	For drug manufacturers, patient safety is of the utmost concern, and efforts to prevent cross-contamination with highly potent active pharmaceutical ingredients (HPAPI) are a crucial part of a safe manufacturing process. Likewise, the safety of workers who make APIs or finished drug products, and the environment in which they work, is also paramount, particularly when manufacturing with compounds that require high containment. Inadequate containment of these compounds can put patients, employees, and the environment at increased risk, while decreasing product yields.  Manufacturing costs can also rise with additional requirements for personal protective equipment and medical surveillance for workers, or for pollution controls and special housekeeping for manufacturing areas.

	To ensure that employee exposures are kept within accepted limits and to protect the environment while containing costs, pharmaceutical companies and their contract partners who manufacture and handle high-containment compounds must carefully select equipment, outline processes and procedures, and deploy appropriate containment technologies.

	Applying engineering controls in the manufacturing process reduces the risk of contamination of the manufacturing environment and is the preferred method of controlling employee exposure. Occupational hygiene monitoring techniques and methods of analysis can then be used to verify the performance of the engineering controls.


	The first step in avoiding HPAPI environmental contamination is to identify the exposure potential. Factors to be considered include the quantity of material handled and the percent active, the potential for dust, and the duration of the task. Small (gram) or medium (kilogram) quantities of API with low dust potential and a short duration (minutes) would have the lowest exposure potential, while high volume (ton), high-dust potential with a long duration (hours) provides the highest exposure potential. 

 illustrates the selection of exposure potential from lowest (EP-1) to highest (EP-4).


	Once the exposure potential and containment level is determined, a control approach can be selected. AbbVie Contract Manufacturing uses a four-tier containment band and five containment strategies to guide its containment controls (see 

). The containment band runs from 1S ( > 100 mcg/m

). These bands are related to employee exposure limits (EEL). For example, two compounds with an EEL of 2 and 7 would both fall in containment band 3 at AbbVie, and be handled in the same manner.

) range from the least restrictive-open transfer with general ventilation-to the most restrictive, which involves glovebox isolators with rapid transit ports (RTP), split butterfly valve with extraction and/or liquid rinse, a Hicoflex (GEA) transfer system, and a closed or dust-tight system with closed transfer. The containment strategy that is chosen is verified with environmental health and safety (EHS) personnel prior to selection of the containment equipment and technologies to be used.


	Once the exposure potential is identified and a containment strategy selected, the equipment and technologies used to manufacture the HPAPI must be selected. Factors to consider include the materials or compounds involved, the processes being used, environmental and safety considerations, and GMP requirements. A risk-based approach should be applied when selecting the type of containment strategy to use for a particular process. In general, the approach should consider the exposure limit, percent active, quantity, task duration, and material properties such as dust potential.

	It should be noted that employee exposure limits (EELs) are not standard, as they are established by consensus guidelines, various regulatory authorities worldwide, and individual manufacturers’ internal standards. These limits and levels apply to manufacturing facilities and pilot plants, as well as any laboratories handling certain containment levels.  


	Factors that can affect the worker and the environment include the physical characteristics of the highly active or highly potent compound, such as its cohesion. A granular, dense compound that is more prone to clumping may be much easier to contain than a light, fluffy one. The material’s form, whether liquid, solid, vapor, or gas, affects the choice of containment control strategies, equipment, and processes, as does the particulate size, adhesion, and viscosity qualities. Nanomaterials, high adhesion, and dusty materials are more difficult to contain. Other chemical characteristics to evaluate include the compound’s flammability, combustibility, reactivity, and explosivity.


	Containment strategies must consider whether the process used involves direct or indirect handling or limited or repetitive handling, as well as the number of transfer steps. Processes should be designed with a minimum number of transfer points or make/break connections, to limit operator exposure. Other considerations include product sampling requirements such as size, quantity, location, container type, and any limitations of the receiving lab. Manufacturers must anticipate and account for any in-process adjustments and visibility issues, including tooling changeovers, equipment malfunctions, equipment inspections, line clearance to remove product for the next batch, and visibility to inspect material flow.


	Standardization of types and sizes of valves and containers, and compatibility with upstream and downstream processes also contribute to containment strategy selection. For cleaning, determine whether a process is dedicated or not, which cleaning materials will be used for deactivation, and which cleaning methods--manual, wash in place, clean in place, or a combination--will be used. Ergonomics is another factor in equipment selection; accessibility to valves and the ability to clean equipment or make adjustments help determine the best choice.


	For pharmaceuticals in the environment (PIE) control, the data generated from environmental risk assessments of products can provide the knowledge to make intelligent, risk-based control decisions for cost-effective manufacturing. Studies of predicted no-effect concentrations for the APIs involved allow manufacturers to identify water-quality control technology for the predicted environmental concentrations in the vicinity of the manufacturing facility. AbbVie’s goal is to keep site effluents tenfold below the no-effect concentration, on top of containment measures; therefore, the company has implemented effective segregation of concentrated streams and, where needed, state-of-the-art design of specific wastewater treatment for manufacturing facilities.


	Having standards in place for engineering controls is the first line of defense against harm from cross-contamination or exposure to the patient, manufacturing employees, or the environment when working with HPAPIs. These standards must take into account and guide the selection of equipment, processes, and technologies used to contain HPAPIs. While such standards are not set by industry, each manufacturer should have practices in place to handle HPAPIs without adverse effects.


	Olindo Lazzaro is Director, Environment, Health, and Safety, Global Manufacturing Operations at AbbVie, 

:
	When referring to this article, please cite it as O. Lazzaro, "Choosing Containment Strategies For Highly Potent APIs," 

Articles

Troubleshooting

Safe handling of HPAPIs requires determining exposure potential and selecting appropriate containment strategies.

Choosing Containment Strategies For Highly Potent APIs

	INTERPHEX 2016 (April 26–29, New York, NY) featured more than 100 first-time exhibitors. Many of the newcomers displayed packaging innovations for serialization, solid-dosage forms, and parenteral products.


	Laetus, a familiar name in machine vision, simplifies the transition to serialization, shortens integration time, and reduces the capital investment with its MV-50

 standardized serialization solution. Requiring only 18 inches of line space, the system fits on most packaging lines. The system transports cartons for printing by a continuous inkjet printer. The software accepts serialized data from an upper level system or memory stick and transmits the codes to the printer and camera so the camera can confirm code correctness and print quality. A fail-safe rejection system prevents cartons with incorrect or poorly printed codes from proceeding down the line.  

	Another first-time exhibitor that supports serialization, Nutec Systems, demonstrated a single BlackBox controller capable of managing multiple print technologies for serializing at the unit dose, label, carton, and case level. The same BlackBox system can also control multiple vision-inspection systems including smart sensors to detect print presence or perform pattern matching or a smart camera for print character and code verification. Customized systems can be supplied with Nutec’s Track & Trace software and cheQAssure Quality Assurance Software Suite for use with GS1 codes.

	Ellis Paper Box produces metallized, folding cartons with mirror-like, Fresnel lens patterns. The company also produces conventional cartons with anticounterfeiting features such as cold foil, a coin-reactive strip for authentication, two-dimensional DataMatrix code, serialization, micro type, pattern coating, and radio frequency identification (RFID) tags. RFID tags interact with a Smartphone to display information such as a patient insert in a specified language or enable the consumer to contact the brand owner directly. “A QR code can’t be changed, but an RFID message can be,” Steve Kerr, senior account manager, Ellis Paper Box, explained in an interview on the show floor. The company also can tip (attach) inserts to the interior of the carton, emboss Braille messages, add tamper-evident devices, and apply electronic article surveillance tags. 

	Holo-Technologies offers three layers of security: one for end users; one for distributors, which is authenticated with ultraviolet light; and one for the brand owner, which is verified with a microscope. Its substrate, metallized polyethylene terephthalate film in gauges from 25–250 mils, can be laminated to paper or paperboard, and features difficult-to-duplicate technologies such as bas-relief, microtext, nanotext, 3D animated image, laser-etched barcoding, embossed light diffraction patterns, and microswitch effects, where the message changes as the viewing angle shifts. A tamper-evident security seal also is available.

	Offset push tabs unlock access to blister packs in a child-resistant/senior-friendly carton from Locked4Kids. The design, which is available for licensing, can be produced by any carton manufacturer and loaded on standard cartoning machines. As a result, “No new machines are needed, and a brand owner can use its own [carton] supply chain,” Sanjeet Saxena, director Business Development at Locked4Kids told 


	In the parenteral space, Colanar displayed a servo-driven, tabletop filling line available in three options: laminar flow workbench, restricted access barrier system, or isolator. Nests of vials, syringes, or cartridges ride on a platform that indexes forward for filling, and a pick-and-place arm applies stoppers. Syringe plungers are placed using vacuum. Vials can be handled at 30 per minute in a single station machine or 60 per minute in the duplex model. Syringes are filled slower, at 15 per minute. Applications include research and development, biotech, contract packagers, and compounding pharmacies.  

	A first-time exhibitor from France, Nemera, offers multi-dose dispensers for preservative-free products such as eye drops. Preservative-free technology is well established in Europe and also was featured by Ursatec Verpackung (a first-time INTERPHEX exhibitor in 2015), and Aptar Pharma.

	Prestige Brands has adopted Aptar Pharma’s Ophthalmic Squeeze Dispenser for multi-dose formulas of Clear Eyes Pure Relief eye drops. It’s reportedly the first over-the-counter, preservative-free, multi-dose eye drop available in the United States (1). A valve in the dispenser opens to release a drop and recloses to seal contents from the outside environment. An integral filter cleans the air that enters the bottle to replace the fluid. 

	Nemera’s latest design for multi-dose, preservative-free products is the Novelia BFS system. Utilizing bottelpack blow-fill-seal (BFS) machines from Rommelag, containers can be produced in many sizes and shapes. A one-way valve associated with a permeable Pureflow silicone membrane prevents ingress of contaminants. A blue tip aids aiming for accurate drop dispensing, and calibrated drops ensure a precise dose. Three variations handle viscosities up to 1500 cP.

	A square-bottom, metallized polyester, standup pouch prototype from Bernhardt can be sized to hold between 1–5 L of liquid and is easy to fill and pour through a standard fitment. The sturdy pouch structure survives 80-cm drop tests and eliminates the need for a secondary box. A cube-efficient shape permits top-to-bottom or side-to-side stacking to fit up to 30% more product per pallet. A handle or hanging holes can be diecut top and/or bottom.

		Prestige Brands, Clear Eyes Pure Relief, www.cleareyes.com/purerelief, accessed May 6, 2016. 

Packaging

Packaging technologies for serialization, parenteral products, and solid-dosage forms were displayed at INTERPHEX 2016.

First-time Packaging Exhibitors Bring Innovations to INTERPHEX

	The US government’s National Science and Technology Council (NSTC), which sets national goals for Federal science and technology investments, listed continuous manufacturing of pharmaceuticals as one of five manufacturing technology areas of emerging priority in its April 2016 report on advanced manufacturing (1). As reported in the 

, continuous biopharmaceutical manufacturing and other advanced biopharmaceutical manufacturing technologies are also listed as emerging priority areas. Government support can make a difference in promoting continuous manufacturing of pharmaceuticals, say the report authors, who suggest that, “Future Federal investments may focus on broadly applicable and enabling technologies, demonstrating their return-on-investment required for mainstream adoption” (1).

	Multiple US government agencies already involved with projects include the National Science Foundation (NSF), National Institutes of Health, National Institute of Standards and Technology, Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), and FDA’s Center for Drug Evaluation and Research (CDER). FDA has often stated its support of continuous manufacturing, which it sees as having the potential to contribute to quality. FDA’s guidance, 

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base

 (2), published in December 2015, outlines how CDER’s Emerging Technology Team (ETT) is working with companies to facilitate understanding of such technologies in order to appropriately regulate it, Michael Kopcha, PhD, RPh, director of FDA’s Office of Pharmaceutical Quality, told 

 (3). Some potential regulatory concerns, such as the definition of a batch, have already been resolved, and two continuous manufacturing processes for tablets have been approved for commercial production: a Vertex process is described in the report (1), and approval of a Janssen process was


	One of the most significant achievements in developing continuous processing for pharmaceuticals has been using a science-based approach to developing engineering systems, says Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academic–industry consortium that has been working on continuous manufacturing with NSF support for the past ten years. “This approach to formulation is different from the old way of looking primarily at pharmacokinetics; now we’re looking at materials characterization and how minor changes affect manufacturability as part of a system,” Hausner explains. “Modeling is a key tool in development of these systems; it can show you where variability exists and what the failure modes are so that you can control the process.” C-SOPS has worked closely with developers, regulators, as well as users in both academia and industry to help drive this technology forward. While there is currently a gap between the cutting-edge of research and what is available commercially for modeling software, this could quickly close as adoption picks up and as regulators look to use this as a communication tool for relating process understanding, says Hausner.

	“Models allow you to understand how materials and processes relate. This greater understanding is valuable because it allows more rapid development. You can potentially ‘skip’ some of the traditional process development steps. Some of our current work, for example, involves using multivariate analysis to elucidate similarities between processes and determine how many tests you really need to do to get to an answer,” says Hausner. The ability to have faster development, which can translate to the business benefit of market exclusivity, is a potential driver for greater use of continuous manufacturing.


	Experts agree that a broader understanding of continuous manufacturing is needed to drive greater commercial use. A 2015 FDA grant included funding for training at C-SOPS. “Part of this training includes hands-on, intensive training, initially for FDA’s ETT team, and then for the broader industry. Trainees will gain experience running the integrated line at the Rutgers University C-SOPS lab. We want to give people exposure to this and thereby grow the level of continuous manufacturing expertise in the industry,” says Hausner. 

	A template or “road map” for development, based on the experiences learned by early adopters, would help the industry adopt continuous manufacturing, suggests Hausner. Regulatory science is another challenge, although progress is being made in understanding the risks and developing appropriate requirements for continuous manufacturing. Equipment, including having more standard connections and communication between PAT and processing equipment, is another challenge that will need to be overcome.

	Another step forward for equipment for continuous processing was the development and installation of a prototype 

Portable Continuous Miniature Modular (PCMM)

 system for tablet production in Pfizer’s Groton, CT facility in 2015. The prototype was built as a collaboration between Pfizer, G-Con, and GEA, and the system won the International Society for Pharmaceutical Engineering Facility of the Year 

Equipment Innovation Category Award in 2016.

Executive Office of the President, National Science and Technology Council

 “Advanced Manufacturing: A Snapshot of Priority Technology Areas Across the Federal Government,” by the Subcommittee for Advanced Manufacturing of the National Science and Technology Council (April, 2016).	

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base  

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM478821.pdf

FDA Insights on Quality in Solid Dosage Manufacturing

," Sidebar to S. Haigney, "Ensuring Quality in Solid and Semi-Solid Dosage Forms," 

		PharmTech, “FDA Approves Tablet Production on Janssen Continuous Manufacturing Line,” 

www.pharmtech.com/fda-approves-tablet-production-janssen-continuous-manufacturing-line

Production Trends

A US government report on advanced manufacturing promotes continuous manufacturing of pharmaceuticals, which has had recent commercial success but faces challenges for widespread adoption.

Equipment and Processing Report-05-18-2016

Choosing Containment Strategies For Highly Potent APIs

First-time Packaging Exhibitors Bring Innovations to INTERPHEX

Next Steps for Investment in Continuous Manufacturing Research