IPEC e-newsletter - Excipients Insight August 2017 - 11-08-17



Dear colleagues,

Here’s our mid-summer offering of Excipients Insight - and here's hoping it manages to reach you, as no doubt many will be away from your offices enjoying a well-deserved break on sun-kissed beaches! Nevertheless, in our world of excipients, there are still matters of interest to share with you so please enjoy this month’s contributions.

For August, we have two features of note from IPEC Europe ‘champions’, Kate Denton and Andy Teasdale. Both are extremely active in important areas for us and the articles included here provide informative updates on excipients and ‘high-tech’ biological products and a subject which likely needs no introduction, ICH Q3D requirements for elemental impurities in excipients. We think this is a good way to keep you aware of developments, where you hear directly from experts in these fields on the current state-of-play on key subjects. If you feel there are other topics which would benefit from this approach or you, yourself feel you’d like to be involved in an article, please don’t hesitate to get in touch with us.

The pieces themselves contain some thought-provoking issues. For example, the highly proprietary and innovate nature of novel excipients require not only systems to protect confidential data but also to promote their use to support therapeutic advances. It begs the question though, when would be the right time to discuss these matters to help deliver greater benefit to patients? As currently, these processes are not part of the EU regulatory framework, is a DMF system necessary? Do we need an independent review process to encourage the use of novel excipients without fear of regulatory barriers? Let us know what you think!

And while it’s great to hear that the ICH Q3D requirements are not revealing many significant issues thus far, national and regional pharmacopoeias seem to be adopting divergent approaches in managing the removal of residual heavy metals test from individual excipient monographs. IPEC Europe has expressed its support of the approach adopted by EDQM, to remove specific elemental impurities tests for monographs with the understanding that there is no evidence of patient safety risk by doing so. Once again though, this serves to remind us that harmonisation as one of the original pretexts for the creation of IPEC, is still relevant and there is still a need to have it on our agenda. The IPEC Federation will have its annual meeting with the Pharmacopoeial Discussion Group at the USP headquarters in Rockville, on 13 September where IPEC Europe representatives will attend and harmonisation matters will be discussed.

And finally, it gives me great pleasure to welcome Ilias Grampas, to the IPEC Europe Secretariat team. As part of an internship programme, Ilias will be with us for six month and while September’s edition will include a full profile of his role, I wanted to introduce you to him now as he came on board on the end of July. I am sure you will join me in wishing him a full and rewarding assignment with IPEC Europe.

Happy holiday reading!


Frithjof Holtz

Chair of IPEC Europe



No 'smoking gun' with elemental impurities for excipients

Efforts by a pharma consortium and Lhasa Limited to develop a database of elemental impurities for excipients in response to the ICH Q3D Guideline are now "getting close to critical mass," according to Andy Teasdale of AstraZeneca (pictured), who chairs the company's impurities advisory group and the IPEC Europe Q3D taskforce.

There are around 2,000 data points in the repository, spanning a host of key excipients and multiple suppliers, he told Excipients Insight, while noting that there is still work to be done to identify and fill certain gaps in the database.

"What this resource is showing is that there is really no smoking gun in this area," said Teasdale. "We have not encountered any examples of excipients with high levels of elemental impurities, even among some of the mined excipients like titanium dioxide which at the outset were considered likely to have not only high but also variable levels of metals."

The levels of metals are in fact remarkably consistent – even for mined materials such as iron oxides which are used as colorants for tablet coatings for example – and not high enough to be significant.

"We're not seeing the huge variability that many people feared," said Teasdale. Preparations are underway to publish a peer-review paper on the database and the consortium's findings later this year.

There is also a hope that the resource may be of use in tackling issues raised by the removal of the outdated heavy metals limit test from individual pharmacopoeial monographs in the ICH Q3D guideline, but the retention in many monographs of element-specific tests that are of questionable value.

ICH Q3D was finalised at the end of 2014 and came into force for new products in June 2016, introducing a risk-based approach to the control of elemental impurities in the finished dosage form, taking into account potential sources such as the active pharma ingredient (API), excipients, manufacturing equipment, processing aids such as catalysts or water and container closure systems.

It will be extended to include established products from 31 December 2017 – just a few months away. While it is likely that larger pharma companies will have carried out the large volume of work needed to prepare risk assessments that might be requested by regulatory inspectors, there is speculation that smaller manufacturers and companies in emerging economies may not be ready in time.



Biologic drugs pose excipient challenges - and opportunities

There has been a massive increase in the proportion of large-molecule biologic drugs coming though pharmaceutical pipelines – providing big benefits for patients but also challenges for formulation scientists.

The higher level of structural complexity makes them some of the most challenging molecules to formulate, thanks to physical factors such as higher viscosity as well as other factors such as a shift towards less frequent dosing and longer storage times and the move towards combining drugs and medical devices.

The formulation and handling of biologic drugs pose unique challenges that are generally not experienced with small molecules. For instance, they are generally more susceptible to physical and chemical degradation that can have a dramatic impact on their safety and efficacy.

"Pharmaceuticals continue to evolve from traditional proteins and peptides to more complex molecules such as antibody drug conjugates and cell-based therapies," according to Kate Denton of Albumedix Limited, who serves on the IPEC Europe Quality & Regulatory Affairs Committee.

"This causes many challenges for formulation of these newer more complex drugs, in the context of both stabilisation and bioavailability," she told Excipients Insight. In fact, it has become apparent that standard formulation technologies are often no longer adequate and more advanced formulation strategies are required for this new generation of therapies.

It is estimated that somewhere between 5% and 15% of all drugs require advanced formulation agents that are not typically provided by the standard 'toolkit' of excipients used for formulation development, namely sugars, amino acids, detergents and surfactants. Now, added to these well-established excipients is an increasing range of more advanced formulants such as cyclodextrins, polymers and complex polysaccharides. Although many of these agents are effective stabilisers, their use requires careful consideration in terms of local toxicity and potential immunogenicity. However, human albumin demonstrates a number of benefits as an effective stabiliser with a low toxicity and immunogenicity profile. Biotechnologically-derived novel excipients, such as the recombinant form of human albumin, are valuable additions to the advanced excipients portfolio.

"Novel excipients generated by biotechnology such as recombinant human albumin can help address some of these challenges as they can be tailored more towards drug manufacturers' needs," says Denton. But they can be tough to bring to market, due to the lack of an independent regulatory review procedure or formal mechanism for demonstrating their acceptability. Therefore, pharma manufacturers are sometimes reluctant to use them and add an additional 'unknown' element to their drug development projects.

However, the regulatory environment for excipients is improving with the implementation of internationally-recognised schemes such as EXCiPACT, increased GMP guidance and global efforts for harmonised standards in recent years. Together with an efficient master file system which in many regions allows a novel excipient manufacturer to provide extensive product details while protecting their confidential manufacturing information, the perceived regulatory hurdle for use of novel excipients is decreasing.



IPEC Europe webinar is GDP masterclass

In June IPEC Europe held a webinar intended to provide educational materials on topics that impact excipient supply into and out of Europe.

The programme on Good Distribution Practices for Excipient Supply Chain was presented by Allan Whiston, a 40-year veteran of the pharma industry and former IPEC Europe GDP Committee chair who runs a consultancy that supports both suppliers and users of pharma starting materials.

Whiston explained the importance of GDP in an increasingly globalised and complex market for starting materials, highlighting some of the risks and pitfalls – including examples of patient harm and deaths – that can occur if pharma manufacturers and their supplier partners don't share responsibility for the integrity of the entire supply chain.

He ran through the regulations, standards and guidelines applicable to excipient GDP – including the EU Falsified Medicines Directive, the US Food and Drug Administration Safety and Innovation Act (FDASIA) and the new World Health Organization Good Trade and Distribution Practices Guide, as well as industry standards such as EXCiPACT and ANSI/IPEC/NSF 363.

The most frequently observed problems with supply chains were also highlighted in the webinar, along with recommended measures to minimise them, including the use of the WHO GTDP guide and IPEC Europe's just-updated GDP Guide.



Last call for exhibitors and sponsors - APV/IPEC Europe conference

Aside from a fantastic way to keep abreast of key developments in the areas of excipient regulation and technology, the 6th Annual APV/IPEC Europe conference is a great opportunity to present your company, products and services to a truly focused target market.

As an exhibitor you will be invited to attend the conference sessions and to network at the social programme in the evening at the APV/IPEC Europe Excipient Conference 2017, which will take place in Berlin on 19-20 September. The catering station will be integrated in the exhibition, ensuring that participants are around the table top stands as much as possible, and there are also attractive sponsoring packages to choose from. For more details, contact Antonia Herbert (ah@apv-mainz.de).

As a reminder, the conference will focus on 'hot topics' in the area of excipient regulation and technology. In contrast to the market for finished drugs and active pharmaceutical ingredients the market for excipients is extremely difficult to quantify. For the first time one lecture of the conference will provide an overview of the global excipients market with the focus on oral solid dosage forms.

As part of the programme, three parallel workshops will be offered to provide practical, hands-on insights and discussion on pressing regulatory topics, with a view to developing joint solutions. These workshops will focus on data integrity in excipient manufacture and supply chain, quality agreements and stability testing of excipients.

Beyond that the regulatory session will highlight the multifaceted challenges to ensure excipient compliance such as multi-compendial compliance of excipients, excipient packaging systems and excipient supply chains. How to verify that excipient suppliers work in compliance with the regulations and the transport of excipients will be reviewed as well.

The technical and scientific part of the conference will deal with important excipient functionalities such as diluents for direct compression, the role of excipients in inhalation drugs and transdermal drug delivery. Further topics include the requirements of excipients for continuous manufacturing processes and the impact that excipient grades have on the bioequivalence of generic drugs.



IPEC Europe Annual Excipient Forum heads to Bordeaux

IPEC Europe has selected a fresh venue for the 2018 Excipients Forum, and is delighted to announce that this will be held in Le Grand Hotel de Bordeaux in the heart of the famed Gironde wine-growing region in southwestern France.

Acclaimed for its wine and vineyards, Bordeaux boasts beautiful classical and contemporary architecture, superb cuisine, and an increasingly lively artistic and cultural scene, earning it the title of Best City of 2017 from Lonely Planet. Set in an 18th-century building with a neoclassical-inspired façade, the hotel can be found right in the centre of the city, a stone's throw from the Grand Théâtre and 11th century Cathédrale Saint André de Bordeaux.

Registration for the annual event - which along with the usual regulatory and scientific programme will this year will delve into the future of the EU regulatory environment in the post-Brexit - will open on 11 September. Keep an eye out for the programme and registration details, which will appear on the IPEC Europe website and in a later edition of this newsletter.



See you at Powtech 2017!

IPEC Europe will welcome PowTech visitors at stand 3A-531 next to the stand APV Forum Pharmaceutical Manufacturing Excellence (3A-S50).

Two representatives of the Board will present on Wednesday 27 September from 10:00 to 11:00 on Risk Assessment for Excipients GMP and on Co-Processed Excipients. The IPEC Europe Board will hold its third face-to-face meeting of 2017 the day before the conference on 26 September.

PowTech 2017, being held in Nuremberg from 26 to 28 September and will give experts and users from all over the world the opportunity to talk about innovations in the process industries.

"About 900 exhibitors will display their latest developments for mechanical processes and accompanying technologies such as measurement, analysis, control and automation [while] manufacturers and plant operators in the chemical industry will discover specific technical solutions for the burning questions affecting the industry," say the organisers.



Symrise joins IPEC Europe

IPEC Europe is delighted to welcome Symrise AG, a global supplier of fragrances, flavourings, cosmetic active ingredients and raw materials, as well as functional ingredients, to its membership.

With sales of €2.9bn in the 2016 fiscal year and a market share of 11 per cent, Symrise is one of the leading global suppliers in the flavours and fragrances market. The Holzminden, Germany-headquartered group is represented with locations in over 40 countries in Europe, Africa, the Middle East, Asia, the US and Latin America.

Symrise said it decided to join IPEC Europe to "actively participate in committees for quality standards and regulation, network in a community of experts, access to globally accepted industry guidance documents and to receive current information about upcoming regulation and quality standards and learn about the impact on our processes."

The new addition brings IPEC Europe's membership to 71 suppliers, distributors and users of pharmaceutical excipients.



IPEC Europe calendar

Group Q2/Q3 2017
IPEC Europe Board 26 September - Nuremberg / 28 November - Brussels
GDP Committee 13 August
Pharmacopoeial Review & Harmonisation TBC
Quality/Regulatory Affairs 28 September - Brussels / 16 November - Darmstadt



CPhI adds Excellence in Pharma: Excipients category to 2017 awards

For the first time, this year's CPhI Worldwide Pharma Awards will include a dedicated category for excipients, according to the conference and exhibition's organizer UBM.

The category will concentrate on innovations in inactive pharmaceutical ingredients "to improve the manufacturing process or the formulation, including, but not limited to stability, solubility, taste masking, controlled release, or other factors," according to the organization.

In previous years, the relevant CPhI award covered both formulation and excipients, but the two categories have now been separated out.

The winners of the CPhI awards will be announced during the CPhI Worldwide exhibition due to take place in Frankfurt, Germany, in October. More information is available here.



Gender affects excipient functionality - in rats

Researchers in the UK have demonstrated that the excipient-mediated bioavailability of a drug product can be altered by the gender of the recipient.

The team from University College London (UCL) School of Pharmacy made the observation in a study that compared various drugs formulated with polyethylene glycol 400 (PEG 400) in male and female rats. PEG 400 is widely-used to increase the solubility and bioavailability of active pharmaceutical ingredients (APIs).

They found that PEG 400 significantly increased the bioavailability in male rats compared to females for some drugs, but not others, and set out to test the hypothesis that the difference depended on interactions between the excipient and P-glycoprotein (P-gp), a molecule involved in the transport of some drugs across cell membranes.

They compared ampicillin, a drug known to be bind to P-gp and transported out of cells, to metformin, which does not interact with P-gp. PEG 400 significantly increased the bioavailability of ampicillin in male but not female rats, something that has also been seen with ranitidine, another P-gp substrate.

In contrast, there was no difference between male and female rats in the bioavailability of PEG 400-formulated metformin.  As a further test, they pre-treated the animals with a P-gp inhibitor - cyclosporin A - and found that this eliminated the differences between the genders for ampicillin and ranitidine, and had no effect on metformin bioavailability.

"The work reported in this paper further enhances our understanding of the influence of the supposedly inactive excipient PEG 400 on drug bioavailability," write the authors in the European Journal of Pharmaceutical Sciences

"Given that many compounds are P-gp substrates and/or modulate P-gp activity, increasing attention to this topic is needed for an optimal usage of excipients."



Recommended reading

How to identify and manage ‘problem’ excipients in medicines for children

Children may be exposed to potentially harmful excipients, essential components of drug formulations, through unlicensed and off-label use of adult medicines. Excipient exposure should be minimised, although a medicine containing a problem excipient may be indicated, but only after a careful risk–benefit assessment.

The Pharmaceutical Journal

How to recycle lightly used drugs

Scientists develop a green process to recover valuable pharmaceuticals during drug development so they don't go to waste.

Chemical & Engineering News

Perspective: Focus on Excipients

Excipients play a key role in the development in emerging dosage forms but attention to quality is crucial, says IPEC-Americas chair Priscilla Zawislak.


FDA takes aim at opioid epidemic

German drugmaker Grünenthal's Intac technology, which uses a high-molecular-weight polyethylene oxide and proprietary excipients can be used to make it difficult to break pills into fine particles and to make them gel when dissolved.

Chemical & Engineering News

Overcoming excipient challenges in spray-dried dispersions

The choice of excipients for spray-dried formulations has a direct impact on the stability and efficacy of these amorphous solid dispersions (ASDs).


Coatings sweeten pharma tablet production

Materials and equipment innovations have advanced tablet coating from sugar to copolymers and simplified pharma production.




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.

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

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

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