA will work with [the] IQ Consortium and IPEC to coordinate a mutually agreeable date and time to meet with CDER leadership to further discuss possibilities of collaboration," said the EFG.



Less than a year to go before FDA's eDMF rules come in

From May 5, 2018, new drug master files have to be submitted using the current electronic Common Technical Document (eCTD) standard – and all submissions must be filed electronically even if the remainder of the master file is on paper.

In April, the FDA agreed to extend the deadline for eDMFs by 12 months by a year in response to industry comments and an internal review. At the time, it said: "Among other factors, FDA recognizes that there have been challenges with submission of master files in eCTD format, and eCTD uptake data for master files in particular indicated that adhering to the May 5, 2017 date could have led to high rejection rates of master files and thus slower FDA review processes, and, therefore, potential unnecessary delay in the review of some drug applications."

Other documents, such as new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs) were still held to the 2017 deadline.

According to the FDA, implementing electronic DMFs will improve the efficiency of the DMF review process, and will make it easier for the agency to review applications supported by DMFs.

The regulator says the first step to submitting DMFs electronically through FDA Electronic Submissions Gateway (ESG) is to request an ESG test account.



Spore-inspired excipients could improve antibody formulations

Researchers from Cambridge University in the UK and AstraZeneca's Medimmune subsidiary have come up with an ingenious approach to improving the formulation of antibody drugs – the spore-forming behaviour of some bacterial species.

Bacterial spores are rich in a substance called pyridine-2,6-dicarboxylic acid (dipicolinic acid or DPA), in fact it accounts for around 10%-15% of spores by weight, and it seems to be intimately involved in keeping the structures stable while dormant.

"Considerable effort has been made in recent years to identify and develop new excipients that mitigate the physical and chemical instability of biological drugs," write the scientists in the International Journal of Pharmaceutics.

"Given the apparent protective role of DPA in spores, we conjectured whether it would be able to fulfil a similar function as an excipient to pharmaceutical proteins of interest."  At the moment excipients, such as arginine hydrochloride (Arg), are added to biopharmaceutical drugs in order to supress aggregation, minimise phase separation, reduce viscosity and increase shelf life.

The researchers used DPA and a quinolinic acid analogue seemed to be more effective than Arg in stabilising antibodies in liquids, as measured by reductions in the viscosity of formulations and preventing unwanted phase separation - the separation of solutions into dense (protein-rich) and diluted (protein-lean) phases.

"This work introduces a new class of organic acids − inspired by their association with bacterial spores − as novel excipients in the context of protein formulation," they conclude. "While precise mechanisms of action remain to be identified, our preliminary data suggest that these DPA salts are worthy of further investigation as novel ionic excipient for biologics formulation."



Excipients 'have potential as imaging agents'

Excipients are generally considered pharmacologically and toxicologically inactive, which allows them to be used at the levels needed in drug formulations without affecting the active ingredient. However, some have properties that could make them interesting contrast agents for use with medical imaging techniques, for example to image tumours in high detail, according to researchers in Italy.

The team are focusing on magnetic resonance imaging (MRI), which has become a go-to tool for healthcare, and in particular a variant called chemical exchange saturation transfer (CEST) that makes use of contrast agents to enhance the diagnostic power of the technology.

They have investigated the MRI-CEST properties of several excipients - ascorbic acid, sucrose, N-acetyl-d-glucosamine, meglumine and 2-pyrrolidone - and tested them as tumour-detecting agents in two animal models. They found a moderate to marked increase in CEST contrast with all the excipients, with meglumine and ascorbic acid performing the best, and suggest that these are superior to glucose - which has already been investigated for this application - as they reside within tumour cells for longer.

The excipients "show remarkable MRI-CEST properties as demonstrated by the in vivo visualization of tumours in two murine models," conclude the authors. "The extremely good safety profile of the excipients provides support to the view that these molecules may be considered reliable candidates for clinical translation."

The research is published in the International Journal of Pharmaceutics.



Recommended reading

Trends in excipient demand

Pharma manufacturers are seeking out innovative excipients that address bioequivalence development and solubility challenges, while enhancing formulation


Wanted: New excipients to meet the demands of a challenging industry

Current trends in the pharma market, such as the discovery of increasingly lipophilic APIs, macromolecules, and biological actives have created a need for a more in-depth understanding of existing excipients, as well as the creation of new excipients, says Karen A. Coppens, Global Marketing Manager for Dow.


Roquette expands into Brazilian pharma excipient space

Ingredients manufacturer Roquette says it will acquire Blancer’s Brazil-based excipient division, Itacel, to meet market demand.


New antidumping/countervailing duty petitions on citric acid from Belgium, Columbia and Thailand

Archer Daniels Midland Company, Cargill, Incorporated and Tate & Lyle Ingredients America, LLC (“Petitioners”), on June 2, 2017, filed an antidumping duty petition on citric acid and certain citrate salts from Belgium, Colombia and Thailand. In addition, Petitioners filed a countervailing duty petition against Thailand. There are already existing US AD/CVD Orders on these products from the People’s Republic of China.

National Law Review



Download IPEC Europe guides

All of IPEC's guides are available for free download via our website. Follow the links below to make your selection. 

  • 2017 The Joint IPEC-PQG Good Manufacturing Practices Guideline - Updated version
    Download PDF
  • 2017 The IPEC Good Distribution Practices Guideline - Updated version
    Download PDF
  • 2016 IPEC Europe 'How-To' document on Risk Assessment
    Download PDF
  • 2014 The IPEC Glossary of Terms
    Download PDF
  • 2014 The IPEC Significant Change Guide: Third revision
    Download PDF
  • 2013 The IPEC Certificate of Analysis Guide
    Download PDF
  • 2012 IPEC Excipient Information Package (EIP): Template & User guide
    Download Word or PDF
  • 2011 The IPEC Good Distribution Practices Audit Guideline
    Download Word or PDF
  • 2010 The IPEC Excipient Stability Program Guide
    Download PDF
  • 2009 IPEC Quality Agreement Guide & Template
    Download Word or PDF
  • 2008 Qualification of Excipients for Pharmaceutical Use Download (Word) or (PDF)
    Download Word or PDF
  • 2008 The IPEC-PQG GMP Audit Guideline
    Download Word or PDF
  • 2008 The IPEC GDP Audit Guideline
    Download Word or PDF



Events calendar

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.

ExcipientFest Asia
Beijing, China - 19-20 July, 2017
More information here.

APV/IPEC Europe Excipient Conference 2017
- an update on regulatory and application developments

Berlin, Germany - 19-20 September 2017
More information here.

Conference on the place of the Certification Procedure in the global regulatory environment
Prague, Czech Republic - 19-20 September 2017
More information here.

9th Conference of the European Paediatric Formulation Initiative
Warsaw, Poland - 19-21 September
More information here.

PowTech 2017
Nuremberg, Germany - 26-28 September 2017
More information here.

The Bioprocessing Summit - Overcoming formulation challenges for biopharmaceuticals development
Boston, USA - 21-22 August
More information here.

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

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