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licensing

Technology Transfer Challenges


for In-Licensed Biopharmaceuticals
by Lori Nixon and Scott Rudge

D
uring the lifecycle of a as an active molecule proceeds through
biopharmaceutical, occasions its development lifecycle. That
arise in which the facility and complexity makes technology transfer
support organization a significant undertaking if it occurs
responsible for ensuring that it is after an investigational new drug
manufactured according to schedule, (IND) application has been filed.
demand, and quality specifications Although tech transfer can occur at
must change, either in whole or in preclinical stages, the value of a
part. The reasons for this vary: some therapeutic moiety doesn’t seem to
related to scale, some related to build very steeply until it can be
clinical development phase, some demonstrated in humans (5). So the
related to internal manufacturing most valuable licensing deals happen
capacity and program ownership. The after the start of clinical development,
industry has adopted the term at which point an IND — or a even
technology transfer to describe these new drug application (NDA) or
events. Many such situations have biologics license application (BLA) —
been discussed previously (1–4). Here, is transferred to a new sponsor
we discuss a scenario in which a organization. ICH Q10 briefly
product has been bought or licensed acknowledges the importance of
by another organization. Our maintaining a system of quality control
perspective is mostly that of a buyer or www.photos.com (QC) over the course of changes in
licensee. We focus mostly on activities product ownership, and it explains that
related to chemistry, manufacturing, organization (4). When more than one responsibilities should be defined for
and controls (CMC) because covering organization is involved, the resulting both companies, directing
all the aspects of licensing a product in challenges are worth examining. management to ensure that the
development would be too much for a necessary information is transferred (6).
single article. Background Key elements for successful
With no change in ownership Changes in product ownership are technology transfer generally include
involved, technology transfer increasingly common and can happen the following:
commonly occurs under the control of at any stage of a product’s lifecycle. • Direct involvement and
a sponsor company — e.g., in scaling Figure 1 shows an increase in engagement among technical staff on
up from a development laboratory to a mid-stage and late-stage deals to the both sides throughout the course of
clinical or commercial manufacturing highest proportions in a decade, and transfer activities
facility or in transferring a method Figure 2 shows the value of such deals • Well-defined leadership and
from one laboratory to another. In increasing 500% over the same period. governance and competent project
such cases, it is relatively The rising values do not in themselves management
straightforward for the sponsor to indicate that the volume of deals has • Multifunctional involvement
exert control over all practices and increased 500%, but more product (matrixed teams) with appropriate
protocols to ensure a robust and transfers are surely part of the picture. competencies on both the transferring
successful transfer. Particularly in Enabling technology and historical and receiving ends
large corporations, technology transfer information are transferred along with • Meaningful demonstration of
may be developed as an important the rights to develop a product. The success (e.g., a successful good
“core competency” within an degree of complexity usually increases manufacturing practice [GMP]
10 BioProcess International November 2010
manufacturing campaign resulting in Figure 1:  Proportion of early, mid-, and late-stage product transfers (McCully MG, Van Brunt J. Alliance
Trends: Deal Values Soar. Signals Mag. 10 April 2007)
comparable material)
• Good documentation of what is Late Mid Early
transferred, how it is to be transferred, 100%
and the results of that transfer. 17.9%
90% 19.3% 23.3%
A change in product ownership 26.8% 31.5%
multiplies the challenges of 80%
technology transfer. First, the scope is 11.7%
70% 25.1% 9.1%
very broad (encompassing not just a 12.8%
60% 14.9%
set of methods or manufacturing
procedures, but all critical information 50%
supporting the drug development
40%
program to date). Quite often,
technology elements applied by a 30%
licensor are broad or “platform” 20%
technologies that it may be unwilling
to part with for any one specific 10%
product outlicensing. Untangling all 0%
technology ownership supporting a 1992−1994 1995−1997 1998−2000 2001−2003 2004−2006
product can often be difficult and
contentious in such cases. Figure 2:  Value of biotech deals, 1992–2006; B:B = biotech–biotech deals, D:B = drug–biotech deals
Also, the ability of both companies
to implement the best practices 2,000
B:B D:B
described herein may be limited. 1,800
Practices and motivations are usually 1,600
different among licensee and licensor 43.5% 41.3%
1,400
organizations. Some “translation” of
procedures from one organization’s 1,200
quality system to the other’s will be 1,000 54.0%
required. In addition, licensees often 800
have less expertise in at least some 600 67.9%
aspects of the technology being
400
transferred, and they may in fact 73.6%
200
transfer it to a third-party
organization to execute. 0
Finally, the desire to recognize 1992−1994 1995−1997 1998−2000 2001−2003 2004−2006
transfer-related milestone payments
quickly may cause unusual timeline new sponsor as well as the overall development. Failure to have such
pressures. Those may often coincide development timeline. A good data can lead to negative regulatory
with a sharp cut-off of access to the licensing agreement will include large consequences, such as FDA warning
transferring organization’s expertise. incentives for the licensor to ensure letters (7). Clinical-stage products also
To ensure the best outcome for their that technology transfer is complete require transfer of current GMP
in-licensed product, the onus is on a and successful. Such incentives could (CGMP) procedures, processes,
licensee to account for such realities in include milestone payments and/or methods, and/or materials that must
planning and negotiating technology royalties on the marketed product. be comparably maintained, controlled,
transfer activities. and/or executed by the new sponsor.
Although licensees have the Planning and Negotiating Often there are legacy clinical trial
greatest stake in making transfers Technology Transfer materials and ongoing legacy clinical
successful and robust, they may be As mentioned above, “technology trials, such as compassionate use and
unable to control many elements of transfer” in a licensing situation covers treatment IND applications. The
transfer processes. Even when best a very broad range of activities in participants have a responsibility to
practices cannot be applied, a transfer many areas of an organization continue those trials and serve those
will still get done, but the outcome is (manufacturing, development, patients while the product is
likely to be less robust and/or entail preclinical, clinical, regulatory, and so developed under the new organization.
significant additional work (usually by on). One part is simply transmitting Usually a licensee will have a new
the licensee) to cover gaps or rework relevant historical information to each idea for the product or insight into
processes or methods. This can area that gives scientific support for what caused difficulty for the licensor
change the value of the deal to the the current state of product (thus driving the idea to license the
12 BioProcess International November 2010
Table 1:  Some CMC documents critical to technology transfer exactly what information, materials,
GMP Documents Regulatory Documents Supporting Documents and equipment will be included.
Master batch records IND, NDA, BLA, and CTD Process flow diagrams, campaign Consider also how you can ensure
drafts and submissions summaries, control charts, and completed appropriate involvement of technical
batch records for key clinical and experts in the licensor organization.
toxicology drug substance and drug
product Will you have access to the original
Specifications Pharmaceutical Justification or rationale for specifications, development scientists (across the
development report risk assessments on formulation, and range of relevant disciplines) during
excipient compatibility and experimental transfer of information as well as
results
during subsequent demonstrations of
Stability testing Stability tables Trend analyses and statistical treatments,
packages technical reports the technology? How much of their
Process validation Process validation report Process development reports, process time will be available to support these
protocol and master characterization data, and risk assessments activities?
plan Here is where you may easily run
Analytical testing Test method Method development and validation into conflicts if licensor and licensee
methods descriptions and reports, customized software or
validation summary spreadsheets, and control charts have different expectations around the
scope of their technology transfer. It is
important to understand the
product). In such cases, the drug may ability to understand or freely perform
relationship between the parties and
be reformulated or its manufacturing certain processing steps, acquire
the incentives on both sides. How
process changed to make it more pure, appropriate raw materials, or execute
involved will the licensor be after the
more potent, or less expensive. Such test methods, for example. Aside from
transfer, over what timeframe, and at
changes must be managed so as to arranging secondary licensing
what cost? Will it have any continuing
derive the most benefit from existing agreements, if necessary, you should
rights to the product or stake in its
patient data. consider the potential complications
success? Is the company’s motivation
The Importance of Due Diligence: that may arise from transferring a
to simply close the deal and make the
Assessment of technology transfer process in which certain elements may
product “go away” with the least
should be part of evaluation and due remain outside of the full control of
amount of effort and expense? Because
diligence activities before a licensing the licensee.
the licensee usually has the most at
agreement is struck. Due diligence Licensees should evaluate whether
stake in ensuring success, it may be
typically focuses on assessing the a potentially licensed product has been
important to ensure that at least some
commercial value of a product to be developed according to current GMP
best practices are specifically agreed
licensed and assessing whether it is a and other regulatory expectations and
upon per contract. Otherwise you’re
good strategic fit (5, 8). Consider also industry standards. Have appropriate
likely to have trouble getting interest
at this stage whether the new product activities relative to each development
from and traction with the licensor.
is a good technology fit. How much stage been executed and documented
expertise do you have in-house relative (e.g., process and method
What Information
to the operations used to produce and characterization or validation)? What
Should Be Transferred?
test the drug? Although lack of is the state of the documentation
From the licensee perspective, as
in-house manufacturing expertise is (batch records, SOPs, regulatory
much information as possible should
usually not a show-stopper, it will submissions)? Does it adequately cover
be transferred. Clearly the licensor
affect the value of the deal to the all development activities (process,
will not want to or be able to deliver
receiving organization, where that analytical, formulation, and so on),
absolutely every scrap of information
expertise will need to be built or and is the documentation readily
or material associated with a product.
hired. With less experience, retrievable for transfer? Ideally it
Some information may not be well
companies tend to underestimate the should be comprehensive,
documented or may be proprietary,
difficulty and resources required to systematically organized, and available
too difficult to retrieve, or considered
ensure a robust transfer of technology in electronic formats. Companies also
unnecessary. Some equipment,
(5). So it is a good idea to involve should secure the records of signatures
materials, or proprietary information
multifunctional team representatives on the transferred documents.
may need to be retained by the
in evaluating a licensing deal. The Contract: As the contractual
licensor to support other products in
Intellectual property (IP) stage approaches, make sure both
its development pipeline.
considerations should include not only parties agree on exactly what
Nevertheless, the licensee should push
the patent life and rights to the technology and information will be
for as much as possible. Development
molecule itself, but all associated transferred and how that transfer will
information may be particularly
technologies required for producing be executed. Depending on negotiated
difficult to obtain, but it may also
and testing it. The associated incentives, it may be important to
give you greater technical insight into
technologies could affect the licensee’s delineate in the contract agreement
the product and prevent you from
14 BioProcess International November 2010

spending resources on repeating work It is worth noting that it is typical
that’s already been done. to have a number of critical analytical
Table 1 lists examples of CMC standards and reagents that may not
documents that should be requested. be easy to replenish or replace. One
Other items to review include expert example is a process-specific host-cell Licensees should
reports from third parties or protein ELISA (enzyme-linked
consultants, manufacturing immunosorbent assay), which may rely objectively
investigations, and out-of- on a specific set of antibodies and evaluate their
specification (OOS) reports and antigens developed and created by the expertise in, e.g.,
material safety data sheets (MSDSs) licensor. Such reagents can actually manufacturing unit
for both drug substance and drug take years to replace, and no
product. comparable or suitable replacements operations, facilities,
Materials may need to be may be commercially available. process chemistry,
transferred as well as information, The licensee should ensure that engineering, and
such as adequate quantities of those analytical analytics.
• Previously manufactured drug materials are transferred (as part of
substance or product (toxicology, the contract) to support anticipated
GMP materials, primary reference activities until such time as new
batches) or retains sources can be created and requalifed. stability-tesing materials, cell banks,
• Cell banks Keep in mind that activities such as and so on. Especially where these
• Materials held in stability assay transfer and validation — and materials are used to support GMP
programs process development support — can activities, appropriate control must be
• Reference and working standards consume many more analytical ensured over the entire course of the
• Impurities standards reagents and reference standards than transfer.
• Assay controls do routine activities such as release If partnered transfer activities
• Critical analytical reagents (e.g., and stability programs. Don’t end up include demonstrating a manufacturing
antibodies/antigens, primers/probes, with a situation in which you cannot process and/or methods in the licensee
and complex matrices) perform batch release or other critical facility, then that facility’s physical
• In-process and/or development activities because you lack the capabilities should be assessed.
retains appropriate analytical reagents. Technical staff are needed on both
• Certain critical raw materials sides with competencies in the
(e.g., single-sourced or proprietary Prepare to Accept the Technology technologies in use. If a licensee has
process materials) Have a plan for receiving documents little experience with the technology
• Equipment (particularly, custom that ensures efficient transfer of being transferred, then its personnel
or proprietary equipment). information. This might include a may not ask the right questions, with
For many of those materials, it may single point of contact on each end, a the result that the transfer is not
be important as well to obtain tracking system for status and request, robust. Licensees should objectively
associated documentation supporting a central location for electronic file evaluate their expertise in the relevant
storage history and relevant chain-of- storage, and a system of organizing areas. Those may include
custody information. Inventory received information. You need a manufacturing unit operations,
information should be obtained, mechanism for capturing informal facilities, process chemistry and
including applicable expiries. (Expired communications during transfer: e.g., engineering, and analytics. If expertise
materials may still be useful for questions and clarifications among gaps are an issue, it is advisable to
development purposes.) For some technical staff of the two companies. bring in outside help (expert technical
analytical reagents, it may be Once the transfer is complete, you consultants or groups) for support.
important to obtain qualification may have limited or no opportunity to
protocols and reports, as well as go back to the licensor with additional During Execution
procedures detailing how they were questions. Good project management practices
originally manufactured and tested (if, Other logistical considerations are extremely valuable in executing a
for example, they are proprietary come up in receiving a new transfer of technology. This includes
reagents or standards manufactured by technology. The licensee needs the development of timelines and
the original sponsor). For critical raw appropriate capabilities to manage and objectives, assigning responsibilities,
materials, it may be necessary to share organize information and inventories and tracking progress toward
or transfer previously developed supply as well as the appropriate physical agreed-on milestones. To the extent
chain agreements and relationships. facilities for storing and organizing possible, try to build and promote
For custom equipment (including materials. For example, consider how good relationships among team
software), specifications should be and where to ship and store GMP raw members. Ensure that consistent
included. materials, reference standards, expectations for supporting transfer
16 BioProcess International November 2010
activities are communicated across the smaller ones covering individual Plan for Success
levels of both organizations (from activities (such as the transfer of With any project in biotechnology and
developing scientists to project individual analytical methods). Use pharmaceutical development, planning
managers to executives). If developing meaningful, predefined acceptance ahead and doing your homework up
scientists are engaged, but their criteria to demonstrate success. For front” will pay dividends. Teams that
managers are not, then they are likely example, in analytical methods understand the project objectives and
to be diverted to other projects. If the transfer, compare results of materials timelines, the technology being
licensee’s scientists have a “not- tested at both the transferring and transferred, and the contractual and
invented-here” mindset and resist receiving laboratories. For transfer of a regulatory obligations associated with
implementing licensed technology as it manufacturing process, compare their projects will ultimately do well.
was originally developed, then the product quality attributes against Having a preconceived expectation of
success of the transfer (as measured by in-process control limits, historical what data, materials, and equipment
such concepts as product limits, specifications, and/or other will be necessary to conduct a transfer;
comparability) may be at risk. measures. Unlike with internal experts to interpret, use, and operate
A Responsibility Matrix: Common transfers, contractual obligations can transferred materials; and places to
project management tools make sense surround the acceptance criteria for store, disseminate, archive and retrieve
to use here. A licensee should develop such a protocol. A licensor will them will allow a licensee to begin
a responsibility matrix. A map of probably look for broad limits to replicating the expertise required for
connectivities to all parties should be demonstrate success, whereas a successful product development.
drawn and maintained because players licensee’s interest is better served by
change during the course of a project. narrow limits. Good, transparent, and References
If licensor and licensee motivations consistent science is required to set 1 ISPE Good Practice Guide: Technology
Transfer. International Society for
conflict, then a steering committee those limits fairly so they will be
Pharmaceutical Engineering: Tampa, FL,
should be empowered to interpret the useful for regulatory purposes as well. March, 2003.
contract and authorize expenditures to Some detailed examples have been 2 Haas C. Ten Steps to Success. Euro.
maintain timelines and achieve the published of elements to include in Pharmaceut. Rev., May 2005.
goal of the license — that is, to transfer protocols (1). 3 Patel DS. Technology Transfer, an
market a product to improve Use good change-control practices. Overview for Pharmaceutical Industry. Int.
healthcare for patients. In some cases, it will be necessary to Biopharmaceut. Assoc. Newslet., April 2006.
Action items and deliverables make changes to a technology as it is 4 De Palma A. Tech Transfer: Don’t
Fumble the Hand-Off. PharmaManufacturing.
should be tracked and tied to specific transferred from one organization to
com 2006; www.pharmamanufacturing.com/
points on the timeline. If delivery is another. Although it is advisable to articles/2006/216.html.
late, then its timeline impact should minimize changes until transferred 5 Fitzgerald JD. Technology Transfer
be assessed and communicated to the technology has been successfully Issues in Licensing Pharmaceutical Products.
steering committee. If activities are demonstrated by the licensee, some R&D Management 22(3) 1992: 199–208.
not directed toward points on the change is unavoidable (e.g., due to 6 ICH Q10. Pharmaceutical Quality
timeline, then they should be stopped differences in manufacturing System. Fed. Reg. 74(66) 2009: 15990–15991;
www.ich.org/MediaServer.jser?@_ID=
or the timeline modified to account equipment or operating practices). Any
3917&@_MODE=GLB.
for the oversight. It is useful for a such alterations of a CGMP process
7 FDA Warning Letter to Replidyne, Inc. 18
project manager to update action items should be documented and evaluated January 2008: www.fda.gov/downloads/Drugs/
off-line, so the group can focus on with appropriate oversight from the GuidanceComplianceRegulatory
forward-looking activities and quality and regulatory units of the Information/EnforcementActivitiesbyFDA/
information at a larger scale. The licensee. Product comparability arningLettersandNoticeofViolationLettersto
PharmaceuticalCompanies/ucm054149.pdf.
whole group involved in technology protocols may also be advisable for
8 Mendes P. Licensing and Technology
transfer should meet regularly to biopharmaceuticals, and demonstration
Transfer in the Pharmaceutical Industry. World
ensure that cross-disciplinary issues of product comparability is usually a Intellectual Property Organization: Geneva,
are heard by all and to disseminate final endpoint for assessing successful
pharma_licensing.html. •
Switzerland; www.wipo.int/sme/en/documents/
information on next steps and project completion of the transfer.
status relative to the timeline, budget, Even in the best cases, transfer of
and management expectations. technology to a new product owner
Dr. Lori Nixon is a senior consultant, and
However, details and minutiae of can result in some loss of historical
corresponding author Dr. Scott Rudge is a
specific disciplines should be kept to a knowledge. This could be attributable principal consultant at RMC Pharmaceutical
minimum and reserved for regular to incomplete or missing Solutions, Inc., 2150 Miller Dr. Suite A,
subteam meetings. documentation or to loss of a gap in Longmont, CO 80501; lnixon@rmcpharma.
Complex technology transfer expertise or “tribal knowledge” at the com, srudge@rmcpharma.com.
activities such as demonstration runs new organization. The licensee should
should use written protocols: an attempt to document all known gaps
overarching protocol and/or several and make plans to address them.
18 BioProcess International November 2010

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