Earlier this month University of California at Davis stem cell researcher and blogger Paul Knoepfler wrote that sources were telling him that in April 2012 investigators from the Food and Drug Administration “visited” Celltex Therapeutics Corporation. Knoepfler’s sources informed him that “reportedly, Celltex is telling stem cell insiders that the outcome was positive with the FDA identifying only ‘minor’ issues.” Knoepfler’s sources were right about the timing of Celltex’s inspection by FDA. Two FDA investigators inspected Celltex’s stem cell facility in Sugarland from mid-to-late April. However, contrary to what Celltex executives are saying about the inspection, what the FDA investigators found is far from “minor.” A copy of the Inspectional Observations Form 483 provided to Celltex is now available. I would like to thank the FDA’s Dallas District Office for providing me with a copy of this document.
In February, I wrote to the FDA’s Center for Biologics Evaluation and Research and urged the FDA to investigate Celltex Therapeutics Corporation. I do not know whether my letter to the FDA prompted FDA’s inspection of Celltex’s laboratory and stem cell bank. Given considerable news media coverage of Governor Rick Perry’s stem cell procedure (performed by Dr. Stanley Jones, a physician and senior executive at Celltex) and the opening of Celltex’s stem cell facility, I would not be surprised to learn that FDA began investigating Celltex well before I sent my letter. Whatever events prompted the FDA to conduct an inspection of Celltex’s facility, the Inspectional Observation report prepared by FDA investigators reveals importance of FDA scrutiny of Celltex’s operation. The report identifies a litany of problems observed by the two investigators who visited the facility.
483 forms are quite technical documents. I have therefore taken key observations from the 483 form and embedded them within a question and answer format. I hope to draw attention to key observations in the inspection report. Of course, I encourage you to read this comprehensive inspection report in its entirety.
I’ll end this short preface with an important statement noted on the first page of the 483. The form contains statements that are “inspectional observations, and do not represent a final Agency determination regarding your compliance.” 483 forms are sometimes followed by untitled letters from the FDA or warning letters. After companies receive 483 forms they can respond with objections and/or describe “corrective actions” taken in response to observations. In short, the 483 does not contain Celltex’s response to these observations or the FDA’s response to Celltex’s reply to this form. Acknowledging the exchange that will presumably follow issuance of the 483, this document is important because it provides considerable insight into what FDA investigators found when they visited Celltex’s stem cell lab and bank. To date, Celltex executives have tried to “control the message” by declining to respond when journalists and other interested parties pose even the most elementary questions about Celltex’s activities. Now that the 483 is in the public domain I suspect that this strategy is going to be much less effective. It is my hope that Celltex executives provide forthright responses to the many questions generated by observations noted in this inspection report.
483 Form Observations Edited for Brevity and Converted to Question-and-Answer Format
Comments in quotations are drawn from the 483. Answers that are not placed in quotation marks are my summary of information available in the 483.
When did FDA inspection of Celltex occur?
The inspection began April 16, 2012 and ended April 27, 2012.
Who received the 483 form?
The report was issued to David Eller, CEO and President of Celltex.
Where is Celltex’s stem cell facility located?
The laboratory and stem cell bank is based in Sugarland, Texas.
How is Celltex Therapeutics Corporation categorized by FDA Investigators?
Form 483 classifies Celltex as a “Biological Drug Manufacturer.”
How do stem cells processed and banked by Celltex reach patients?
The inspection report does not directly address the question of precisely how stem cells processed and banked by Celltex reach patients. However, in Observation 1, the report states: “You have manufactured (mesenchymal stem cells) MSC’s which you have released for distribution at least (redacted) times between 7/1/11 and to the present.”
Did the FDA inspectors observe any violations of good manufacturing practices?
“1A. You have not performed a process validation for manufacturing MSC’s to assure batch uniformity and integrity as related to each of the following finished product characteristics: viability of cells, the specified cell count, cell type, and appearance of cells.”
When patients receive adult autologous stem cells provided by Celltex, what exactly is given to them?
“1C. You have not verified the final product…to assure the identity of the cell type in the final MSC’s.”
Does banking and cryogenically preserving mesenchymal stem cells have any effect upon viability of MSCs?
“1F. You have not performed a validation of your banking and thawing process to assure viability of MSC’s.”
How does Celltex compartmentalize “clean rooms” from other rooms in the processing and banking facility?
1G. “You have no requirements for pressure differential between the clean rooms and the exterior rooms to assure that non-controlled air does not flow in the cleanrooms.”
Is there careful monitoring of temperature and humidity in processing rooms where manufacturing of mesenchymal stem cells occurs?
“1H. You have not monitored the temperature or humidity of the processing rooms where you manufactured mesenchymal stem cells (MSC’s).
Are there procedures in place to prevent microbiological contamination of stem cells?
2. “Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed.”
Are the stem cells produced by the facility and released for distribution sterile?
2. (continued) “You have manufactured MSC’s which you released for distribution at least (redacted) times between 7/1/11 to the present. The MSC’s are intended to be administered to patients either intravenously or injected intra-articularly and must be sterile. This inspection revealed…You have failed to validate your aseptic (mesenchymal stem cells) MSC’s manufacturing process in order to prevent microbiological contamination. Sterility test failures have occurred…”
Are there microorganisms in the manufacturing area and, if so, do they fall within acceptable limits?
2D. “Environmental test results of the clean room, biosafety cabinets, and gowning area show the isolation of microorganisms as the result of the use of settling plates. Some of the microbiological counts documented are beyond the established specifications. There is no data to show that the microorganisms isolated have been identified or investigated.”
Are records kept of investigations into failures of batches?
3. “Written records are not made of investigations into the failure of a batch or any of its components to meet specifications.”
What does sterility testing, endotoxin testing, and environmental testing reveal?
3.A, 3B, 3C. “Sterility test results show the following MSC’s failed initial and repeat testing for sterility…Endotoxin test records show the following MSC’s units failed initial endotoxin testing…Environmental testing: Bacteria and Fungi test results have been exceeded” in the Biosafety cabinet, clean Room, growing area, and other test sites.”
Are quality control mechanisms in place and are they effective?
4. “Drug product production and control records, are not reviewed by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed.”
Do batch production and control records contain all required information?
5. “Batch production and control records do not include complete information relating to the production and control of each batch.”
Do you document in proper fashion identity of individuals involved in packaging mesenchymal stem cells for release and delivery?
5E. “You do not document the identity of personnel involved in the packaging of the finished product (MSC’s) for release and delivery to the consignee/physician for use.”
Do you provide all required document for supplies and reagents used during process of manufacturing mesenchymal stem cells?
5F. “You do not document in the Manufacturing Record the lot numbers used, or the expiration dates, of the following supplies and reagents used during the manufacturing of the mesenchymal stem cells (MSC’s).” (Identifies of supplies and reagents all redacted.)
Is all laboratory equipment positioned where it should be?
6. “Equipment used in the manufacture, processing, packing, or holding of drug products is not suitably located to facilitate operations for its intended use.”
Are stem cells labeled in proper fashion before distribution?
7. Labels fail to indicate 7a) “The identity of the product (type of tissue), including whether or not it is sterile”; 7b) “strength of the product”; 7e) “instructions for use related to the prevention, transmission, or spread of communicable diseases. Labels also do not contain 7d) “biohazard legend” or 7c) “the statements ‘autologous use only’ or “not evaluated for infectious substances.’”
Is there an adequate record of receipt of all supplies and reagents used to manufacture mesenchymal stem cells?
8. “You did not maintain a record of the receipt of supplies and reagents that you used to manufacture mesenchymal stem cells (MSC’s) including: reagent or supply type; Quantity; Manufacturer; Lot number; Date of receipt; Expiration.”
How many supplies and reagents are used during the manufacture of mesenchymal stem cells?
Twelve. Names are all redacted.
Are lots properly identified with regard to being quarantined, approved or rejected?
9. “Each lot of components was not appropriately identified as to its status in terms of being quarantined, approved or rejected.”
Do all Certificates of Analysis for supplies and reagents indicate that supplies are intended for therapeutic purposes?
9, “The Certificate of Analysis that you obtained for the Investigators during this inspection for (redacted) states, ‘FOR RESEARCH USE ONLY. CAUTION: Not intended for human or animal diagnostic or therapeutic uses.”
Is all equipment carefully checked and calibrated according to documented standards?
10. “Routine calibration and checking of equipment is not performed according to a written program designed to assure proper performance.”
Is proper record-keeping used when preparing batch records?
11. “The batch records do not record the distinctive identification number and code to identify major equipment to show the specific equipment used in the manufacture of a batch of a drug product.”
Are components used in manufacturing area properly identified?
12. There were four observations of mislabeled components.
Are distribution records comprehensive?
13. “Distribution records do not contain the name and strength of the drug product, description of dosage form, name and address of consignee, date and quantity shipped, and lot or control number of drug product.”
Is there space within the stem cell laboratory for staff members to clean themselves?
14. “You have no hand washing facility in the Stem Cell Laboratory where you manufacture mesenchymal stem cells (MSC’s).”
Correction: 3rd sentence in 1st para stated FDA site visit was in May. Site inspection was from mid-to-late April. Post corrected at 9:13 PM June 25, 2012.