A decision by FDA to require separate BLAs for batches of Myozyme alglucosidase alfa manufactured in two different facilities is certain to play into debates about legislation and regulation of biosimilars.

In April 2006, the agency approved a BLA for Myozyme for Pompe's disease as manufactured in a 160-liter bioreactor. The EMEA also approved Myozyme in April 2006, but only when produced in the company's 2,000-liter commercial-scale bioreactor.

Under an sBLA submitted in October 2007, Genzyme Corp. had been seeking U.S. approval of Myozyme produced in the 2,000-liter facility, and had hoped for approval by May.

But last week, the company said FDA has decided that the batches manufactured in the two facilities are so different that they constitute distinct products that must be licensed separately and marketed under different trade names.

The unusual decision is based on "slight differences in the carbohydrate structures" in Myozyme manufactured in the 160-liter bioreactor that produced the drug used in registration trials and in the product produced in a 2,000-liter bioreactor, Chairman and CEO Henri Termeer said on a conference call.

Genzyme executives cited the situation as evidence the agency will set a high bar for demonstrating similarity of biosimilar products.

Generic companies are likely to put a different spin on the outcome. The probable approval of two BLAs for products that Genzyme has argued are clinically indistinguishable probably will be cited as supporting their concerns that exclusivity provisions in proposed U.S. biosimilars legislation will allow pioneers to perpetually extend the exclusivity of their products.

However it plays into biosimilars debates, FDA's concerns about discrepancies in preclinical analyses of Myozyme produced in Genzyme's 160- and 2,000-liter bioreactors highlight the difficulty of manufacturing complex biologic products.

The normal challenges of biologics manufacturing were intensified in this case because Myozyme treats Pompe's, a condition so extremely rare that clinical trials involved tens of patients rather than the hundreds or thousands typically studied.

Differences between FDA's and EMEA's approaches to the Myozyme manufacturing situation also accentuate the subjective nature of comparability assessments.

Hard to make

Pompe's is an autosomal recessive condition in which a deficiency of alfa-glucosidase leads to lysosomal accumulation of glycogen, which then destroys muscle tissue, causing myopathy, cardiomyopathy and respiratory failure. Untreated disease is rapidly fatal when it occurs in infants and leads to varying degrees of morbidity in patients who develop symptoms later in life.