IPEC e-newsletter - Excipients Insight December 2017 - 18-12-17


Inside this issue


Conference report: WHO meeting on pharma preparations

Adrian Boneby Adrian Bone - Senior Advisor to IPEC Europe

IPEC was privileged to receive invitation as an observer to this important meeting which ran from 16-20 October at the WHO’s Geneva Headquarters. As well as global WHO representatives and advisers, international organisations, non-state actors (which includes IPEC) and pharmacopoeias were in attendance. While there were not many issues on the agenda directly related to excipients, this is a great opportunity for IPEC to raise the subject of excipients appropriately to ensure their unique challenges are not overlooked in the supply of medicines.

The opening session focussed on general policy issues such as those which cut across other WHO groups active on biological standardization, traditional and complimentary medicines, essential medicines, substandard and falsified medical products and antimicrobial resistance. Updates from international collaboration agencies, the Global Fund, UNDP and UNICEF all mentioned that a common difficultly they encounter as part of their procurement of medicines is the lack of harmonisation between analytical methods in use and their pharmacopoeial counterparts. An update on the recent PDG meeting from Dr Kevin Moore (USP) in September in Rockville, USA some weeks ago restated those key points presented in the October edition of Excipients Insight. A recent survey conducted on the use of international non-proprietary names (INNs) indicated that they are not well understood, and this has led to a series of educational initiatives.

Compendial matters

The audience was informed of the launch of the 7th edition of the International Pharmacopoeia (Ph. Int.) where major changes relate to new and revised monographs for drug substances and finished products, but not excipients. This review did result in many monograph deletions and prioritisation for future action. The Committee considered multiple monograph creations / revisions by therapeutic categories which did highlight that there is currently no Ph. Int. strategy for heavy metals / elemental impurities in line with ICHQ3D requirements. Meanwhile, current expectations apply. It was noted later that monographs (and the associated international reference standard) are only deleted after consultation and confirming that those impacted are not included in Essential Drugs / Expression of Interest listings. In the course of reviewing the (many) new/revised API and drug product monographs, an expedited process was put in place and request was made that this is subsequently formalised by the Secretariat. Essentially, for well-established monographs, even though the document had been through expert review but not public consultation, comments could be incorporated and proceed to publication rather than bringing the final version back to the next Expert Committee meeting in the following year. Also, it was restated that where specification limits are broadened to align with other compendia, this is sufficient rationale as the Ph. Int. does not want to be more stringent that other pharmacopoeias. It was generally agreed that describing deleted monographs / reference standards as ‘omitted’ should be replaced by ‘retired’ or other suitable wording. Retaining reference standards for one year after ‘omission’ was accepted with due recognition that after this period neither monographs or standards are maintained. The International Reference Standards workplan for 2017/2018 was approved but the lack of RS availability for new but already available monographs was recognised. This is largely due to difficulties in obtaining materials from manufacturers. The Custodian Centre for Ph. Int. reference standards is EDQM, which provided an update on recent activities.

Following a major project in cooperation with the International Atomic Energy Agency (IAEA), all monographs for radiopharmaceuticals have been revised, for which the final technical decisions were made by IAEA, in view of their expertise in this field.

Some time was devoted to discussion on world pharmacopeia activities. WHO jointly hosted a meeting in Brazil in July 2017 where agenda items included Good Pharmacopoeial Practices (GPhP) chapters on compounding and herbal medicines (which were extracted from the main GPhP text). An outcome on herbals after discussion with the WHO Traditional and Complimentary medicines team was the development of Good Herbal Processing Practices. A statement on Antibiotic resistance was agreed and posted on the ANVISA web site. The 2018 forum will be in Vietnam. The Expert Committee approved both chapters subject to the British Pharmacopoeia (BP) making edits based on the latest comments received.

The high-level outcomes of the WHO survey on GPhP were presented which was completed by a broad range of stakeholders. In general, feedback indicated that of the 134 respondents, 68% were aware of WHO GPhP but in terms of implementation, only parts had been adopted. It was interesting to note that of the comments made, a theme was that this document would not be so useful until all pharmacopoeias embraced the need for harmonisation.

Quality & GMP

The WHO External Quality Assurance Assessment Scheme continues which assesses the proficiency of WHO accredited laboratories. In the latest phase which focuses on dissolution testing, there were eleven participants. WHO supports any failing laboratories with advice on improvements but errors can be basic. This is now a fee-paying scheme which has reduced participants (mostly from well developed countries as fees are higher) but the incentive to get involved is that is forms part of WHO accreditation.

The WHO Guidance on Testing of ‘Suspect’ substandard / falsified medicines has been renamed Guidance on Testing of ‘Suspect’ Falsified Medicines. Reference to substandard products was removed so as not to confuse with authentic products (which could be substandard, too). The redraft presented, is also intended to provide guidance to testing laboratories so details of other processes such as chain of custody, will be delivered through training rather than in this document. Wording suggesting that samples could always be frozen to protect their integrity was removed.   

WHO is still engaged in a quality monitoring process of its pre-qualified quality control labs to test products on its EML.  Five more labs have been certified in 2016 and 47 are in process. A variety of deficiencies were found for which WHO may provide technical assistance through training or peer audits. Auditors have been provided training by WHO. The results of a study with anti-retrovirals (ARVs) identified that the majority of Patient Information Leaflets (PILs) provided with product did not comply with WHO information. It has not been clarified if discrepancies were related to changes requested by National Regulatory Authorities (NRAs) (as EML products must also receive local regulatory approval). However, all QC tests were compliant. A pilot study for anti-malarials showed that NIR technology was useful but not Raman spectroscopy to assist in their rapid identification.

A session on GMP guidelines informed that a sterile products GMP Guide is under development as a collaboration between WHO, EMA and PIC/S. The document is currently under review within the European Commission and it is expected to be issued for comment before the end of 2017. Appendices (systems/utilities/equipment; analytical methods; computerised systems) to the WHO Validation document are being revised to include comments following consultation but due to resource issues within the Secretariat and Working Groups, delays for the next round of consultation are not known. The main issues with the revised guide on GMP for HVAC of non-sterile facilities related to risk management and a requirement to perform recovery rates of the air system. Despite challenges that this is not a requirement in other GMPs, it was retained but qualified with ‘as required’. The document was approved as Part I. Part II, providing explanatory notes and interpretation will follow at a later date.

Revisions to the QAS/16.694 Stability Testing of API and Finished Product were agreed subject to some amendments and clarifications. Most discussion centred on the permissible window and storage conditions of time point samples awaiting testing. Work continues to establish a process and pilot for solubility profiles of essential drugs which will allow biowavers for drugs on the EML. Brazil and China offered the services of laboratories to pilot the proposed procedure.   

Regulatory processes

Much effort is being dedicated to establishing guidance for key regulatory processes, one of which is to expedite access to medicines (Procedure in assessment of accelerated national registration of pharmaceutical products and vaccines approved by Stringent Regulatory Authorities). This is complemented by guidance where NRAs wish to determine when a desk review may be substituted for a GxP on-site inspection and Good Regulatory Practices. Discussions were extensive but ultimately it was agreed that all would continue through the development process with implementation beginning in 2018. The GRP will be supported by training tools and establishing centres of excellence to support other NRAs. A concept paper was also adopted whereby guidance helping NRAs to implement the various procedures planned. An accelerated process already exists for Pre-qualified products (Collaborative Regulatory Procedure, CRP) but now there will be provision for non-prequalified products. Despite its scope being limited to small molecules and generics for now, it is believed this expedited procedure may help liberate capacity within NRAs.

To support the strengthening of NRA’s in terms of efficiency and effectiveness, the Expert Committee approved a proposal to develop guidelines to implement Quality Management Systems at NRAs. These will be based on IS09001:2015 with the emphasis being on implementation rather than achieving certification. Following a survey and gap analyses by WHO, strong support will be needed from to achieve this goal in LMICs (Lower/Middle Income Countries).

Sessions on pre-qualification of priority essential medicines and APIs and nomenclature, terminology and databases were not attended.

Considering IPECs participation at this meeting, the items of most relevance to IPEC were those relating to pharmacoeial activities. However, in future, it is good if IPEC representative(s) can attend the whole meeting but have the breadth of knowledge to contribute to other topics beyond compendial matters. Of course, there may be items directly applicable to excipients! As the meeting dates are reliably predictable, the attendee(s) should be identified as early as possible to allow adequate time for proper review of the documentation and consultation within IPEC, if appropriate. 





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