A drug man­u­fac­tur­ing fa­cil­i­ty at one of Boston’s top hos­pi­tals has re­ceived a warn­ing let­ter from the FDA af­ter its man­u­fac­tur­ing prac­tices for positron emis­sion to­mog­ra­phy drugs were not found to be up to reg­u­la­to­ry code.

The FDA ad­dressed Brigham and Women’s Hos­pi­tal in a let­ter dat­ed April 11. The let­ter is ad­dressed to Sunil Eap­pen, the in­ter­im pres­i­dent and CMO at the hos­pi­tal.

Fa­cil­i­ties were not ad­e­quate­ly pre­pared to pre­vent the con­t­a­m­i­na­tion that could lead to side ef­fects in the prod­ucts, the let­ter said. The hos­pi­tal al­so did not en­sure that the equip­ment is suit­able for asep­tic op­er­a­tions. “Wa­ter in­fil­tra­tions” that oc­curred be­tween Ju­ly and Oc­to­ber 2020 were in close prox­im­i­ty to equip­ment used in the PET asep­tic pro­duc­tion op­er­a­tion, in­clud­ing hot cells, bi­o­log­i­cal safe­ty cab­i­net, and the lam­i­nar flow hood. An over­head wa­ter pipe was ac­tive­ly leak­ing on­to the floor in the same room in which raw ma­te­ri­als were stored too, and there were fun­gal species found in the ISO 5 clas­si­fied cells.

“Your in­ves­ti­ga­tion states that the wa­ter in­fil­tra­tions were due to mul­ti­ple fail­ures as­so­ci­at­ed with the me­chan­i­cal suite above your man­u­fac­tur­ing area and with the roof pen­e­tra­tions lead­ing in­to the plenum spaces above your clean­room ar­eas,” the FDA said. “No­tably, the EM da­ta in­di­cates that the wa­ter in­fil­tra­tion prob­lem pre­ced­ed the date of de­tec­tion and man­i­fest­ed as a loss of en­vi­ron­men­tal con­trol in your asep­tic pro­duc­tion fa­cil­i­ty. The fail­ure to ap­pro­pri­ate­ly de­sign and main­tain the fa­cil­i­ty led to a lack of con­trol and sub­ject­ed drug prod­ucts to the risk of con­t­a­m­i­na­tion.”

Sev­er­al fun­gal or­gan­isms were al­so found in the air qual­i­ty of crit­i­cal ar­eas of man­u­fac­tur­ing that should not be con­t­a­m­i­nat­ed, the let­ter said. Fludeoxyglu­cose for in­jec­tion, which is used to help di­ag­nose can­cer, heart dis­ease and epilep­sy, and am­mo­nia for in­jec­tion, used for PET imag­ing, were both pro­duced in the area. The team at BWH al­so ac­knowl­edged that there was not enough con­tact time for spo­ri­ci­dal dis­in­fec­tant used in the area of bi­o­log­i­cal safe­ty cab­i­nets and hot cells.

The FDA deemed BWH’s re­sponse from a pre­vi­ous Form 483 in­ad­e­quate be­cause, while it in­di­cat­ed that it would con­tin­ue PET drug man­u­fac­tur­ing while mak­ing the nec­es­sary changes, it didn’t pro­vide a suf­fi­cient plan for im­prove­ment.

“Fur­ther­more, you did not ex­plain what ad­di­tion­al steps you would take to pre­vent con­t­a­m­i­na­tion while you con­tin­ue man­u­fac­tur­ing dur­ing re­me­di­a­tions,” the FDA said. “Your re­sponse al­so failed to suf­fi­cient­ly ad­dress your ISO 5 de­con­t­a­m­i­na­tion pro­gram to im­prove its ro­bust­ness such as as­sess­ing the po­ten­tial for in­creas­ing dis­in­fec­tion fre­quen­cy, en­sur­ing more com­pre­hen­sive ap­pli­ca­tion of dis­in­fec­tants to all sur­faces in crit­i­cal en­vi­ron­ments and sur­round­ing en­vi­ron­ments, and oth­er steps that would en­sure more ef­fec­tive dis­in­fec­tion.”

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

As the global biologics market is expected to hit nearly the half-trillion-dollar mark this year, new JAMA research points to the importance of timely biosimilar entry, particularly as fewer biosimilars are entering the US than in Europe, and as monthly treatment costs for biosimilars were “substantially higher” in the US compared with Germany and Switzerland.

Among the three countries, biosimilar market share at launch was highest in Germany, but increased at the fastest rate in the US, the authors from the University of Zurich’s Institute of Law wrote in JAMA Network Open today.

The European Medicines Agency said Friday that it’s pulling from all European markets pholcodine-containing medicines, which are an opioid used in adults and children for the treatment of dry cough and in combo with other drugs as a treatment for cold and flu.

The decision to pull the medicines comes as the EMA points to the results from the recent ALPHO study, which show that use of pholcodine during the 12 months preceding anesthesia is linked to a risk of an anaphylactic reaction related to the neuromuscular blocking agents (NMBAs) used (with an adjusted OR of 4.2, and a 95% confidence interval of 2.5 to 6.9).