10.5731/pdajpst.2016.006718Access the most recent version at doi: 596-59970, 2016 PDA J Pharm Sci and Tech

 Robert Toso, Jonathan Tsang, Jasmina Xie, et al. Risk Management in Biologics Technology Transfer  

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COMMENTARY

Risk Management in Biologics Technology TransferROBERT TOSO, JONATHAN TSANG, JASMINA XIE, STEPHEN HOHWALD, DAVID BAIN,and DEREK WILLISON-PARRY*

ABSTRACT: Technology transfer of biological products is a complex process that is important for productcommercialization. To achieve a successful technology transfer, the risks that arise from changes throughout theproject must be managed. Iterative risk analysis and mitigation tools can be used to both evaluate and reduce risk.The technology transfer stage gate model is used as an example tool to help manage risks derived from both designedprocess change and unplanned changes that arise due to unforeseen circumstances. The strategy of risk assessmentfor a change can be tailored to the type of change. In addition, a cross-functional team and centralized documentationhelps maximize risk management efficiency to achieve a successful technology transfer.

KEYWORDS: Risk management, Technology transfer, Biopharmaceutical processes.

1. Introduction

Risk management is an integral part of biologic pro-cesses technology transfer in industrial biologics man-ufacturing. Within a technology transfer project, mul-tiple categories of risks are often discussed. Table Icategorizes some typical risks encountered throughouta technology transfer.

The focus of this article will be on the management ofcomparability risks; manufacturing process, equip-ment, utilities, facility, and project risks are beyondthe scope of this article. Comparability risks are dif-ferentiated from project risks, even though compara-bility failure will almost always result in a projecttimeline delay.

The circumstances of each technology transfer arealmost always different, and so there should always bean evaluation of how to best use technology transfermanagement tools. As an example, this article willdescribe leveraging the Stage Gate Model for Tech-nology Transfer to systematically assess and managerisks. Risks to comparability can be assessed itera-tively at different stages and sub-stages throughouttechnology transfer. Figure 1 shows a stage gate model

for technology transfer (see “Overview of Best Prac-tices for Biopharmaceutical Technology Transfers”for more details).

Change is inherent (purposeful or otherwise) to tech-nology transfers and often leads to comparabilityrisks. This article discusses two types of changes:known changes/differences and unanticipated chang-es/differences. Assessments are performed on risksdue to both known changes and unanticipated changes.

2. Known Changes

Known changes are often forced due to equipment orfacility needs, such as scale-up of the manufacturingprocess or engineering constraints. Known changesmay be unavoidable due to availability of identicalraw materials, equipment, personnel, analytical instru-mentation, or fundamental differences between thesending unit (SU) and receiving unit (RU) manufac-turing utilities and facilities. Other known changesmay be due to scale change or process improvement.Risk management for these types of changes can usu-ally be easier to address because assessment of thechanges can be performed upfront, when there is timeto evaluate impact and plan for mitigations.

2.1. Assessment of Known Changes

Using the Stage Gate Model (Figure 2) example, thereis an initial high-level risk assessment of the knowndifferences between the SU and RU during the ProcessTransfer Initiation, Gap Analysis Sub-stage. Largedifferences are usually known at this stage of a tech-

* Corresponding Author: Derek Willison-Parry, Bio-Phorum Operations Group, 5 Westbrook Court, Shar-row Vale Road, Sheffield, S11 8YZ, United Kingdom,derek@biophorum.com

doi: 10.5731/pdajpst.2016.006718

DISCLAIMER: The following article is a special editorial contribution from the BioPhorum Operations Group (BPOG). Pleasenote that it did not go through the PDA Journal and Pharmaceutical Science and Technology regular peer review process.

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nology transfer, thus a risk assessment can be initi-ated. Through this risk assessment, mitigation actionsare identified and added to the project plans in thesubsequent Process Transfer Planning Sub-stage. Thisrisk assessment is then routinely updated throughoutthe entire project at subsequent stage gates to capturenewly identified risks as well as update the remedia-tion of previously captured risks.

Figure 3 is a sample flow chart of using the processdescription of the SU as the basis for risk assessingknown changes. A draft of the RU process descriptioncan be first created based on the SU process descrip-tion. Known changes at the RU can then be evaluatedagainst the SU process description during a technicalreview to determine the risk. Also, if a product ismanufactured at more than one facility, changes canbe assessed not only against the defined SU, but allapproved facilities’ manufacturing processes. Only ac-cepted changes based on the risk would be incorpo-rated into the RU process and included in the RUprocess description. Often, the RU will prefer to mit-igate longer term risk of new processes by havingthese types of changes built in as optional, or revers-ible to an earlier proven state. However, this may notbe possible if the change is regarded by the regulatory

agency as a significant improvement over a previousprocess, so caution may be warranted in the actiontaken to mitigate risk of these types of changes.

In the Process Transfer Stage (Figure 2), the risksderived from known changes (to process, equipment,facilities, etc.) can be assessed individually and holis-tically (aggregated) by system. It is preferable to per-form these assessments before capital expenditure onequipment procurement or facility modifications.

2.1.1. Assessment of Individual Changes: Individualassessment of risk due to changes is often performedwhen design concepts for the facility, equipment,and process are first being developed during theProcess Transfer, Planning Sub-stage. Once the de-sign is finalized, the changes can be aggregated persystem and the risk for the system can be holisti-cally evaluated.

2.1.2 Assessment of Aggregated Changes: Oftenthere are multiple changes to an equipment system orprocess unit operation. In these cases it is often im-portant to evaluate risk due to the interplay betweenthe multiple changes to the one system. For example,a change in the thickness of a product preparationvessel wall and a change in the cooling medium (e.g.,chilled water to ethylene glycol) used in the vesseljacket may be individually assessed to be low risk andnot affect the process. However, when the changes areevaluated together, it may be realized that the dif-ference in the wall thickness compounded with thedifferent cooling medium could affect the tempera-ture-controlling capabilities of the vessel and mayhave unintended impact to the product. As part ofthe known change risk assessment, the aggregatedchange risk assessment can be performed during theProcess Transfer, Planning Sub-stage and through-out the subsequent stages of the technology transferprocess.

TABLE ITypes of Risks Associated with Technology Transfer

Risk Type Description

Comparability Leads to non-comparability of process or product between sending and receiving units

Manufacturing Process Risks to routine manufacturing., e.g., microbial contamination risks, operator error, etc.

Equipment, Utilities,and Facility

Risks associated with equipment, utilities, or facilities failure

Project Leads to delay in project timeline (often related to planning, resources, etc.)

Figure 1

Stage gate model for technology transfer.

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3. Unanticipated Changes

In addition to known changes, there will often be anumber of unanticipated changes that occur. Theseunanticipated changes are usually small in scope dueto the vigorous process of risk assessing knownchanges. Unanticipated changes may be discoveredduring Process Transfer Planning, Execution, or evenCompletion/GMP campaign Sub-stages and are risk-assessed as they arise. Unanticipated changes that arediscovered during Startup, Shakedown, Engineering,or Process Performance Qualification runs of the Pro-cess Transfer Execution Stage may benefit from usingqualified small-scale models (if available) to assess therisk.

3.1. Assessment of Unanticipated Changes

One strategy for commercial-to-commercial trans-fers is to risk-assess the unanticipated changes andthen bundle the low-risk items into one change

control evaluation. Changes that are discoveredwith higher risk are separated and assessed individ-ually. A flow chart for this type of strategy is shownin Figure 4.

Figure 2

Stage gate model with risk assessment.

Figure 3

Example flow for integration of planned changes toa process description.

Figure 4

Change control strategy for unanticipated changes.

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4. Risk Management Structure and Organization

Organization of people and documentation is a criticalaspect of risk management in technology transfer.Having an integrated technology transfer team struc-ture allows all relevant functions to address and mit-igate change in a timely manner and to escalate issuesquickly. The example structure in Figure 5 allowscross-functional assessment of risk in a fairly rapidmanner and provides links to the operations andquality groups for potential escalation of issues. Aschanges are not always predictable, the availability ofcross-functional teams on a continuous basis isneeded.

Risk assessment documents generally capture defini-tion of risk and justification for controlling risk. Stor-ing risk assessments in a centralized repository allowsfor efficient cross-functional cooperation because theyare often initiated by process development or technicalsupport groups and supported and approved by man-ufacturing and quality groups.

5. Conclusion

Risk management is an integral part of technologytransfer that occurs throughout the technology transfer

process. While larger changes are often well recog-nized and mitigated, smaller, unplanned changes canarise in a technology transfer and cause issues if thereis not capacity to handle them. Evaluation, re-evalua-tion, addition of new risk, and documentation ofchange can be best managed by recognizing that it willhappen and by having a cross-functional team andcentralized documents in place to manage risk. Effec-tive risk management will reduce the risk of a failureto produce comparable product during a technologytransfer and help ensure success of the transfer.

Acknowledgements

The authors wish to acknowledge John Bowers(Merck) and other members of the BioPhorum Oper-ations Group (BPOG) Technology Transfer work-stream for their contributions to this article. Since itsinception in 2004, the BioPhorum has become theopen and trusted environment where senior leaders ofthe biopharma industry come together to openly shareand discuss the emerging trends and challenges facingtheir industry. BioPhorum currently comprises morethan 1200 active participants in six forums—DrugSubstance, The Development Group, Fill Finish, TheTechnology Roadmap, BioPhorum IT Group, BioPho-rum Supply Partners.

Figure 5

Example cross-functional technology transfer team structure.

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