Automation: Regarding operator training and other tasks relating to new or novel fill–finish operations — to what degree can/will robotics/automation replace human operators?
Outsourcing: How do contract manufacturing organizations (CMOs) see the future of fill–finish technologies, especially regarding management of multiproduct operations and preparation of formulations for shipment to various geographic areas?
Fill and finish wasn't one of the first areas that came to mind when biopharmaceutical companies started talking about disposables. However, in 2007, the Institute of Validation Technology (IVT) held a meeting at which participants identified “how disposable technologies can do far more than reduce cleaning requirements and minimize risks of cross contamination.” The group pointed out that single-use technology “can also help save money, manufacture products previously unprofitable, and be used in areas not otherwise considered” (3). Recently, Ryan Hawkins (vice president of drug product operations at Cook Pharmica, a contract manufacturer) told BPI, “Disposables could certainly be leveraged further [in fill–finish operations]. We at Cook are particularly excited, however, about ready-to-use vials that will help eliminate washing and depyrogenation equipment upstream of the filling line. With adoption and volume, I believe this will increase effectiveness and provide the opportunity, eventually, for overall cost savings” (4).
At the same IVT meeting four years ago, Roland A. Heinrich (Millipore's vice president of bioprocess R&D) anticipated that “disposables will become an enabling technology for production of small-scale products.” And Millipore's Robert Blanck predicted that “disposable filling systems will change the way fill–finish is done.” Blanck added that the use of disposables in fill–finish operations “will reduce downtime between filling campaigns and provide added product safety” because of the ability to simply dispose of product-contact surfaces after use of related equipment. Other meeting attendees cited faster changeover and lower staff training requirements as advantages that single-use technology could create in fill–finish operations (3).
Case Study: BPI has addressed this topic before. In April 2010, for example, John Boehm of Colder Products Company wrote, “Product safety concerns and overall value are highest during final formulation and dose filling. Like other applications, traditional filling processes involve stainless steel equipment connected through reusable valves, rigid tubing, and steel piping. Single-use technology can be integrated in the form of bulk storage containers, filters, tubing, connectors, and even disposable filling manifolds to minimize contamination risk and reduce operational downtime” (5).
Boehm illustrated a filling operation using a disposable manifold system with a sterile filter to transfer drug product between a bulk storage bag and filling equipment in an isolator. To address product quality and reduce waste, both pre-and postfiltration integrity testing were conducted at this final stage. After filter integrity is confirmed, the line to the f lush bag is clamped off, and the filter assembly is aseptically connected to an isolator transfer line. That line can be preinstalled on a vial-filling system using a steam in-place (SIP) connection to minimize downtime. The f low clamp is then opened for filtration to begin. Once filtration is complete, the filter can be removed from the assembly using aseptic disconnect couplings to maintain sterility until postfiltration integrity testing can be performed. By conducting both integrity tests, operators can be assured that product purity has been maintained in the finaldrug formulation so it is ready for release (1). More recent BPI articles from Pall and EMD Millipore have described other approaches to single-use filling (6,7).
Filling machinery maker Robert Bosch Packaging Technology, Inc. introduced its PreVAS family of single-use liquid dosing systems in response to the industry trend toward single-use product path solutions. “The other area we have been working toward,” says marketing and communications manager Tony Miller, “is increasing the flexibility of our filling lines to handle multiple products with one line. This is especially important for contract manufacturers and smaller companies worried about investing in a one-use tool.”
Material Concerns for Biotherapeutics: Cold-chain and other special requirements of biotherapeutics concern fill and finish operations in ways that don't affect most classical pharmaceutical products. As Cook 's Hawkins told us, “designer plastics have emerged because biologics can be sensitive to the glass, silicone, tungsten, and such in some traditional components.” We asked him whether issues such as cold-chain requirements are being dealt with effectively and got a resounding yes: “There are multiple commercial options — or soon-to-be commercial options,” Hawkins said, “for plastic containers and their closures.”
As disposables have become increasingly popular in all phases of biopharmaceutical manufacturing, the technical committee of the Bio-Process Systems Alliance (BPSA) keeps up by forming subcommittees to address best practices for major categories of single-use technologies, including films and containers, filter capsules, tubing, connectors, and fittings. One issue related to disposables that we've explored in depth with BPSA and other groups is test methods for leachable and extractable contaminants that can come from plastic materials used to construct single-use equipment (8,9,10). This complex scientific topic is just as important — maybe even more so — to final-product containers and their closures, but it is beyond the scope of our discussion here. Like many considerations in formulation and inspection of drug products, it varies according to the types of materials and products involved.
Aseptic processing describes the final stage of manufacturing, wherein a sterile (aseptic) product is packaged in a sterile container in a clean, controlled environment using methods and technologies that maintain sterility. The US FDA published a guidance document on aseptic processing in September 2004, which defines asepsis as “a state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product.” Lack of sterility assurance is a major reason for drug recalls.
Many classical pharmaceuticals can be subjected to terminal sterilization procedures. Product containers are filled and sealed under high-quality environmental conditions designed to minimize contamination (but not to guarantee sterility), and those final containers are subjected to sterilization processes such as heat or irradiation. this is not possible with biologics, which are far more sensitive to such procedures. Their formulation, fill, and finish operations must be performed under aseptic conditions. Containers and closures are subject to sterilization separately, then brought together with the drug products. Because no process can sterilize these products in their final containers, it is critical that those be filled and sealed in an extremely high-quality environment.
According to tom Burkett of the Northeast Biomanufacturing Center and Collaborative (www.biomanufacturing.org), the four pillars of a robust aseptic process are personnel training and monitoring; environmental monitoring; facility design and heating, ventilation, air-condition (HVAC) validation; and process simulation (using media fills). Preventing contamination requires understanding its potential sources: personnel, equipment, air and fluids, the drug product itself, containers/closures, and even the outside environment. Anything brought into contact with or in the vicinity of a drug product can be a potential source of contamination. A simple sneeze produces hundreds of thousands of aerosol droplets (some containing spores or organisms) that can attach to dust particles and, without air filtration, remain suspended for weeks. Particularly problematic contaminants include bacterial endotoxins, virus particles, and spores — all are more resistant to inactivation methods than the biologic products themselves! Particles of dust, fibers, or other material from the air have been known to contaminate drug products, with or without microbes or spores present. The more particles are present in its surrounding air, the more likely a product is to get contaminated.
Standards for particulate contamination were initially developed by NASA for lunar exploration and later adopted by the pharmaceutical and semiconductor industries. In addition to gowning and other procedures used to lessen the potential for workers to introduce contamination, environmental monitoring is regularly performed. Typical tests involve contact plates and swabs, and particle counters are useful instruments. Trending data helps companies evaluate disinfection efficiencies and determine whether certain microbes are migrating into their aseptic processing areas. Metabolic-based assays (such as from vendors Biolog and Vitek) and genotypic assays (e.g., MicroSeq from Applied Biosystems) help identify contaminating microbes. The Limulus amebocyte lysate (LAL) assay is used for endotoxin testing — and the FDA has published a guidance on its use. Air, floors, walls, and equipment surfaces are tested and regularly cleaned. Disinfectants used to clean potentially contaminated surfaces include alcohol, chlorine dioxide, and aldehydes, as well steam-in-place/clean-in-place (SIP/CIP) utilities for reusable equipment. Small instruments and accessories can be autoclaved. Many companies minimize cleaning efforts with disposables. Isolator technology has been very helpful as well.
Facility designs incorporate cleanrooms to establish aseptic areas and combinations of filtration, air exchange, and pressure differentials to maintain a clean environment. Lower-quality clean areas (higher classifications) should not be placed next to high-quality areas (lower classifications). Sterilizing filters clean the air as well as product formulations before fill and finish. They are validated with challenge testing that involves model organisms and contaminants. Media fills are performed using the same process as will be used in a real product campaign, and the resulting containers are monitored for signs of microbial growth.
Burkett says, “All personnel authorized to enter the aseptic processing room during manufacturing should participate in a media fill at least once a year, and their participation should reflect the extent of their duties in production.”
Labeling and Anticounterfeiting
The fight against counterfeiting involves companies far beyond pharmaceuticals and biotherapeutics. Many products are sold to unsuspecting consumers as “authentic” when they are, in fact, “knock offs” or counterfeits (11). But the drug counterfeiting industry threatens lives as well as profits. The pharmaceutical industry as a whole has been developing tools to combat drug counterfeiting. Many of us have heard frightening accounts of mail-order delivery of incorrect product concentrations — and even horror stories of counterfeit products making their way into legitimate pharmacies. Increasing the economic threat posed by counterfeiting is the attraction of high-value biotherapeutics compared with those of “classical” pharmaceuticals. Biologics are almost always injected parenteral dosage forms for which a single dose can cost >US$1,000, and some are even more expensive. Enbrel etanercept injection, for example (Amgen/Pfizer), reportedly cost ≥US$1,500/month in 2009 (12), and Dendreon's recently approved Provenge immunotherapy for late-stage prostate cancer is widely reported at >$90,000 for a one-month, multiinjection regimen. So there is considerable profit to be made through criminal means — and therefore considerable risk associated with not protecting such products against counterfeiting
The Structured Product Labeling (SPL) document is a mark-up standard approved by Health Level Seven (www.hl7.org), the global authority on standards for interoperability of health information technology, with members from more than 55 countries. This standard was adopted by the FDA as a mechanism for exchanging product information (13). The agency has established its own Step-by-Step Instructions for Creating Structured Product Labeling (SPL) Files for Drug Establishment Registration and Drug Listing. That document lays out rules for establishing computerized (generally bar-code) labeling, which is unique not only to each drug type, but also to each batch and each individual vial or syringe. Both industry and the agency hope such efforts will make it difficult to impossible for criminal enterprises to sell counterfeit injectable drugs.
The US FDA states online (12): “Counterfeit medicine. .. may be contaminated or contain the wrong or no active ingredient. .. could have the right active ingredient but at the wrong dose.” The agency takes all reports of suspect counterfeits seriously. To combat this crime, the FDA is working with other government agencies as well as members of the private sector to help protect the US drug supply from the threat of counterfeits. In 2009, it issued a draft guidance for industry on drug anticounterfeiting — though that focuses solely on orally administered solid dosage forms. It suggests, among other things, “use of inks, pigments, flavors, and other physical-chemical identifiers (PCIDs) by manufacturers to make drug products more difficult to duplicate by counterfeiters, and to make it easier to identify the genuine version of the drug” (13).
But what about biologicals — products that don't arrive as distinctly shaped or colored tablets or flavored oral formulations? Biopharmaceutical companies must focus on advancing labeling and RFID technologies. Many service providers specialize in creating labeling systems for parenteral products (see the “Labeling” box). And questions are already being asked about how existing labeling requirements will be applied to marketed biosimilar products.
By contrast with single-use technology, fill–finish was an early manufacturing process to become automated. “Most of the systems we build today require minimal human interaction during the filling process,” Bosch's Miller told us, “with the exception of loading raw materials, systems changeover, and cleaning.” Craig Mastenbaum of Oso Biopharmaceuticals said that “new innovations to fill– finish equipment have evolved in a linear and progressive manner.” New delivery methods — such as prefilled syringes rather than vials or ampules from which syringes are filled in a clinical setting — have necessitated few changes in filling operations (see the “Prefilled Syringes” box).
PREFILLED SYRINGES:THE NEXT STEP in LYOPHILIZATION
Lyophilization — freeze-drying — is beneficial for products with stability problems or when providing an exact dosage is challenging (e.g., very small and highly concentrated doses or those for which absolute precision is vital), as well as for substances that are sensitive to heat, humidity, and/or oxygen. this is a three-step process: freezing (a product frozen in its final container as low as –60 °C), primary drying (using a vacuum, water and/or diluents are extracted from the formulation), and final drying, which produces a porous, stable, and dry “cake.” this can take two full days depending on the compound and drug-delivery system involved.
Unlike ambient and high-temperature drying methods, lyophilization protects drug products from denaturation caused by heat because they remain frozen throughout the process. With proper storage, the shelf life of a freeze-dried product can be three years — rather than a few days for the same drug in liquid form.
According to Vetter Pharma International GmbH, a recent Visiongain report (June 2010) estimated that half of the injectable drugs approved over the next five years will require lyophilization. Vetter's expertise includes lyophilization and complex biological compounds, having begun freeze-drying such products in 1981. The company has recently introduced dual-chamber technology through its Lyo-Ject syringe and V-LK cartridge dual-chamber systems. Lyophilized drug resides in one chamber; diluent in the other. Pushing the syringe plunger mixes those with one stroke. A drug that is currently packaged in vials may be transferred to such a system, for example to make it more user-friendly as part of a lifecycle management plan. this may pose a solution for some innovator products facing biosimilar competition.
“Despite some changes to end products delivered to consumers, the actual filling process remains relatively unchanged,” Miller added. “The few adaptations that have been needed to run novel solutions have been accommodated relatively easily. Processing dual-chamber cartridges is one example. This type of device contains two separate products in one cartridge, such as two separate liquids or a liquid and a lyophilized product.”
We asked Hawkins whether he thinks robotics and other automation will replace human operators. What functions will remain in human hands for the time being, and what training issues have arisen to meet those needs? “Automation is welcome,” he replied. “Ideally, qualified and trained operators should control as well as monitor automated equipment operations — as well as feed and remove components from the line/equipment. Automated equipment will require a higher level of understanding and comfort level with an interface than mechanical, hands-on adjustments.”
To the same question, Mastenbaum commented, “Automation has had a major effect in reducing the number of human operators over the past 30 years. A fill–finish line feeding a lyophilizer may have had eight to 10 human operators 30 years ago. Newer equipment that takes advantage of modern advances in technology may use only two or three human operators. Some specialty lines use only one human operator. However, as good as modern automation is, there will continue to be the need for human intervention with respect to problem resolution and maintenance of the equipment.”
We also asked what new issues are arising as, for example, robotics are used to “visually” inspect final products. Hawkins responded: “No question that automated inspection provides a more robust and consistent inspection for all drug product defect criteria. I would expect that as container shapes and materials evolve from traditional glass, handling mechanisms will need to adjust to perform the inspections, not scratch material, and transport units effectively.”
And Mastenbaum cautioned, “For some time, automated inspection equipment has been on the market. Great care must be taken when purchasing specialized inspection machinery because it is difficult to change vial sizes or defect categories without specialized assistance from the equipment manufacturer.”
Quadrel Labeling Systems offers a pressure-sensitive rotary system that features programmable bottle platforms. It can accommodate up to four label applicators and applies front/back, wraparound, neck, and/or spot labels on up to 250 containers per minute.
Axon Corporation's Aurora line of shrinksleeve applicators feature PackML programming and Allen-Bradley control technologies. A combination of mechanical design, programming, and control significantly shorten machine delivery times, creates an easily customizable modular platform, and provides high-performance servo-controlled applicators. They use color touch-screen human–machine interfaces (HMIs), programmable logic controllers (PLCs), and communication hardware. Find more information online at www.axoncorp.com.
Labeling Systems LLC's Model 1400 corner-wrap system can be configured to apply labels to the leading/side panels or trailing/side panels of a box. Suitable for most corner-wrap applications, this system can be designed to fulfill e-pedigree or track-and-trace initiatives. Interfacing with third-party data management, the labeler uniquely marks and identifies each product and case as a unique and individual unit for tracking and tracing products throughout the distribution chain. Individual product units are encoded using radio-frequency identification (rFID) tags with unique identifiers or serial numbers. Units are typically gathered into bundles and packed into a case. the cases are then introduced to an LSI Model 1400 case labeling system. Data are transferred to an LSI print-and-apply labeling head, which prints a label and encodes a second embedded rFID tag. A final label is applied to the case before it continues down the line, where an rFID reader reads encoded tags on both the case and individual units inside it. this system aggregates case-label information with that for individual products and stores all information on a third-party server for archival record keeping.
Who Specializes in Biopharmaceutical Labeling?
Serving the United States, European Union and global markets, ALMAC performs secondary labeling and packaging of biopharmaceutical products in vials, ampules, and cartridge formats. The company labels and packs refrigerated drug products from two dedicated lines for just-in-time supply to market. Supported by an in-house package design team, ALMAC customizes packaging to facilitate multicountry supplies, allowing for country-specific and blue-box information to be added online or at dispatch. The company considers itself expert in product launches for european markets, particularly orphan-drug launches and niche biologics. It offers significant 2–8 °C storage capacity and client-dedicated –80 °C freezer capacity. Third-party logistics services extend labeling and packaging to distribution of products to end users.
AAIPharma Services “recognizes that packaging and distribution are critical next steps after painstaking biological drug development and manufacture.” For clinical trial supplies, the company provides custom packaging, labeling, and kitting services — including distribution and quality services for materials destined for studies anywhere in the world. The company can also package and label commercial supplies manufactured in-house or supplied by third parties.
Boehringer Ingelheim's biopharmaceutical operations in Biberach, Germany, supplies liquid and lyophilized preparations in vials and prefilled syringes. The company covers the entire fill–finish chain from filling through lyophilization, visual inspection, and labeling, to packaging. Find more information online at www.boehringer-ingelheim.com.
Next Generation Pharmaceutical's Torbjörn Gunnarsson says, “Within the labeling and packaging area, increased demands for more information on packages — and often also requests for multilanguage versions — create demands of extended patient product information. A challenge in some situations is how to add and handle these requests on an already small package. Use of a booklet label is a possible solution. Problems with counterfeiting are increasing dramatically. Demands for track-and-trace within the logistic supply chain and securing authentication of products need solutions. technologies using two-dimensional barcodes, rFID, and other security features to creating smarter labels and packaging solutions will have an impact. Authorities globally are looking for how to prevent such problems through recommendations, directives, and even legislation. Braille marking is another issue, as well as design for child-resistant and safe solutions and senior-friendly packages.” For further reading, check out his article online: www.ngpharma.eu.com/article/the-challengesof-biopharmaceutical-manufacturing.
Because filling was one of the first process steps to be automated, BPI asked a number of people whether companies had encountered difficulties as new innovations in packaging and delivery were developed. Mastenbaum said, “New equipment can minimize waste while maximizing the theoretical yield of a batch to be produced. Newer equipment can also adjust fill volumes while in operation after [the equipment] detects data trending in one direction or the other. The biggest issue for any organization is in determining when to pull the trigger and spend millions of dollars to upgrade equipment systems. This can be done using both the classic return-on-investment model and a risk-assessment model.”
The ability of fill–finish systems to benefit from technology innovations can influence their initial design elements. For example, the Filamatic website (www.filamatic.com) touts that the company's use of servomotor motion control technology in fill–finish packaging machinery “will provide for system reconfiguration in reaction to delivery or packaging innovations.”
Hawkins presents a different view: “The opportunity to make new innovations easier to deal with, from an automation standpoint, is in having some kind of standardization. Unfortunately, that efficiency or effectiveness often doesn't come at the beginning of a product lifecycle ‘curve.’” We asked what kinds of challenges have been met and resolved and what are still puzzling industry. And he offered, “Speed of processing — automated handling — is a challenge that has been met and resolved. Although good work has been done, more work is needed on extractables/leachables, disposables, timely decontamination for barrier isolators, and online residual monitoring (such as vapor hydrogen peroxide), to name a few.”
CMO Perspectives: the Future of Fill and Finish
BPI asked a number of people what additional advances in fill and finish need to be addressed. Oso Bio's Mastenbaum told us that although newer equipment can fill containers faster with less waste, companies need to assess whether they are ready to invest “millions of dollars associated with the new equipment and also must take into consideration the time necessary to validate that new equipment and receive approvals from various regulatory bodies.”
“I am unaware of any significant changes in GMP requirements,” Miller said. “However, we have noticed that many of our customers are taking a proactive approach: including aseptic barrier systems on their filling equipment to reduce potential contamination and perhaps keep ahead of the curve. Most such systems are fitted with air-quality measuring devices to monitor environment inside the barrier.”
What about the expected move to smaller runs as a result of personalized and more specialized medicines? Miller told us, “There has been an overall trend in the industry for smaller, more flexible systems. This has lead to development of several new systems and innovations in the machinery.” And Mastenbaum pointed out, “The move to smaller batches has forced many companies to be much more efficient than in the past. Smaller runs mean more frequent changeovers, more batch documents created, and more lots to be released. Use of six-sigma techniques to minimize and/or eliminate process errors is a key to moving in this direction.”
FILLERS and FINISHERS
In addition to companies mentioned in the text, the following offer expertise in final filling systems/equipment, technologies, and procedures for biopharmaceutical operations. Given the range of product classes and contractor specialty areas throughout the industry, this is not an exhaustive list.
Althea Technologies www.altheatech.com/aseptic-fill-and-finish/overview
Avrio Biopharma www.avriobiopharma.com
Boehringer Ingelheim www.boehringer-ingelheim.com/contract_manufacturing.html
Corden Pharma Switzerland LLC www.genzymepharmaceuticals.com
Elan Drug Technologies www.elandrugtechnologies.com/manufacturing
Enzon Pharmaceuticals, Inc. www.enzon.com
Fisher Clinical Services www.fisherclinicalservices.com
GEA Process Engineering Inc. www.niroinc.com
Lonza Viral-Based Therapeutics (following acquisition of Vivante GMP, Inc.) www.lonza.com/viral
Omnia Biologics www.omniabiologics.com/filling.shtml
Recipharm Cobra Bio www.recipharm.com/en/biologics
Vetter Pharma International www.vetter-pharma.com
West Pharmaceutical www.westpfssolutions.com
Hawkins added, “From a contract manufacturing perspective, we are accustomed to seeing a wide range of batch sizes. Quick changeovers and working effectively with smaller run sizes have always been part of providing that service well. But making more batches with the same capital equipment requires technical transfer, analytical, operational, and quality functions to reach a new level of throughput.”
Still Outsourced? Are biopharmaceutical manufacturers still primarily using CMOs for fill and finish operations, or do those smaller runs allow companies to bring such operations in house? Miller summed up the basic trade-off: “Contract manufacturers do play a big role in the bio and smaller pharma companies that may not have the ability to invest in expensive facilities and equipment to package their products. Many larger pharma companies essentially have their own in-house contract packaging services, allowing them to save on third-party costs and control the process better.”
“OsoBio is a contract manufacturer,” Mastenbaum reminded us. “We see trends showing greater use of CMOs by both small and large proprietary drug companies.”
And Hawkins agreed: “Smaller companies typically do not have the infrastructure to perform manufacturing, no matter the batch size. To have fill–finish manufacturing capabilities is still a very expensive proposition. Most companies are dialed in to what they do best and where they add value as a business. As a result, we see indications of more and more outsourcing of all types, including fill-finish.” It comes down to knowing your core competencies and realizing what others can do better. Aseptic processing is a stringently controlled endeavor, much like viral safety testing upstream of the process, so many companies would rather leave it to those with the necessary infrastructure and expertise.
We wondered whether adequate technologies exist to detect biocontaminants — or whether that is becoming less of a problem as technology replaces humans in functions such as visual inspection. And Hawkins echoed Miller: “Barrier isolators and closed restricted-access barrier systems (RABS) provide the highest level of aseptic processing because of the ‘removal’ of people from the immediate aseptic filling zone. No doubt this helps ensure fewer problems and possible contaminants are mitigated.”
Recent conferences have generated speculations about replacing visual (human) with robotic examination of finished vials. Increasingly sensitive analytical technologies may reveal contaminants and particulates that have existed all along in marketed products but were undetectable until recently (14). Companies are now trying to further characterize those particulates and evaluate their impact, if any, on product stability, safety, and efficacy. If a commercial product has yielded no adverse patient reactions, can such particulates be ignored — and how much data and documentation will the FDA expect to see for such a decision to justified? BPI is scheduled to publish a consensus paper from the 2011 CMC Strategy Forum on this topic later this year.
Lorna McLeod is a contributing editor, S. Anne Montgomery is editor in chief, and Cheryl Scott is senior technical editor of BioProcess International.