IPEC e-newsletter - Excipients Insight March 2017 - 31-03-17
Spring is upon us and as ever there is a lot of activity on-going, both within IPEC and the excipient world in general. At the beginning of April, the IPEC Europe Board will meet in Brussels and we will make our first review of the objectives which were presented at our recent Annual General Meeting in Monte Carlo. As ever, we have established ambitious targets to help us move towards our 2020 Agenda goals and in the next edition we’ll provide an update on the more significant steps which have been taken, both within IPEC Europe and those which relate to the IPEC Federation. We always like to hear from you our members, and if you think there is something the Board needs to be discussing, please feel free to let us know soonest through our Secretariat.
In the external environment, this month’s edition provides some interesting features on the regulatory world, not least the draft excipient labelling guidelines issued by the European Commission. It is important that IPEC Europe responds to all excipient-related legislation and so we have distributed this across our membership. While we know member companies may submit their comments directly, in IPEC’s own feedback, we like to represent the breadth and diversity of our association so I would urge you to send your comments back to us. It also allows us to emphasise those points which have the greatest impact on our industry as you, the members see it. Likewise, revised EXCiPACT standards used for excipient supplier certification are open for comment, to align them with ISO / ISE where your feedback will be invaluable. We look forward to hearing from you!
We hope you find the articles on Certificates of Analysis and Supplier Qualification of interest, too. It is good to note that we believe the IPEC Guidance on CoAs is aligned with the applicable EU regulatory requirements, another example of the value of IPEC Guides and why it is worth investing in them. The summary on supplier qualification regulations also reminds us that a common understanding across the excipient supply chain can help compliance and to forge good customer relations. And as I’m sure we'll see the themes outlined in the US FDA data integrity inspection deficiencies article echoed many times this year and beyond. This is an area focus for the IPEC Federation as it attempts to provide some context for excipient suppliers, which we will report on in Excipients Insight soon.
Meanwhile, enjoy this issue!
Chair of IPEC Europe
EXCiPACT excipients certification standards revision public consultation opens
The EXCiPACT asbl Board is pleased to announce the draft 2017 revision of the GMP and GDP standards used in their independent, 3rd party international certification scheme for manufacturers, suppliers and distributors of pharmaceutical excipients. The document is now open for comment and EXCiPACT invites interested parties to participate in the public consultation.
In 2016, the EXCiPACT asbl Board commissioned a project team to prepare a draft revision of the
EXCiPACT standards to undertake an alignment to ISO 9001:2015 and ISO/IEC 17021-1:2015 without
change or enhancement of any individual requirements, other than to correct errors in the January 2012 publication.
The draft 2017 Standards Revision document completed by the project team and a mandatory Review Template for the submission of comments are both downloadable from the home page of the EXCiPACT website: www.excipact.org.
The deadline for comment is Friday 5 May 2017. It is important to note that only those comments received by this date on a correctly completed Review Template with proposed alternative wording will be considered. Any other form of comments, or failure to propose alternative wording, or any anonymous comments, will be disregarded.
The target date for publication of the new 2017 EXCiPACT Revised Standards is third quarter 2017.
Save the date: APV/IPEC Europe Conference
Registration has now opened for the APV/IPEC Europe Excipient Conference 2017, which this year will be held in Berlin, Germany, on 19-20 September.
This is the sixth time the conference will run and as in prior years will focus on “hot topics” in the area of excipient regulation and technology. The conference brochure is now available for download, and you can register for the conference here.
In contrast to 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 a 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.
Last but not least, networking and exchange of information is a key feature of the event as well as table-top exhibitions aligned to the conference encouraging communication between suppliers and users.
IPEC Europe calendar
|IPEC Europe Board
||4 April and 27 June
|Pharmacopoeial Review & Harmonisation
Updated excipient labelling guideline out for comment
The European Commission is revising the guidelines for excipients in labelling and package leaflets of medicinal products for human use adopted in 2003, and has produced a new draft that is open for comments until 22 May.
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.
"An amended version of the guideline has been prepared in order to reflect the development since publication of the original version," says the Commission. It includes a list of excipients which should be stated on the label and outlines the information for those which must appear on the package leaflet.
"According to Directive 2001/83/EC all excipients in parenteral, ocular and topical medicinal products must appear on the labelling," says the guideline. "Topical medicinal products can be taken to include those medicinal products applied externally to the skin (including transdermal patches), respiratory products delivered to the lung by inhalation and any medicinal product delivered to the ear-, oro-, nasal-, rectal- or vaginal mucosae, i.e. where the delivery may be local or transdermal."
"For all other medicinal products, only those excipients known to have a recognised action or effect, included in this guideline, should be declared on the labelling (outer package, or, if no outer package, then on the immediate package)."
IPEC Europe has circulated the draft document to the members with the intent of collating feedback for submission back to the EC. More updates will be provided in due course.
European Parliament passes access to medicines resolution
The European Parliament (EP) has the affordability of medicines in its sights and is calling for measures to improve "the traceability of R&D costs, public funding and marketing expenditure."
The prices of new medicines in the EU have risen over the past few decades, to the point of being "unaffordable for many EU citizens and threatening the sustainability of national health care systems," says the EP in a statement.
The new resolution – drafted by MEP Soledad Cabezon Ruiz - was approved by 568 votes to 30, with 52 abstentions on 2 March. Ruiz said that the pharma industry "must be competitive when it comes to producing quality innovation, while at the same time responding to patients' needs with medicines which are safe, effective and accessible."
In particular, the proposals ask for more clarity on R&D costs by medicine developers, and that the "high level of public funds" that go into R&D is taken into account when the pricing of new products is set.
"Public health systems in Europe are a key part of the identity of the EU and something which we value highly. Access to medicines must be guaranteed and in order to achieve that, we need to rebalance the negotiating power of EU member states compared to that of the pharmaceutical industry," continued Ruiz.
The MEPs call on the Council of the EU and the European Commission to strengthen the negotiating capacity of member states in order to ensure affordable access to medicines across the EU, and reduce market fragmentation.
Meanwhile, other measures on the table include a new Transparency Directive to ensure "effective controls and full transparency on the procedures used to determine the prices and the reimbursement of medicinal products", and the development of a "robust" Health Technology Assessment (HTA) system which gives priority to genuine therapeutic advances.
The proposals have been warmly received by the European Public Health Alliance, a patient representative organisation, which said it welcomed calls for proper enforcement of competition rules in the pharmaceutical sector "as drug manufacturers may profit from the absence of the forces of robust competition, leading to higher prices and cutting some patients off from treatment."
EMA publishes implementation strategy for ICH Q3D
The European Medicines Agency (EMA) has published a guidance document to enable the practical implementation of the ICH Q3D Guideline for Elemental Impurities in the EU.
ICH Q3D came into force for new products in June, 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 in December 2017.
The new document is "intended to provide guidance for applicants/MAHs, drug product, drug substance and excipient manufacturers, as well as regulators," says the EMA. It covers the different approaches to risk-management – i.e. focusing on the drug product or the components or a combination of the two at the manufacturer’s discretion – and provides additional information on intentionally-added elements as well as the dossier requirements and assessment strategy.
EU and US will recognize each other's GMP inspections
Earlier this month, the US Food and Drug Administration (FDA) and the European Commission agreed to recognise each other's inspection assessments at pharmaceutical manufacturing facilities.
The Mutual Recognition Agreement – which was signed on 2 March – has been three years in development and amends a prior 1998 agreement on Good Manufacturing Practices (GMP) which was not fully implemented because of legal issues.
The new transatlantic agreement builds on collaborative measures such as the joint audit programme "will help to make better use of inspection capacity and reduce duplication," said the European Medicines Agency (EMA) in a statement.
The EU already has MRAs in place with other countries including Australia, Canada, Japan, Switzerland and New Zealand.
"Each year, national competent authorities from the EU and the US FDA inspect many production sites of medicinal products in the EU, the US and elsewhere in the world, to ensure that these sites operate in compliance with GMP," said the EMA. "In future, the need for an EU authority to inspect a site located in the US, or vice versa, will be limited to exceptional circumstances."
Many provisions of the agreement have already entered into force and others will enter into force on November 1, 2017. By that date, the EU will have completed its assessment of the FDA and the FDA is expected to have completed its assessment of at least eight EU Member States, and will be gradually expanded to all Member States.
The MRA covers both medicinal products and APIs, but excludes human blood, plasma, tissues and organs, as well as veterinary immunologicals.
In a blog post on the MRA published towards the end of last year, the FDA said stressed Brexit will have "no impact on FDA’s relationship with our UK counterparts at this time." Once the UK finalizes its departure from the EU, FDA and the UK will re-examine existing commitments and, if necessary, renegotiate any existing agreements.
Supplier qualification is "more than auditing"
The current EU rules for supplier qualification are "wide-ranging and complex" and more than auditing is required to be confident that suppliers, vendors and contractors are able to supply materials, components and services of consistent quality and in compliance with the regulations.
That's the verdict of a recent ECA article, which lists the relevant EU directives and regulations and describes a process that includes identifying and specifying the regulatory requirements for the material, auditing (if required) to show compliance and – after a contract is signed – periodic evaluations of compliance and monitoring any pertinent changes at the supplier's site.
"Excipient suppliers should be aware of the requirements detailed in this article," according to IPEC Europe senior advisor Adrian Bone. "While of course they are only applicable to pharmaceutical manufacturers, IPEC guidance documents have been developed with due reference to these 'user requirements' to establish common expectations for excipients (as starting materials) facilitating regulatory compliance across the excipient supply chain."
It is also important for excipient manufacturers to be properly aware of the requirements placed upon their users so that they themselves can enter into a good dialogue with their customers, he said. This should help to ensure that relative roles and responsibilities and well understood, to deliver, for example, meaningful quality agreements.
"Attaining this 'level playing' field of understanding also helps customers develop higher quality 'Formalised Risk Assessments of Excipients', a very important new requirement," concluded Bone.
EDQM discloses top 10 CEP deficiencies
The European Directorate for the Quality of Medicines and Healthcare (EDQM) has published a document detailing the most common questions raised after initial evaluations of Certificates of suitability (CEP) for chemical purity.
The document "is intended to help applicants to improve the quality of their CEP dossiers, in order to facilitate and speed up the granting of their CEPs," according to the EDQM.
The top 10 deficiencies are as follows:
- TOP 1 (S.3.2) Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance.
- TOP 2 (S.2.3) Absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance.
- TOP 3 (S.2.2, S.2.4) Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (synthesis, narrative description, flow charts, recovery and reprocessing procedures). Incongruences noted between information given in section S.2.2 and section S.2.4.
- TOP 4 (S.2.3) Non-acceptable starting materials, necessity to redefine them earlier in the process.
- TOP 5 (S.2.3) Non-adequate or poorly justified specifications in place to control the quality of starting materials.
- TOP 6 (S.2.3) Non-adequate or missing specifications (and analytical methods) for reagents and solvents (recovered and recycled included) used to manufacture the substance from the introduction of starting materials.
- TOP 7 (S.3.2) Non-adequate or missing discussion on carryover of reagents and elemental impurities to the final substance.
- TOP 8 (S.2.4) Non-adequate or poorly justified specifications in place to control the quality of isolated intermediate.
- TOP 9 (S.3.2) Absence or insufficient discussion on fate and carryover of impurities from synthetic intermediates (included) to the final substance.
- TOP 10 (S.2.3) Non-adequate or missing information on the synthesis of starting materials and their manufacturers.
The document - which includes together with expectations and recommendations on how to address the specific deficiencies - should be taken into account in combination with the EDQM Guideline 'Content of the Dossier for Chemical Purity and Microbiological Quality (PA/PH/CEP 04 1)', according to the EDQM.
ECA on GMP requirements for Certificates of Analysis
A recent article in ECA's GMP Newsletter reviews the requirements for Certificates of Analysis, the significance of which is growing owing to outsourcing and globalisation.
ECA notes that there are CoAs for excipients, active pharmaceutical ingredients (APIs), packaging materials and finished products, but adds that some regulatory requirements are "often unknown". Requirements can be found in the following sets of rules:
- EU GMP Guide Part I (Chapter 4 and Chapter 6)
- EU GMP Guide Part II - Section 11.4
- EMA Guideline on batch certification (Internationally harmonised Requirements for Batch certification)
- WHO Annex 10 - Model Certificate of Analysis
- USP General Chapter <1080> Bulk Pharmaceutical Excipients - CoA
- IPEC CoA Guide for Pharmaceutical Excipients
Ultimately, the user of such certificates has to rely on their accuracy and completeness, says the ECA. The IPEC Certificates of Analysis guidance is compliant with all of these regulations but please note they were specifically designed for excipients, not other products or materials.
Data integrity citations loom large in FDA warning letters
An analysis of warning letters issued by the US Food and Drug Administration (FDA) for Good Manufacturing Practice (GMP) violations in fiscal 2016 has revealed that 80 per cent cited deficiencies in data integrity.
The analysis by Barbara Unger of Unger Consulting – published by PharmaceuticalOnline.com - notes that the percent of warning letters that cite deficiencies in data integrity for ex-US sites is now reached about the same level as US sites, with the increase in the latter representing a "significant increase" on previous years.
There were 46 warning letters citing data integrity sent in FY2016, with 8 of 11 (73 per cent) issued for US sites and 29 of 35 (81 per cent) for overseas sites. "FDA continues to refine the requirements for data integrity remediation that they include in warning letters with the most egregious deficiencies," writes Unger, pointing to one good example.
"Firms should monitor publicly available health authority enforcement actions and trends as part of a comprehensive GMP intelligence program, because FDA expects firms to monitor these actions and to correct similar deficiencies at their site(s)," she adds.
Data integrity in the context of pharma manufacturing has led to a rising number of regulatory enforcement actions citing failures in the recording and review of manufacturing data, including not only warning letters but also bans on imports from some manufacturing facilities.
A comprehensive body of information on data integrity can be found in a library set up by supply chain security body Rx-360 here.
EMA considers revision of pharmaceutical water quality note of guidance
The European Medicines Agency (EMA) has published a concept paper that addresses the need to update and revise the Note for Guidance on Quality of water for pharmaceutical use, which came into operation in 2002.
There have been ongoing discussions for many years as to whether there is a need to include non-distillation technologies as a method for production of water for injections (WFI), and a revised European Pharmacopoeia (Ph. Eur.) WFI monograph which incorporated this method has been adopted and comes into effect in April, bringing the European requirements into alignment with the US and Japan.
The changes to the monograph (0169) will allow WFI to be produced by techniques other than distillation, including reverse osmosis which is an acceptable methods in the US and Japanese pharmacopeia monographs.
The current guideline needs to be updated to reflect imminent changes in Ph. Eur., says the concept paper. "Consequently, the opportunity will be taken to review current requirements to ensure that they are still appropriate and, if necessary, to amend."
The public consultation period on the document opened on 6 March and will conclude on 6 June.
FDA readies launch of quality metrics
FDA expects to start collecting quality metrics data from biopharmaceutical manufacturers at the beginning of next year to help it assess how well a firm can measure key elements of a quality drug production operation. The agency's current plan is to launch the initiative in January 2018 by opening an electronic portal that will accept metrics data for 2017. FDA staffers will keep the portal open for three months and then will evaluate and compare the data and issue a report later in the year.
Turmeric bioavailability enhancer could be used with APIs, Wacker
Wacker Biosolutions says an excipient shown to increase the bioavailability of a food supplement by a factor of 40 could have implications in the API space.
ExcipientFest Americas showcases pharma and biotech breakthroughs
Pharmaceutical and Biotech sciences are constantly amazing both patients and doctors with drugs and delivery methods that seem to be out of fiction movies. It is hard to believe that innovations like 3D printing of drugs, traceable protein biomaterials, marijuana-based new cures, and sugarless taste masking are real, and all of them will be discussed during ExcipientFest Americas, along with the latest pharmaceutical regulatory updates and sourcing solutions affecting the global marketplace on 25-26 April in Providence, Rhode Island.
Increasing efforts to innovate production techniques fosters growth prospects of global pharmaceutical excipients market
The burgeoning demand for functional excipients, owing to their extensive use in advanced drug delivery, is providing a significant boost to the growth of the global pharmaceutical excipients market. Moreover, several players, with the help of latest technologies, are focusing towards innovating techniques used in the production of excipients. This, in turn, is working in favor of the market. Continuous advancements in nanotechnology and biotechnology are also augmenting the global market.
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.
- 2016 IPEC Europe 'How-To' document on Risk Assessment
- 2014 The IPEC Glossary of Terms
- 2014 The IPEC Significant Change Guide: Third revision
- 2013 The IPEC Certificate of Analysis Guide
- 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
- 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
- 2006 The IPEC GDP Guideline
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.
Providence, Rhode Island, US - 24-27 April, 2017
More information here.
Coventry, UK - 25-26 April, 2017
More information here.
APV Expert Workshop: The Preformulation Tool Box: The Key to Enter Successful Drug Development
Berlin, Germany - 8-9 May. 2017
More information here.
APV Expert Workshop: Manufacturing Classification System (MCS) Expert meeting
Berlin, Germany - 9-10 May, 2017
More information here.
Philadelphia, US – 16-18 May, 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.