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Safety of Nanotechnology Focus of New EMA, MHLW Joint Reflection Paper

Posted 05 February 2013 | By Alexander Gaffney, RAC

The European medicines Agency (EMA) has released a new draft reflection paper on the development of nanomedicines made with block copolymer micelles (BCMs), aiming to provide basic information for the development of a common type of investigational nanomedicine.

The paper is unusual in that it is being developed alongside Japan's Ministry of Health, Labour and Welfare (MHLW), the parent organization of the Pharmaceuticals and Medical Devices Agency (PMDA). Between EMA and MHLW, two-thirds of the International Conference on Harmonization (ICH) is represented, leaving out only the US Food and Drug Administration (FDA).

Background: Promise and Concern

The development of nanotechnology has been heralded and feared-often in equal measure-by regulatory authorities. On one hand, the technology is at times praised for its potential to become one of the building blocks for the future of medicine, allowing new delivery and distribution mechanisms to treat difficult-to-access conditions, such as tumors and other cancers. But regulators have also been wary about the drug's potential risks, particularly to those accidentally exposed to the drug. The drug particulars can be as small as a single nanometer (nm) and as large as 100 nm, making them easy to accidentally inhale and sometimes difficult to control.

"Numerous questions remain to be addressed before NPs can be widely utilized in the field of medicine," explained Nathalie Ross, RAC, in a Regulatory Focus article in December 2011. "Additional studies are needed to assess the long-term toxicity of nanomaterials in medicine. The biological behavior and toxicological properties of new nanomaterials must be carefully assessed."

"At the present time, the biological effect on humans of intentional (medical) or unintentional exposure to engineered nanomaterials is unknown," added Ross. "In this regard, more effort is needed to improve the standardization of assays used for in vitro and in vivo nanomaterial testing."

"Occupational hazards associated with the use of NPs are hot-button issues," explained Aastha Kohli and Shrenik Desai in a January 2012 article in Focus. "Animal studies conducted with some types of engineered NPs have found NPs to cause adverse lung effects (e.g., pulmonary inflammation and progressive fibrosis), cardiovascular effects (e.g., inflammation, blood platelet activation, plaque formation and thrombosis) and translocation of NPs from lungs to the bloodstream."

In a study cited by Kohli and Shrenik, many companies expressed concern that they were unsure about the correct way to protect employees handling or working with nanomaterials, as well as how to safely dispose of the materials or their byproducts.

BCMs: A Roadmap for other Nanomaterials?

The European Commission (EC) recently initiated a regulatory review-its second-on the development of safe nanomaterial, citing many of those same concerns.

The concerns of each nanomaterial are specific to its particular qualities, and thus need to be assessed on a case-by-case basis, the EC wrote.

EMA and MHLW's paper seems reflective of that conclusion, tackling the safety issues associated with just a single type of nanomedicines: nano-sized BCMs. "BCMs are self-assembled micelles, and they are typically prepared from AB block copolymers," EMA and MHLW explain in the paper.

Several medicines predicated on the technology are currently "in preclinical or clinical development," EMA explained in a statement, likely helping to spur the need for a scientific guideline.

But while the reflection paper extensively lists a number of ICH guidelines that may form the basis for much of the evaluation process, it also notes that the unique characteristics of the BCMs require additional specificity.

EMA/MHLW said that, "due to the complexity of the system … it is recommended that an early dialogue with the regulators takes place to discuss the likely critical product attributes of each particular BCM product."

Manufacturing Issues at Core of Assessment Process

Sponsors of the products should also be able to be able to define its parameters, characteristics, and physicochemical properties, the paper notes. This is to make sure the sponsor can ensure its quality. This includes (more generally) the product's size, chemical structure, stability, impurities, and (more specifically) its morphology, zeta potential, concentration dependency, in vitro stability and degradation, validated manufacturing process, osmolarity and release rate.

Manufacturing has the potential to be quite difficult, the paper explains. "A well-defined manufacturing process with its associated process controls is needed to ensure that acceptable product is produced on a consistent basis. It is known that small changes to BCM products may significantly influence their performance."

"Detailed descriptions of the synthetic process, extraction, and purification procedures should be provided as applicable," as well as the specifications for all starting materials and key intermediates, EMA/MHLW wrote.

Clinical and Non-Clinical Considerations

From a non-clinical development perspective, BCM products should undergo pharmacokinetic and pharmacodynamics (PK/PD) studies in its nanomaterial form, as regulators noted that significant PK changes can occur to a product when it is administered as a BCM product.

"Moreover, it has been noted that certain block copolymers (not containing an active substance) can display inherent biological activity, which would have an impact on clinical efficacy and/or safety," they added.

"Comparing the PK of the block copolymer micelle product and the active substance administered by itself is recommended," the paper continues.  It may also be important to consider the protein and cellular interaction of BCMs administered intravenously as these factors are known to have potential to influence the distribution, stability and safety of nanomedicines."

From the perspective of clinical development practices, "It will be essential to consider non-clinical pharmacokinetic data specific to the block copolymer micelle product e.g. the block copolymer micelle, the active substance, the proposed clinical use and the route of administration, using sampling time points and sampling duration that is carefully selected so as to accurately quantify the time course of block copolymer micelle products for total active substance and for free active substance and metabolites."

Comments on the reflection paper are due on 1 July 2013.

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