EU Regulatory Roundup: MHRA temporarily eases GMP rules

| 23 April 2020 | By Nick Paul Taylor 

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) has relaxed its interpretation of good manufacturing practices (GMPs) in light of challenges created by the COVID-19 pandemic.
MHRA’s more flexible approach to GMPs is intended to achieve two goals. Firstly, MHRA hopes to free up quality system capacity to help companies “focus on ensuring continuity of supply using quality risk management principles.” Secondly, the agency intends to “address specific challenges created by international travel restrictions.” Those goals led MHRA to take a new approach to several aspects of GMPs.
Under the relaxed rules, manufacturers can limit retesting to identification “where supplier history, material criticality, and the finished product quality control strategy permits.” Companies that make use of that flexibility will rely on the supplier’s certificate of analysis for other quality attributes.
MHRA is also allowing companies to ship products from manufacturing sites under quarantine while quality control tests and batch certification are ongoing. If a company ships a product under those circumstances, it must establish a system for ensuring it only comes to market once it has been qualified person (QP) certified.
The other flexibilities relate to pharmaceutical quality systems. MHRA is permitting companies to put supplier audits and investigations of “minor” events on hold. Companies that stop investigating minor events should look for trends in the reports and initiate investigations as needed, while those that pause supplier audits should consider doing desk-based assessments and taking a risk-based approach to prioritizing on-site visits once governments lift travel restrictions.
Other quality system flexibilities offered by MHRA include the extension of routine reviews of standard operating procedures, the temporary cessation of internal audits and GMP refresher training and holds on post-inspection commitments related to deficiencies classed as “other.”
Manufacturers should involve the QP in decisions about whether to take advantage of flexibilities offered by MHRA and inform the agency when they do so. If the affected product is sold outside the UK, MHRA expects the manufacturer to inform the relevant competent authorities of the use of the flexibility. MHRA wants manufacturers to pass on objections raised by other competent authorities.
MHRA Guidance
Swissmedic Revises Rules on Authorization of Chemically Synthesized APIs
The Swiss Agency for Therapeutic Products (Swissmedic) has changed the rules on the authorization of chemically synthesized active pharmaceutical ingredients (APIs) in light of the risk of nitrosamine contamination.
Nitrosamines, potentially carcinogenic molecules, have triggered recalls of drugs containing sartans, ranitidine and nizatidine. Regulators do not expect nitrosamines to form during production of most medicines. However, the risk of cross contamination and the accidental introduction of amines and nitrites led regulators to expand their investigations to cover all chemically synthesized APIs.
Swissmedic’s position reflects concerns that nitrosamines could be found in medicines containing any chemically synthesized API. Guided by the concerns, Swissmedic has changed its authorization rules for products that contain chemically synthesized APIs.
Under the new rules, which are now in effect, companies that file for approval of affected products should include an evaluation of the risk of contamination with nitrosamines. If the evaluation finds a risk in a manufacturing step or in the stability behavior, the applicant should assess the risks and benefits and propose a risk minimization strategy and testing plan as part of a more comprehensive assessment of the threat.
The rules also apply to medicinal products that are already notified for new authorization. In that situation, Swissmedic will request missing risk evaluation documents in the list of questions. Failure to provide the documents will prevent authorization.
Swissmedic Notice
Dutch MEB permanently closes portal in response to cybersecurity risk
The Dutch Medicines Evaluation Board (MEB) has permanently closed a portal that it took offline in January in response to a cybersecurity vulnerability. MEB took the action after failing to resolve the problems that led it to temporarily disable the portal.
In January, MEB switched off systems developed by Citrix, a software and networking provider, after discovering that hackers had exploited a vulnerability. MEB brought some systems back online by the end of January, ending a brief window in which employees were “unable to do their work,” but continued to prevent access to the portal.
At the time, MEB said it was keeping the portal offline “because additional research into safety is still ongoing.” This week, the Dutch regulator that “the problems cannot be resolved.”
The permanent closure of the portal has stopped MEB from offering certain services to the industry including overviews of open and recently closed cases, case status updates and information about MEB contacts. In explaining the implications of the closure, MEB directed affected companies to a question and answer document about variations.
MEB Notice
EMA finds risks outweigh benefits of Leo Laboratories’ Picato
The European Medicines Agency (EMA) has found the risks of Leo Laboratories’ Picato, a treatment actinic keratosis, outweigh the benefits. The conclusion follows the assessment of data linking the drug to an increased risk of skin cancer.
Picato came to market in 2012. In 2017, Leo updated the label to reflect the findings of a study that found more patients who took Picato developed benign skin tumours, as compared to those in a control group. Two years later, cases of squamous cell carcinoma led EMA to start a review of the risks and benefits of the treatment.
In January, EMA’s Pharmacovigilance Risk Assessment Committee recommended suspending Picato. The next month, the European Commission withdrew the marketing authorization at the request of Leo.
EMA now has ruled that the risks of Picato outweigh the benefits after analyzing evidence including results from a study that compared the drug to imiquimod, the active ingredient in Aldara and Zyclara. Skin cancers, especially squamous cell carcinoma, were more common in parts of the skin treated with Picato.
That finding, coupled to evidence that Picato’s effectiveness wanes over time, led EMA to conclude the risks outweigh the benefits. Other treatments, such as imiquimod, are available for patients with actinic keratosis.
EMA Notice
France’s ANSM offers support to 3D printers to ease COVID-19 shortages
The French National Agency for Medicines and Health Products Safety (ANSM) has detailed the steps it is taking to support companies that want to 3D-print medical devices for use in the COVID-19 pandemic.
ANSM has developed a temporary framework to support the development, testing and use of new devices made using novel manufacturing processes, such as 3D printing, to ease shortages created by the pandemic. The French regulator wants companies to show the performance and safety of their devices is sufficient to support their use in addressing a particular need created by COVID-19.
After receiving the evidence, ANSM will assess and, potentially, authorize the device for use in the emergency situation. ANSM has committed to providing decisions on devices very quickly.
So far, ANSM has authorized a closed suction system and protective mask under the program. ANSM is continuing to evaluate other 3D printing files to get more emergency COVID-19 devices to market.
ANSM Statement (French)


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