IPEC e-newsletter - Excipients Insight October 2018 - 31-10-18


Inside this issue


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.




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