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Volume 37, Issue 10
Recent FDA enforcement activity reveals issues with vial-filling, adequacy of QA/QC procedures, particulate matter in inhalation powders and injectables, and drug labeling.
Quality is crucial to ensure drug safety. A review of FDA’s enforcement reports and related information from September 2013 highlights issues relating to vial-filling, adequacy of quality assurance/quality control (QA/QC) procedures, particulate matter in inhalation powders and injectables, and drug labeling.
AstraZeneca and Bristol-Myers Squibb reported in September 2013 that they voluntarily recalled approximately 92,000 vials of their jointly marketed Type 2 diabetes treatment, Bydureon (exenatide extended-release injectable suspension), in several European countries because some vials were not fully filled.
The affected batches were recalled in the United Kingdom, Germany, Romania, the Netherlands, Ireland, Sweden, Finland, and Spain, according to Bristol-Myers Squibb. The Bydureon recall was issued after a review of manufacturing records indicated at least one of the batches may have had a very small number of underfilled vials, according to a Sept. 16, 2013 alert distributed by the UK Medicines and Healthcare products Regulatory Agency (MHRA).
The affected batch (C164827) was a 4 x 1 single-dose kit (1 vial and 1 syringe) with an expiration date of Aug. 31, 2015. It was first distributed on July 12, 2013. The low fills affect approximately 0.2% of the batch and range between 30% and 75% of the labeled dose. No batches distributed in other markets were affected, and the companies don’t expect any supply issues. There is little evidence that patient safety would be compromised as a result of injecting an underfilled vial, and any health consequences would likely be minimum, according to Bristol-Myers Squibb.
Bydureon is part of the diabetes alliance between AstraZeneca and Bristol-Myers Squibb. Bristol-Myers Squibb acquired Bydureon through its 2012 acquisition of Amylin Pharmaceuticals. AstraZeneca and Bristol-Myers Squibb formed a diabetes alliance in 2007 for certain drugs and later expanded that collaboration following Bristol-Myers Squibb’s acquisition of Amylin to include the diabetes portfolio of Amylin, including Bydureon.
Adequacy of QA/QC procedures
FDA issued an import alert under which US officials may detain at the US border drug products manufactured at Ranbaxy Laboratories’ facility in Mohali, India. The firm will remain on the import alert until the company complies with US cGMPs, according to a Sept. 16, 2013 FDA statement.
FDA also ordered that the Mohali facility be subject to certain terms of the consent decree of permanent injunction entered against Ranbaxy in January 2012. The decree contains provisions to ensure cGMP compliance at certain Ranbaxy facilities, including in Paonta Sahib and Dewas, India, as well as provisions addressing data-integrity issues at those two facilities. Ranbaxy’s Paonta Sahib and Dewas facilities have been on FDA import alert since 2008. FDA exercised its authority under a provision in the consent decree permitting it to order that terms of the decree be extended to a Ranbaxy-owned or operated facility if an inspection determines that the facility is in violation of the Federal Food, Drug, and Cosmetic Act or FDA regulations, including cGMPs.
In September and December 2012, FDA inspections identified cGMP violations at Ranbaxy’s Mohali facility, including failure to adequately investigate manufacturing problems and failure to establish adequate procedures to ensure manufacturing quality.
Under the decree, Ranbaxy is prohibited from manufacturing FDA-regulated drugs at the Mohali facility and introducing drugs into interstate commerce, including into the United States, from the Mohali facility until the firm’s methods, facilities, and controls used to manufacture drugs at the Mohali facility are established, operated, and administered in compliance with cGMPs. Ranbaxy is required to hire a third-party expert to conduct an inspection of the Mohali facility and certify to FDA that the facilities, methods, processes, and controls are adequate to ensure continuous compliance with cGMPs. Once the agency is satisfied that Ranbaxy has come into compliance with cGMPs, Ranbaxy will be permitted to resume manufacturing and distribution of FDA-regulated drugs at the Mohali facility.
Particulate matter in inhalation powders
Boehringer Ingelheim Roxane, based in Columbus, Ohio and a subsidiary of Boehringer Ingelheim, initiated a voluntary nationwide recall in the United States of certain lots of its Spiriva HandiHaler (tiotropium bromide inhalation powder) capsules, 18 mcg per dose (prescription only), according to FDA’s weekly enforcement report of Sept. 25, 2013. Spiriva is used to treat chronic obstructive pulmonary disease. The Class III recall was initiated on Aug. 30, 2013 due to the potential for extrinsic foreign particles in the API used to manufacture Spiriva Handihaler. The product distribution quantity was 15,385,232 capsules, according to the FDA report. The recall applies to several products types: a 10-count blister (NDC 0597-0075-27), 30-count blister (NDC 0597-0075-41), 90-count blister (NDC 0597-0075-47), and 5-count blister physician sample (NDC 0597-0075-75). A Class III recall refers to products that are unlikely to cause any adverse health reaction, but that violate FDA labeling or manufacturing laws.
A federal judge approved a consent decree of permanent injunction against Shamrock Medical Solutions Group, Lewis Center, Ohio, and four of its corporate officers and employees for continued drug manufacturing and labeling violations that resulted in the distribution of mislabeled drugs, according to a Sept. 18, 2013 FDA press statement. Shamrock Medical repackaged and distributed solid and liquid oral nonsterile drug products for human use to hospitals throughout the United States. FDA reported that inspections found several violations at the facility, including failure by the quality control unit to fully follow its own QC procedures and to examine packaged and labeled products to ensure correct labeling. The FDA previously had sent warning letters to Shamrock Medical for violating cGMPs and distributing incorrectly labeled drugs. The September 2013 announcement followed an FDA alert issued in April 2013 advising healthcare providers to remove drugs distributed by Shamrock Medical from supply stock due to the possibility that they were mislabeled. The warning covered many nonsterile medications and dosage forms, including tablets, vials, ophthalmic and otic solutions, and patches.
Particulate matter in injectable drugs
FDA reported on Sept. 13, 2013 that Hospira had initiated on July 12, 2013 a voluntary nationwide recall to the user level for one lot of 0.25% bupivacaine HCl injection, USP (2.5 mg/mL), 30-mL single-dose vial (NDC 0409-1159-02). An expanded recall was issued on Aug. 29, 2013 for one lot of 0.75% bupivacaine HCl injection, USP (7.5 mg/mL), 30-mL single-dose vial(NDC 0409-1165-02). Bupivacaine is indicated for the production of local or regional anesthesia or analgesia. Both recalls were due to confirmed customer reports of particulate floating and/or embedded in the glass vial, according to FDA. The particulate was identified as stainless steel ranging in size from 542 microns to 1700 microns in Lot 18-136-DK (0.25% bupivacaine) and as iron oxide with an average size of 2000 microns in Lot 23-338-DK (0.75% bupivacaine).
Hospira also initiated a voluntary recall of propofol injectable emulsion, 1%, 200 mg/20 mL (10 mg/mL), packaged in 5 units x 20 mL single-patient infusion vials per carton (prescription only), according to a Sept. 18, 2013 FDA enforcement report. The Class II recall was initiated on Aug. 14, 2013 due to visible particulate embedded in the glass vial being observed and confirmed in a sample bottle during sample inspection. The product distribution quantity was 283,150 vials.