Risk Management: Sterile Manufacturing in Focus

The recent decision by the US National Institutes of Health (NIH) to suspend sterile manufacturing in its pharmaceutical development operations, based on a recent FDA inspection, underscores the challenges in achieving sterility assurance. A look at recent inspection trends in this area.

Sterility assurance is of paramount importance to the quality of finished drug products. As recent FDA inspection trends show, however, sterile manufacturing has been an area of some note. A look into some recent issues that can arise in sterile manufacturing processes, components, and the related supply chain. 

NIH is the latest example
Earlier this month, the National Institutes of Health (NIH) suspended production of sterile materials at its operations at the Pharmaceutical Development Section (PDS) at the NIH Clinical Center. All production of sterile materials in the PDS were suspended, but production of other materials, which were not the focus of concern and do not require sterile manufacturing practices, will continue, according to a NIH statement. The NIH suspended operations due to the discovery of serious manufacturing problems and lack of compliance with standard operating procedures. Upon receipt of a complaint, the US Food and Drug Administration (FDA) representatives inspected the PDS between May 19 and May 29, 2015 and found a series of deficiencies that will require the NIH Clinical Center to take a number of corrective actions.

The facility makes products for certain clinical research studies conducted in the hospital and collaborating facilities. In April, two vials of albumin, used for the administration of the drug interleukin in experimental studies, were found to have fungal contamination. Among the problems the FDA identified in its inspection were deficiencies in the physical facility, including flaws in the air-handling system, and operational failures, including inadequate quality control, insufficient employee training, and lack of compliance with standard operating procedures. Deficiencies of lesser significance were identified in the Clinical Center Pharmacy.

Following suspension of sterile operations of The Pharmaceutical Development Section, no products will be made or distributed until all problems are fully understood and corrected, according to a NIH statement. Materials produced by the PDS Section are being systematically tested for contamination. An external group of experts in microbiology and sterile manufacturing practices will be appointed to conduct a thorough review, including an assessment of all standard operating procedures, policies, staffing, and training, and make recommendations to the NIH director on the corrective actions required. In addition to the immediate steps NIH is taking, it will provide an interim corrective action plan to the FDA by Friday, June 19, 2015.

Manufacturing processes, components, and the supply chain
A review of voluntary recalls for select injectable products over the last year shows the various issues, such as the presence of particulate matter that might arise from a sterile manufacturing process, components used in sterile manufacturing, and/or the related supply chain. Although the scope was confined to a few incidents for select lots for certain products and no adverse events were reported, it shows the types of issues that might arise.  

For example, earlier this month, Mylan’s Institutional business extended a nationwide voluntary recall of select lots of two injectables, gemcitabine and methotrexate to the hospital/user level due to the presence of visible foreign particulate matter observed during testing of retention samples. Gemcitabine for injection, USP is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between January 8, 2014, and February 10, 2015, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801084 and 7801110 are packaged with a Pfizer Injectable label. The recall applies to seven lots. Methotrexate injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis and adult rheumatoid arthritis. The lot was distributed in the US between December 8, 2014, and December 19, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company. The recall applies to one lot. In April 2015, Mylan had also initiated a voluntary nationwide recall to the hospital/user level of select lots of injectable products (gemcitabine, carboplatin, methotrexate, and cytarabine). The recall applied to five lots of gemcitabine, and one lot each of carboplatin, methotrexate, and cytarabine). The recall was initiated due to the presence of visible foreign particulate matter observed during testing of retention samples.

In May 2015, Teva Parenteral Medicines announced a voluntary recall of eight lots of Adrucil (fluorouracil injection, USP) 5 g/100 mL (50 mg/mL) due to the potential presence of particulate matter identified as aggregate of silicone rubber pieces from a filler diaphragm and fluorouracil crystals.

In April 2015, Hospira, Inc. issued a voluntary recall of one lot of preservative-free bupivacaine HCl Injection, USP, 0.5% (5 mg/mL), 30 mL single due to one confirmed customer complaint of orange and black, visible particles embedded and free floating within a single-dose glass teartop vial. The particles were identified as iron oxide. This recall was carried out to the user level (both human and veterinary). In its recall notice, Hospira said it was working with its glass supplier and initiated an investigation to determine the root cause and corrective and preventive actions.

In December 2014, Hospira initiated a voluntary recall of 10 lots, MitoXANTRONE (both human and veterinary), due to confirmed subpotency and elevated impurity levels. In October 2014, Hospira, initiated a voluntary recall of one lot of 1% lidocaine HCI for Injection, USP, 10 mg per mL, 30 mL single-dose, preservative-free to the user level due to a confirmed customer report of particulate in a single unit. Hospira identified the particulate as a human hair, embedded in and attached to a pinched area of the stopper. In October 2014, Hospira, Inc had a voluntary nationwide user-level recall of one lot of vancomycin hydrochloride for Injection, USP, equivalent to 1 g vancomycin (sterile oowder) because the product may have experienced temperature excursions during shipment to a customer and then was further distributed by the customer. In July 2014, Hospira initiated a voluntary nationwide user-level recall of one lot of lactated ringers and 5% dextrose injection, USP, 1000 mL, flexible container due to one confirmed customer report where particulate was identified within the solution of the primary container. The particulate was identified as a filamentous-like structured particulate indicative of mold. Analysis of the primary container and overwrap indicated a puncture in the same physical location, causing the primary container to leak. Also, in July 2014, Hospira initiated a voluntary recall of one lot of lidocaine HCI Injection, USP, 2%, 20 mg per mL, 5 mL single-dose vial, preservative-dree to the user level due to a confirmed customer report of discolored product with visible particles in the solution as well as particulate embedded in the molded glass container, identified as iron oxide.

In December 2014, Baxter International Inc. voluntarily initiated a recall in the US of two lots of 0.9% sodium chloride injection USP in 100 mL MINI-BAG PLUS Container to the hospital/user level. The recall was initiated as a result of two complaints (one per lot) of particulate matter that was identified as a fragment of the frangible from the vial adapter. The issue was identified upon standard visual inspection prior to patient administration. In July 2014, Baxter recalled four lots of intravenous (IV) solutions to the hospital/user level. These products have been found to contain particulate matter identified as cellulosic fibers and/or plastics. Baxter received four complaints over a period of six months from customers whose visual inspection identified the appearance of visible particulate matter prior to administration to a patient.

In August 2014, Cubist Pharmaceuticals, Inc (which was subsequently acquired by Merck & Co.) issued a voluntarily recall of nine lots of Cubicin (daptomycin for injection) to the user level following complaints of foreign particulate matter in reconstituted vials.That voluntary recall followed an earlier voluntary recall in August 2014 for the same product to the user level due to the potential presence of glass particulate matter in vials produced by a contract manufacturer.

De-risk Your Pharma Manufacturing Supply Chain

Learn from leading experts from J&J, Pfizer, and DuPont on best practices in risk management, at DCAT’s Sharp Sourcing 2015, an education program and networking event for pharma sourcing, procurement, and supply professionals. Sharp Sourcing will feature:

Supply Assurance and Risk Management Roundtable:  Experts from within and outside the industry discuss risk management processes, metrics, and implementation strategies. The roundtable features:

  • J&J: Joseph Agresta, Vice President, Johnson & Johnson Supply Chain Procurement Excellence;
  • Pfizer: Ron Perry, Vice President, Global Procurement, Pfizer Global Supply and Global Operations;
  • DuPont: Sidney Goldberg, Ph.D., Sourcing Compliance Manager;
  • Ernst & Young (EY): Niul Burton, Principal, Advisory Services
  • Leaders from Academia: Joseph Sandor, Hoagland-Metzler Endowed Professor of Purchasing and Supply Management, Michigan State University.

Plus presentations from Bristol-Myers SquibbMerck & Co.,  Biogen, and Shire on category management, single versus dual sourcing, and supplier relationship management as well as insight on value-based metrics for supplier performance.    

For more information, including how to register, go to DCAT Sharp Sourcing 2015.

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