Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

 on Jan. 5, 2016 that Regeneron and Sanofi must pull the monoclonal antibody (mAb) Praluent (alirocumab) from the market because it allegedly infringes two Amgen patents that describe and claim monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9). Amgen has a similar mAb on the market that treats heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), and clinical atherosclerotic cardiovascular disease.

	Both Praluent and Repatha facilitate the removal of low-density lipoprotein from the blood by blocking the protein PCSK9. Compared with placebo, Repatha reduced low-density lipoprotein (LDL) by approximately 60%, while trial participants taking Praluent had an average reduction in LDL cholesterol ranging from 36–59%. PCSK9 inhibitors are thought to help reduce the risk of a cardiovascular event, although investigations about this assertion continue.

	The move is surprising, especially considering Regeneron’s cholesterol-lowering medication 

, nearly a month before Amgen’s Repatha (evolocumab). Although Amgen’s drug initially had an action date before Regeneron’s version, Regeneron’s inhibitor received Priority Review from FDA as a result of a voucher 

 from BioMarin for nearly $68 million. To add another wrinkle, Amgen’s Repatha was actually approved in Europe prior to either drug’s approval in the US.

	According to an Amgen press release, Sanofi and Regeneron actually admitted in some capacity that they had infringed Amgen’s patents in the manufacture of Praluent. Regeneron countered in a press release, however, that it believes Amgen’s patents to be invalid because they exceed the scope of the original discovery and plans to appeal the court’s decision. In the meantime, Praluent will be pulled from the market in 30 days unless the decision is overturned. Amgen said it could immediately fill the hole in the market and supply its product to patients wishing to switch from Praluent to Repatha.

	Regeneron believes that the products are not equivalent anyway; it argues its product offers a competitive advantage. According to a press release, “Praluent is the only PCSK9 inhibitor that offers two doses with two levels of efficacy, allowing healthcare providers the flexibility to adjust the therapeutic dose based on their patient's LDL cholesterol-lowering needs." An injunction, said Regeneron, would harm the treatment of patients on the low-dose version of the drug. Regeneron also marketed its product as the “first” approved in the US, which Amgen 

 caused “harm to their reputation as the innovator in the PCSK9 cholesterol-lowering medicine.”

	Both drugs are exceedingly expensive, and were tagged as having the potential to be the highest-selling class of medication in history. Praluent and Repatha are currently the only PCSK9 inhibitors on the market. Their approvals caused payers to begin pitting the drugs against one another, effectively lowering the price of both drugs. In the ruling, Amgen said the existence of Regeneron’s drug caused the company “irreparable harm.” Amgen said it would not be pacified by royalties from Regeneron, as Amgen intended to use its patent “to maintain market exclusivity.” 

Articles

A judge ruled that Regeneron’s mAb be removed from the market after Amgen alleged that the marketing of Praluent hurt its reputation as innovator of this class of drugs.

Regeneron and Sanofi Ordered to Withdraw PCSK9 Inhibitor Praluent from Market

	In an attempt to battle low production volumes of hard-to-manufacture biopharmaceuticals, GE Healthcare announced on January 4, 2017 that it will partner with Synpromics on the development of synthetic promotors. The goal of the collaboration is to identify promoters that will work most effectively with GE’s existing expression system for optimal transcription.

	GE will couple its cell line with a library of bar-coded synthetic promoters from Synpromics to improve platform performance. Promoters drive stronger expression levels of a desired protein, so the partnership could help GE strengthen its platform for future manufacturing projects. Synthetic promoters are said to be capable of driving higher expression levels than do naturally occurring promoters. "One of the attractive features of our technology is that we can design synthetic promoters to be active at the desired expression strength...our technology essentially allows us to find the optimal expression level for the particular protein of interest in the environment and cell type of interest,” David Venables, CEO of Synpromics, wrote via email.

	In December 2016, Synpromics announced a similar deal with Sartorius Stedim Cellca. Both the Sartorius and GE projects focus on the discovery of promoters in Chinese hamster ovary (CHO) cells, but Sartorius and GE each have their own proprietary platforms. Synpromics has also created promoters specific to other human cell types, such as liver, skin, lung, cells of the eye, muscle, and cancerous cells.

In an attempt to battle low production volumes of hard-to-manufacture biopharmaceuticals, GE Healthcare announced on January 4, 2017 that it will partner with Synpromics on the development of synthetic promotors. The goal of the collaboration is to identify promoters that will work most effectively with GE’s existing expression system for optimal transcription.

GE Healthcare Looks to Boost Biopharmaceutical Production with Synpromics Partnership

	FDA’s Center for Drug Evaluation and Research (CDER) approved 22 new molecular entities (NMEs) in 2016, according to a January 4, 2016 release from the agency. Of the 22 NMEs, 12 were large-molecule therapeutics. Of CDER’s 45 novel drug approvals in 2015, 17 were considered large-molecule therapeutics (larger than 900 Daltons).

	In 2016, 11 of the 12 large-molecule drugs that were approved were biologics. This includes seven monoclonal antibodies (mAbs), one hormone, and three DNA-derived medications. The remaining large-molecule medication was a diagnostic agent.

	Although the overall number of drugs approved by CDER in 2016 was lower than it was in 2015, FDA officials said the medical value of the medications that were approved was high. The 2016 approvals included the first-ever treatments for spinal muscular atrophy and Duchenne muscular dystrophy. Approximately 37% of the novel drugs approved were the first in their class (as of Dec. 9, 2016).

	The agency also said that CDER approved five novel drugs in 2015 that had Prescription Drug User Fee Act (PDUFA) dates in 2016, which affected overall numbers for 2016. "While the number of novel new drug applications received for review in 2015 was similar to our most recent 10-year average of 35 applications per year, the natural fluctuation of the timing of application submissions and their PDUFA goal dates, meant there was a smaller pool of novel drug applications to target action on than in recent years," wrote John K. Jenkins, MD, director of CDER’s Office of New Drugs, in a FDA blog post.

	Manufacturers should take note, however, as Jenkins asserted that many of the issues listed in the complete response (CR) letters to manufacturers were related to quality. “In examining the deficiencies cited in the CR letters issued to novel drugs in 2016, it is notable that the primary deficiency for several of the applications was failure to comply with FDA’s current good manufacturing practice (cGMPs) regulations.” Jenkins added, “The number of CR letters that cited failure to comply with cGMP regulations was unusually high for a single year.”

	It’s difficult to know exactly what the most common cGMP deficiencies were in 2016, as FDA does not disclose all information in CRs-and even if a sponsor chooses to post about receiving a CR letter, the company does not often elaborate on what the specific deficiencies are or the sponsor redacts certain offenses in official documents.

	In 2016, Sanofi and Regeneron disclosed they received a CR letter for sarilumab (an investigational drug to treat rheumatoid arthritis). The 

 of sarilumab was the root of the problem in that instance. Biopharmaceutical company 

 had a problem with one of its suppliers; this issue was revealed after a site inspection. Drug manufacturer 

 received a CR letter because of an issue with one of its third-party manufacturers. 

 received a CR letter centered around cGMP practices at its Florida facility for an eye drug candidate.

 received a complete response letter from FDA for biosimilar pegfilgrastim candidate (Neulasta), although the company did not disclose the reasons for the letter. Amgen, AstraZeneca, Vertex, Teva, Dynavax, Novo Nordisk, and Takeda were a few of the other pharmaceutical manufacturers that received CR letters in 2016, although the letters were not necessarily issued because of cGMP issues. According to documents from a meeting led by Jenkins, as of Dec. 9, 2016, there were 12 new molecular entity/biologics license applications that received a CR letter in 2016, compared with only two in 2015.

FDA’s Center for Drug Evaluation and Research (CDER) approved 22 new molecular entities (NMEs) in 2016, according to a January 4, 2016 release from the agency. Of the 22 NMEs, 12 were large-molecule therapeutics. Of CDER’s 45 novel drug approvals in 2015, 17 were considered large-molecule therapeutics (larger than 900 Daltons).In 2016, 11 of the 12 large-molecule drugs that were approved were biologics. This includes seven monoclonal antibodies (mAbs), one hormone, and three DNA-derived medications. The remaining large-molecule medication was a diagnostic agent.

Deficiencies in Manufacturing Derail CDER Approvals in 2016

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.

 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.”

	Patient requirements drive change to fill/finish processing

	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 

, “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 (

). 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 

 <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, 

 (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.

	When referring to this article, please cite as R. Hernandez, "Parenteral Advisory: Outmoded Fill/Finish Technology," 

Improvements to aseptic manufacturing procedures are long overdue. But how feasible is it for manufacturers to modernize fill lines of legacy products?

Parenteral Advisory: Outmoded Fill/Finish Technology

	Amgen executives don’t seem too concerned that a viable competitor to the company’s Neulasta (pegfilgrastim) franchise will threaten its 

, the company revealed in a second-quarter investor call on July 27, 2016. The company attributes some of the continued success of Neulasta to its unique drug-delivery system-the pre-timed, worn-on-body injector called Onpro. The adoption of the Onpro system “is growing due to its ability to ensure maximum benefit of Neulasta while improving the patient experience versus the traditional prefilled syringe. We exited the second quarter with Onpro representing about 40% of Neulasta units and still growing,” said Anthony C. Hooper, executive vice-president of global commercial operations. “We do not expect long-acting filgrastim biosimilar competition this year, so there remains a significant opportunity to further increase the adoption of Onpro,” Cooper added.

	Neulasta is a granulocyte colony-stimulating factor that is used to treat neutropenia in patients receiving chemotherapy. Although Sandoz submitted a biosimilar application to FDA in November 2015 for Neulasta, the company recently said in a second-quarter media release that it received a complete response letter from FDA rejecting the application. Meanwhile, the European Medicines Agency agreed to review Mylan/Biocon's biosimilar to pegfilgrastim on July 22, 2016.

Dose accuracy key to chronic migraine medications


	Amgen may rely on an innovative drug-delivery system to eventually market its investigational treatment for chronic migraines as well. It is co-developing 

 with Novartis, which targets the calcitonin-gene-related-peptide (CGRP) receptor, which is thought to be involved in the transmission of pain. In Phase II clinical trials, erenumab was shown to significantly reduce migraine pain in both the 70 mg- and 140 mg-dose cohorts.

	Sean Harper, executive vice-president of R&D, said that he has not seen “any data to suggest that [currently available CGRP inhibitors] are different from one another with respect to what they can achieve when they are dosed and saturating quantity.” Thus, he says, a competitive advantage could lie with how easily administered the antibody is and what would be the minimal dose that would still be effective. Harper concluded, “Let's say we believe a monthly subcutaneous disposable auto-injector would be a very nice solution to this otherwise healthy active type of population.”

Amgen discussed the drug-delivery approaches to two of its biologics in a recent second-quarter earnings call.

Amgen: Neulasta Safe for Now; Dose Accuracy of Erenumab a New Focus

	Merck gave the rights to three sublingual allergy immunotherapy tablets back to Denmark-based manufacturing company ALK-Abello, according to an announcement released on July 27, 2016. The end of the partnership agreement will mean that Merck will no longer hold the rights to Grastek, Ragwitek, and an investigational SLIT tablet. The drugs seek to treat allergies to grass, ragweed, and dust mites, respectively.

	ALK-Abello admitted in a press release that sales performance over the past two years has been below expectations in the United States, but believes the further development of its SLIT-tablet for the treatment of allergic asthma will be fruitful, as it has been in Europe. However, the company is now left looking for a new co-development partner in North America.

	The rights to the drugs will revert to ALK-Abello in the next six months, and will be complete by early 2017. Merck committed to completing the current clinical study that is underway on the SLIT-tablet, but will slowly transition the product registration process over to ALK. Merck 

 FDA acceptance of its biologics license application (BLA) for the dust mite tablet (MK-8237) in April 2016.

	The return of the rights to these three therapies to ALK follows an inspection letter from FDA to the immunotherapy manufacturer that cited multiple problems with the company’s aseptic manufacturing capabilities. Although many of the citations surrounded the fill/finish of a non-oral product (Pharmalgen), FDA also concluded that ALK-Abello had no written procedures surrounding how the stability of their products is tested, nor any documentation on the sampling and testing of its grass and ragweed drug product and drug substance samples. FDA estimated that the stability of the sublingual grass and ragweed tablets had not been tested since 2014.

The move follows a warning from FDA wherein FDA cited ALK-Abello with numerous manufacturing violations.