Guidelines for Risk-Based Changeover of Biopharma Multi ... · With the growth of biopharma product...

10.5731/pdajpst.2016.007419Access the most recent version at doi: 91-10372, 2018 PDA J Pharm Sci and Tech

Rob Lynch, David Barabani, Kathy Bellorado, et al. Multi-Product FacilitiesGuidelines for Risk-Based Changeover of Biopharma

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COMMENTARY

Guidelines for Risk-Based Changeover of BiopharmaMulti-Product Facilities

Authors:

ROB LYNCH, (GSK)DAVID BARABANI, (Pfizer)KATHY BELLORADO, (Pfizer)PETER CANISIUS, (AbbVie)

DOUG HEATHCOTE, (AbbVie)ALAN JOHNSON, (Amgen)NED WYMAN, (AZ)DEREK WILLISON PARRY*

ABSTRACT: In multi-product biopharma facilities, the protection from product contamination due to the manufacture ofmultiple products simultaneously is paramount to assure product quality. To that end, the use of traditional changeovermethods (elastomer change-out, full sampling, etc.) have been widely used within the industry and have been accepted byregulatory agencies. However, with the endorsement of Quality Risk Management (1), the use of risk-based approachesmay be applied to assess and continuously improve established changeover processes. All processes, including changeover,can be improved with investment (money/resources), parallel activities, equipment design improvements, and standard-ization. However, processes can also be improved by eliminating waste. For product changeover, waste is any activity notneeded for the new process or that does not provide added assurance of the quality of the subsequent product. Theapplication of a risk-based approach to changeover aligns with the principles of Quality Risk Management. Through theuse of risk assessments, the appropriate changeover controls can be identified and controlled to assure product quality ismaintained. Likewise, the use of risk assessments and risk-based approaches may be used to improve operational efficiency,reduce waste, and permit concurrent manufacturing of products.

KEYWORDS: Quality risk management, Risk, Risk management, Changeover, Change-out.

Introduction

With the growth of biopharma product pipelines andthe desire to improve operational efficiency as well asreduce the cost of goods sold (COGS), companiesseeking to improve operational efficiency are in con-stant pursuit of streamlining their operations. An areaof opportunity for improved efficiency is productchangeover. For this paper, changeover is defined asthe activities specifically performed to mitigate cross-contamination of products (e.g., changeover sampling,line clearance, elastomer change-out, etc.). Activitiesthat may occur during changeover (i.e., calibrations,planned maintenance, and change controls), thoughessential to manufacturing, are considered outside thescope. Product changeover is a process that preparesand configures the facility and equipment for the next

manufacturing process, and includes actions taken toprotect the subsequent process against contaminationfrom the previous process. Historically, the change-over between two products within a multi-productfacility has created a great deal of operational ineffi-ciency. With the use of risk-based tools and supportingdata, the changeover activities of multi-product facil-ities can be significantly reduced and, under well-controlled and characterized operations, concurrentmanufacturing may be achieved. Specifically, thechange-out of small parts and elastomers as well as thecollection of changeover cleaning samples may besignificantly reduced or eliminated. This article isprimarily intended for the manufacture of bulk bio-logic drug substance; however, the principles may beapplied to finished drug product as well.

Changeover Overview

It is a regulatory expectation by various boards ofhealth to verify the cleanliness of equipment betweencampaigns of different products to eliminate the riskof cross-contamination. “Contamination of a startingmaterial or of a product by another material or product

* Corresponding Author: Derek Willison Parry,BPOG 5 Westbrook Court, Sharrowvale Rd., SheffieldS11 8YZ UK; e-mail: [email protected]

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must be avoided” (2). Additionally, “control measuresto remove the organisms and spores before the subse-quent manufacture of other products” (3) must be inplace in a multi-product facility. These referencesemphasize that preventing cross-contamination is par-amount in a robust changeover process so as not toadversely affect the safety, identity, strength, purity,or quality of the subsequent product.

The scope of changeover is typically limited to non-dedicated product contact equipment (e.g., cell cul-ture/fermentation, purification, and filling operations.)Process support areas (media and buffer preparation)may not be changed over, as this equipment does notcontact any product containing material that wouldnecessitate verification of removal. In addition, theintroduction of single-use equipment to the processstream can also reduce the scope of changeover, as thisequipment is disposed of after use and does not requireverification of cleanliness.

As a prelude to this article, an industry survey wasconducted to assess the current practices and identifythe key areas deemed to be opportunities to improvechangeover. Survey results were collected from 15representative companies and included products man-ufactured both internally and externally (contract man-ufacture). It also included manufacturing across thespectrum of potency from low-potency products (suchas monoclonal antibodies) through medium- and high-potency (cytokines and tumor necrosis factors). Asummary of the survey results for the current change-over practices and the percentage of companies cur-rently following each of the practices is shown inTable I. The table shows the tasks associated withnormal lot to lot (no product change) and the addi-tional percentage of companies that perform the tasksduring product changeover. The table is divided intothree sections:

● Changeover activities performed (lot to lot/addi-tional at product changeover)

● Release criteria (prior to starting the next lot/product)

● Samples collected (during lot to lot/productchangeover)

The activities are ranked based on additional percent-age performing each activity as part of productchangeover.

This paper will discuss the optimization of changeoverpractices through the reduction of waste. Lean SixSigma identifies eight forms of waste (Figure 1).Many, if not all, of these forms of waste may bepresent during traditional product changeover. In par-ticular, this paper focuses on the elimination of wasteassociated with cleaning and verification of equipmentcleanliness during product changeovers. Table II usesthe lean forms of waste associated with changeoverand identifies the benefits of applying risk-basedchangeover approaches.

Optimization of a changeover practice is the processof determining the most efficient and effective methodto achieve the product changeover from Product A toProduct B without adversely affecting the quality andsafety of Product B. A robust risk program can be usedto drive changeover optimization to assure the appro-priate actions and controls have been established andexecuted to defend the quality and safety of Product B.

The results in Table I show that there is variability inthe changeover activities performed by survey respon-dents, with “equipment cleaning” the only activityperformed by all. So what actions are really neededand which are not?

Risk assessments (RAs) are an industry-accepted toolto establish the changeover requirements. The RAdefines the criteria that need to be met during thechangeover, the potential threats to meeting these cri-teria, and the controls (design and procedures) neededto mitigate, control, or detect these threats.

Cleaning and protection of the next process fromcontamination are major quality concerns during thechangeover process. There are many potential contam-ination threats to the coming product associated withchangeover.

The RA allows a systematic assessment of each potentialthreat and how each of these threats is mitigated/con-trolled (design, cleaning, procedures, documentation)and/or how the threat to quality is detected before it canaffect the marketed product (sampling, verification, in-spection).

All of the items listed in Table I are types ofcontrols; the opportunity for optimization is to de-fine— based on the quality threat—which of thesecontrols is actually needed to defend and demon-strate that the quality of the next process will not be

92 PDA Journal of Pharmaceutical Science and Technology



affected by the changeover processes. This alsoensures that the changeover activities are commen-surate with the threats to quality.

With robust risk assessments, companies can provide asolid defense that can support reduction in changeoveractivities. This may include the following:

● Elimination or reduction of elastomer change-out

● Elimination or reduction of changeover sampling

● Reduction of line clearance activities

● Concurrent manufacture of multiple productswithin a single manufacturing area

It is important to realize that, if using risk assessmentto justify a reduction in changeover, the risk assess-

TABLE ISummary of Survey Practices

Note: The data was also analyzed to compare the differences in practices between manufacturers handling high- andmedium-potency products versus low-potency products but showed no significant differences and is not presented.




ment must be defendable. By building up technicaldocuments to support this defense, it is possible todemonstrate control while minimizing activities.

Figure 2 is an overview of the types of defenses thatcan be established to support a reduced changeovereffort. Each of the elements in the diagram is dis-cussed in the following sections. A risk assessmentwill use inputs defined in Figure 2 to determine therelative risk associated with the controls establishedwithin a given organization. Once the risks and con-trols are understood, higher level risks may be miti-gated with additional controls or may dictate moretraditional changeover practices if accepted. Figure 3depicts an example of the outputs from a risk assess-ment including potential changeover benefits. As with

Figure 1

Lean Six Sigma waste.

TABLE IIChangeover Benefits




Figure 2

Risk-based changeover process flow diagram.




Figure 3

Risk-based changeover flowchart (example).




all risk assessments, risk tolerance will vary fromorganization to organization and will result in differ-ing levels of potential benefits. Guidance for QualityRisk Management and representative case studies canbe found within PDA Technical Reports 54 (4) and54-4 (5).

New Product Introduction

The introduction of new products, or new productintroductions (NPIs), to a multi-product facility posesunique challenges to existing changeover processes ofvalidated products. As a result, more traditionalchangeover activities may be required. Because thevalidation of NPIs may be incomplete, the executionof cleaning validation/verification is a major compo-nent of the NPI process. Small-scale studies are usedto assess the product to be introduced into the manu-facturing facility. These include coupon recoverystudies, cleanability studies and degradation/denatur-ation, and inactivation as discussed below. The find-ings of these small-scale studies determine the level ofthe commercial-scale cleaning validation/verificationwork required to demonstrate that the validated clean-ing processes remove any residual material to accept-able levels. These acceptance levels are determined toverify that potential residual Product A remainingwould not be expected to affect the safety or productquality of Product B.

Without the controls of validated cleaning processesand routine monitoring, the use of risk-based change-over practices for new products is impractical. Basedupon product knowledge, small-scale studies, andcleaning validation, risk-based changeover practicesmay be implemented for future campaigns.

Changeover Assessments

The sections that follow identify activities which maybe considered and leveraged to support a risk-basedchangeover. In addition to these, your organizationmay have additional program data that may be lever-aged to support further risk-based changeover prac-tices.

Recovery Studies

The use of rinse and swab recovery studies in sup-port of cleaning validation is routinely performed.These studies demonstrate how the soil of interest(cleaning agents, product, or process) adheres to the

representative materials of construction (MOC)throughout the manufacturing process. These stud-ies can be used to support that the residues areeasily solubilized so if present within a system theywill be present in rinse water samples collected atthe system outlet or on swab samples of equipmentsurfaces. These studies support the use of single-point sampling as well as the collection of swabsamples of the actual equipment surfaces. In addi-tion, the studies demonstrate that the residues arereadily removed from elastomer and gasket materi-als and are a critical element supporting a risk-basedapproach to the change-out of elastomers (e.g., gas-kets, o-rings, valve diaphragms, etc.).

When recovery studies have been conducted for allproducts and MOC, a matrix can be created that ge-nerically suggest worst-case MOC for each product aswell worst-case MOC across products. The data asso-ciated with recovery studies become valuable inputs torisk assessments determining the extent of elastomerchange-out and reduced sampling.

Cleanability Studies

Bench-scale cleanability studies are performed prior tointroducing a new soil in to the manufacturing facilityto give assurance that the existing cleaning cycle(s)will be effective. These studies are common in theindustry, as referenced by the Parenteral Drug Asso-ciation (PDA): “Generally, the cleaning effectivenessof the existing system for new soils can be tested byperforming laboratory experiments using coupons ofrelevant materials. These experiments can be de-signed to test both the effectiveness of the proposedcleaning regimen and the relative difficulty of clean-ing the new soils that have already been introducedto the plant” (4).

A well-designed cleanability study will assess themanufacturing process conditions and soil(s) as wellas the cleaning cycle(s). During testing, both the soiland cleaning cycles can be manipulated to furtherchallenge the effectiveness of the cleaning cycle(s).While the primary goal of these studies is to determineif the process soil is a new-worst case situation andthat the cleaning cycles are appropriate, the data alsoindirectly supports changeover. Through demonstrat-ing that the process soils are cleanable at the labora-tory scale, the risk associated with decreasing or elim-inating elastomer change-out or changeover samplingmay be assessed.




Product Degradation/Denaturing/Inactivation

For multiproduct equipment cleaning validation,cleaning acceptance limits for residual process ma-terials are typically set based upon the productdosage and/or health-based exposure limits such asacceptable/permitted daily exposure (ADE/PDE) orthreshold of toxicological concern (TTC) of ProductA. These values are used to calculate the maximumallowable carryover (MAC) of residue from ProductA to Product B. However, the activity of biologicalproducts such as monoclonal antibodies and thera-peutic proteins rapidly degrade/denature when ex-posed to pH extremes and/or heat, and therebybecome pharmacologically inactive (5, 6). Whenproduct degradation and inactivation can be demon-strated, the relative risk of product-to-product car-ryover is significantly reduced. From a risk-basedperspective, demonstration of degradation/inactiva-tion lowers the associated risk of foregoing elasto-mer change-out and drastically reduces or elimi-nates the primary risk of product carryover betweenproducts. Furthermore, when product inactivation isdemonstrated and cleaning validation has been com-pleted, the requirement for changeover samplingmay be assessed to reduce or eliminate sampling. Byreducing or eliminating elastomer change-outs andchangeover sampling, the overall waste (e.g., mate-rial disposal, equipment and resources availability)associated with changeover is reduced.

Product Toxicity/Potency

It is important to ensure that the potent or toxicprocess soil risk can be reduced during productchangeover in order to prevent cross-contaminationinto the subsequent or concurrent product being man-ufactured within the facility. If process soils are toxicor highly potent, then additional safeguards need to beconsidered in order to ensure pure, safe, and effectiveproduct for patients. Safeguards that can be takeninclude product-dedicated equipment, use of cleaningcycles that degrade or denature process soils, and/orproduct/component-specific assays.

It is also important to understand the impact of thecleaning cycles on the toxic or potent process soil. Ifthe cleaning cycle degrades, denatures, or in somemanner eliminates the potent or toxic aspect of theprocess soil, and this can be proven, then the cleaningacceptance criteria can be set using a non-specificlimit rather than a specific assay. In addition, proving

that the toxic or potent component has been degraded ordenatured allows for product contact equipment to beshared and not dedicated to a product. This also allowsfor other methods for calculating acceptance criteria tobe used (8, 9). If removal of toxic or highly potentresidues is demonstrated, changeover activities of asso-ciated equipment may be reduced based on risk assess-ments.

Cleaning Validation/Verification

Cleaning validation establishes documented evi-dence that a cleaning system (including cleaningequipment, cleaning cycles, and associated proce-dures) performs as expected and that the parametersof the cleaning cycle are adequate to ensure processequipment is cleaned in an effective and consistentmanner. With scientific guidance from the laborato-ry-scale cleanabiltiy studies, the validation may beapplied in a grouping approach to multiple productsthat are proven through laboratory-scale cleanabil-ity studies to be less challenging to clean. Theadvantage to changeover gained through cleaning vali-dation is the potential reduction and/or elimination of theneed to perform extensive sampling at each changeover,thereby reducing changeover time.

Cleaning verification is the process of collectingevidence to demonstrate that the equipment is prop-erly cleaned. Cleaning verification is typically usedwhere there are not sufficient process lots to per-form validation, or in support of investigations, aswell as during product changeover. The challengewith verification is that to fully demonstrate that theresidues have been removed from all surfaces, ex-tensive sampling (rinse and swab) throughout theequipment is required. This often necessitates dis-assembly and/or intrusive actions that can signifi-cantly add to changeover times, especially whenlock-out/tag-out and other safety requirements (e.g.,confined space tank entries) and post-sample re-cleaning are factored in. Therefore, if cleaning valida-tion has not been completed and cleaning verification isperformed to support changeover, the reduction or elim-ination of changeover sampling and elastomer change-out are more difficult to justify.

Routine Monitoring

Routine monitoring of cleaning cycles is required toprovide ongoing evidence that the cleaning processesare effective in ensuring the equipment is clean and




suitable for use. “Cleaning procedures should be mon-itored at appropriate intervals after validation to en-sure that these procedures are effective when usedduring routine production” (7). This is the core prin-ciple behind lifecycle management of cleaning pro-cesses. This is supported by the statement, “Processesand procedures should undergo periodic critical re-validation to ensure that they remain capable ofachieving the intended results” (8). Both statementsemphasize that validation does not end upon comple-tion of performance qualification (PQ) and that it isimportant to periodically verify that the cleaning pro-cesses are still operating as originally qualified as partof lifecycle management.

As part of lifecycle management, a cleaning monitor-ing program verifies the cleanliness of equipment on apre-determined frequency (quarterly, yearly, etc.)based on risk or usage. The same assays utilizedduring PQ are typically used to verify that the cyclesare still working as intended. These data can be uti-lized to identify trends in cleaning processes or tore-evaluate current acceptance criteria.

Changeover cleaning verification and cleaning moni-toring are similar, as the equipment is verified as cleanusing the same (or similar) analytical testing in addi-tion to a visual inspection; they are also linked in aninversely proportional way. For example, a strongcleaning monitoring program could lead to reducedsampling during changeover as the cleaning monitor-ing team demonstrates and documents control of thecleaning processes throughout the year. Conversely, ifa facility undergoes multiple changeovers in a year,these data could be used to support cleaning monitor-ing and reduce the number of samples required for thatprogram.

In addition to cleaning monitoring, other aspects oflifecycle maintenance can include preventive mainte-nance, re-validation, and change controls. Each ofthese programs ensures that the equipment is operatingas intended and any changes do not negatively affectthe validated state of the equipment.

“Inspection of equipment for cleanliness immediatelybefore use” (9) is a specific requirement of the U.S.Food and Drug Administration. This inspection isroutinely performed by manufacturing personnel fol-lowing clean-in-place (CIP) and prior to subsequentmanufacturing steps. This is an additional safeguardthat can provide real-time feedback of the effective-ness of the lifecycle management program.

Changeover Sampling

With a robust data set encompassing the topics previ-ously covered, changeover sampling can be risk-as-sessed for reduction and/or elimination. A combina-tion of data points including equipment complexity,materials of construction, cleanability/recovery, deg-radation/denaturing, and cleaning validation may beused to assess typical changeover sampling operations.In high-risk applications, typical changeover sampling(rinses and swabs) may still be necessary. However, inlow- and medium-risk application, a reduction or theelimination of changeover sampling will likely bescientifically justifiable. Table III provides examplesof risk-based changeover activities.

This is especially true for organizations that haveactively implemented process analytical technology(PAT) to actively monitor and control critical processparameters (CPPs) associated with cleaning processes.The use of in-line and at-line technologies—for exam-ple, total organic carbon (TOC), conductivity, etc.—that enable proactive control of cleaning processesmay be leveraged to reduce or eliminate typicalchangeover sampling methods.

With the reduction or elimination in changeover sam-pling, several modes of waste are minimized. Re-sources are freed up to attend to other activities,quality control (QC) testing is decreased, equipment isreleased in a timely manner, and the overall efficiencyof changeover may be significantly improved withoutimpact to product quality.

Elastomer Change-Out

Historically, the change-out of elastomers was an es-sential component of product cross-contaminationprotection during changeover. Through the replace-ment of elastomers, multi-product facilities assuredcross-contamination of product from elastomer sur-faces was eliminated. However, using risk-based ap-proaches and other supporting data, the requirement ofelastomer change-out to mitigate product cross-con-tamination is being revisited.

Elastomers must comply with USP Class VI and thematerials of construction must be compatible with theexisting manufacturing processes. Selection and utili-zation of elastomers are critical to ensure not onlyeffective cleaning and steaming of the process equip-ment, but also to avoid leaching during normal oper-




ations. Valve diaphragms are evaluated for a smoothsurface finish and components that minimize wearfrom repeated toggling or use. The selection of elas-tomer materials of construction ensures that they aresuitable for use in a multi-product environment andthat a comprehensive training program is in place toensure that elastomers are installed, maintained, andhandled in a manner that reduces the potential forelastomer failure and subsequent potential productcross-contamination.

As noted above, soil cleanability of new or modifiedproduct and process materials is determined throughbench-scale cleaning evaluations. Using this data, arisk assessment may be conducted to minimize oreliminate elastomer change-out from one product tothe next. Once assessed, the need for elastomerchange-out may be based on defined preventive main-tenance intervals (10).

Closure Analysis

“Closure analysis is a type of a risk assessment thatshould focus on the probability and severity of expos-ing a process system to the surrounding environment

before, during, and after the process operations” (11).The International Society for Pharmaceutical Engi-neering (ISPE) Baseline Pharmaceutical EngineeringGuide, Volume 6, provides guidance on performingclosure analysis. The ISPE guide breaks the processinto three fundamental phases: Review and Selec-tion ➜ Calculations and Definitions ➜ Outcome.

Although closure analysis is typically performed toassess viral and microbial control within the process,the principles may be applied to the risk of simulta-neous manufacture of multiple products. In the contextof changeovers, closure analysis can be used to iden-tify unit operations with sufficient controls to permitconcurrent manufacturing. Systems or processes aredefined as being briefly exposed, closed, functionallyclosed, or open. Once the systems and processes havebeen defined, an assessment may be performed todetermine which unit operations have adequate con-trols to permit concurrent manufacturing. Concurrentmanufacturing allows the simultaneous manufactureof multiple products within a well controlled area.From a lifecycle perspective, the changeover path toconcurrent manufacturing may occur incrementally.When closure analysis has been completed and all

TABLE IIIRisk-Based Changeover Examples




controls required by quality risk assessments havebeen assessed and are in use, concurrent manufactur-ing may be implemented. With each new product, theprocess must be performed; however, data can beleveraged, potentially shortening the process.

Once the requisite data has been generated to supportconcurrent manufacturing, logistical efficiencies arealso necessary to facilitate concurrent manufacturing.The staging of changeover parts must be both efficientand timely. Sufficient trained resources must be avail-able to guarantee the efficient changeover betweenproducts. Tools such as single-minute exchange of die(SMED) may be used to improve logistical change-over efficiency. In an ideal state, sufficient controls arein place, cleaning processes are validated, products arenon-toxic and non-potent, and product degradation hasdemonstrated that the requirement for changeover maybe minimized or even eliminated.

Viral Reduction and Segregation

Another consideration of risk-based changeover is theviral reduction and viral segregation controls of theprocess. Viral reduction studies are typically per-formed to demonstrate the ability of cleaning pro-cesses, steam-in-place (SIP) or autoclave processes, toreduce viral loads to acceptable levels. The studiesmay be used to assess the risk associated with change-overs in which pre-viral inactivation portable equip-ment are moved to post-viral inactivation steps. De-pendent on the viral reduction studies and viralcontrols, a risk assessment of the need for elastomerchange-out may be performed to prescribe the appro-priate level of elastomer change-out. For systems suchas portable tanks that incorporate SIP unit operations,the need for elastomer change-out may not be neces-sary. However, for systems that are incapable of SIPoperations, the change-out of elastomers as well asother decontamination processes must be consideredand may be required.

Disposable Technology

The use of disposable technology in biologics man-ufacturing allows for the complete adoption of risk-based changeover principles by eliminating thesources of potential product carryover: the perma-nent stainless steel, glass, or acrylic surfaces thatrequire cleaning in between use and the elastomersurfaces that require replacement for absolute as-surance of residual product removal.

With disposable technology, the permanent surfacesare replaced by disposable plastic surfaces with inher-ent appurtenances that enable process control of thecontents. Current examples include single-use biore-actors (SUBs), single-use mixing systems (SUMs),and disposable skids for depth filtration, chromatog-raphy, and ultrafiltration.

The advantage of disposable technology, aside fromthe elimination of cleaning, is the minimizing of mov-able parts and piping connections, which reduces theneed for change-out of gaskets, o-rings, valve dia-phragms, and other elastomers. By being entirely non–product contact, the replacement of any elastomericsurfaces on disposable equipment is dictated by a PMschedule only and is not required during productchangeover, further enabling the implementation ofrisk-based changeover practices.

Examples of Risk-based Application

The examples provided in Table III and Figure 3 arenot intended to explicitly define the changeover re-quirements for the systems discussed; they merelyprovide a general guidance on what the application ofrisk assessments to determine changeover controlsmay permit. The level of risk tolerance and product-specific considerations of those performing the assess-ments may result in different outcomes than thoseshared below. The intent is to demonstrate how theguidance may be generically applied.

Conclusion

Traditional changeover philosophies and methods arebeing revisited as the needs of the industry havechanged over time. Current regulatory guidance sup-ports the use of appropriate, scientifically justified,risk-based changeover methods, some of which havebeen outlined in this article. Utilizing a risk-basedapproach supported by a strong data set comprised ofitems such as bench-scale studies, cycle validation,and lifecycle management, the efforts and inefficien-cies of the traditional changeover model can be re-duced. However, any reduction in changeover activi-ties must be able to be readily defended to demonstratethat the appropriate product carryover controls are inplace to ensure both product and patient safety.

Glossary

Briefly Exposed—Open processes containing processand/or product components that are rendered closed by




means of an appropriate closing process (e.g., mediaand buffer operations) (12).

Carryover—Contaminants detected in process streamsarising from insufficient removal of contaminatingcomponents from previous manufacturing steps orbatches (14).

Changeover—The steps taken for switching multi-product equipment from the manufacture of one prod-uct to the manufacture of a different product (13).

Closed System—A process system that is designedand operated such that the product is never exposed tothe surrounding environment. Additions to and drawsfrom closed systems must be performed in a com-pletely closed fashion. Sterile filters may be used toprovide effective barriers from contaminants in theenvironment. A system is closed (or isolated fromthe environment) when the risk of contamination tothe product or process cannot be mitigated by housingthe operation in a bioburden-free or particulate-freeenvironment (14).

Crossover—Contamination of a system by compo-nents or contaminants found in neighboring system.Crossover typically occurs with open processes shar-ing environments. Crossover can also occur whenthere is a breach of integrity of a closed system in anenvironment shared with an open process or whenthere is a breach in integrity of two closed processes(14).

Functionally Closed—Process systems that may beopened but are “rendered closed” by a cleaning, san-itization, and/or sterilization process that is appropri-ate or consistent with the process requirements,whether sterile, aseptic, or low bioburden. These sys-tems shall remain closed during production within thesystem (14).

Open Process—A process that is exposed to the envi-ronment and therefore requires environmental condi-tions to mitigate the risk of contamination from theenvironment (14).

Product Changeover—Procedural steps taken forswitching from the manufacturing of one product toanother product (16). The program by which the pro-cessing area is cleared of supplies and componentsused in the manufacture of a previous product and thenreadied for production of a new product. This often

includes parts changeover and/or special cleaning toeliminate cross-contamination (17).

Acknowledgments

Jeremy Bollinger (Biogen), Beatrice Johnson (AbbVie),Heather Otenti (AbbVie) Jason Stillman (Janssen), An-toine Wermeille (Merck Serono).

Since its inception in 2004, the BioPhorum hasbecome the open and trusted environment wheresenior leaders of the biopharma industry come to-gether to openly share and discuss the emergingtrends and challenges facing their industry. BioPho-rum currently comprises more than 1200 active par-ticipants in six forums—Drug Substance, TheDevelopment Group, Fill Finish, The TechnologyRoadmap, BioPhorum IT Group, BioPhorum SupplyPartners.

More information can be found at www.biophorum.com.

Conflict of Interest Declaration

The author(s) declare that they have no competinginterests.

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17. ISPE Baseline Guide for New and RenovatedFacilities




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copyright information or notice contained in the PDA Journal·Delete or remove in any form or format, including on a printed article or photocopy, anytext or graphics·Make any edits or derivative works with respect to any portion of the PDA Journal including any·Alter, modify, repackage or adapt any portion of the PDA Journaldistribution of materials in any form, or any substantially similar commercial purpose·Use or copy the PDA Journal for document delivery, fee-for-service use, or bulk reproduction orJournal or its content·Sell, re-sell, rent, lease, license, sublicense, assign or otherwise transfer the use of the PDAof the PDA Journal ·Use robots or intelligent agents to access, search and/or systematically download any portion·Create a searchable archive of any portion of the PDA JournalJournal·Transmit electronically, via e-mail or any other file transfer protocols, any portion of the PDAor in any form of online publications·Post articles from the PDA Journal on Web sites, either available on the Internet or an Intranet,than an Authorized User· Display or otherwise make any information from the PDA Journal available to anyone otherPDA Journal·Except as mentioned above, allow anyone other than an Authorized User to use or access the Authorized Users are not permitted to do the following:



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