IPEC e-newsletter - Excipients Insight June 2014 - 30-06-14


IPEC Europe has moved!

IPEC Europe has started a new chapter with the move to a new office - located in the heart of Brussels - that will officially open on July 1.  

The location (Rue du Luxembourg 16 B, 4th Floor B-1000 Brussels) is within the European quarter of Brussels and will be familiar to many of you as the headquarters of the European Association of Chemical Distributors (FECC).

The office will include a meeting room - available without extra cost for IPEC Europe meetings - as well as dedicated offices for the two-person IPEC Europe team.

The secretariat will be headed by Ms Carole Capitaine - who you already know well and will now be working full time for IPEC Europe - with support on a part-time basis from Ms Sarah Anhorn.

Carole has been working for IPEC Europe for more than six years now and has an in-depth knowledge of our association. She also holds a Masters in European Law and has an in-depth knowledge of our association. Sarah has 10 years' experience in administrative management and speaks five languages (French, Portuguese, English, Spanish and Italian).

The general email address of the association remains unchanged: info@ipec-europe.org. The phone number will also change to .+32 2 213 74 40 and is scheduled for activation on 3 July.

Should you have the opportunity to be in Brussels during summer, please feel free to pass by and visit our new office!



Technically-unavoidable particle profile guide on its way

IPEC Americas recently finalised its Technically Unavoidable Particle Profile Guide and has passed it on for review by IPEC Europe and the IPEC Federation.

The Guide - which is scheduled for publication later this year - tackles the tricky subject of visibly different particles (also known as off-colour or 'black specks') in excipients. While these particles have always been present in excipients and in many cases are inherent to the product, recent regulatory actions have made it important to develop guidance.

"A central cause of the increased concern is the issuance of several US FDA Form 483s (adverse findings from an inspectional observation) (483) to pharmaceutical companies by FDA investigators for insufficient or incomplete investigations of unusual, visible particles," according to IPEC Americas.

Previous guidance from IPEC, the US Pharmacopeial Convention (USP) and the Food and Drug Administration (FDA) has not dealt with this issue effectively and as a result, "materials, and in some cases entire excipient lots, are rejected unnecessarily," it goes on.

This has resulted in both excipient users and makers spending time, money and resources investigating particles that are technically unavoidable and do not pose a risk to patient safety.

The guide encourages a risk-based approach for evaluating visible particles in excipients and promotes the sharing of information between excipient manufacturers and users for the purpose of understanding technically unavoidable particles. It also provides an approach for investigation for those rare occurrences when a previously unobserved particle is found by the end user.

It is hoped that the guide will be published during the third quarter of 2014 as an IPEC Federation document.



IPECs provide comments on Chinese Pharmacopeia

IPEC Europe and IPEC Americas have provided feedback to the Chinese Pharmacopeia (ChP) - via IPEC China -  on various elements of the ongoing revision of excipient monographs for the forthcoming 2015 edition.

ChP has said it intends to dramatically increase the number of excipients included in the 2015 revision to more than 380 from just 132 in the 2010 edition. The IPECs are trying to ensure the new version is as harmonised as possible with the pharmacopeias of the US, Europe and Japan, to avoid out-of-specification (OOS) problems for imported excipients.

IPEC Europe's Pharmacopoeial Review and Harmonization (PR&H) Committee and IPEC America's Compendial Review Committee (CRC) have forwarded comments on: Appendix II A - Pharmaceutical Excipients; Appendix XIX R - Pharmaceuticals Excipients Functionality-Related Characteristics (FRCs); and Appendix VI G - Viscosity, as well as the proposed monographs for: Maltodextrin; PEG 300 and PEG 400; Poloxamer 118 for injection; and Polyoxyethylene 35 castor oil for injection.

There were no comments from the IPEC membership on two other monographs among the first batch proposed by ChP, namely Polysorbate 80 for injection and Propylene Glycol for injection.

The 2015 edition of the ChP is scheduled for completion by the end of the year.



PR&H Committee meets in Hanau

Much of the discussion at the recent Pharmacopoeial Review and Harmonization (PR&H) Committee concerned the Chinese Pharmacopeia 2015 edition (see our article here), but the panel also tackled several other topics, including progress with draft monographs for silicon dioxide and copovidone and test methods for aldehydes.

Items added to the agenda for the Committee included the revision to Ph. Eur.'s Substances for pharmaceutical use (Monograph 2034), the India Pharmacopeia's requirements for microbiological test for non-sterile substances, and a USP request to add viscosity a test to differentiate pregelatinized starch and partly pregelatinized starch.

It was also confirmed that a member of the PR&H Committee will represent IPEC Europe at Ph. Eur.'s 50th anniversary event on October 6-8 in a session entitled Experiences with Ph. Eur. Monographs.



EXCiPACT to review ISO 19011 and ISO 17021 annexes

A small sub-committee has been formed to amend the ISO 19011 and ISO 17021 annexes to EXCiPACT to bring them into alignment with the 2011 versions of these standards.

Inconveniently, ISO issued new versions of the 2002 and 2006 editions of ISO 19011and ISO 17021 standards as EXCiPACT was finalising the two annexes and the decision was taken to use the older versions of the ISO standards than further delay the project. The work should be completed this year.



IPEC Europe calendar

Group Q3 2014 Q4 2014
Board  16 Sep - Brussels  13 Nov - Brussels
GDP  16 Sep  
Pharmacopoeial Review & Harmonisation  14 Oct  
Quality/Regulatory Affairs    Oct (TBA)



ANSI-NSF 363 scheduled for release this summer?

Rumours are building that the ANSI-NSF 363 Excipient GMP Standard will be finalised sometime over the summer.

The standard is intended to provide a stand-alone, quality system-based GMP standard that industry and regulatory agencies can use in evaluating, auditing, and certifying excipient manufacturing and quality.

The US standard is derived from the EXCiPACT GMP standard, which in turn was developed from the IPEC/PQG Excipients GMP guide 2006.

While the EXCiPACT standard assumes the supplier already holds certification to ISO 9001, or will be assessed simultaneously, ANSI NSF 363 also includes quality system requirements so would be suitable for suppliers not wishing to hold certification to ISO 9001, as is common in the US.

NSF acquired International Pharmaceutical Excipient Auditing (IPEA) from IPEC Americas in February allowing it to offer third-party auditing and certification.



ISPE starts quality metrics pilot

The International Society for Pharmaceutical Engineering (ISPE) has started a pilot programme on the use of quality metrics, designed to identify and define measures that give an indication of quality in the manufacturing facility.

ISPE is now seeking drug manufacturing companies that are registered with the US Food and Drug Administration (FDA) to take part in the project.

The team at ISPE charged with setting up the programme have tried to come up with metrics that "reflect quality and determining metrics to be applied to sites versus those applied to products," according to the organisation.

ISPE's primary objectives include testing harmonization definitions within the pharma manufacturing industry for both leading and lagging indicators, as well as feasibility data collection across companies.

Participants in the programme will gain valuable knowledge, stemming from blind comparison among technology platform peers, a head start to establish internal metrics procedures, and insights into implications for metric implementation.

A key aim is to establish a confidential database with blinded comparisons of many different types of participating companies that produce a wide range of technologies
"Attention to the ‘right’ metrics can help promote positive behaviours and instil in companies a corporate culture of responsibility for quality," commented Nancy Berg, ISPE’s chief executive.

The pilot "also will explore the opportunities and challenges associated with how metrics are collected and interpreted, as well as consider possible next steps in metrics implementation," she added.

The pilot was announced at the third Annual ISPE-FDA CGMP Conference, held in Baltimore, Maryland in early June.



In brief: FDA adopts ICH document on dose uniformity

The US Food and Drug Administration (FDA) has issued a guidance document that aims to clarify the International Conference on Harmonisation's (ICH) Q4B guideline on the use of pharmacopoeial texts.

The document - entitled Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 6: Uniformity of Dosage Units General Chapter  -  is "intended to avoid redundant testing by industry," according to the agency.

The guidance notes that the official pharmacopoeial texts of the three ICH regions - i.e. Ph. Eur. 2.9.40. Uniformity of Dosage Units; JP 6.02 Uniformity of Dosage Units; and USP General Chapter <905> Uniformity of Dosage Units - can be used as interchangeable in the ICH regions subject to certain conditions.



EU court case clarifies EC powers on GMP deviations

A lawsuit that was heard in the EU Court of Justice in April has clarified the measures that can be taken by the European Commission when critical deviations from Good Manufacturing Practices (GMP) are found during inspections.

The ECJ judgment ruled that the EC can suspend the manufacture for the EU market of medicinal products in question and order the recall of affected batches of product - without having to prove that there is a risk to public health.

Moreover, the judgment establishes that it is the EC, not the European Medicines Agency (EMA), which has to decide the enforcement measures that must be taken in cases of critical GMP deviations based on the opinion of the EMA.

The judgment was delivered in a case involving a German drugmaker whose facility in India - manufacturing antiplatelet drug clopidogrel - failed a GMP inspection carried out by the German regulatory authorities.

Deficiencies included re-writing of manufacturing standards, quality system failures and inadequate hygiene standards.



Excipient profiling could expand biowaiver use

A database of excipient effects on active pharmaceutical ingredients should be drawn up to help encourage and improve the use of the biowaiver system, according to a new study.

Biowaivers for oral dosage forms have been introduced in the US and Europe to provide a regulatory basis for waiving in vivo bioequivalence studies for medicines, predicated on an understanding of the solubility and gastrointestinal permeability of a drug substance.

The biowaiver approach is based on the biopharmaceutics classification system (BCS), which introduced in the mid-1990s, and has been implemented by regulators in the EU, US and other countries around the world. A biowaiver can be granted to drugs in the class I BCS category (high solubility/high permeability) or Class III BCS (high solubility/low permeability).

It can be deployed, for example, when providing proof to regulators that a medicinal product intended for the market is therapeutically equivalent to prototype batches used in trials.

"Regulatory guidelines on biowaivers for immediate release formulations require an in-depth understanding of the biopharmaceutic effects of excipients in order to establish bioequivalence," note the authors of the study, who have developed a 'top-down' approach to model the effect of excipients on APIs in various BCS classes.

Using lactose, they showed that changes in the excipient content had a low chance of 'bioinequivalence' for NCS Class I APIs, a medium chance with Class III and Class II (low solubility/high permeability).

For APIs in Class IV (low solubility/low permeability) the chance of bioinequivalence was high, according to the researchers.

"No longer can excipients be regarded simply as inert or inactive ingredients and a detailed knowledge of these materials is essential for formulators throughout the world," write the authors, from the Medicines Evaluation Board and National Institute for Public Health and the Environment in the Netherlands and Johannes Gutenberg University Mainz in Germany.

"If repeated for other excipients, this retrospective, top-down approach may lead to a new database and more widespread applications of the biowaiver approach," they conclude.

The research is published in the European Journal of Pharmaceutical Sciences.



Recommended reading

Top excipient DMF problem areas for FDA include authorization letters, paper filings and annual reports

FDA wants the excipient industry to better understand the challenges that the agency faces in reviewing drug master files (DMFs) and to improve their filings so that they do not impede the drug application process

ipqpubs.com (registration required)

Confusion Abounds in Elemental Impurities Testing for Pharma, Excipients

As the USP, ICH and US FDA all aim to tackle elemental impurities testing for pharmaceuticals and excipients, questions still remain on whether the manufacturers will be able to comply with the looming requirements.


China's FDA voices interest in developing an excipient DMF system

China is among countries giving consideration to Establishing a drug master file (DMF) system for excipients, as regulators world-wide seek to rationalize and improve their approaches to excipient oversight.

ipqpubs.com (registration required)

Advances in controlled-release drug delivery

Industry experts share their perspectives on key advances in controlled-release drug delivery and future innovations in this arena.




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. 

  • 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

  • 2006 The IPEC-PQG GMP Guideline
    Download PDF

  • 2006 The IPEC GDP Guideline
    Download 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.


Interphex Japan
Tokyo, Japan - 2-4 July
More information here.

In-Pharma Japan
Tokyo, Japan - 2-4 July
More information here.

APV and IPEC Europe Excipient Conference
Düsseldorf, Germany - 23 to 24 September
More information here.

EDQM: 50 years of leadership in the quality of medicines
Strasbourg, France - 6-8 October
More information here.

CPhI Worldwide 2014
Paris Nord Villepinte, France - 7-9 October
More information here.

Excipient GMP Auditing Workshop
Arlington, Virginia, USA - 14 to 16 October
More information here.

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