Excipients Insight - October 2018

Editorial

Dear Excipients Insight readers,

Welcome to the latest edition of our newsletter.

As I think of what’s been happening in recent weeks, once more we are in a hurry to consider some draft guidance documents from the China Pharmacopoeia (ChP) Commission on excipients of animal origin and excipient suitability studies. These have been distributed to our IPEC Europe members and relevant committees, and as I’ve mentioned before we greatly appreciate your contributions in very short turnaround times. Increasingly, we present excipient perspectives to stakeholders through the IPEC Federation which accesses all IPEC worldwide to deliver a more global viewpoint. However, while harmonization is a goal, it is important to ensure that any unique regional requirements are considered. So we rely on you to help identify those critical matters for members operating in Europe and whose business interests extend to China. We are working with IPEC China to get better visibility of the ChP workplan to manage our responses better and the process being developed by our QRAC (Quality & regulatory Affairs Committee - see our article here) should facilitate improvements on how we do this. We will feature this new procedure in a future edition.

And so to the meeting the IPEC Federation held with the Pharmacopoeial Harmonisation Group (PDG) hosted by EDQM in Strasbourg on 3 October. Representatives included the European Pharmacopoeia, Japanese Pharmacopoeia and the United States Pharmacopeia. WHO participated as an Observer. Topics discussed included monographs on cellulosics, polyethylene glycol, pregelatinised starch and silicon dioxide. PDG reported on the success of its technical (video) conferences to accelerate their work programme but at this time, attendees at PDG will not be extended to include other world pharmacopoeias. So, IPEC will continue to develop its strategy at the Federation level which will aim to promote harmonisation to those emerging pharmacopoeias, such as China, which are extremely active and important in the global market. Very much "one to watch!"

And finally, I’d like to draw your attention to our next webinar ‘Using Risk Assessment to Define a GMP Strategy for Excipients’ to be held on 8 November. It’s hard to believe nearly two years have passed since our inaugural webinar which focussed on the ’how to’ of formalised risk assessments for the appropriate GMP for excipient. In our latest event, the emphasis will be on using risk assessment to identify GMP hazards offering a means to improve the quality management system within excipient manufacturers. Dr Iain Moore is the speaker, a true expert on this subject and we’ll be piloting some new interactive technology (for us!) to gather attendee inputs during the broadcast and better inform the dialogue. So, please join us!

Until next month, enjoy this edition.

Frithjof Holtz

IPEC Europe chair

APV/IPEC Europe 2018 conference report

The 7th APV/IPEC Europe Excipient Conference 2018 took place last month in Cologne, Germany, providing the usual insights into important areas in the areas of pharmaceutical excipient regulation and technology.

Three parallel workshops started proceedings - covering the use of IPEC guidelines to adopt best practices in Good Manufacturing Practices (GMP), auditing and supplier oversight, and outsourcing of excipient testing to suppliers - and were well attended with a high level of engagement by all involved.

Kicking off the main conference proceedings, Anne Garnier-Poidevin of the European Pharmacopoeia (Ph. Eur.) gave an update on the organization’s modernisation programme. She summarised recently completed revisions – including General Methods on Melting point, IR absorption spectrophotometry, and Loss on drying – as well as ongoing revisions such as Chromatographic separation techniques, Elemental impurities, and UV-VIS spectrophotometry.

She also highlighted some new General Texts working their way through the revision programme , including sections on Evaporative light scattering, Direct amperometric and pulsed electrochemical detection, and Congealing point using rotating thermometer. The revision process is challenging for a number of reasons, including issues with the visibility of the revision process, finding information on new instruments, getting input from method specialists and deciding whether to perform lab testing.

Giving the perspective from the US, John Giannone and Catherine Sheehan of the US Pharmacopeia (USP) informed delegates on USP’s progress in updating excipients standards to help improve quality control testing, which included a focus on General Chapter <1059> Excipient Performance, which provides an overview of the key functional categories of excipients identified in USP-NF along with tests that relate to excipient performance.

Updating <1059> is important because so many new drugs are entering the market using specialised drug delivery systems, which in turn creates a need to control excipient material properties outside the scope of monographs. The revision aims to add missing NF functional categories, identify and develop standardised physical/chemical procedures that measure excipient properties, and identify monographs that may need performance and consistency testing.

Kicking off the session on hot topics in regulatory compliance, Dr Thilo Jahr of Boehringer Ingelheim Pharma GmbH took on the topic of preventing and controlling particulate matter in pharmaceutical starting materials and drug products, with reference to IPEC Federation’s Technically Unavoidable Particluate Profile (TUPP) guide.

Foreign particles can pose a risk to patient safety and trigger market alerts or recalls that can disrupt the supply chain – with potential damage to company reputation and finances – and a control strategy is a necessary component of any quality system even though there is limited regulatory guidance on the issue, he said. The TUPP guide helps differentiate between avoidable and unavoidable particulate matter, and how to evaluate and reduce the risk of contamination.

Dr Dieter Röthlisberger of Lonza Ltd, tackled the regulatory and safety issues for excipients in parenteral formulations, telling attendees that drug product databases and the FDA’s inactive ingredients list can be a good starting point for excipient selection – when combined with assessments of factors such as pH, buffering capacity, titratable acidity and osmolarity, as well as other considerations like injection duration and frequency.

Pharmaceutical assessment must be completed by a safety excipient assessment with the support of preclinical and clinical safety data, he continued. Overall, it is wisest to avoid using any excipient unless there is a compelling reason to do so.

Switching to oral dosage forms, Prof Dr Sandra Klein of the University of Greifswald gave a presentation on the impact of excipients on bioavailabiity, saying that important factors to consider when selecting them include drug dose and potency, therapeutic window, absorption site, and the rate-limiting factor in drug absorption (permeability or solubility). One should also consider whether drug metabolism, efflux, complexation or degradation at absorption sites will have an impact, she said.

A mechanistic understanding of drug-excipient interactions and their impact on drug release and absorption can help in the development of dosage forms that exhibit optimum drug bioavailability, she added. However, “many of the studies screening the impact of excipients on oral drug bioavailability are old…and the clinical relevance of many of the interactions is not clear.” Success depends on clear understanding of the API, excipient, gastrointestinal physiology and the use of relevant in vitro models for formulation screening.

The topic of lipid-based drug delivery systems (LBDDS) is increasingly important as the proportion of new chemical entities (NCEs) that are poorly-soluble in aqueous solutions has been on the increase for years, and now accounts for more than 70% of pipeline drugs. Dr Frank Romanski of BASF SE Pharma Solutions, gave an introduction to lipid-based excipients and drug delivery solutions that can help solve this problem, and explained the criteria that can be applied when choosing excipients for complex, multiphase formulations.

He described LBDDS – and specifically self-emulsifying drug delivery systems (SEDDS) – that are highly dependent on excipients for their functional characteristics, pointing out that the proper balance of surfactants is critical for complex delivery systems.

Dr Thomas Quinten of Janssen Pharmaceutica picked up the baton on the theme of poorly-soluble drugs, but changed course to cover solid dispersion formulations for small molecules, and how excipients can affect their oral bioavailability and long-term stability.

He discussed the role of excipients in solid dispersions, screening techniques for excipient selection, and provided an overview of the common techniques used to manufacture them, including hot-melt extrusion and spray-drying, along with the pros and cons of each approach.

A presentation on the selection of excipients for formulations involving biological drug molecules – based on molecular interactions – was delivered by Dr Christoph Brandenbusch of the Technische Universität Dortmund, who explained that drug such as antibodies present specific formulation challenges such as solubility, stability and viscosity issues.

While there has been a tendency to adopt a ‘trial and error’ approach to these formulations, he described a modelling system based on mechanistic understanding of the molecular interactions between excipients and drug molecules, as well as ways to measure multi-excipient interactions, that can help guide appropriate excipient selection and formulation development.

After a break for lunch, the afternoon session was kicked off by Dr Matthias Knarr of Dow Food & Pharma Solutions, who covered the topic of applied rheological characterisation of cellulose ether and explained that the formation of a gel layer is of key importance for the controlled release performance of matrix tablets. He went on to discuss the use of Methocel cellulose ether excipients in controlled release formulations and new rheological analysis techniques that can be used to predict their performance.

Dr Mirja Palo of Abo Akademi University followed that up with a review of the use of inkjet printing techniques to create ‘personalised’ medicines, and specifically the role that excipients can play in this this emerging area of pharmaceutical production. She explained how excipients can be incorporated in ink formulations – for example as solvents, viscosity modifiers and drug carriers – to create tailored drug delivery devices, but noted that the regulatory requirements are not yet addressed fully and it may be 10 years or more before 2D and 3D printing of medicines is “in widespread use and publicly accepted.”

Finally, to round off the day, Dr Eva Faulhammer of RCPE examined the use of continuous feeding in pharmaceutical production and described the key attributes required for excipients that can be used in continuous manufacturing– one of the biggest growth trends in solid dosage form manufacturing. She examined the key material attributes of excipients used for this purpose, along with suitable process characterisation and modelling approaches, discussed how excipient variability can be handled and provided a case study on the impact of excipient material attributes on continuous feeding.

QRAC covers master files, packaging and more at September meeting

The most recent meeting of IPEC Europe’s Quality & regulatory Affairs Committee (QRAC) core team was a teleconference on 26 September, which involved bringing several initiatives closer to conclusion. These include documents presenting positions on excipient master files, primary packaging materials for excipients and the QRAC process for the review of new or modified regulations. Much effort has been spent lately on new requirements in China and also, the impact of the latest regulations in Vietnam on excipients is under consideration.

Also, the committee agreed to encourage members to complete the survey issued by the USP based on its Stimuli article “Complexity of Setting Compendial Specifications for Excipient Composition and Impurities” which can be accessed via this link: https://uspta.qualtrics.com/jfe/form/SV_estdZM9mb8CVvN3

The next committee meeting will be held in Brussels on 28 November where time will be devoted to getting the collective input of QRAC members on several 2018 initiatives and to intitiate the 2019 work plan.

Register now for the 2019 IPEC Europe Annual Excipients Forum!

Registration for our 2019 Annual Excipients Forum at the Westin Dragonara, St Julian's, Malta, is now open.

Join us in Malta on Thursday 31 January 2019 for a dynamic conference recognised to be one of the key events for pharmaceutical excipients in Europe.

The theme of the 2019 Forum is "excipient Integrity". The programme will cover many ‘hot’ topics including best practices and insights that can help your company adapt to current and future challenges.

The detailed schedule will be released in the coming days on our website www.ipec-europe.org.

Accommodation for the 2019 Annual Excipients Forum will be on site at The Westin Dragonara, enabling all participants to share their views and experiences beyond the Forum sessions with renowned specialists in the field.

We look forward to welcoming you in Malta!

Webinar: Using risk assessment to define a GMP strategy for excipients

On 8 November, IPEC Europe will run the latest in its new webinar series, this time covering the importance of appropriate Good Manufacturing Practices (GMPs) in an excipient manufacturing site – and how risk assessment will allow you to identify the GMPs hazard and improve your quality management system.

The webinar will be led by Dr Iain Moore, Head of Global Quality Assurance at Croda International plc and past president of board at EXCiPACT asbl which runs the GMP and GDP Certification scheme for pharmaceutical excipients.

Learning/Awareness Objectives

After completion of this webinar you should be able to:

Adjust your risk assessment approach
Be aware of the GMPs hazards in your plant
Understand the benefit of EXCiPACT certification
Discuss best practices for evaluating risks

Who should attend

This Webinar is recommended for Quality Assurance manager, Auditors and Regulatory Affairs managers.

IPEC Europe calendar

Group	Q4 2018
IPEC Europe Board	27 November
GDP Committee	29-30 October (Germany)
Pharmacopoeial Review & Harmonisation Committee	TBC
Quality & Regulatory Affairs Committee	28 November (Brussels)

WHO revises Analytical Method Validation guideline

The World Health Organization (WHO) is inviting comments on a draft working document entitled Guidelines on Validation – Appendix 4 – Analytical Method Validation, with a deadline of 15 November.

The IPEC Federation intends to respond to the draft by the deadline and, to help achieve that objective, IPEC Europe has asked members of its Quality and Regulatory Affairs Committee (QRAC) to submit comments to the Secretariat by 30 October so that a unified response can be put together. As a reminder, the Federation is currently going through the process to be formally recognised as a WHO collaboration partner, so it is important to provide feedback in this initiative.

For further information or to submit comments, please contact the Secretariat.

EMA updates on Brexit contingency plans

The European Medicines Agency’s (EMA) Brexit preparedness business continuity plan (BCP) entered into its third phase on 1 October 2018, as announced earlier this year.

The agency says the temporary suspension or reduction of additional activities will allow it to safeguard core activities related to the evaluation and supervision of medicines while preparing for the consequences of the UK's exit from the EU - both in terms of the impact on the agency’s operations, as well as its physical move to Amsterdam. It will also help it cope with anticipated staff losses.

“EMA will now temporarily suspend or scale back additional activities to ensure that resources can be redeployed so that its core activities can continue without interruption and to the same quality,” commented Noël Wathion, EMA’s Deputy Executive Director. “Over the next few months, EMA will continue to carefully monitor staff intentions to relocate and the anticipated impact on its activities whilst planning for the critical time period when the agency will be moving to its new premises in Amsterdam.”

The measures announced on 1 August included, among others, the scaling back of guideline development and revision and the putting on hold of non-product related working parties from 1 November 2018. More information here.

USP seeks input on specifications for excipient composition and impurities

Setting specifications for pharmaceutical excipients is complex due to the vast array of materials that are used in drug product formulation, and is becoming increasingly more complicated with the need to update excipient monographs through the introduction of modern analytical techniques.

To help address the challenge in ongoing revisions, the US Pharmacopeial Convention (USP) has published a stimuli article to discuss the issues with setting specification for excipients – including the lack of clear consensus on how to address excipient composition and impurities – and has launched a survey to collect feedback from stakeholders on how specifications for excipient composition and impurities should be set.

IPEC Europe recommends that its members read the USP stimuli article and, as a follow up, to answer to the survey, which should take around 10 minutes to complete. The results of this survey will help USP better identify and address stakeholder overall needs and challenges regarding USP’s current written standards on impurities in excipients.

Comments on the article are welcome by contacting the author below:

Galina Holloway
Senior Scientific Liaison
US Pharmacopeial Convention
12601 Twinbrook Parkway, Rockville, MD 20852-1790
Phone: +1.301.816.8133
e-mail: gvh@usp.org

France plans to ban TiO2 as food additive by year-end

France has followed through with its plans to introduce a ban on titanium dioxide (E171), ruling that as of 2019, no food product can contain TiO2 in France. TiO2 is also used in pharmaceutical preparations as an excipient.

The Brune Poirson, a junior minister in France’s environmental ministry, said: “We want to suspend the use of this substance as a food additive by the end of the year.” The move is part of a basket of measures agreed by France’s National Assembly towards the end of September that are aimed at improving the quality of processed foods in France, including reducing the number of approved additives from 338 to 48 by 2025.

Some food and confectionary companies have already pledged to phase out the use of TiO2, most recently supermarket chain Casino which said it would remove the ingredient from all of its products by the end of this year. Earlier this year, confectionary manufacturers also pledged to remove TiO2 from all their products by 2021.

The debate about the safety of the ingredient stems from a 2017 French scientific study highlighted the potential carcinogen risks of nanoparticles of Ti02. The European Food Safety Authority (EFSA) stated in 2016 that Ti02 poses no health concerns – a position that it reiterated in July after being requested by the European Commission to look again into the data available on the ingredient.

Portugal joins EU-US MRA for inspections

Portugal has become the 15th EU member state that the US Food and Drug Administration (FDA) recognises as being able to replace its own inspections, reports the European Medicines Agency (EMA).

The decision last month comes after an FDA assessment under the banner of the mutual recognition agreement (MRA) between EU and the US to recognise inspections of manufacturing sites for human medicines conducted in their respective territories.

Plans for the MRA to be operational in all EU member states by 15 July 2019 are “on track”, says the EMA.

Chinese Pharmacopoeia presents new framework for excipients

The Chinese Pharmacopoeia (ChP) gave a comprehensive rundown of its roadmap for ensuring the quality of excipients in China at a workshop hosted by the European Directorate for the Quality of Medicines (EDQM) last month.

The ChP illustrated the application of the new regulatory framework for pharmaceutical excipients. Under the new system, both excipients and pharmaceutical packaging materials play an increasingly prominent role in the manufacture of preparations and finished products. During the welcome speech, Susanne Keitel, Director of the EDQM, reminded how “the quality of medicines depends not only on the API, but also the performance of the excipients” and explained that the initiative was part of “the EDQM’s commitment to facilitate exchanges on regulatory aspects among medicine producers and authorities, a key aspect for ensuring quality of medicines from a global perspective”.

The event was attended by more than 60 participants, while another 181 participants joined the video broadcast of the event from remote in more than 30 different countries. Other covered topics included updates on current priorities of the ChP e.g. chemicals and traditional Chinese Medicines, the participation of China in international initiatives such as ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) and how the ChP is going to implement ICH guidelines in the future, as well as the latest developments in the cooperation between the ChP and the European Pharmacopeia (Ph. Eur.).

The presentations and the broadcast of the event are now available on-line on the EDQM website. More information here.

New USP project tackles impurities in pharma development

USP has launched a new programme to assist manufacturers in their drug development efforts, entitled Impurities for Development (IfD). The aim is to help pharmaceutical manufacturers meet quality standards and regulatory requirements to control impurities that may be harmful to patients’ health.

Characterising and controlling impurities in drugs under development can present significant challenges to manufacturers because they can occur for several reasons: arising naturally within the source materials, being added as part of a product’s synthesis, occurring inadvertently during processing and manufacturing, or forming during the shelf life of the product.

USP says it new IfD program aims to help pharmaceutical manufacturers with custom-designed services to identify, isolate, synthesize and characterize impurities in medicines under development, allowing manufacturers to focus on other development processes. Prior to its launch, the IfD program was piloted for nine months with several companies.

More information here.

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.

CPhI & PMEC India 2018
Mumbai, India – 12-14 December 2018
More information here.

IPEC Europe Annual Excipients Forum
St Julian's, Malta – 31 January 2019
More information here.

Excipient World Conference & Expo
National Harbor, MD, US – 6-8 May 2019
More information here.

DCAT Week ‘19
New York City, US – 18-21 March 2019
More information here.

CPhI Worldwide
Frankfurt, Germany – 5-7 November 2019
More information here.