Frequently Asked Questions (FAQs) for requesting stem cell lines made by the Regenerative Medicine Program

 

1.    What types of stem cell lines are available from the Regenerative Medicine Program (RMP)?

There are 14 research grade induced pluripotent stem cell (iPSC) lines generated by the RMP available to the scientific community through Rutgers University’s RUDCR Infinite Biologics.  A brief description of available iPSCs, along with publications using these cells, can be found on the RMP program resources website. Researchers can use this link to request these RMP research grade iPSC lines.

There is one cGMP iPSC clinical grade stem cell line generated by the RMP available to the scientific community. Additional information about this line is provided in the remaining FAQs below. The cGMP iPSC clinical grade and corresponding research grade iPSC line generated by the RMP are stored and distributed through Rutgers University’s RUCDR Infinite Biologics. Researchers can use this link to request the cGMP iPSC clinical grade line (i.e. MCB) and corresponding research grade iPSC line (i.e. WCB) generated by the RMP.  

2.    What is the difference between the cGMP iPSC master cell bank (MCB) and the iPSC working cell bank (WCB)?

The cGMP iPSC MCB was generated by Lonza Walkersville from CD34+ cord blood using – and is being stored under – current Good Manufacturing Practices (cGMP) which is a requirement if iPSCs are to be used in clinical studies, which is the intended use. 

The iPSC WCB (also generated by Lonza Walkersville) is a matched research grade iPSC bank developed from the MCB. After the MCB was derived and certified as cGMP, a vial of MCB was expanded under non-cGMP condition at Lonza Walkersville process development (PD) laboratory to generate the WCB. The WCB was generated for researchers to develop and optimize protocols and standard operating procedures, such as evaluating differentiation potential, before requesting the MCB. The costs and specialized facilities necessary to generate and maintain cGMP iPSC cells necessitates that they only be used once procedures have been optimized and streamlined for clinical studies to preserve resources. The generation of the cells is described in the following publications: 

Baghbaderani BA, Syama A, Sivapatham R, Pei Y, Mukherjee O, Fellner T, Zeng, Rao MS. Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications. Stem Cell Rev. 2016 Jun 10.
Baghbaderani BA, Tian X, Neo BH, Burkall A, Dimezzo T, Sierra G, Zeng X, Warren K, Kovarcik DP, Fellner T, Rao MS. cGMP-Manufactured Human Induced Pluripotent Stem Cells Are Available for Pre-clinical and Clinical Applications. Stem Cell Reports. 5:647-659, 2015 Oct 13


3.    How do I obtain the cGMP iPSC master cell bank (MCB)?

The costs and specialized GMP facilities necessary to generate and maintain cGMP iPSC MCBs necessitates that they only be used once procedures have been optimized and streamlined for clinical studies. Thus, cGMP iPSC MCB are only needed in the late stage of a therapeutic development project when the requester is ready to start testing the therapy in humans. To ensure that only serious and properly prepared investigators receive the cGMP iPSC line requesters will need to demonstrate proof of a pre-Investigational New Drug meeting with the FDA related to the program for which the cells are sought or a letter of cross-reference for the Drug Master File (see number 7 below). View a flow chart of the procedure for obtaining the iPSC WCB and the iPSC MCB. The MCB is stored and distributed through Rutgers University’s RUCDR Infinite Biologics. Researchers can use this link to request the cGMP iPSC clinical grade line (i.e. MCB) and corresponding research grade iPSC line (i.e. WCB) generated by the RMP.  

4.    How many cells are included with each request?

One vial of cells, containing approximately 1-2 X 106 cells, is shipped to the requester.  

5.    What documents are included with the iPSC working cell bank (WCB)? What about the cGMP iPSC master cell bank (MCB)?

Documents included with the WCB
•    Certificate of Analysis
•    Tissue sourcing document with copy of IRB approval (covers MCB & WCB)
•    Material Transfer Agreement for WCB
•    End-user agreements document*
•    Instructions for culturing 

Documents included with the MCB
•    Official Certificate of Analysis
•    Tissue sourcing document with copy of IRB approval (covers MCB & WCB)
•    Material Transfer Agreement for MCB
•    End-user agreements document*
•    Data Package containing additional characterization data 
  
*The end-user agreement document was approved by iPSC Academia Japan, Inc., the company who holds the iPSC intellectual property patents used to generate the MCB and WCB. Obligations required by the document apply to requestors who receive WCB and MCB cells from Rutgers. 

6.    Where can I obtain the intellectual property (IP) license requirements for the method(s) to induce pluripotency? 

The MCB and WCB cells were manufactured by Lonza Walkersville under a contract with NIH, using technology licensed from iPS Academia Japan, Inc. (IPSAJ), the holding company of iPSC intellectual property patents developed by Nobel Laureate Shinya Yamanaka at Kyoto University. Researchers wishing to use the cGMP iPSCs should read closely the end-user agreement document included with the cells and consult the IPSAJ license policy: http://ips-cell.net/e/license/policy.html. Additional third party licenses may be needed by third-parties who receive the MCB line. However, an additional license is not needed from Lonza to use the MCB and WCB. Each Party receiving the MCB should conduct their own due diligence to determine if their actions or products have freedom to operate and to determine whether or not additional licenses from third parties are necessary.

7.    Which organization submitted the Drug Master File (DMF) and can I obtain a letter of cross-reference for the DMF?

Lonza has deposited the DMF with the Food and Drug Administration (FDA). To obtain a letter of cross-reference to the DMF please fill out the MF Cross Reference Request Template provided by Lonza making sure to follow the instructions provided in the Master File Access Request, also provided by Lonza. 

8.    Is there publically available information, such as publications or registered clinical trials, from Researchers/Companies/Institutes using the cGMP iPSC MCBs to generate a human therapeutic product?

The RMP will track publically available publications, patents and clinical trials associated with the cGMP iPSC line and post them (semi-monthly) to the RMP publications webpage. The generation of the cells is described in the following publications:

Baghbaderani BA, Syama A, Sivapatham R, Pei Y, Mukherjee O, Fellner T, Zeng, Rao MS. Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications. Stem Cell Rev. 2016 Jun 10.
Baghbaderani BA, Tian X, Neo BH, Burkall A, Dimezzo T, Sierra G, Zeng X, Warren K, Kovarcik DP, Fellner T, Rao MS. cGMP-Manufactured Human Induced Pluripotent Stem Cells Are Available for Pre-clinical and Clinical Applications. Stem Cell Reports. 5:647-659, 2015 Oct 13

9.    What is the role of the Food and Drug Administration (FDA) in using the cGMP iPSCs?

Researchers/Institutions/Companies wanting to use the cGMP iPSC line in non-human, pre-clinical studies should determine the obligations to the FDA, if any.  Currently, for non-human, pre-clinical studies users do not have to notify or file any paperwork with the FDA. Researchers/Institutions/Companies wanting to use the cGMP iPSC line in human clinical trials must first submit – and receive approval of – an Investigational New Drug (IND) application with the FDA. The FDA will consider the merits of each IND according to its guidelines and make the final decision whether or not the specific cGMP iPSC line in question can be used in clinical investigations. Additional questions about this process should be directed to the FDA.

10.    What is 21 CFR 1271 and was it followed during the generation of the Master Cell Bank?

21 CFR 1271 is a Code of Federal Regulations dealing with Human Cells, Tissues, and Cellular and Tissue-Based Products. Of the six subparts of 1271 (A – F) that apply to use of human cells and tissues in regenerative medicine, subpart B-Registration and Listing, subpart C-Donor Eligibility, and subpart D-Current Good Tissue Practice, were followed to register and list, screen and test donors to determine Donor Eligibility, and to recover tissue (umbilical cord blood) that was used as the starting material to isolate CD34+ cells to generate the Master Cell Bank. Lonza Walkersville, Inc. has responsibility for ensuring that 21 CFR 1271 requirements were followed during the manufacturing process.

11.    How were cord blood samples obtained? 

The cord blood was collected on Lonza’s behalf by a partner tissue recovery agency based in a hospital with active labor and delivery services. The hospital has granted permission to access medically suitable patients and the hospital IRB has approved the informed consent document and processes necessary for donor screening and testing and tissue recovery at their site. LWI is responsible for all procedures, training, reviews and approvals required by applicable regulations, and holds the FDA establishment registration listing to cover this tissue recovery activity.

12. What are the statements in the informed consent that allow me permission to use this Master Cell Bank?

To obtain permission to use umbilical cord blood to create an iPSC MCB, the informed consent process includes a verbal explanation, questions and answers, plus the informed consent document itself states what will happen to the cord blood. Some of the critical information included in the informed consent document include:

“If you choose to participate in the Program, your baby’s umbilical cord blood will become the property of Lonza. Cells will be isolated from the umbilical cord blood, iPS cells will be made, and the iPS cells will be sent to the National Institutes of Health (NIH), commercial companies, and non-commercial organizations including universities and research institutes.” 

“iPS cells may be used for the development of cell therapies for the treatment of many diseases, may be used in clinical trials and may be eventually sold as patient treatments.”

“Researchers will own the cells and the research results, may file patents or otherwise legally protect the development of products to be sold, and may financially profit.”

“You will not be paid for this donation of cord blood. There will be no financial benefit to you, your baby, or your family, from the research results or from the sales of products.” 


13.    Has viral testing been conducted on the iPSC WCB and the cGMP iPSC MCB and where can I receive the documentation?

Viral testing has only been performed on the cGMP iPSC MCB and the results are summarized in the MCB Certificate of Analysis which will be provided to all recipients of the cGMP iPSC MCB (see number 5 above). For any additional questions regarding the viral testing, the questions shall be submitted to NIH, which will then be discussed with appropriate contact persons at Lonza. 
 

14.    Are there any contractual limitations associated with the iPSC WCB or the cGMP iPSC MCB?
 
The iPSC WCB has no contractual restrictions when used only for research and development. 
 
The iPSC MCB has contractual restrictions that are described in the end-user agreement.

For both the WCB and the MCB there are no contractual limitations as far as it concerns Lonza.
 
Each Party receiving the WCB and the MCB should conduct their own due diligence to determine if their actions or products have freedom to operate.
 

15.    Do any of NIH’s guidelines on human stem cell research apply to the iPSC WCB or the cGMP iPSC MCB?

Yes, there are two restrictions for scientists who conduct research with NIH funding using the iPSC WCB or the cGMP iPSC MCB. Section IV of the NIH stem cell guidelines state: Research Using hESCs and/or Human Induced Pluripotent Stem Cells That, Although the Cells May Come from Eligible Sources, is Nevertheless Ineligible for NIH Funding. 

This section governs research using hESCs and human induced pluripotent stem cells, i.e., human cells that are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers. Although the cells may come from eligible sources, the following uses of these cells are nevertheless ineligible for NIH funding, as follows:

•    Research in which hESCs (even if derived from embryos donated in accordance with these Guidelines) or human induced pluripotent stem cells are introduced into non-human primate blastocysts.
•    Research involving the breeding of animals where the introduction of hESCs (even if derived from embryos donated in accordance with these Guidelines) or human induced pluripotent stem cells may contribute to the germ line.

Please see http://stemcells.nih.gov/policy/pages/2009guidelines.aspx for the complete National Institutes of Health Guidelines on Human Stem Cell Research. 

Update from September 23, 2015: NIH released a guide notice slightly modifying the above restrictions; NIH will not fund any new or competing grant applications or contract proposals for research in which human pluripotent cells are introduced into non-human vertebrate animal pre-gastrulation stage embryos. 
Update from August 4, 2016: NIH is considering amending Sections IV and V of the NIH Guidelines for Human Stem Cell Research and published a guide notice requesting public comments by the close of September 6, 2016. Submit comments here.
 

16.    What is the cost of the iPSC WCB and the cGMP iPSC MCB?

The iPSC WCB and the cGMP iPSC MCB are priced reflecting a cost recovery model for recouping shipping costs (e.g. cGMP shipping requirements for the cGMP iPSC MCB) and costs to expand the lines. The iPSC WCB will be distributed according to established NHCDR guidelines: $500 per vial for non-profit investigators and $1,500 per vial for commercial recipients. The cGMP iPSC MCB will be distributed at a slightly higher cost reflecting the additional cGMP conditions these cells are required to be maintained under: $1,000 per vial for non-profit investigators and $5,000 per vial for commercial recipients. Sharing of the cGMP iPSC MCB is not be permitted. 

17.    How can I obtain a copy of the infectious disease test results for the cord blood donor?

 The “Summary of Records” (SOR) which is required in 21 CFR part 1271 for HCT/P donors will be provided as a Certificate of Analysis (CoA) with the iPSC when shipped. Tests and results are included on the CoA. Donor blood tests for infectious diseases for cord blood donors are:
Antibody HIV-1/HIV-2/plus O, Hepatitis B surface Antigen, Antibody Hepatitis B core – total, Antibody Hepatitis C, Antibody HTLV I/II, Antibody Cytomegalovirus – total and CMV IgM if reactive, Syphilis serology – T. pallidum specific antibody, NAT for HIV-1, HBV, HCV and West Nile Virus (WNV).
Risks for other relevant communicable disease agents and diseases (RCDAD) are assessed by donor risk assessment interview, medical examination and review of medical records. Donors with any risk of RCDAD are not determined to be eligible and their tissue would not be used. 
 

18. What is the procedure used to detect residual imparities in a reprogramming plasmid?

TaqMan qPCR is used to quantify residual level of plasmid.  The assay detects the EBNA portion of plasmid and LOD of the assay is 52.3±5.8 copies of plasmid. Please contact Dr. Behnam baghbaderani at behnam.ahmadianbaghbaderani@lonza.com for additional information.
 

19.  In the publication “Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications”, was whole genome sequence (WSG) evaluated for the presence and absence of plasmid sequences? 

No, WGS was completed as part of additional characterization of the IPSC MCB. It does offer comprehensive germline information about the cell line, which is highlighted in the publication. The data analysis for presence or absence of plasmid sequence need to be performed by interested customers.
 

This page last reviewed on December 7, 2017