Home > Parenteral Advisory: Outmoded Fill/Finish Technology

Parenteral Advisory: Outmoded Fill/FinishTechnologyImprovements to aseptic manufacturing procedures are long overdue. But howfeasible is it for manufacturers to modernize fill lines of legacy products?Sep 01, 2016By Randi Hernandez [1]BioPharm InternationalVolume 29, Issue 9, pg 14–21

MarkGillow/E+/getty imagesThe demandfor fill/finish services has significantly increased in recent years, according to PeterPekos, president and CEO at contract manufacturing organization (CMO) DaltonPharma Services, and many companies have expanded capacity to meet thatdemand. Don Paul Kovarcik, technical marketing specialist from CMO AjinomotoAlthea, Inc., estimates that just about every large biotech/pharma company has somefill/finish capabilities, regardless of if they outsource these services or not. BioPlanAssociates asserts that that fill/finish operations are the most heavily outsourcedoperations. According to a 2016 estimate from BioPlan, nearly 36% of fill/finish

operations. According to a 2016 estimate from BioPlan, nearly 36% of fill/finishoperations in the biopharma industry are outsourced, trumping other popularlyoutsourced services such as analytical testing, toxcity testing, plant maintenanceservices, and API biologics manufacturing. Greater than 74% of respondentsindicated 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 thoughthis processing step is a crucial part of a manufacturing lifecycle. Although somenovel delivery systems and combination products have been introduced, the asepticportion of the medicine­making process has, for the most part, remained relativelyunchanged.

Advances in automation and barrier isolators have been touted by FDA as bestpractices to keep drugs sterile (2). The US government has also recently beeninvolved in many initiatives to proactively set up fill/finish facilities to meet pandemicdemand in the event of an outbreak­­but these initiatives rarely involve a largenumber of companies that are focused on fill/finish activities. Because pandemicvaccines require production batches in the tens of millions and require high­capacityfilling lines, says Kovarcik, public­private partnerships are typical to ensure securityof supply. Kovarcik adds that traditional manufacturers and CMOs would sufferfinancially if they undertook these types of ventures, as the “overhead associatedwith underutilized facilities can have a strong negative impact on the financialperformance of a company.” Says Pekos, “There are economic challenges forcompanies engaged in the development and manufacture of effective vaccines­­assoon as the outbreak is under control, the funding also fades.”

Nonetheless, improvements to fill/finish operations could benefit businesses involvedin the manufacture of biopharmaceuticals and prevent more quality­based drugrecalls. Outlined below are ways to improve operations and possible disruptions thatcould impede otherwise seamless fill/finish business operations.

What specific improvements can be made?

Closed aseptic processing systems are preferred over open systems. Thispreference can be a problem with owners of manufacturing sites that do not want tomodernize. According to a DME white paper, a survey carried out to gauge the viewsof manufacturers on the latest trends and technologies affecting the life­sciencesindustry showed that nearly half of survey respondents said they would use isolatorsif and when they modernized legacy manufacturing facilities (3). The DME report alsostated that nearly 80% of survey respondents plan to upgrade their facilities withinthe next 10 years.

Drug manufacturers or CMOs choose whether to use restricted access barriers(RABs) or isolators based on user requirements and intended applications, saysSimon Cote, principal engineer at West Pharmaceutical Services, Inc. Isolators arecommonly used when campaigning is occurring, where the manufacturer is runningbatch after batch of a drug product and only changing the liquid contact path, or inany scenario where increased drug product and operator separation is required.Conversely, RABs are often considered more flexible and are used when lines needto be frequently changed over to accommodate different drug products or packagingcomponents.

Single use and CIP

Fill/finish operations were reportedly among the first in the bioprocess chain tobecome disposable, according to Eric Langer of BioPlan Associates (1). The use of

single­use product contact parts and the clean­in­place (CIP) of non­contact partsinside of barriers, specifically, are two promising ways to keep fill/finish systemssterile, says Hite Baker from facility engineering firm DME. Some companiesacknowledge, however, that single­use systems may not be the best option (or themost practical) for all organizations or all drug products. “Single­use systems areenormously flexible, enabling a great deal of customization with a wide variety ofparts,” note Martin Gonzalez, PhD, senior group leader of R&D, and Matt Dunlavy,principal engineer, both at Pfizer CentreOne, a global contract manufacturer thatfocuses on API synthesis and fill/finish for sterile injectables. “For CMOs, thatflexibility adds much complexity from a purely practical standpoint. Procurement,validation, and compatibility studies are multiplied across potentially hundreds ofdifferent single­use parts and partner projects.”

Gonzalez and Dunlavy state a typical batch of a biologic uses a wide variety ofsingle­use components (from tubing, aseptic connectors, and pump diaphragms todisposable packaging to ship APIs). The company says some of the filling lines at itsfacility in McPherson, Kansas are capable of using complete single­use systems,“from accepting a preformulated bulk in a disposable bag, to the connecting tubingsterile filtration units, sampling ports, waste lines, pumping system, and fillingneedles.”

Bosch’s prevalidated, preassembled, presterilized single­use filling system(PreVAS)­­developed in partnership with Sartorius Stedim Biotech­­is a gamma­sterilized 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 toexisting fill lines and hooked up.

Kovarcik tells BioPharm International that Althea has transitioned exclusively tosingle­use disposables for components that are in direct contact with product.Although there are many known benefits of single use, Kovarcik also admits, “single­use components are not always the most cost­effective option and in fact, don’t makesense from a cost perspective at a certain scale for particular products.” Thus, somestainless­steel parts may never truly become obsolete.

A general guideline for the use of disposable technology is that it is most suitable infields where drug substances come into direct contact with equipment, says BerndStauss, senior vice­president 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 generalguideline with regard to the size of the run is that the smaller the volume ofprocessed units, the more suitable disposable systems usually are,” Stauss adds.

In sum, Baker estimates that single­use filling using a disposable wetted path makesup approximately 30% of new filling line sales. Chris Procyshyn of aseptic fillingmachine manufacturer Vanrx Pharmasystems guesses that, currently, about 50% ofcompanies use completely disposable filling systems. Because single use eliminatesthe need for cleaning and related validation, the cost savings of disposable systemsare notable: “No significant capital investment is required for most of the systems,”says Procyshyn. As such, “we should see wider applications of the single­usefill/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 single­use connectors are polymer­based, Cote stresses these change parts must bethoroughly characterized to assess the potential impact of leachables on the finaldrug product. “Process validation is managed differently because these change partsare effectively new every time, thus requiring a larger statistical sampling to ensure a

controlled and validated process. In addition, scrutiny on the change parts suppliermust increase, typically through supplier agreements and incoming inspectionprocesses.”

Gonzalez and Dunlavy say the CIP of non­product contact parts “can be difficult tomanage inside the filling room Grade A areas,” and change parts must be washedand sterilized independently from the machine. Gonzalez and Dunlavy explain thatrather than cleaning the parts in place, a better approach would be “to remove theparts from the line, place them into automated CIP washing cabinets in Grade C or Dareas, then re­enter Grade A via steam­sterilizing autoclave for RABS applications orvaporized hydrogen peroxide chamber for barrier isolator applications.” Coteconcurs that RABS are not easily cleaned in place given that they are “intentionallynot airtight” and are meant to exchange air with the surrounding environment. Cotealso points out that the use of vaporized hydrogen peroxide as a decontaminationagent cannot be readily used to support the CIP process for RABS, which can beanother limiting factor.

A robotics revolution

According to Stauss, the “era of blockbusters and their corresponding high­volumerequirements” contributed to the boom in automation within the direct filling process.During a session at INTERPHEX 2016, Hite Baker suggested removing humanintervention from the fill/finish process altogether. The feasibility of such a suggestionis a popular topic among industry professionals. Many contend that fill/finishoperations are already largely automated. Anthony Cannon, head of drug producttechnology at Samsung BioLogics, for example, estimates that 40% of tasks havealready been automated. Gonzalez and Dunlavy say, “Automation and validatedcontrol systems are essentially now a regulatory expectation for critical processingsteps 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 modernfacilities, as these “manual processes are among the weakest links in the asepticchain in legacy sterile manufacturing facilities.”

Automated systems typically include environmental monitoring filling machines withtool­less changeovers, single use, dosing, in­process weight checks, self­adjustingfill volume controls, and blow/fill/seal operations. Even visual inspection cansometimes be relegated to machines. As Cote notes, excluding all testing,inspection, and documentation management, only a few operators are typicallyrequired to run the fill line. As Klaus Ulherr, senior product manager at BoschPackaging Technology observes, “No one line is currently able to run completelywithout an operator; someone is still needed to start and stop the line, to performviable monitoring, to survey the processes, and to perform required format changes.”Although completely automated machines exist, Cote says these models require allpackaging formats to be ready­to­use and they must be in a nested configuration.

Replacing manual operation in clinical manufacturing and for the manufacture ofsmall batches of high­value products is not recommended nor ideal, say manyindustry professionals. “To be responsive to customer needs and to controldevelopment cost, manual processes for fill/finish are frequently applied for themanufacturing of small batches of clinical supplies at the early stages of drugdevelopment,” says Pekos. As Stauss notes, manual handling of small volumes of afew hundred units “often makes better sense as compared with the time­intensiveefforts associated with the installation of high­tech automatic­focused operations.”

“In some cases, manual operation may actually be preferred,” say Gonzalez andDunlavy. “For complex biologics with very expensive, small batch sizes, [manualoperation] may be advisable and provides a sense of comfort to have experiencedsubject matter experts directly involved throughout the manufacturing process­­at theshop 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 thelarge capital investment needed and longer, more complicated implementation andvalidation requirements.”

A promising long­term strategy to formulate and fill sterile drug products is toincrease the use of a robot inside a barrier with no glove port access, according toBaker. Gloves are a weak link, and experts predict there will be fewer glove ports inaseptic manufacturing in the future. But, Baker says, pharma is painfully slow atimplementing new technologies, even though he said during a presentation at theINTERPHEX 2016 meeting that “nirvana may be gloveless isolators for asepticfilling.” Suppliers said in the DME report that puncture­resistant gloves would be atop, most­desired advancement. The report noted that there is currently “no recourseuntil robots replace glove ports, and/or new material science gives the industry apuncture­proof glove” (3). Glove ports need to be inspected on a daily basis and area common cause of system failures (4). There is a strong, growing trend toward theuse of gloveless isolators. Procyshyn says that gloveless robotic systems arecapable of reducing the personnel requirements from a traditional isolated line offour to six operators to a single operator. “In a gloveless robotic system, the roboticsare used to conduct aseptic interventions, if any are necessary,” commentsProcyshyn. “Initial use cases for gloveless robotic isolators include filling potent orcytotoxic products, or for small batch production of sensitive biologics or celltherapies.”

Recent innovations in fill/finish

Many of the experts agree that the introduction of 100% automated weight checks fordose control and the net­weight filling at the beginning and end of batch processinghave increased the reliability of filling machines greatly. In addition, the introductionof adaptive or flexible fillers that can accommodate a variety of container types in thesame line has been an important innovation, observes Cote. Being able to usedifferent types of packaging on one platform has been extremely helpful, especiallyin the case of containers with multiple chambers, says Pekos. A dual­chambercontainer (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 designedsystem­­and Pekos asserts demand for innovation in this field is growing.

Rapid air locks have also helped to eliminate some capping issues when finishing aproduct. “Another relatively recent change in the fill/finish operations has been therequirement to cap vials within Grade A air (supporting the change to Annex 1 of theEU GMP regulations),” says Cote. As a result of this new requirement, he says, “Thelayout of filling lines and processes and procedures dictating the capping operationshad to change.”

Improvements to barrier integration, dosing pump accuracy, sensor/automaticfeedback controls, and other engineering design enhancements have helped driverecent fill/finish progression, say experts. Cannon lists modular isolator filling lines,ASEP­TECH filling lines (blow/fill/seal), and new innovations in glass formulation asemerging trends in fill/finish. As Gonzalez and Dunlavy conclude, “Quality andcompliance are continuously improved by feedback from fill/finish machine users andcustomers, 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 triggersome changes to existing fill/finish procedures. The fill volume for certain productshas, in the past, had to be validated as a result of FDA mandates. In 2012, theapproval for ThromboGenics’ Jetrea (ocriplasmin) for the treatment of symptomaticvitreomacular adhesion required a post­marketing feasibility adjustment “to adjustthe drug product final fill volume or concentration to reduce the likelihood that morethan one patient could be dosed from the same single use vial due to excessreconstituted drug product remaining in the vial after the initial dosing” (5). FDA wasconcerned a larger fill size for Jetrea would encourage re­use of the product. Gary D.Novack, PhD, wrote in The Ocular Surface, “Pharmaceutical firms need to continue tobe mindful of the needs of patients in providing the most appropriatecontainer/closure systems and fill volumes for convenient and compliant use relativeto the indications” (6).

Equipment may need to be modified to accommodate new fill volumes, as some linesmay not be able to handle multiple fill volumes, say Gonzalez and Dunlavy. “Suchcircumstances require new engineering runs to assess a fill­line change, properhandling 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 requiredtypically include additional aseptic process simulation for the new container size,supplemental stability data for the new packaging configuration, confirmation ofcontainer closure integrity, and packaging material compatibility with the drugproduct­­and the changes would need to be filed with FDA.”

Gonzalez and Dunlavy explain that for lyophilized parenterals, a change in volumewill also have implications. Vial size changes often require changes to thelyophilization process, and it may be necessary to request new container sizes fromglass manufacturers with specific dimensions. “Such steps could require severalmonths of development work­­and enough API to perform the necessary studies,”Gonzalez and Dunlavy state. “Furthermore, samples produced using the newcontainer size and/or new lyophilization cycle need to be placed on stability andtested to ensure changes do not adversely affect product quality, safety, or potency.”Although some changes (such as a change in a glass supplier) could becommunicated via a company’s annual report, others, such as the change in size orshape of a container, have to be accompanied by a Prior Approval Supplement toFDA.

Fill/Finish operation disruptions

Creative solutions to solve fill/finish problems do not just lie with improvements inmachines and equipment. Operational improvements must also occur to preventdisruptions in commercial business. For example, splitting the manufacturing andfill/finish operations up into two separate locations can be problematic, in somecases. The dangers of breaking up these processes are driven by an increase in thenumber of steps involved to get to a finished product. Some of the major challengesassociated with outsourcing fill/finish include “streamlining the manufacture activitiesof the parent company with the fill/finish operation of the third party, sharing productand process knowledge with the third party, integrating quality system andrequirements, and effectively managing logistics,” says Pekos.

Gonzalez and Dunlavy point out that sufficient communication between the partiescan mitigate the risk associated with outsourcing fill/finish: “For example, if one of ourbiopharma 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 planproper control of bulk and final container headspace to prevent oxidation or light­induced degradation, and determine if we need to dim or apply filters to the fillingroom lights.” They add, “The more we know, the better we can recommend theappropriate fill/finish strategy and equipment, and develop manufacturing andvalidation plans that safely control product sensitivities.” Kovarcik asserts that evenwithin the same company (between different sites of operation), there can be thesame risks for packing, handling, storage, and transfer as there could be withworking with a CMO (see Sidebar [2]). Contends Kovarcik, “if validated proceduresare in place and you are working with trusted and reputable shipping vendors,” thedistance between third­party sites doesn’t present any additional risk.

Will fill/finish recalls ever cease?

Many product recalls that have recently been in the news center around particulatesin vials that appear to be glass in origin. Mechanical causes for glass particulatescan include shipment, abrupt heating or cooling, pinch points in a filling line,lowering of lyophilization shelves to stopper vials, capping issues, a blockage in aline 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 ofthe glass and drug product are even more difficult to address, as these particulates­­also known as delamination flakes or lamellae­­are harder to identify. The flakesshed from the interior of glass containers under certain conditions such as high pH,high salt concentrations, high temperature, aggressive washing or depyrogenation,freeze­thawing, and the presence of certain excipients or buffers (such as citrate ortartrate) in a drug product. Drug products exposed to the inner surface of containersfor extended periods of time, stored at room temperature, or those that have beenterminally 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 drugproduct, according to Cote. Even though the glass lamellae can often be the reasonfor a major lot recall, Pekos reports that to date, “no adverse events have beenreported nor can be directly attributed to glass lamellae in injectable drugs.”

An alternative polymer­based container could be a viable solution, as Cote pointsout: “Given the industry’s concern over glass particulates, the use of polymer­basedcontainers has grown considerably.” Kovarcik says glass is currently three to fourtimes less expensive than other options and Gonzalez and Dunlavy assert that glassis still the preferred material for vials “due to its perceived inertness andcompatibility.” However, Gonzalez and Dunlavy add, “Many companies are makinggreat efforts to put biologics into plastic containers such as clear olefin polymers(COP) to reduce the potential for delamination and the need for siliconization. Butthese materials can lead to product oxidation from gas permeation, [which is] achallenge to protecting sensitive compounds.” In addition, states Kovarcik, “thepharmaceutical industry is conservative and change is difficult­­other materials couldprove to be superior, however, it will require time for adaptation.” Pekos says heexpects packaging changes to occur gradually, as it will “be costly and time­consuming to introduce new packaging materials for existing, legacy products due topost­market filling requirements.”

References

1. BioPlan Associates, Inc., Thirteenth Annual Report and Survey ofBiopharmaceutical Manufacturing Capacity and Production, April 2016.2. FDA, Pharmaceutical cGMPs for the 21st Century­­A Risk­Based Approach, Final

Report [3], (Rockville, MD, Sept. 2004), accessed May 6, 2016.3. H. Baker, DME, “Facility Focus: Trending Technologies in Aseptic ManufacturingFacilities,” White Paper, April 2016.4. R. Hernandez, BioPharm Int. 28 (11), pp. 14­19 (2916).5. FDA, Application Number: 125422Orig1s000, Approval Letter for Jetrea [4] (CDER,Rockville, MD, Oct. 17, 2012), accessed May 6, 2016.6. G.D. Novack, The Ocular Surface 11 (4), pp. 285­287 (2013).7. FDA, Questions and Answers on Current Good Manufacturing Practices, GoodGuidance Practices, Level 2 Guidance­­Control of Components and Drug ProductContainers and Closures [5], (Rockville, MD, Aug. 4, 2004), Accessed June 24, 2016.

Article Details

BioPharm InternationalVol. 29, No. 9Pages: 14–21

Citation

When referring to this article, please cite as R. Hernandez, "Parenteral Advisory:Outmoded Fill/Finish Technology," BioPharm International 29 (9) 2016.

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Links:[1] http://www.biopharminternational.com/randi­hernandez­0[2] http://www.biopharminternational.com/puerto­rico­regional­difficulties­related­fillfinish[3]http://www.fda.gov/Drugs/Development%20ApprovalProcess/Manufacturing/QuestionsandAnswerson%20CurrentGoodManufacturingPracticesc%20GMPforDrugs/ucm137175.htm[4] http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125422Orig1s000Approv.pdf[5] http://www.fda.gov/Drugs/GuidanceComplianceRegulatory%20Information/Guidances/ucm124780.htm#11