Review of Developments in GMP and the Regulation of Medicines January 2020
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INTRODUCTION
During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the Australian, EU and PIC/s regulatory authorities; unusually there is nothing of significance to report from the US FDA.
The topics covered in this edition of the “Update” include:
EMA Management Board: highlights of December 2019 meeting
Updated Q&A on “Information on nitrosamines for marketing authorisation holders”
Availability / shortages of medicines
International collaboration on GMP inspections – manufacturers of sterile medicines.
Post-authorisation procedural advice for users of the centralised procedure
Q&A on comparability considerations for advanced therapy medicinal products (ATMP)
FAQ about parallel distribution
European Paediatric Formulary online
Pharmeuropa 32.1
Reforms to the generic medicine market authorisation process: implementation update
Uniform recall procedure for therapeutic goods (URPTG)
Medicinal cannabis manufacture
Export of therapeutic goods from Australia
PIC/s
Draft PIC/S Recommendation on How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management
PIC/S events in Toyama, Japan, 11-15 November 2019
Estradiol-containing (0.01% w/w) medicinal products for topical use
EMA & TGA update on metformin diabetes medicines
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EMA
EMA Management Board: highlights of December 2019 meeting
Executive Director Guido Rasi stressed the challenges that the Agency now faces in reinitiating its activities following three years of relocation and Brexit and postponed investment into business-critical infrastructure. In the meantime, important new demands have been placed on the Agency that will need to be prioritised, such as the implementation of the new legislation for veterinary medicines and on medical devices.
The Agency now has an available workforce of 775 which is significantly less compared to end 2017 when EMA’s relocation plans took shape.
In defining its work programme for 2020 and beyond, EMA will focus on the core activities identified in the last phase of business continuity as a baseline and will prioritise additional tasks depending on available resources. The Agency will continue to monitor staff levels and review whether additional activities can be relaunched in June 2020.
To help the Agency make best use of available resources and be best prepared for future challenges, EMA is currently conducting an in-depth review of its organisation.
This future-proofing exercise will help EMA to strengthen its ability to perform important new activities together with the European regulatory network and to tackle important challenges ahead such as big data, digitalisation and new scientific methods and technologies.
Highlight topics from the meeting include:-
EMA budget for 2020
The 2020 budget is set at EUR 358 million, a 3.3% increase on 2019.
EU cooperation on medicines’ availability
The Board heard an update on the outcome of the first phase of a pilot on the EU SPOC (single point of contact) network for cooperation on availability of human and veterinary medicines.
A second phase is foreseen for 2020 during which additional responsibilities of the SPOCs will be tested which are expected to improve the handling of shortages. Before moving to the second phase, however, it is important to ensure that necessary resources can continue to be made available by EMA and the national authorities in the Member States.
More information will be published once the second phase of the pilot is completed.
Update on the EU IT systems required by the Clinical Trial Regulation
The Board endorsed the outcome of the ‘audit readiness assessment’ and endorsed the proposal to commence the audit in December 2020.
In the first few months of 2020, product owners will work with EMA and the IT supplier to perform the analysis and design of the items that have been prioritised as still needing to be fixed/developed before the audit can begin. The approach will be carried out in a way that ensures efficient delivery.
Handling new information on nitrosamine presence in medicines
The European medicines regulatory network has agreed to reinforce the use of interim limits for the evaluation of cases where nitrosamines are identified, in line with the report issued by the Agency on the sartan review. Should the interim limits be exceeded this will be handled through the EU network’s existing rapid alert systems. The Board welcomes the cooperation on the issue that is already ongoing at European level and encourages continued discussion with regulators from outside the EU.
Other meeting highlights were:-
Mandatory use of international standard for reporting side effects to improve safety of medicines
HMA-EMA Joint Big Data Taskforce Report
Key principles and roadmap on electronic product information (ePI)
Key principles and roadmap on electronic product information (ePI)
Updated Q&A on “Information on nitrosamines for marketing authorisation holders”
This very important Q&A document was updated on Dec 20 2019.
Q&As subject to update were:-
#1 Are all products to be reviewed?
#6 Are all products to be reviewed?
#11 What limits will apply for nitrosamines detected in any products?
#12 What are the currently identified root causes for presence of nitrosamines?
New Q&As are :-
#13What is the approach for new and ongoing marketing authorisation applications (MAA)?
#14 Are biological products containing excipients potentially at risk of contamination with Nitrosamines in the scope of the review?
#15 What to do if after completing step 1 and /or step 2 new information on new potential root causes is identified?
#16What limits will apply for nitrosamines in medicinal products based on lifetime and less than lifetime use?
Availability / shortages of medicines
Since April 2019, the task force has been running a pilot programme on establishing a single point of contact (SPOC) network to improve information sharing between Member States, EMA and the European Commission on important medicine shortages of human and veterinary medicines and to coordinate actions to help prevent and manage shortages. This includes information sharing on alternative medicines that are available in other Member States.
The first phase of the pilot ran from April to August 2019 to test the functioning and usefulness of the information exchange via the SPOCs. During this phase, 24 Member States used the SPOC system and circulated 52 notifications of shortages.
The task force plans to run a second phase of the pilot in 2020, to test the criteria for identifying cases deserving EU-wide coordinated action and for network alerts of upcoming public communications that could have a high impact on patients.
The task force will publish more information after completion of the second phase of the pilot.
International collaboration on GMP inspections – manufacturers of sterile medicines.
In December 2019, EMA and its European and international partners launched a pilot programme to share information on GMP inspections of manufacturers of sterile medicines located outside the participating countries and to organise joint inspections of manufacturing sites of common interest.
The products in scope include sterile medicines for human use of chemical origin and certain therapeutic biotechnology -derived products, such as monoclonal antibodies and recombinant proteins.
Vaccines, cell and gene therapies and plasma-derived pharmaceuticals are currently out of the scope of this pilot.
For the terms of reference, objectives and full scope, see:
Participating authorities and organisations include:
EU Member States (France and the United Kingdom);
the United States FDA;
the Australian TGA;
Health Canada
the Japanese PMDA;
the World Health Organization (WHO).
The pilot will last for a minimum of two years. After this period, participating authorities will assess the programme and determine the next steps.
This initiative builds on the success and experience with the API inspection programme.
Post-authorisation procedural advice for users of the centralised procedure
Grouping of variations: Q&A – This updated document lists questions that marketing-authorisation holders (MAHs) may have on grouping of variations. It provides an overview of the EMA's position on issues that are typically addressed in discussions or meetings with MAHs in the post authorisation phase. Revised topics are marked 'New' or 'Rev.'.
Q&A on comparability considerations for advanced therapy medicinal products (ATMP)
This document addresses questions on how to demonstrate comparability for gene and cell-based medicinal products following change to the manufacturing process or due to introduction of additional manufacturing sites.
FAQ about parallel distribution
This page lists questions about parallel distribution of human & veterinary medicines. The information is available as Q&As, which the EMA revises as necessary.
EDQM
European Paediatric Formulary online
Launched by the European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH) and the European Pharmacopoeia Commission, the European Paediatric Formulary project is carried out by experts of a dedicated working party. The aim is to bring together, for the first time, formulations of appropriate quality from all around Europe to allow pharmacists and clinicians to prepare paediatric treatments when no licensed alternative is available.
The formulary can be accessed free of charge.
Pharmeuropa 32,1
All new texts and texts that have undergone technical revisions are published in Pharmeuropa for public consultation. The deadline for comments is 31 March 2020.
International
Australia
Reforms to the generic medicine market authorisation process: implementation update
In early 2019, TGA consulted on proposed reforms to the generic medicine market authorisation process. In response to the feedback received, TGA implemented the following changes:
Reduced requirements for use of overseas reference products in bioequivalence studies.
Options to use new internationally aligned templates for summarising bioequivalence or biowaiver study data.
Uniform recall procedure for therapeutic goods (URPTG)
A new version of the Uniform Recall Procedure for Therapeutic Goods (URPTG) (V2.2, December 2019) has been implemented, with effect from 12 December 2019.
This version updates V2.1 to include:
additional clarity on the provision of surgeon contact details for implanted therapeutic goods
amendments related to the online notification of recall and non-recall actions
removal of the placeholder referring to the National Patient Contact Principles for Patients with Implanted Medical Devices subject to Hazard Alerts
a second example template for the sponsor's customer letter.
This version also includes a number of other minor editorial amendments.
Medicinal cannabis manufacture
This guidance is for manufacturers of medicinal cannabis products. It outlines and provides information on:
manufacturing license and certification requirements
differences between Therapeutic Goods Administration (TGA) and Office of Drug Control (ODC) requirements
TGA interpretation and expectations for compliance with specific sections of the current PIC/S Guide to GMP.
Export of therapeutic goods from Australia
The TGA is seeking comments from interested parties on an update to guidance for
Export of medicines from Australia
Export certification for medical devices
Comments were to be submitted by 3 Feb 2020
PIC/S
Draft PIC/S Recommendation on How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management
PIC/S has published on a draft basis a Recommendation on How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management (PI 054-1 (Draft 1)) developed by the PIC/S Expert Circle on Quality Risk Management (QRM).
This draft Recommendation will be applied on a 6-month trial basis by PIC/S Participating Authorities.
The purpose of this draft document is to provide guidance on evaluating and demonstrating the effectiveness of a PQS in relation to risk-based change management. This is in recognition of the fact that the PIC/S GMP Guide requires companies to demonstrate the effectiveness of their PQS and to apply quality risk management (QRM) principles to change control activities. Further information on the background to this Recommendation and the anticipated benefits of this guidance are provided in PIC/S Concept Note (PS/INF 88/2019).
This draft document is not open for comments by industry.
PIC/S events in Toyama, Japan, 11-15 November 2019
PIC/S Committee met on 11-12 November 2019 in Toyama (Japan). The meeting was followed by the PIC/S annual training Seminar on 13-15 November 2019. The topic of the seminar was "Quality Assurance of Sterile Medicinal Products - Annex 1".
The press release regarding these events is available in newsletter format.
Products
Estradiol-containing (0.01% w/w) medicinal products for topical use
EMA’s safety committee (PRAC) has recommended limiting the use of high-strength creams containing 100 micrograms/gram (0.01%) of estradiol to a single treatment period of up to 4 weeks. This measure is intended to minimise the risk of side effects caused by estradiol absorbed into the bloodstream from creams applied inside the vagina to treat symptoms of vaginal atrophy in women who have been through menopause.
Following the PRAC,s recommendation of 3 October 2019, one of the marketing authorisation holders involved with this review has requested a re-examination. Upon receipt of the grounds for the request, the PRAC will start a re-examination, which is expected to conclude at the meeting of 13-16 January 2020.
EMA update on metformin diabetes medicines
Trace amounts of an impurity, N-nitrosodimethylamine (NDMA), have been found in a small number of metformin diabetes medicines outside the EU.
The levels of NDMA in the affected non-EU metformin medicines are very low and appear to be within or even below the range that people can be exposed to from other sources, including certain foods and water.
At this point, there are no data indicating that EU metformin medicines are affected. Authorities in the EU are in the process of working with companies to test EU medicines and will provide further updates as more information becomes available.
A similar position has been taken by the Australian TGA.
And finally…
Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.
We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.