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Although shortages, quality, and regulatory challenges remain, improved technologies and new investments suggest that the worst may be over.
The past five years have been extremely challenging for parenteral pharmaceutical manufacturers. For commodity workhorse products, the aftershocks of manufacturing and quality issues and pricing pressures continue to be felt in operating rooms, neonatal facilities, ambulances, hospitals, and healthcare facilities, particularly in the United States.
On the large-volume (i.e., 100 mL or higher volume) side, intravenous fluids and compounds used for dialysis, nutritional supplementation, and irrigation have been in short supply due to contamination, manufacturing problems, or product discontinuation. On the small-volume side, supplies of chemotherapy agents and anaesthetics may have emerged from the crisis they faced in 2013, but continue to be tight.
In 2015, Baxter had to recall some basic large-volume parenterals such as intravenous saline and dextrose, which were found to contain particulates. The same problem had prompted the company and other suppliers, including Hospira and B. Braun, to recall large-volume parenterals in 2013 and 2014 (1). For large-volume products, most of which are heat-sterilized, the major problem continues to be particulates. Small-volume products are vulnerable to both microbial and particulate contamination, which has been traced to glass and packaging materials, and problems such as leaching and sorption (Table I).
Lactated Ringer’s Injection
Dianeal (for peritoneal dialysis)
Mold and particulates
As experts from the Parenteral Drug Association (PDA) have pointed out (2), particulates are either extrinsic or intrinsic, based on whether they originate from outside or within the project. Recalls called out both types of particulate contamination. Between January 2013 and June 2014, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom found that 11 out of 42 drugs listed on its Drug Alert website were listed because of particulate contamination. Between 2008 and 2012, particulate contamination issues led to 22% of all injectable drug recalls (3).
Microbial contamination can have several sources. In an interview with Pharmaceutical Technology, consultant Barry Friedman traces many recent cases to inadequate sampling plans and media fill studies. Ideally, media fill studies should be designed to account for worst-case conditions (4), and they should be repeated periodically and adjusted for batch size.
“With both small-and large-volume parenterals, people often come up with sampling plans based on small lots. They do media fills and get acceptable results, but then lot sizes increase,” Friedman says, “and some of them don’t increase the size of media fills to a comparable degree.”
Another problem is failing to follow United States Pharmacopeia (USP) <71> guidance in the number of samples taken as the drug moves from Phases I to commercial production, says Friedman. The number of samples required is based on the size, volume, and number of containers to be filled (5). In addition, Friedman notes the need to reduce the potential impact of operators on the process and product. Investing in isolators can often be the best way to go, he notes, as long as the equipment is properly maintained and operators are adequately trained to recognize potential sources of problems. “It’s important to check seals and to examine sample ports and gloves for cracks,” Friedman says.
Solutions to parenteral manufacturing challenges focus on technology, new materials, and components. A number of companies are using automated systems to reduce the potential for operators to contaminate product. Vetter AG, a contract development and manufacturing organization (CDMO) in Germany, has invested EUR 300 million to more than double its sterile fill and finish and other capacity (6). The expanded sites are expected to become fully operational in 2017. Central to Vetter’s efforts is its “Improved RABS Concept,” developed inhouse, that combines the features of an isolator with those of a restricted access barrier system (RABS). The Improved RABS Concept creates a design with two barriers, including a walk-in isolator to reduce risk. Cleanroom staff work in a Class 10,000 area that can be entered only after proper gowning and passage through air locks. The RABS contains the filling line in an ISO-5 area, providing redundancy so that problems can be detected, contained, and fixed before they affect product (7).
Vetter’s equipment includes an automated hydrogen peroxide decontamination module, and can reportedly complete a sterilization cycle in three hours. After successful pilots, the company plans to implement this module in all its cleanrooms within the next few years.
In September 2015, Italian equipment manufacturer Fedegari opened a technology innovation center in Philadelphia that features advanced equipment and aims to facilitate collaboration on development of new processes (8). It also launched a new website, www.Sterilize.it, where specialists can share data and collaborate.
Other companies are developing prefilled technologies to improve ease of use and protect product safety. On November 3rd and 4th, PDA will focus exclusively on this topic with a specialized event, The Universe of Prefilled Syringes and Injection Devices.
Driving innovations include high heat-resistant and non-leaching plastics, new processes such as blow-fill-seal (BFS), and new configurations for bottles, closures and caps. The CDMO, Catalent, used quality-by-design (QbD) principles to develop its glass-free Advasept vial design to improve BFS systems. The process aims to reduce particulates, the number of process steps, and the need for operator intervention, thereby, reducing contamination risk. By using medical-grade polypropylene, the risk of glass delamination and breakage is eliminated (9).
West Pharmaceutical Services has developed closure and capping technologies to reduce risk (see Addressing Parenteral Manufacturing Challenges). The company established a center of excellence in Ireland in 2014, devoted to improving new generations of this technology.
Companies are also investing in new capacity and buying CDMOs that have special expertise wotking with parenterals. Pfizer, for instance, bought Hospira in September 2015 (10), while a number of Indian pharmaceutical companies have acquired contract manufacturing organizations (CMOs) in the US (Table 2). Piramal Enterprises’ Pharma Solutions CMO division bought Kentucky-based Coldstream Labs earlier in 2015 (11). Coldstream has special expertise in advanced aseptic manufacturing equipment and highly potent API (HPAPI) handling and processing.
The large-volume parenterals market is fairly staid, with competitive pressures and low profitability. In 2014, some manufacturers withdrew long-established products for financial reasons. Small parenterals, however, are seeing healthy innovation and growth, according to Vivek Sharma, CEO of Piramal Enterprises’ Pharma Solutions, who summarized market developments in CPhI’s 2015 Annual Industry Survey (12).
Over the past 15 years, Sharma says, 900 new injectable drugs have been approved, and another 2400 are currently in the pipeline. Innovation is being seen in oncology, particularly in the use of targeted delivery systems using liposomes, PEGylation, and depot injections. Prefilled syringes, which reduce safety risks, will experience major growth, Sharma predicts, with biologics accounting for half of the injectables R&D budgets for the top 15 pharmaceutical and biopharma companies.
Generic injectables, which were a $37-billion market in 2013, should grow to $70 billion in 2020, he says, while the need to reduce risk will drive more pharma companies to outsource parenterals development and manufacturing to CDMOs and CMOs. Currently, injectables outsourcing is a $6-billion business, and Sharma expects it to show 10% annual growth for the next five years.
1. FDA, FDA Updates on Saline Drug shortage, accessed Oct. 20, 2015.
2. PDA,Industry Perspective on the Medical Risk of Visible Particulates in Injectable Drug Products, accessed 20 Oct. 2015.
3. S. Tawde, J Pharmacovigilance online, Jan. 5 2015.
4. M. Akers, “Parenteral Preparation,” Chapter 26 in Remington Essentials of Pharmaceuticals, Ed. Felton, L, Pharmaceutical Press, 2013.
5. E. Kastango, Understanding USP 71 Sterlity Tests and Extending Beyond Use Data, accessed Oct. 20, 2015.
6. Vetter, “Vetter Embarks on a 300 Million Euro Investment Strategy for Further Development To its Manufacturing Sites,” Press Release, Sept. 30, 2015, accessed Oct. 22, 2015.
7. Vetter, “Improved RABS concept combines two proven aseptic processes,” accessed Oct. 22, 2015.
8. Fedegari, “Official Opening of Fedegari $2.9M State-of-the-Art Technology Centre,” Press Release, 15 Sept. 2015.
9. Catalent, Advanced Aseptic Processing, www.catalent.com/index.php/offerings/A-Z-Offerings/advanced-aseptic-processing/.
10. Pfizer, “Pfizer Completes Acquisition of Hospira,” Press Release, Sept. 3, 2015.
11. Pharmaceutical Technology news, “Piramal Invests $30.6 Million in Coldstream Acquisition” Jan. 26, 2015, accessed Oct. 22, 2015.
12. Pharmaceutical Technology news, “Injectables to Show Double-Digit Growth Through 2020,” Oct. 14, 2015, accessed Oct. 22, 2015.
Article DetailsPharmaceutical Technology
Vol. 39, No. 11
When referring to this article, please cite it as A. Shanley, “Better Days for Parenterals?,” Pharmaceutical Technology 39 (11) 2015.