Because nanosized solubilizers known as block copolymer micelles (BCM) contain highly functional polymers, drugmakers that use them are recommended to apply quality-by-design (QbD) principles within a “well-defined manufacturing process” to ensure consistent quality.

Simply testing the finished product is insufficient to define”quality,” as small changes to drugs containing BCMs may significantly influence their performance, reads a joint paper published Friday by the European Medicines Agency and Japan’s Ministry of Health, Labour and Welfare.

Sponsors of new drugs are increasingly turning to BCMs because they are believed to improve delivery of poorly soluble, highly toxic or unstable drugs, the regulators say. However, the potential for BCMs to accumulate in solid tumors requires manufacturing controls robust enough to minimize their potential safety and efficacy impacts in all proposed applications, they add.

The regulators’ guidance focuses primarily on products that intravenously deliver active substances in the form of compounds, nucleic acids and biologics such as peptides and proteins.

The regulators urge sponsors of BCM-containing drugs to seek early dialogue to discuss the technology and any emerging methods that might be used to define quality, the paper states.

Drugmakers’ non-clinical pharmacodynamic studies should include demonstration of pharmacodynamic response in appropriately justified in vitro (where possible) and in vivo models. In vivo evaluations should involve an appropriate administration pathway, acceptable dose levels and a justified dosing regimen depending on the proposed application, the paper says.

The starting dose for first-in-human studies should remain compliant with both ICH M3(R2)and regional guidelines, and follow careful consideration of all related non-clinical data, including:

• Critical product attributes;
• Pharmacological dose-response;
• Pharmacokinetics; and
• Pharmacological/toxicological profiles.

Data showing a consistency in quality should be provided, as should details about the sponsor’s controls for critical steps and intermediates, the regulators say. The sources and specifications for starting materials and intermediates should be submitted as well.

Experience with BCMs is currently limited, with most BCM-containing drug candidates in pre-clinical or early-stage clinical development. The emerging candidates are mostly oncology drugs.

View the joint recommendations at www.fdanews.com/ext/resources/files/01/01-13-14-EMApaper.pdf. — Johnathan Rickman