The comment follows the publication of a report calling for dissolution testing to be added to the British Pharmacopoeia monograph for levothyroxine after patients and physicians raised concerns about quality and efficacy inconsistences between different generic versions of the hormone drug.
In February last year the Medicines and Healthcare products Regulatory Agency (MHRA) suspend Teva’s license to produce levothyroxine 100mg tablets after tests revealed it “may differ from other products in the amount of levothyroxine that is released over time.”
The agency confirmed that these quality concerns had prompted the new testing rules, telling in-pharmatehcnologist.com that: “Levothyroxine is known to be sensitive to apparently minor changes to formulation or manufacture, which may adversely affect therapeutic response.
“Thus, more stringent regulatory oversight to support changes to manufacture are intended to minimise the risk of unforeseen clinical consequences.”
The plan is to replace the existing levothyroxine monograph with this draft version that includes a dissolution analysis requirement in early 2014 after which marketing authorization holders – which include Recipharm, Goldshield and Wockhardt – will be legally conduct the tests.
Teva did not respond to in-pharmatechnologist.com’s request for comment.
Manufacturing review
The MHRA also looked at methods used to manufacture the hypothyroidism treatment, explaining that: “All UK marketing authorisation holders of levothyroxine tablets were requested to review their registered details concerning the manufacture of their products to confirm that this adequately reflects their manufacturing processes.
“Companies were requested to submit variations to update this information as appropriate. Good Manufacturing Practice (GMP) inspectors will verify that companies have complied with the above requirement at the next routine site inspection.”
Clinical costs
in-Pharmatechnologist.com asked the MHRA whether the new testing rules – and the requirement that producers report minor variations in formulation manufacturing as Type 1B or Type II variations rather than Type IA – will increase the costs.
The agency’s responses focused on the potential ‘clinical cost’ of not ensuring quality and the risk product inconsistency poses to patients.
Adverse reactions “inevitably exact higher costs in terms of remediation and reputational damage to the manufacturer, quite apart from the impact on the patient. As a result, a robust understanding of process and formulation is justified. No concerns about any cost impact of the changes have been formally communicated to us.
The agency also rejected the suggestion that the additional cost of complying with the new rules will prompt manufacturers to leave the levothyroxine market.
“To date, marketing authorisation holders have not indicated to MHRA that they are having difficulty meeting the new regulatory standards for quality or that they are considering to cease manufacturing.”