Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
EMA Overhauls Manufacturing Cross-Contamination Q&A After Industry Savages Draft
The European Medicines Agency (EMA) has overhauled a regulatory question and answer document about preventing cross-contamination at multi-product manufacturing facilities after a draft version was strongly criticized by leading drugmakers and trade groups.
EMA created the Q&A after receiving feedback about its 2015 cross-contamination guideline from regulators and industry. The feedback questioned the need to apply the guideline to all products, leading EMA to discuss different approaches to highly hazardous substances and lower-risk materials in its Q&A. This proved to be a contentious decision among manufacturers, including Gilead Sciences and the trade groups that represent them.
“The introduction of the ‘highly hazardous’ classification, which in our view is not scientifically sound, is highly problematic. EFPIA considers this is a major issue and proposes to delete the classification as such and adjust any other Q&As relating to this,” the trade group EFPIA wrote in feedback to EMA.
Manufacturers and trade groups shared similar views at a workshop held by EMA in the months after the public consultation. As well as questioning the scientific rigor of the categorization, companies told EMA they had already begun assessing all products against the original guideline. The Q&A’s differentiation between highly hazardous substances and other materials would limit the value of some investments made to comply with the guideline.
EMA accepted the call to drop the highly hazardous term and associated approach from the Q&A. The term is absent from the final version — which applies to all products — but the concept of assessing hazard risk by looking at levels of permitted daily exposure (PDE) has survived the rewrite.
Other parts of the Q&A underwent similar significant changes after EMA heard the views of industry. EMA removed a question about the use of occupational exposure limits (OEL) or occupational exposure bands (OEB) to approximate PDE. That action reflected concerns that the Q&A validated a simplified view of health-based exposure limits (HBELs) that fails to account for differences in the target population.
“Many believe that one can simply take an OEL or OEB from a safety data sheet, multiply it by 10 and is done with the establishment of a HBEL. These people will feel that their view has been confirmed,” Roche wrote in its feedback to EMA.
EMA made multiple other changes to the final Q&A in response to industry feedback, but it opted against making all of the requested revisions. EFPIA, for example, took EMA to task for not talking to industry about the questions covered in the Q&A prior to publication. That resulted in the draft lacking discussions of some topics of interest to the industry. EFPIA proposed five extra questions for EMA to address, but the agency has not dealt with all these points in the final Q&A.
Having received written feedback and discussed the Q&A at the workshop, EMA felt it had a clear understanding of the perceived shortcomings of the draft. As such, EMA has finalized the Q&A without putting the revised version out for comment.
, Revised Q&A
, Industry Feedback
EMA GMP Inspections of Chinese Plants and Noncompliance Rate Fall Again
EMA conducted 29% fewer good manufacturing practice (GMP) inspections of Chinese plants last year than in 2016. The dip continues the downward trend seen in recent years.
In 2015, the first year EMA shared a geographic breakdown of its GMP inspections, the regulator assessed 72 facilities in China. The figure fell to 55 in 2016 and dropped to 39 last year. That means the number of Chinese manufacturing facilities inspected by EMA has fallen by almost 50% since 2015.
The downward trend has coincided with a reduction in the rate of GMP non-compliance. Of the 72 plants inspected by EMA in 2015, six failed to meet GMPs, resulting in a non-compliance rate of 8%. The figure dipped slightly in 2016 before dropping sharply last year, when one of the 39 inspections led to a GMP non-compliance statement. That amounts to a non-compliance rate of less than 3%.
EMA’s retreat from China covers a period in which its overall GMP inspection activity and interest in other countries has fluctuated. The overall number of EMA GMP inspections of plants based in third countries increased last year, moving the figure back up toward the high hit in 2015. The number of inspections of plants in India and the United States followed the same pattern, dipping in 2016 before rising back toward their former levels last year.
The Good Manufacturing and Distribution Practice Inspectors Working Group published the data in its 2017 annual report this week. Unlike many recent reports from EMA units, the document makes no mention of the current or forecast impact of Brexit on its operations.
EMA Seeks Feedback on Plan to Cut Need for in-Vivo Bioequivalence Studies
EMA is seeking feedback on a plan to reduce the need for in-vivo
bioequivalence studies. The draft International Conference on Harmonisation (ICH) guideline would allow the use of Biopharmaceutics Classification System (BCS)-based biowaivers as surrogates for in-vivo
Typically, drug products containing the same active substance are considered to be bioequivalent if in-vivo
studies show their rates and extents of drug absorption fall within a certain range. However, a desire to avoid unnecessary in-vivo
tests has led regulators to assess whether bioequivalence can be demonstrated using in-vitro
The BCS-based biowaiver is the result of these assessments. The approach is applicable to drugs that fall in BCS Class I and Class III — meaning they have high or low permeability, respectively — that are formulated into immediate release solid oral dosage forms or suspensions.
If a drug meets these criteria, EMA and ICH are proposing to allow companies to use biowaivers to show bioequivalence. This would entail submitting data on the solubility and permeability of a drug. The ICH guideline released for consultation by EMA details the assessments companies can perform to generate this data. The guideline also discusses what companies must do to show how differences in the excipients used are likely to affect in-vivo
ICH and EMA expect companies to run in-vitro
tests comparing the developmental and reference products, too. Other requirements include the submission of information on the critical quality attributes of both products.
EMA is accepting feedback on the draft until 6 February.
’s Veterinary Dictionary for Drug Regulatory Activities
(VeDDRA) subgroup will not revise its lists of clinical terms next year because of the move to Amsterdam and Brexit
-related cutbacks. The subgroup typically discusses the lists at its annual meeting. However, VeDDRA will not hold an annual meeting next year. VeDDRA will next revise its lists in 2020. EMA Update
has issued a notice about a shortage of Shire
. The C1 inhibitor could temporarily be in short supply in 11 European countries. Shire attributed the shortage of the hereditary angioedema drug to an increase in demand that exceeds its current production capacity. Work to increase output is underway, but in the meantime EMA wants prescribers to consider alternatives. EMA Notice
has published the annual report about its interactions with industry stakeholders. Annual Report