Technology Transfer Challenges for in-licensed Biopharms

8/8/2019 Technology Transfer Challenges for in-licensed Biopharms

1/5

10 BioProcess International November 2010

FOCUS ON... liCeNSiNg

During the lifecycle of abiopharmaceutical, occasionsarise in which the facility andsupport organization

responsible for ensuring that it ismanufactured according to schedule,

demand, and quality specificationsmust change, either in whole or inpart. The reasons for this vary: somerelated to scale, some related toclinical development phase, somerelated to internal manufacturingcapacity and program ownership. Theindustry has adopted the termtechnology transferto describe theseevents. Many such situations havebeen discussed previously (14). Here,we discuss a scenario in which aproduct has been bought or licensed

by another organization. Ourperspective is mostly that of a buyer orlicensee. We focus mostly on activitiesrelated to chemistry, manufacturing,and controls (CMC) because coveringall the aspects of licensing a product indevelopment would be too much for asingle article.

With no change in ownershipinvolved, technology transfercommonly occurs under the control ofa sponsor company e.g., in scaling

up from a development laboratory to aclinical or commercial manufacturingfacility or in transferring a methodfrom one laboratory to another. Insuch cases, it is relativelystraightforward for the sponsor toexert control over all practices andprotocols to ensure a robust andsuccessful transfer. Particularly inlarge corporations, technology transfermay be developed as an importantcore competency within an

organization (4). When more than oneorganization is involved, the resultingchallenges are worth examining.

Background

Changes in product ownership areincreasingly common and can happenat any stage of a products lifecycle.Figure 1 shows an increase in

mid-stage and late-stage deals to thehighest proportions in a decade, andFigure 2 shows the value of such dealsincreasing 500% over the same period.The rising values do not in themselvesindicate that the volume of deals hasincreased 500%, but more producttransfers are surely part of the picture.

Enabling technology and historicalinformation are transferred along withthe rights to develop a product. Thedegree of complexity usually increases

as an active molecule proceeds throughits development lifecycle. Thatcomplexity makes technology transfera significant undertaking if it occursafter an investigational new drug(IND) application has been filed.

Although tech transfer can occur atpreclinical stages, the value of atherapeutic moiety doesnt seem tobuild very steeply until it can bedemonstrated in humans (5). So themost valuable licensing deals happenafter the start of clinical development,at which point an IND or a evennew drug application (NDA) orbiologics license application (BLA) is transferred to a new sponsororganization. ICH Q10 brieflyacknowledges the importance of

maintaining a system of quality control(QC) over the course of changes inproduct ownership, and it explains thatresponsibilities should be defined forboth companies, directingmanagement to ensure that thenecessary information is transferred (6).

Key elements for successfultechnology transfer generally includethe following:

Direct involvement andengagement among technical staff on

both sides throughout the course oftransfer activities

Well-defined leadership andgovernance and competent projectmanagement

Multifunctional involvement(matrixed teams) with appropriatecompetencies on both the transferringand receiving ends

Meaningful demonstration ofsuccess (e.g., a successful goodmanufacturing practice [GMP]

Tchnoo Transfr Chans

for in-lcnsd Bopharmacutcas

b lor Nxon and Scott Rud

www.photos.com


2/5


3/5


product). In such cases, the drug maybe reformulated or its manufacturingprocess changed to make it more pure,more potent, or less expensive. Such

changes must be managed so as toderive the most benefit from existingpatient data.

The Importance of Due Diligence:

Assessment of technology transfershould be part of evaluation and duediligence activities before a licensingagreement is struck. Due diligencetypically focuses on assessing thecommercial value of a product to belicensed and assessing whether it is agood strategic fit (5, 8). Consider also

at this stage whether the new productis a good technology fit. How muchexpertise do you have in-house relativeto the operations used to produce andtest the drug? Although lack ofin-house manufacturing expertise isusually not a show-stopper, it willaffect the value of the deal to thereceiving organization, where thatexpertise will need to be built orhired. With less experience,companies tend to underestimate thedifficulty and resources required toensure a robust transfer of technology(5). So it is a good idea to involvemultifunctional team representativesin evaluating a licensing deal.

Intellectual property (IP)considerations should include not onlythe patent life and rights to themolecule itself, but all associatedtechnologies required for producingand testing it. The associatedtechnologies could affect the licensees

ability to understand or freely performcertain processing steps, acquireappropriate raw materials, or executetest methods, for example. Aside from

arranging secondary licensingagreements, if necessary, you shouldconsider the potential complicationsthat may arise from transferring aprocess in which certain elements mayremain outside of the full control ofthe licensee.

Licensees should evaluate whethera potentially licensed product has beendeveloped according to current GMPand other regulatory expectations andindustry standards. Have appropriate

activities relative to each developmentstage been executed and documented(e.g., process and methodcharacterization or validation)? Whatis the state of the documentation(batch records, SOPs, regulatorysubmissions)? Does it adequately coverall development activities (process,analytical, formulation, and so on),and is the documentation readilyretrievable for transfer? Ideally itshould be comprehensive,systematically organized, and availablein electronic formats. Companies alsoshould secure the records of signatureson the transferred documents.

The Contract: As the contractualstage approaches, make sure bothparties agree on exactly whattechnology and information will betransferred and how that transfer willbe executed. Depending on negotiatedincentives, it may be important todelineate in the contract agreement

exactly what information, materials,and equipment will be included.Consider also how you can ensureappropriate involvement of technicalexperts in the licensor organization.Will you have access to the originaldevelopment scientists (across therange of relevant disciplines) duringtransfer of information as well as

during subsequent demonstrations ofthe technology? How much of theirtime will be available to support theseactivities?

Here is where you may easily runinto conflicts if licensor and licenseehave different expectations around thescope of their technology transfer. It isimportant to understand therelationship between the parties andthe incentives on both sides. Howinvolved will the licensor be after the

transfer, over what timeframe, and atwhat cost? Will it have any continuingrights to the product or stake in itssuccess? Is the companys motivationto simply close the deal and make theproduct go away with the leastamount of effort and expense? Becausethe licensee usually has the most atstake in ensuring success, it may beimportant to ensure that at least somebest practices are specifically agreedupon per contract. Otherwise yourelikely to have trouble getting interest

from and traction with the licensor.

What information

should Be transferred?

From the licensee perspective, asmuch information as possible shouldbe transferred. Clearly the licensorwill not want to or be able to deliverabsolutely every scrap of informationor material associated with a product.Some information may not be welldocumented or may be proprietary,

too diff icult to retrieve, or consideredunnecessary. Some equipment,materials, or proprietary informationmay need to be retained by thelicensor to support other products inits development pipeline.Nevertheless, the licensee should pushfor as much as possible. Developmentinformation may be particularlydifficult to obtain, but it may alsogive you greater technical insight intothe product and prevent you from

Table 1: s cmc g f

GMP Documents Regulatory Documents Supporting Documents

Master batch records IND, NDA, BLA, and CTDdrafts and submissions

Process flow diagrams, campaignsummaries, control charts, and completedbatch records for key clinical andtoxicology drug substance and drugproduct

Specifications Pharmaceuticaldevelopment report

Justification or rationale for specifications,risk assessments on formulation, andexcipient compatibility and experimentalresults

Stability testingpackages

Stabili ty tables Trend analyses and statistical treatments,technical reports

Process validationprotocol and masterplan

Process validation report Process development reports, processcharacterization data, and risk assessments

Analytical testingmethods

Test methoddescriptions andvalidation summary

Method development and validationreports, customized software orspreadsheets, and control charts


4/5


spending resources on repeating workthats already been done.

Table 1 lists examples of CMCdocuments that should be requested.Other items to review include expertreports from third parties orconsultants, manufacturinginvestigations, and out-of-specification (OOS) reports and

material safety data sheets (MSDSs)for both drug substance and drugproduct.

Materials may need to betransferred as well as information,such as

Previously manufactured drugsubstance or product (toxicology,GMP materials, primary referencebatches) or retains

Cell banks Materials held in stability

programs Reference and working standards Impurities standards Assay controls Critical analytical reagents (e.g.,

antibodies/antigens, primers/probes,and complex matrices)

In-process and/or developmentretains

Certain critical raw materials(e.g., single-sourced or proprietaryprocess materials)

Equipment (particularly, custom

or proprietary equipment).For many of those materials, it may

be important as well to obtainassociated documentation supportingstorage history and relevant chain-of-custody information. Inventoryinformation should be obtained,including applicable expiries. (Expiredmaterials may still be useful fordevelopment purposes.) For someanalytical reagents, it may beimportant to obtain qualification

protocols and reports, as well asprocedures detailing how they wereoriginally manufactured and tested (if,for example, they are proprietaryreagents or standards manufactured bythe original sponsor). For critical rawmaterials, it may be necessary to shareor transfer previously developed supplychain agreements and relationships.For custom equipment (includingsoftware), specifications should beincluded.

It is worth noting that it is typicalto have a number of critical analyticalstandards and reagents that may notbe easy to replenish or replace. Oneexample is a process-specific host-cellprotein ELISA (enzyme-linkedimmunosorbent assay), which may relyon a specific set of antibodies andantigens developed and created by the

licensor. Such reagents can actuallytake years to replace, and nocomparable or suitable replacementsmay be commercially available.

The licensee should ensure thatadequate quantities of those analyticalmaterials are transferred (as part ofthe contract) to support anticipatedactivities until such time as newsources can be created and requalifed.Keep in mind that activities such asassay transfer and validation and

process development support canconsume many more analyticalreagents and reference standards thando routine activities such as releaseand stability programs. Dont end upwith a situation in which you cannotperform batch release or other criticalactivities because you lack theappropriate analytical reagents.

PreParetoaccePtthe technology

Have a plan for receiving documentsthat ensures efficient transfer of

information. This might include asingle point of contact on each end, atracking system for status and request,a central location for electronic filestorage, and a system of organizingreceived information. You need amechanism for capturing informalcommunications during transfer: e.g.,questions and clarifications amongtechnical staff of the two companies.Once the transfer is complete, youmay have limited or no opportunity to

go back to the licensor with additionalquestions.

Other logistical considerationscome up in receiving a newtechnology. The licensee needsappropriate capabilities to manage andorganize information and inventoriesas well as the appropriate physicalfacilities for storing and organizingmaterials. For example, consider howand where to ship and store GMP rawmaterials, reference standards,

stability-tesing materials, cell banks,and so on. Especially where thesematerials are used to support GMP

activities, appropriate control must beensured over the entire course of thetransfer.

If partnered transfer activitiesinclude demonstrating a manufacturingprocess and/or methods in the licenseefacility, then that facilitys physicalcapabilities should be assessed.Technical staff are needed on bothsides with competencies in thetechnologies in use. If a licensee haslittle experience with the technologybeing transferred, then its personnel

may not ask the right questions, withthe result that the transfer is notrobust. Licensees should objectivelyevaluate their expertise in the relevantareas. Those may includemanufacturing unit operations,facilities, process chemistry andengineering, and analytics. If expertisegaps are an issue, it is advisable tobring in outside help (expert technicalconsultants or groups) for support.

during executionGood project management practicesare extremely valuable in executing atransfer of technology. This includesthe development of timelines andobjectives, assigning responsibilities,and tracking progress towardagreed-on milestones. To the extentpossible, try to build and promotegood relationships among teammembers. Ensure that consistentexpectations for supporting transfer

Licensees should

OBjeCTivelyevaluate their

expertise in, e.g.,

manufacturing unitoperations, facilities,

process chemistry,

engineering, and

analytics.


5/5


activities are communicated across thelevels of both organizations (fromdeveloping scientists to projectmanagers to executives). If developingscientists are engaged, but theirmanagers are not, then they are likelyto be diverted to other projects. If thelicensees scientists have a not-invented-here mindset and resist

implementing licensed technology as itwas originally developed, then thesuccess of the transfer (as measured bysuch concepts as productcomparability) may be at risk.

A Responsibility Matrix: Commonproject management tools make senseto use here. A licensee should developa responsibility matrix. A map ofconnectivities to all parties should bedrawn and maintained because playerschange during the course of a project.

If licensor and licensee motivationsconflict, then a steering committeeshould be empowered to interpret thecontract and authorize expenditures tomaintain timelines and achieve thegoal of the license that is, tomarket a product to improvehealthcare for patients.

Action items and deliverablesshould be tracked and tied to specificpoints on the timeline. If delivery islate, then its timeline impact shouldbe assessed and communicated to the

steering committee. If activities arenot directed toward points on thetimeline, then they should be stoppedor the timeline modified to accountfor the oversight. It is useful for aproject manager to update action itemsoff-line, so the group can focus onforward-looking activities andinformation at a larger scale. Thewhole group involved in technologytransfer should meet regularly toensure that cross-disciplinary issues

are heard by all and to disseminateinformation on next steps and projectstatus relative to the timeline, budget,and management expectations.However, details and minutiae ofspecific disciplines should be kept to aminimum and reserved for regularsubteam meetings.

Complex technology transferactivities such as demonstration runsshould use written protocols: anoverarching protocol and/or several

smaller ones covering individualactivities (such as the transfer ofindividual analytical methods). Usemeaningful, predefined acceptancecriteria to demonstrate success. Forexample, in analytical methodstransfer, compare results of materialstested at both the transferring andreceiving laboratories. For transfer of a

manufacturing process, compareproduct quality attributes againstin-process control limits, historicallimits, specifications, and/or othermeasures. Unlike with internaltransfers, contractual obligations cansurround the acceptance criteria forsuch a protocol. A licensor willprobably look for broad limits todemonstrate success, whereas alicensees interest is better served bynarrow limits. Good, transparent, and

consistent science is required to setthose limits fairly so they will beuseful for regulatory purposes as well.Some detailed examples have beenpublished of elements to include intransfer protocols (1).

Use good change-control practices.In some cases, it will be necessary tomake changes to a technology as it istransferred from one organization toanother. Although it is advisable tominimize changes until transferredtechnology has been successfully

demonstrated by the licensee, somechange is unavoidable (e.g., due todifferences in manufacturingequipment or operating practices). Anysuch alterations of a CGMP processshould be documented and evaluatedwith appropriate oversight from thequality and regulatory units of thelicensee. Product comparabilityprotocols may also be advisable forbiopharmaceuticals, and demonstrationof product comparability is usually a

final endpoint for assessing successfulcompletion of the transfer.

Even in the best cases, transfer oftechnology to a new product ownercan result in some loss of historicalknowledge. This could be attributableto incomplete or missingdocumentation or to loss of a gap inexpertise or tribal knowledge at thenew organization. The licensee shouldattempt to document all known gapsand make plans to address them.

Planfor success

With any project in biotechnology andpharmaceutical development, planningahead and doing your homework upfront will pay dividends. Teams thatunderstand the project objectives andtimelines, the technology beingtransferred, and the contractual andregulatory obligations associated with

their projects will ultimately do well.Having a preconceived expectation ofwhat data, materials, and equipmentwill be necessary to conduct a transfer;experts to interpret, use, and operatetransferred materials; and places tostore, disseminate, archive and retrievethem will allow a licensee to beginreplicating the expertise required forsuccessful product development.

references

1 ISPE Good Practice Guide: Technology

Transfer. International Society forPharmaceutical Engineering: Tampa, FL,March, 2003.

2 Haas C. Ten Steps to Success. Euro.Pharmaceut. Rev., May 2005.

3 Patel DS. Technology Transfer, anOverview for Pharmaceutical Industry.Int.Biopharmaceut. Assoc. Newslet., April 2006.

4 De Palma A. Tech Transfer: DontFumble the Hand-Off. PharmaManufacturing.com 2006; www.pharmamanufacturing.com/articles/2006/216.html.

5 Fitzgerald JD. Technology TransferIssues in Licensing Pharmaceutical Products.

R&D Management22(3) 1992: 199208.

6 ICH Q10. Pharmaceutical Qua litySystem. Fed. Reg. 74(66) 2009: 1599015991;

www.ich.org/MediaServer.jser?@_ID=3917&@_MODE=GLB.

7 FDA Warning Letter to Replidyne, Inc. 18January 2008: w ww.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/arningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/ucm054149.pdf.

8 Mendes P. Licensing and TechnologyTransfer in the Pharmaceutical Industry.WorldIntellectual Property Organization: Geneva,

Switzerland; www.wipo.int/sme/en/documents/pharma_licensing.html.

Dr. Lori Nixon is a senior consultant, and

corresponding author Dr. Scott Rudge is a

principal consultant at RMC Pharmaceutical

Solutions, Inc., 2150 Miller Dr. Suite A,

Longmont, CO 80501; lnixon@rmcpharma.

com, [email protected].