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Improvements to aseptic manufacturing procedures are long overdue. But how feasible is it for manufacturers to modernize fill lines of legacy products?
The demand for fill/finish services has significantly increased in recent years, according to Peter Pekos, president and CEO at contract manufacturing organization (CMO) Dalton Pharma Services, and many companies have expanded capacity to meet that demand. Don Paul Kovarcik, technical marketing specialist from CMO Ajinomoto Althea, Inc., estimates that just about every large biotech/pharma company has some fill/finish capabilities, regardless of if they outsource these services or not. BioPlan Associates asserts that that fill/finish operations are the most heavily outsourced operations. According to a 2016 estimate from BioPlan, nearly 36% of fill/finish operations in the biopharma industry are outsourced, trumping other popularly outsourced services such as analytical testing, toxcity testing, plant maintenance services, and API biologics manufacturing. Greater than 74% of respondents indicated in 2016 they outsource at least part of their fill/finish activities (1).
In general, innovation in fill/finish is low on manufacturers’ priority lists, even though this processing step is a crucial part of a manufacturing lifecycle. Although some novel delivery systems and combination products have been introduced, the aseptic portion of the medicine-making process has, for the most part, remained relatively unchanged.
Advances in automation and barrier isolators have been touted by FDA as best practices to keep drugs sterile (2). The US government has also recently been involved in many initiatives to proactively set up fill/finish facilities to meet pandemic demand in the event of an outbreak--but these initiatives rarely involve a large number of companies that are focused on fill/finish activities. Because pandemic vaccines require production batches in the tens of millions and require high-capacity filling lines, says Kovarcik, public-private partnerships are typical to ensure security of supply. Kovarcik adds that traditional manufacturers and CMOs would suffer financially if they undertook these types of ventures, as the “overhead associated with underutilized facilities can have a strong negative impact on the financial performance of a company.” Says Pekos, “There are economic challenges for companies engaged in the development and manufacture of effective vaccines--as soon as the outbreak is under control, the funding also fades.”
Nonetheless, improvements to fill/finish operations could benefit businesses involved in the manufacture of biopharmaceuticals and prevent more quality-based drug recalls. Outlined below are ways to improve operations and possible disruptions that could impede otherwise seamless fill/finish business operations.
Closed aseptic processing systems are preferred over open systems. This preference can be a problem with owners of manufacturing sites that do not want to modernize. According to a DME white paper, a survey carried out to gauge the views of manufacturers on the latest trends and technologies affecting the life-sciences industry showed that nearly half of survey respondents said they would use isolators if and when they modernized legacy manufacturing facilities (3). The DME report also stated that nearly 80% of survey respondents plan to upgrade their facilities within the next 10 years.
Drug manufacturers or CMOs choose whether to use restricted access barriers (RABs) or isolators based on user requirements and intended applications, says Simon Cote, principal engineer at West Pharmaceutical Services, Inc. Isolators are commonly used when campaigning is occurring, where the manufacturer is running batch after batch of a drug product and only changing the liquid contact path, or in any scenario where increased drug product and operator separation is required. Conversely, RABs are often considered more flexible and are used when lines need to be frequently changed over to accommodate different drug products or packaging components.
Fill/finish operations were reportedly among the first in the bioprocess chain to become disposable, according to Eric Langer of BioPlan Associates (1). The use of single-use product contact parts and the clean-in-place (CIP) of non-contact parts inside of barriers, specifically, are two promising ways to keep fill/finish systems sterile, says Hite Baker from facility engineering firm DME. Some companies acknowledge, however, that single-use systems may not be the best option (or the most practical) for all organizations or all drug products. “Single-use systems are enormously flexible, enabling a great deal of customization with a wide variety of parts,” note Martin Gonzalez, PhD, senior group leader of R&D, and Matt Dunlavy, principal engineer, both at Pfizer CentreOne, a global contract manufacturer that focuses on API synthesis and fill/finish for sterile injectables. “For CMOs, that flexibility adds much complexity from a purely practical standpoint. Procurement, validation, and compatibility studies are multiplied across potentially hundreds of different single-use parts and partner projects.”
Gonzalez and Dunlavy state a typical batch of a biologic uses a wide variety of single-use components (from tubing, aseptic connectors, and pump diaphragms to disposable packaging to ship APIs). The company says some of the filling lines at its facility in McPherson, Kansas are capable of using complete single-use systems, “from accepting a preformulated bulk in a disposable bag, to the connecting tubing sterile filtration units, sampling ports, waste lines, pumping system, and filling needles.”
Bosch’s prevalidated, preassembled, presterilized single-use filling system (PreVAS)--developed in partnership with Sartorius Stedim Biotech--is a gamma-sterilized system that can include all of the elements necessary for a filling operation. The company also recently released a fully mobile pump trolley that can be rolled to existing fill lines and hooked up.
Kovarcik tells BioPharm International that Althea has transitioned exclusively to single-use disposables for components that are in direct contact with product. Although there are many known benefits of single use, Kovarcik also admits, “single-use components are not always the most cost-effective option and in fact, don’t make sense from a cost perspective at a certain scale for particular products.” Thus, some stainless-steel parts may never truly become obsolete.
A general guideline for the use of disposable technology is that it is most suitable in fields where drug substances come into direct contact with equipment, says Bernd Stauss, senior vice-president of pharmaceutical production/engineering at Vetter. This would impact areas in which API and excipient weighing, material preparation, compounding, filtration, and general filling typically occurs. “Another general guideline with regard to the size of the run is that the smaller the volume of processed units, the more suitable disposable systems usually are,” Stauss adds.
In sum, Baker estimates that single-use filling using a disposable wetted path makes up approximately 30% of new filling line sales. Chris Procyshyn of aseptic filling machine manufacturer Vanrx Pharmasystems guesses that, currently, about 50% of companies use completely disposable filling systems. Because single use eliminates the need for cleaning and related validation, the cost savings of disposable systems are notable: “No significant capital investment is required for most of the systems,” says Procyshyn. As such, “we should see wider applications of the single-use fill/finish systems in the future, especially by contract research organizations (CROs), to provide responsive and economic manufacturing solutions.”
As single use becomes more prevalent, validation activities may change. If single-use connectors are polymer-based, Cote stresses these change parts must be thoroughly characterized to assess the potential impact of leachables on the final drug product. “Process validation is managed differently because these change parts are effectively new every time, thus requiring a larger statistical sampling to ensure a controlled and validated process. In addition, scrutiny on the change parts supplier must increase, typically through supplier agreements and incoming inspection processes.”
Gonzalez and Dunlavy say the CIP of non-product contact parts “can be difficult to manage inside the filling room Grade A areas,” and change parts must be washed and sterilized independently from the machine. Gonzalez and Dunlavy explain that rather than cleaning the parts in place, a better approach would be “to remove the parts from the line, place them into automated CIP washing cabinets in Grade C or D areas, then re-enter Grade A via steam-sterilizing autoclave for RABS applications or vaporized hydrogen peroxide chamber for barrier isolator applications.” Cote concurs that RABS are not easily cleaned in place given that they are “intentionally not airtight” and are meant to exchange air with the surrounding environment. Cote also points out that the use of vaporized hydrogen peroxide as a decontamination agent cannot be readily used to support the CIP process for RABS, which can be another limiting factor.
According to Stauss, the “era of blockbusters and their corresponding high-volume requirements” contributed to the boom in automation within the direct filling process. During a session at INTERPHEX 2016, Hite Baker suggested removing human intervention from the fill/finish process altogether. The feasibility of such a suggestion is a popular topic among industry professionals. Many contend that fill/finish operations are already largely automated. Anthony Cannon, head of drug product technology at Samsung BioLogics, for example, estimates that 40% of tasks have already been automated. Gonzalez and Dunlavy say, “Automation and validated control systems are essentially now a regulatory expectation for critical processing steps involving sterilization of product contact equipment and components.” In fact, according to a DME report, “manual batch washing, depyrogenation of glass vials, and manual loading of lyophilization cabinets” should be avoided in modern facilities, as these “manual processes are among the weakest links in the aseptic chain in legacy sterile manufacturing facilities.”
Automated systems typically include environmental monitoring filling machines with tool-less changeovers, single use, dosing, in-process weight checks, self-adjusting fill volume controls, and blow/fill/seal operations. Even visual inspection can sometimes be relegated to machines. As Cote notes, excluding all testing, inspection, and documentation management, only a few operators are typically required to run the fill line. As Klaus Ulherr, senior product manager at Bosch Packaging Technology observes, “No one line is currently able to run completely without an operator; someone is still needed to start and stop the line, to perform viable monitoring, to survey the processes, and to perform required format changes.” Although completely automated machines exist, Cote says these models require all packaging formats to be ready-to-use and they must be in a nested configuration.
Replacing manual operation in clinical manufacturing and for the manufacture of small batches of high-value products is not recommended nor ideal, say many industry professionals. “To be responsive to customer needs and to control development cost, manual processes for fill/finish are frequently applied for the manufacturing of small batches of clinical supplies at the early stages of drug development,” says Pekos. As Stauss notes, manual handling of small volumes of a few hundred units “often makes better sense as compared with the time-intensive efforts associated with the installation of high-tech automatic-focused operations.”
“In some cases, manual operation may actually be preferred,” say Gonzalez and Dunlavy. “For complex biologics with very expensive, small batch sizes, [manual operation] may be advisable and provides a sense of comfort to have experienced subject matter experts directly involved throughout the manufacturing process--at the shop floor, in the aseptic areas, and in support and management functions.” Additionally, for facilities that produce large quantities of a large range of products, Gonzalez and Dunlavy say, “intensive automation may be out of reach, due to the large capital investment needed and longer, more complicated implementation and validation requirements.”
A promising long-term strategy to formulate and fill sterile drug products is to increase the use of a robot inside a barrier with no glove port access, according to Baker. Gloves are a weak link, and experts predict there will be fewer glove ports in aseptic manufacturing in the future. But, Baker says, pharma is painfully slow at implementing new technologies, even though he said during a presentation at the INTERPHEX 2016 meeting that “nirvana may be gloveless isolators for aseptic filling.” Suppliers said in the DME report that puncture-resistant gloves would be a top, most-desired advancement. The report noted that there is currently “no recourse until robots replace glove ports, and/or new material science gives the industry a puncture-proof glove” (3). Glove ports need to be inspected on a daily basis and are a common cause of system failures (4). There is a strong, growing trend toward the use of gloveless isolators. Procyshyn says that gloveless robotic systems are capable of reducing the personnel requirements from a traditional isolated line of four to six operators to a single operator. “In a gloveless robotic system, the robotics are used to conduct aseptic interventions, if any are necessary,” comments Procyshyn. “Initial use cases for gloveless robotic isolators include filling potent or cytotoxic products, or for small batch production of sensitive biologics or cell therapies.”
Many of the experts agree that the introduction of 100% automated weight checks for dose control and the net-weight filling at the beginning and end of batch processing have increased the reliability of filling machines greatly. In addition, the introduction of adaptive or flexible fillers that can accommodate a variety of container types in the same line has been an important innovation, observes Cote. Being able to use different types of packaging on one platform has been extremely helpful, especially in the case of containers with multiple chambers, says Pekos. A dual-chamber container (where one is filled with diluent and the other with powder, for example) can either be filled by manual processing or by use of a specifically designed system--and Pekos asserts demand for innovation in this field is growing.
Rapid air locks have also helped to eliminate some capping issues when finishing a product. “Another relatively recent change in the fill/finish operations has been the requirement to cap vials within Grade A air (supporting the change to Annex 1 of the EU GMP regulations),” says Cote. As a result of this new requirement, he says, “The layout of filling lines and processes and procedures dictating the capping operations had to change.”
Improvements to barrier integration, dosing pump accuracy, sensor/automatic feedback controls, and other engineering design enhancements have helped drive recent fill/finish progression, say experts. Cannon lists modular isolator filling lines, ASEP-TECH filling lines (blow/fill/seal), and new innovations in glass formulation as emerging trends in fill/finish. As Gonzalez and Dunlavy conclude, “Quality and compliance are continuously improved by feedback from fill/finish machine users and customers, regulatory guidance, and industry benchmarking.”
Specific indications, or the addition of a new indication for a product, may trigger some changes to existing fill/finish procedures. The fill volume for certain products has, in the past, had to be validated as a result of FDA mandates. In 2012, the approval for ThromboGenics’ Jetrea (ocriplasmin) for the treatment of symptomatic vitreomacular adhesion required a post-marketing feasibility adjustment “to adjust the drug product final fill volume or concentration to reduce the likelihood that more than one patient could be dosed from the same single use vial due to excess reconstituted drug product remaining in the vial after the initial dosing” (5). FDA was concerned a larger fill size for Jetrea would encourage re-use of the product. Gary D. Novack, PhD, wrote in The Ocular Surface, “Pharmaceutical firms need to continue to be mindful of the needs of patients in providing the most appropriate container/closure systems and fill volumes for convenient and compliant use relative to the indications” (6).
Equipment may need to be modified to accommodate new fill volumes, as some lines may not be able to handle multiple fill volumes, say Gonzalez and Dunlavy. “Such circumstances require new engineering runs to assess a fill-line change, proper handling by the filler machine at the new proposed fill volume, and a new container.” Comments Kovarcik, “Depending on the nature (level) of the change, data required typically include additional aseptic process simulation for the new container size, supplemental stability data for the new packaging configuration, confirmation of container closure integrity, and packaging material compatibility with the drug product--and the changes would need to be filed with FDA.”
Gonzalez and Dunlavy explain that for lyophilized parenterals, a change in volume will also have implications. Vial size changes often require changes to the lyophilization process, and it may be necessary to request new container sizes from glass manufacturers with specific dimensions. “Such steps could require several months of development work--and enough API to perform the necessary studies,” Gonzalez and Dunlavy state. “Furthermore, samples produced using the new container size and/or new lyophilization cycle need to be placed on stability and tested to ensure changes do not adversely affect product quality, safety, or potency.” Although some changes (such as a change in a glass supplier) could be communicated via a company’s annual report, others, such as the change in size or shape of a container, have to be accompanied by a Prior Approval Supplement to FDA.
Creative solutions to solve fill/finish problems do not just lie with improvements in machines and equipment. Operational improvements must also occur to prevent disruptions in commercial business. For example, splitting the manufacturing and fill/finish operations up into two separate locations can be problematic, in some cases. The dangers of breaking up these processes are driven by an increase in the number of steps involved to get to a finished product. Some of the major challenges associated with outsourcing fill/finish include “streamlining the manufacture activities of the parent company with the fill/finish operation of the third party, sharing product and process knowledge with the third party, integrating quality system and requirements, and effectively managing logistics,” says Pekos.
Gonzalez and Dunlavy point out that sufficient communication between the parties can mitigate the risk associated with outsourcing fill/finish: “For example, if one of our biopharma partners knows that their compound is sensitive to light and prone to oxidation, we want to know upfront. That way, right from the outset, we can plan proper control of bulk and final container headspace to prevent oxidation or light-induced degradation, and determine if we need to dim or apply filters to the filling room lights.” They add, “The more we know, the better we can recommend the appropriate fill/finish strategy and equipment, and develop manufacturing and validation plans that safely control product sensitivities.” Kovarcik asserts that even within the same company (between different sites of operation), there can be the same risks for packing, handling, storage, and transfer as there could be with working with a CMO (see Sidebar). Contends Kovarcik, “if validated procedures are in place and you are working with trusted and reputable shipping vendors,” the distance between third-party sites doesn’t present any additional risk.
Many product recalls that have recently been in the news center around particulates in vials that appear to be glass in origin. Mechanical causes for glass particulates can include shipment, abrupt heating or cooling, pinch points in a filling line, lowering of lyophilization shelves to stopper vials, capping issues, a blockage in a line resulting in a breakage, or a fall within a depyrogenation tunnel, says Cote. But, Cote also says that the creation of glass particulates due to chemical interactions of the glass and drug product are even more difficult to address, as these particulates--also known as delamination flakes or lamellae--are harder to identify. The flakes shed from the interior of glass containers under certain conditions such as high pH, high salt concentrations, high temperature, aggressive washing or depyrogenation, freeze-thawing, and the presence of certain excipients or buffers (such as citrate or tartrate) in a drug product. Drug products exposed to the inner surface of containers for extended periods of time, stored at room temperature, or those that have been terminally sterilized are also at a higher risk of potential for lamellae formation (7). While USP <1660> provides a method to evaluate glass for potential delamination, this test is accelerated and may not represent the actual shelf life of a specific drug product, according to Cote. Even though the glass lamellae can often be the reason for a major lot recall, Pekos reports that to date, “no adverse events have been reported nor can be directly attributed to glass lamellae in injectable drugs.”
An alternative polymer-based container could be a viable solution, as Cote points out: “Given the industry’s concern over glass particulates, the use of polymer-based containers has grown considerably.” Kovarcik says glass is currently three to four times less expensive than other options and Gonzalez and Dunlavy assert that glass is still the preferred material for vials “due to its perceived inertness and compatibility.” However, Gonzalez and Dunlavy add, “Many companies are making great efforts to put biologics into plastic containers such as clear olefin polymers (COP) to reduce the potential for delamination and the need for siliconization. But these materials can lead to product oxidation from gas permeation, [which is] a challenge to protecting sensitive compounds.” In addition, states Kovarcik, “the pharmaceutical industry is conservative and change is difficult--other materials could prove to be superior, however, it will require time for adaptation.” Pekos says he expects packaging changes to occur gradually, as it will “be costly and time-consuming to introduce new packaging materials for existing, legacy products due to post-market filling requirements.”
1. BioPlan Associates, Inc., Thirteenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2016.
2. FDA, Pharmaceutical cGMPs for the 21st Century--A Risk-Based Approach, Final Report, (Rockville, MD, Sept. 2004), accessed May 6, 2016.
3. H. Baker, DME, “Facility Focus: Trending Technologies in Aseptic Manufacturing Facilities,” White Paper, April 2016.
4. R. Hernandez, BioPharm Int. 28 (11), pp. 14-19 (2916).
5. FDA, Application Number: 125422Orig1s000, Approval Letter for Jetrea (CDER, Rockville, MD, Oct. 17, 2012), accessed May 6, 2016.
6. G.D. Novack, The Ocular Surface 11 (4), pp. 285-287 (2013).
7. FDA, Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance--Control of Components and Drug Product Containers and Closures, (Rockville, MD, Aug. 4, 2004), Accessed June 24, 2016.
Vol. 29, No. 9
When referring to this article, please cite as R. Hernandez, "Parenteral Advisory: Outmoded Fill/Finish Technology," BioPharm International 29 (9) 2016.