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MOU number: UMBC

Memorandum of Understanding

Between
The University of Maryland Baltimore County

and

The Food and Drug Administration

The United States Food and Drug Administration (FDA) and the University of Maryland Baltimore County (UMBC) have a shared interest in scientific progress through an exchange of scientific capital in the diverse fields of science that directly and indirectly affect human and animal health and medicine. Both institutions also endorse scientific training for academicians and students to foster a well-grounded foundation in interdisciplinary science on which scientific learning will grow.

This Memorandum of Understanding (MOU) establishes terms of collaboration between FDA and UMBC to support collaboration on specific projects related to biotechnology process validation, but can serve as the basis for future collaborations in other areas.

I. Background On Biotechnology Process Validation

The University of Maryland, Baltimore County (UMBC) and the FDA propose to collaborate on several projects concerning viral safety and process validation of biotechnology pharmaceuticals. Mammalian cell cultures used in the products of monoclonal antibodies (mAbs) and other recombinant products (RP) concomitantly produce endogenous type C retrovirus particles. An additional safety concern is the potential introduction of adventitious agents into these mammalian cell cultures. Regulatory agencies, including FDA, require a demonstration that mAbs and RPs intended for human use are free of viruses, with an adequate margin of safety. This is usually achieved by validation studies, performed at small scale, to demonstrate that the manufacturing process is capable of removing or inactivating several different model viruses, including a retrovirus. Because the assays currently used in these studies (e.g. TEM, in vitro infectivity assays) are expensive, time consuming and insensitive, our lab and others have been developing improved methods for viral measurement and assessment of clearance/inactivation (Brorson et al., 2001; Brorson et al., 2002a).

Over the past five years a paradigm shift has occurred with the advent of real time, quantitative (Q) PCR-based viral assays, which allow testing of 20-50 samples in ½ day, greatly accelerating the science behind viral safety studies. The Division of Monoclonal Antibodies (DMA), CBER and the Office of New Drug Chemistry (ONDC), CDER has established a scientific collaboration with Genentech, Inc., on viral safety issues because their Process Sciences Department leads the field in the development of Q-PCR assays for biotechnology safety evaluation. This collaboration has used Q-PCR assays to define:

• Cell culture operating conditions that control and minimize endogenous retrovirus expression (Brorson et al., 2002b).
• Purification operating conditions in which controlled, predictable virus removal/inactivation can be achieved, considering the potential impact of multiple re-use of chromatography media (Brorson et al., 2003a; Krejci et al., 2003).
• Bracketed generic virus inactivation/removal conditions, which may be used to exempt some IND sponsors or licensed manufacturers for re-performing certain viral clearance studies. (Brorson et al., 2003b; Krejci et al., 2003).

II. Collaborative Approach

UMBC's Chemical and Biochemical Engineering Department focuses on biotechnology research and is keenly interested in developing a collaborative research program with biotechnology product divisions in the FDA. Faculty members and students in the Chemical and Biochemical Engineering Department of UMBC will participate in this collaboration, covered by a Cooperative Research and Development Agreement (CRADA) or other appropriate legal agreement. Individual project CRADA(s) may include third parties such as biotechnology firms or organizations. For each project, the experimental designs (e.g. relevant control parameters, assays and measured attributes) will be prospectively shared and agreed upon in detail. Relevant data and conclusions from all collaborations are intended to be released to the public in peer reviewed, scientific journals. All parties in the collaboration will assume appropriate authorship and review responsibility and be given appropriate credit for published articles describing the research.

Initial project.

We propose to initiate the FDA/UMBC collaboration by inviting them to participate in a project investigating chromatography resin re-use. Multiple re-use of chromatography resins poses a unique regulatory challenge. Process economics creates an incentive to use expensive resins multiple times. From a regulatory standpoint, there needs to be documentation that used resins have the capacity to clear retroviruses as adequately as new resins. The conservative, but expensive, approach to this issue has been to validate retrovirus removal using new and aged resins. An alternative approach is to look for surrogate performance attributes, such as step yields or eluate impurity content (protein A, DNA, etc.), that decay prior to diminution of retrovirus log10 reduction value (LRV). An on-going collaboration between DMA/CBER, ONDC/CDER and Genetech Inc., has performed accelerated resin degradation experiments to see if such parameters can be defined for commonly used resins. In experiments using a protein A column degraded by multiple purification cycles (150-460) and various cleaning buffers, unit operation step yield appears to be an earlier indicator of column decay than retrovirus LRV (Brorson et al., 2003a).

In FDA's proposed collaboration with UMBC, we will follow up these studies by evaluating resin decay and robustness of LRV with other resins commonly used to purify mAbs (e.g. anion exchange, hydrophobic interaction). FDA and UMBC will design bracketed/matrix experiments using strong (Q-sepharose) and weak (DEAE-sepharose) anion exchange resins degraded by cleaning solutions of different strengths to determine if our observations with protein A resin also apply to anion exchange resins.

Follow up projects.

Other potential project ideas discussed with UMBC include:

• Bracketed/matrix studies to support bracketed generic virus removal validation for additional robust unit operations beyond those already studies (e.g. nanofiltration, heat inactivation)
• Correlative studies of proteomics and endogenous retrovirus expression. We have developed Q-PCR methods to track endogenous retrovirus expression. Our collaborative work with Genentech (Brorson et al., 2002b) revealed that temperature shifts, butyrate addition and pH shifts impact endogenous retrovirus expression, but nutrient additions and production scale up does not. This project may facilitate the identification of proteomic pattern changes that correlate with endogenous retrovirus expression. It is also possible that proteomic differences induced by temperature shifts or butyrate addition are more dramatic than those induced by nutrient addition.
• Developing biosensors to monitor, in real-time, impurities in bioreactors or columns, such as DNA, viruses or deamidated forms in different products.
• Explore whether 2-3 hybridomas or CHO transfectants can be grown together for short periods of time in batch mode to make mAb cocktails. The stability of growth, expression and cell survival can be monitored by Q-PCR assays. MAb cocktails may have applicability for counter-bioterrorism therapeutics or prophylactics. Alternatively, if our project demonstrates that this bioreactor strategy won't work, it will strengthen support for the current FDA approach of requiring that each antibody proposed for use in a mAb cocktail be generated independently.

References

FDA references related to biotechnology process validation science:

1. Brorson, K., Swann, P. Lizzio, E., Maudru, T., Peden, K. and Stein K. Use of a quantitative product-enhanced reverse transcriptase assay to monitor retrovirus levels in mAb cell-culture and downstream processing. Biotechnol Prog. 188-96, 2001.
2. Brorson, K., Xu, Y., Swann, P. Hamilton, E., Mustafa, M., de Wit, C., Norling, L., and Stein, K. Evaluation of a quantitative product-enhanced reverse transcriptase assay to monitor retrovirus in mAb cell-culture. Biologicals, 30:15-26, 2002(a).
3. Brorson, K., de Wit C., Hamilton, E., Mustafa, M., Swann, P., Kiss, R., Polastri, G., Stein K., and Xu, Y. Impact of cell culture process changes on endogenous retrovirus expression. Biotech Bioeng, 80:257, 2002(b).
4. Brorson, K., Krejci, S., Lee, K., Hamilton, E., Stein, K., and Xu Y. Bracketed generic inactivation of rodent retroviruses by low pH treatment for monoclonal antibodies and recombinant proteins. Biotech Bioeng, in press 2003(a).
5. Brorson, K., Brown, J., Hamilton, E., Stein, K. Identification of protein A media performance quality attributes that can be monitored as surrogates for retrovirus clearance during extended re-use. J. Chromatography, in press 2003(b).
6. Krejci, S., Lee, K., Blank, G., Brorson, K., and Xu, Y. Generic/matrix evaluation of viral clearance by chromatography procedures; SV40 clearance by Q-sepharose fast flow chromatography with a flow-through mode. Biotech Bioeng, submitted.

III. In addition to the collaborative research above, additional shared efforts are addressed below:

By the Food and Drug Administration

For the programs listed below, FDA will provide UMBC the following:

• Laboratory and/or office space as needed and available.
• Openness and proactive efforts in establishing additional collaborative research efforts with UMBC faculty, students, and staff.
• Based on available resources, willingness to participate in graduate courses and seminars at UMBC.
• Continuing and frequent communication with faculty and staff.
• Openness and welcome to faculty, staff, and students wishing to visit FDA laboratories.
• Promulgation and communication of this collaborative effort through web pages, informal conversations with colleagues, faculty and students.

In the Sabbatical Program:

• Opportunities to apply for faculty and post-doc salary support, where appropriate, through a variety of funding mechanisms. Request for salary support must coincide with the current federal fiscal year.
• Opportunities to apply for faculty sabbaticals with the agency with terms of the sabbatical to be negotiated between the individual and the agency.
• Opportunity for UMBC faculty, post-docs and students to attend a variety of didactic courses.
• Consistent with UMBC and FDA rules and regulations, and negotiated on a case-by-case basis, FDA mentors can, where appropriate, serve on thesis committees, attend examination and committee meetings, and participate in other aspects of the student's educational program at UMBC.
• As appropriate, openness and welcome to students wishing to rotate through FDA laboratories, as well as an opportunity to obtain short-term training in related areas.

General Appointments:

• Opportunity to submit resumes to apply for Special Government Employee (SGE) appointments.

By the University of Maryland Baltimore County

For the programs listed below, UMBC will provide FDA the following:

• Laboratory and/or office space as needed and as available.
• Openness and proactive efforts in establishing additional collaborative research efforts with FDA scientists and staff.
• Continuing and frequent communication with FDA scientists and staff.
• Openness and welcome to FDA scientists and staff wishing to visit relevant UMBC programs and laboratories.
• Promulgation and communication of this collaborative effort through web pages, informal conversations with colleagues, faculty and students.
• Potential for FDA researchers to co-apply for U01/R01 NIH grants in relevant areas through UMBC.
• Notification of students of internship opportunities to pursue laboratory research in FDA labs on projects relevant to FDA's mission.
• Opportunity for FDA scientific staff to apply for adjunct faculty appointments in appropriate departments at UMBC.
• Scientific exchange on FDA mission relevant science such as biotechnology process research via special interest groups.

In a Sabattical Program at UMBC:

• Opportunities to apply for a sabbatical with UMBC. Terms of the sabbatical will be negotiated between the individual and the appropriate University unit.
• Opportunity to attend and/or participate in a variety of courses at the graduate level.

IV. Coverances

UMBC individuals participating in the MOU will be United States Citizens or Permanent Residents. Regarding the latter, all federal restrictions will be adhered to.

Patent, license, and other legal instruments will be prepared in accordance with federal law and UMBC policy, and written notice referencing the policies will be provided to the individual prior to entering on duty with FDA. UMBC and FDA may decide to enter into a CRADA at a future time to conduct collaborative research. The terms of such a CRADA will address Intellectual Property rights.

This MOU forms the basis for the initial relations between FDA and UMBC for sabbaticals, research, and scientific education. However, as this collaborative effort progresses, it is expected that new and wider areas of mutual interest will evolve and be included in expansions of this document.

V. Finances and Resources

UMBC and FDA agree that this MOU does not commit either to make specific levels of financial or personnel support or to provide specific laboratory or office space for the programs and that the provision of such support will be based on available resources and provided in accordance with the rules, regulations and laws under which FDA operates and the policies of UMBC.

VI. Contact

The individual to whom all inquiries to FDA should be addressed is:

Kurt Brorson, Ph.D.
Staff Scientist
Division of Monoclonal Antibodies
Center for Biologics Evaluation and Research
Food and Drug Administration
Bldg. 29B, Rm. 5E16
29 Lincoln Dr.
Bethesda, MD 20892
Tel: 301-827-0661
FAX: 301-827-0852
Email: brorson@cber.fda.gov

The individual to whom all inquiries to UMBC should be addressed is:

Antonio R. Moreira, Ph.D.
Vice Provost for Academic Affairs
University of Maryland, Baltimore County
1000 Hilltop Circle, ADM 1001
Baltimore, MD 21250
Tel: 410-455-6576
Fax: 410-455-1107
Email: moreira@umbc.edu

Academic MOUs

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