Hovione had to implement corrective action plans across all sites to address concerns, churned by US media reports, that FDA foreign inspections are less tough than those performed domestically.
The FDA is under increasing pressure from bodies such as the Synthetic Organic Chemical Manufacturers Association (SOCMA) to consider a foreign location as a risk factor on account of the less strict inspection processes there.
"The depth and style of both the inspection and its subsequent review has led Hovione management to conclude that the standards FDA expects to be met have moved on and are now more demanding," said Luisa Paulo, responsible for good manufacturing practice (GMP) compliance at Hovione.
"Hovione may not agree with some of the techniques used, but we recognise that this was probably the most thorough and effective inspection ever."
The seven-day inspection was performed by inspector Thomas Arista in September 2005 from which a 483 form was issued with 11 observations.
It was a pre-approval inspection for five different APIs for oral, topical and inhalation drugs, triggered both by abbreviated new drug applications (ANDAs) and new drug applications (NDAs); one product was a polymeric encapsulation formulation.
Hovione claims the names of the individuals conducting the inspection appear connected, with "possibly above average frequency," to warning letters in foreign inspections.
The delay in getting the letter of approval was caused partly, according to Hovione, by the FDA; Arista only filed his report in December, three months after the inspection, while the reviewer was also out of the office on foreign inspection trips for two of the first four months of 2006.
The company is now trying to improve compliance in particle design using spray-drying, wet milling and micronisation - in some cases considered to be a formulation step and no longer part of the API step - and on the commercial and clinical trial supply of inhalers.
The Loures site has been also inspected by the Portuguese Medicines' Agency and has had a GMP certificate for its commercial activities, as well as for its formulations activities in connection with drug product for use in clinical trials, and lastly for medical devices.
By the first quarter of next year Hovione expects to have completed GMP compliance inspections that EU Health Authorities will be performing at its New Jersey and Macau sites and successfully conclude the ISO14000 certification of its environmental management system in Loures site. The Macau plant was awarded such a certifications in July 2005.