Last week’s round-up;
10 -14 August 2020

published 17 Aug 2020

Evaluation of the medicines for rare diseases and children legislation

On 11 August 2020, the EC published an evaluation of the EU orphan and pediatric regulations, adopted in 2000 and 2006, respectively. Following an evaluation comprising several steps, the regulations were analysed according to five criteria: effectiveness, efficiency, relevance, coherence; and EU added value. It was concluded that the regulations met their main objectives of increasing the number of products for patients with rare and paediatric diseases in the EU. Conversely, however, issues were recognised including: · Products may not be equally accessible across the EU or affordable to national health systems; · Circumstances may have changed since the regulations were introduced; · The regulations do not have instruments to counteract observed clustering of products leaving areas of unmet need, or to direct development to areas most relevant to children; · The concept of prevalence as a tool to receive orphan designation and the length of the 10-year market exclusivity period may need to be re-examined. Looking forward, it was noted that some of the issues identified are closely linked to and will be tackled by the Pharmaceutical Strategy for Europe.

EMA addresses risk evaluation, mitigation for nitrosamines

The EMA has updated its Q&A document on nitrosamine impurity testing for marketing authorisation holders. MAHs need to perform a risk evaluation to determine whether chemically synthesized active pharmaceutical ingredients are at risk of containing nitrosamines by 31 March 2021 (extended deadline). This same requirement has now been extended to biologicals, with a deadline of 1 July 2021. Biologicals considered particularly at risk include those containing chemically synthesized fragments, those where nitrosating reagents are added, and those packaged in nitrocellulose blister packs. The document includes further deadlines for confirmatory testing where applicable, as well as related variation submission requirements. It also delineates specific requirements for analytical methods to be used in testing, mitigation measures when nitrosamines are detected, and daily acceptable limits for various nitrosamines.

Tackling serious impurities

Discovery of N-nitrosamines in a variety of medicines over the last two years could have a much wider impact on pharmaceutical manufacturers and regulators than previously expected. The underlying issue in all N-nitrosamine contamination cases was inadequate control of impurities, and so European Union regulators want manufacturers and national regulators to take more effective action in tackling all potentially carcinogenic impurities in APIs and finished products. This decision arises from results published by a ‘lessons learnt’ group within the EU medicines licensing network. The group has proposed a variety of guidance reviews, including those relating to marketing authorization holders, finished product and API manufacturers, active substance master file and CEP holders. Updates to ICH M7 and the EU’s good manufacturing practice guidance have also been proposed.

GMP inspectorate audits, Brexit stockpiling, and MHRA’s Covid-19 divergences

The EMA’s Mutual Recognition partners can now take part in audits of the GMP inspectorates of national authorities. MRA partners could previously participate in audits as observers and, from now on, will also be able to participate as co-auditors if they express an interest in doing so. However, MRA partners still won’t be able to serve as lead auditor, as this role is reserved for European groups. In other regulatory news, the UK government has asked industry to stockpile medicines ahead of the next Brexit deadline at the end of the year. The MHRA has also highlighted nine areas where its COVID-19 flexibilities diverge from EU policies. The list includes MHRA’s positions on qualified person declarations, the 30-day limit for type 1B variation replies, leaflet mock-ups and over-labelling.

Endotoxin levels in investigational cancer treatments

The US FDA has released new draft guidance on setting limits for endotoxins during the clinical trial process for parenteral oncology drugs intended for serious and life-threatening cancers. This new document provides risk-based guidance on endotoxin limits for investigational therapies that are used in early clinical trials in conjunction with other approved treatments or with other investigational medicines. Patients’ possible exposure to endotoxin levels exceeding USP recommendations may be considered an acceptable risk under appropriate circumstances.

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