Regulatory Focus™ > News Articles > European Regulatory Roundup: EMA Offers Draft Proposal on Dissolution of Generics (19 May 2016)

European Regulatory Roundup: EMA Offers Draft Proposal on Dissolution of Generics (19 May 2016)

Posted 19 May 2016 | By Nick Paul Taylor 

European Regulatory Roundup: EMA Offers Draft Proposal on Dissolution of Generics (19 May 2016)

Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.

EMA Posts Draft Reflection Paper on Dissolution of Generic Oral Drugs

The European Medicines Agency (EMA) has released a draft reflection paper about the dissolution specification of generic oral immediate release drugs. EMA has used the paper to propose a decision tree designed to counter doubts about the suitability of dissolution specifications and increase the transparency of the process.

Officials at the regulator have fielded questions about the suitability of dissolution specifications for several years. Discussions of the topic have come up in marketing authorization procedures, as well as in referrals raised at the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh). This has led EMA to address the topic through a draft reflection paper, in which it proposes the use of a decision tree to help drug developers set the specifications based on results generated in the dissolution of a batch of bioequivalent product, dubbed the biobatch. 

When developing oral immediate release generics — defined as dosage forms that dissolve 75% of the active ingredient within 45 minutes — EMA is proposing to derive the specification from quality characteristics of the biobatch. This process starts with the development of a dissolution method that is robust enough to detect batch-to-batch variation in product quality attributes. In general, EMA thinks drug developers should use an aqueous medium, avoid surfactants and limit the starting stirring speed of paddle apparatus to 50 revolutions per minute.

Once a drug developer has a dissolution method, it is positioned to set a dissolution specification, which is defined by a mean value at a predefined point of time. This allows the developer to assess whether a batch is acceptable or not. To guide this process, EMA has created a decision tree that walks the reader through various options. For example, if the dissolution of the batch hits 95% in 15 minutes, the specification should be set at 85% in 15 minutes. The same equation of the dissolution percentage after 15 minutes minus 10 percentage points applies throughout the decision tree.

“This reflection paper should facilitate congruent decisions on setting specifications for in vitro dissolution of generic drug products with immediate release characteristics,” EMA wrote. “The principle is to derive the specification of the drug product on the basis of the quality characteristics of the biobatch.” EMA is accepting comments on the draft until 13 August.   

Reflection Paper

Lack of Response Prompts Roche to Reissue Warning About Insulin Pumps

The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) has issued a second alert about Roche’s Accu-Chek Insight insulin pump system. Officials are concerned that too few people have responded to the initial notice about the risk of hypoglycaemic events faced by users of the device.

Roche first contacted healthcare professionals, caregivers and patients about the issue in March. At that time, the Swiss pharmaceutical company was concerned that a maintenance message could cause confusion. The message reads: “M-83 pump not able to complete task.” The message refers to the breakdown of communication between the pump and handset, but this is not explained in the user manual. As such, some users were unsure whether the incomplete task referred to by the device was the delivery of insulin.

The implications of such uncertainty could be severe. “The task could be initiated a second time erroneously by the user. In case of a remote insulin bolus delivery, this could result in a double bolus dose with the potential risk of a subsequent hypoglycemic event,” Roche wrote in its March letter. Roche is currently working to revise the user manual but, in the meantime, it is advising healthcare professionals to forward the field safety notice to their patients to cut the risk of anyone mistakenly administering two doses of insulin.

Neither MHRA nor Roche are sure if this message has reached patients, though. As is typical with field safety notices, the March alert from Roche asked recipients to send back a form to acknowledge that the message had reached them. However, as it stands, Roche is yet to receive enough of the acknowledgement forms to have confidence that the information has been received by those who need to act on it. This has been a recurring problem for MHRA and the medical device companies it regulates.

MHRA sought to address the issue in a 60-page guidance document for healthcare and social service organizations that it issued in April 2015. The document advocates the establishment of mechanisms to distribute field safety notices and other MHRA alerts to the relevant people within an organization. 

MHRA Alert

PRAC Review Clears Bayer Hemophilia A Products of Antibody Risk

The Pharmacovigilance Risk Assessment Committee (PRAC) has failed to find a link between a pair of Bayer hemophilia A drugs and the risk of factor VIII inhibitors. PRAC, which previously reviewed the safety of the products in 2013, reached the conclusion after performing a meta-analysis on the raw data from three studies.

One of the studies, details of which were published in the New England Journal of Medicine, prompted PRAC’s first review of the safety of the products, Kogenate Bayer and Helixate NexGen. That review, which also pulled in data from European Hemophilia Safety and Surveillance System, failed to find enough evidence to conclude that the Bayer products increase the risk of developing factor VIII antibodies beyond levels experienced by patients taking rival drugs. However, two studies published in the journal Blood in 2014 raised doubts about the validity of this conclusion.

PRAC responded by conducting a meta-analysis of raw data from the NEJM and Blood studies. That review is now complete and, like before, PRAC has cleared the Bayer products of the safety concerns. The meta-analysis looked at outcomes in patients who took the Bayer products alongside data from people who received rival products, namely Baxalta’s Advate and Pfizer’s Refacto. “The currently available evidence does not confirm that Kogenate Bayer/Helixate NexGen is associated with an increased risk of factor VIII inhibitors,” PRAC concluded.

Having reached this conclusion, PRAC has recommended that all marketing authorization holders of recombinant coagulation factor VIII products should monitor the literature for reports linking their drugs to increased risk of developing the inhibitors. The inhibitors, which the meta-analysis suggests develop in a substantial minority of previously untreated patients who take the class of products, can reduce the ability of factor VIII products to control severe bleeds. 

PRAC Statement, Medscape

Other News:

MHRA has begun an investigation into a digital calculator used by some doctors to evaluate the risk of heart disease. The product, TPP’s QRISK2 Calculator in SystmOne, has reportedly delivered incorrect results for some patients. MHRA is asking doctors to stop using the predictive algorithm while it and TPP investigate the matter. Some patients will need to be reassessed. MHRA Letter



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