FAQs – Legal – Regulatory

Regulatory Considerations in Manufacturing, Product Testing, and Preclinical Development of Cellular Products

For Cardiac Repair: Cardio-Matrex
© 2017 W.W. Keesee Trust

Introduction:
In the US, administration of cellular products for cardiac repair remains investigational, and must be conducted under an Investigational New Drug application (IND), that has been reviewed and allowed to proceed by the Food and Drug Administration (FDA). The Office of Cellular, Tissue, and Gene Therapies (OCTGT) in the Center for Biologics Evaluations and Research (CBER), and the FDA have review responsibilities for cellular products. The requirement for an IND application is largely predicated upon the perceived risk to the donor and recipient of the cells. Procedures that involve ex-vivo culture of cells and/or their genetic modifications are classified as “more than minimal” manipulation and must be performed under an IND. This requires that the cell products be prepared under Good Manufacturing Practices (cGMP).
In general, products that are prepared for therapeutic use, and do not require an IND, will be regulated under proposed current cGTP; current good tissue manufacturing. The more than 50,000 various bone marrow “stem cell rescues” performed each year are considered the practice of medicine.
The successful initiation of a clinical trial with an investigational cellular therapy for heart repair requires not just a thorough knowledge of
clinical medicine and clinical trial design, but also a working knowledge of the other disciplines inherent to prudent product development for the cellular therapies; manufacturing and preclinical testing.
Product Manufacturing and Testing:
cGMP are defined as a set of current scientifically sound methods, practices, or principals that are implemented during product development and production to ensure consistent manufacture of safe, pure, and potent products, and are spelled out in Title 21 of the Code of Federal Regulations (CFR) Parts 210 and 211. The regulations were extended to manufactures of blood and blood components, in part 606. The regulations provide a detailed infrastructure to be used for manufacturing these types of products. This includes the design and operation of the facility , training and testing of staff, installation , cleaning and calibration of equipment , standard operating procedures for all aspects of operations, labeling, quality assurance and control programs, records, release testing, controls, and complaint files. It is not completely clear at the time of writing how cGMP will be applied to cellular therapy products. The FDA has indicated that it will use a sliding scale of implementation; such that products prepared for phase I trials will not require implementation of full cGMP or full validation of procedures. However, by phase III studies full validation specified in the pharmaceutical regulations will be required.
The difficultly for establishments manufacturing products that are in transition from phase I to phase III studies is to know what level of cGMP is required. Recently the FDA has requested from holders of IND’s that deal with cell therapy products comprehensive information on manufacturing and quality control systems. The level of detail requested suggests that the bar will not be lowered and that the requirements will become more rigorous.
Product considerations for cardiac cellular therapies:
Whether the mechanisms of the cells involved in repair of cardiac damage is cardiomyocyte generation/regeneration, angiogenesis/revascularization, product of cytokines or other secreted factors, or a combination of these actions, is still being explored. Until these mechanisms are fully understood, many types of cells, alone or in combination, and prepared by a variety of methods will be candidates for clinical studies and investigational therapies, in the US and worldwide.
From the initiation of clinical investigation, product safety is the primary concern. Investigators must demonstrate that all devices and materials used for processing or administration of cellular products are compatible with the cell suspension components. In addition to safety, parameters of product characterization such as the source, phenotype, purity, number and proliferative potential of the cells should be considered early in product development to anticipate issues that may become important in the transition and scale-up from investigational to a licensed product.
Sources and collection of cellular products for heart repair:
Bone marrow-derived cellular products:
Hematopoietic progenitor cells (HPC)
Peripheral blood stem cells (PBSC)
Cord Blood stem cells (CBSC)
Pluripotent HPC’s capable of restoring hematopoiesis in a myeloablated individual are found in the marrow cavities of the bones. These cells may also be capable of repopulating other tissues and organs in the body, including damaged myocardium. These HPC’s can be identified by the expression of CD34, a surface marker, appearing on 2-4% of
normal bone marrow cells. Another surface marker CD133 is expressed as a subset of CD34+ cells including immature myeloid and monocytic progenitor cells.
Although some investigators administer unfractionated bone marrow to the heart immediately after collection and filtration, the products usually undergo additional processing steps to yield a more homogeneous preparation. This processing may consist of one or more of the following procedures: Concentration, isolation, immunomagnetic selection, culture expansion, differentiation, and cryopreservation.
Academic cGMP:
Implementation of cGMP has come as something of a cultural shock to most academic cell therapy facilities, unused to being regarded as product manufacturers. As a result, the interpretation of what is required has varied widely. There has been particular emphasis on the type of facility that has been required. In some cases, manufacturing has been performed in pharmaceutical-grade clean rooms, while in others; modified areas of research laboratories have been used. The reality is that cGMP does not specifically prescribe the precise environmental conditions under which manufacturing occurs. The FDA has not indicated that it will require Class 10,000 clean rooms for preparation of cell therapy products, where the drive has been towards the use of closed handling systems and production in Class 100 biological safety cabinets.
From the laboratory to the bedside:
Cell processing facility (CPF)
To ensure the safety of the cell donor and recipient requires the involvement of the cell processing facility (CFP) in all stages of development from basic research to the bedside. This information must be generated under good laboratory practice conditions (GLP). Although these regulations are described in the Code of Federal Regulations (Title 21 CFR, Part 58), many researchers are unaware of or are poorly
informed about GLP. Sense many components of GLP resemble those of cGMP, review chart supra, a close interaction between the basic research laboratory and the CPF can facility the smooth transition of research into clinical studies. The CPF staff can also provide useful advice on the selection of cGMP-friendly reagents and methods, as well as expertise on the scale-up of cell preparation to a clinically applicable level.
Standard Operating Procedures that describe the production and testing methods used in manufacturing will be required and used in the manufacturing process. A manufacturing flow path and what testing will be used at each stage for monitoring product quality will be submitted and reviewed. Various criteria will be specified as to what tests results must be achieved for product release. Usually a Certificate of Analysis (C of A), which provides a list of all tests to be performed and the requisite level of acceptance, will be issued. Basic HLA typing of the original cell donor and confirmatory typing of the product will be required as an identity check. The panel that is routinely chosen contains assays that reflect product safety and include bacterial and fungal sterility, mycoplasma (all negative); and endotoxin (usually less than 5 EU/ml); product potency (a functional assay for product activity like secretion levels of a product or cytotoxic activity); viability (usually 70%), and purity (usually by flow cytometric analysis).
GMP operation of a CPF:
Regardless of the particulars of the procedures, the CPF must have in place SOP’s that cover the infrastructure and daily operation of the cGMP facility. These include facility management, cleaning procedures, staff training, competency, and proficiency testing, quality assurance and control programs, process and equipment validation, materials management, and equipment maintenance and calibration
Operational SOP’s:
These cover the daily operations and maintenance of the facility. There must be training files on all the staff. These include their job
descriptions, curriculum vitae, documentation of training, mandatory training such as safety; blood borne pathogens, universal precautions, cGMP operations, continuing education, and evaluations. There should be a detailed plan of the facility indicating product, waste, personnel flow, air handling systems, and evacuation routes. The procedure for cleaning the facility must be described and cleaning agents should be validated for their efficacy against potential contaminating organisms. Efficacy of the cleaning and air handling systems must be documented, usually by means of an environmental monitoring program. This specifies the cleaning schedule and agents, monitoring of cleaning and contaminations, and when remedial action is required. The also must be cleaning procedures to describe cleaning procedures between different cellular products, during change over.
Specialized air handling systems must be calibrated, maintained, and shown to be within specifications by particle and viable counts. SOP’s must be developed for ordering, quarantine testing, and release of supplies; reagents and management of inventory. Selection and audit of vendors, and specs for the product acceptance. Systems to track each product prepared using a particular piece of equipment, and all equipment used for the preparation of a particular product.
Each CPL should have procedures on file to deal with emergencies, system failures, evacuation, and actions to be taken in case of equipment alarms. Draft Guideline for the Validation of Blood Establishment Computer System, CBER, 1993; deals with electronic data entry management systems, and the agency has published a Guidance Document on the General Principles of Software Validation (CDER/CBER, 2002)
Cellular Manufacturing SOP’s:
Manufacturing procedures require that procedures cover all aspects of management procedures (infra) and documentation that staff has been trained on specific procedures. Sense few cell therapy products are
highly characterized when introduced into phase I studies, it is important to set realistic expectations in the SOP that provides sufficient flexibility in the procedure, that address biological variables. As the basic structure of all SOP’s are the same; there should be standardized formats and numbering that allow the documents and revisions to be tracked. The format should include title, purpose, materials, reagents, and equipment, procedure, expected results, attachments, references, and sign-off section that show that the SOP has undergone review and acceptance. Effective SOP’s are written in a style that provides sufficient information for an appropriately experienced individual to perform the procedure and achieve expected results. Overly detailed procedures may certainly be counter-productive, sense they tend to be lengthy, difficult to follow, and can result in the creation of multiple documents describing minor and unimportant aspects. The expected results section is important, which indicates when the procedure was performed. In addition, expected results may be written in a manor that allow for normal biological outcomes and variability. Establishment of expected results for cellular manufacturing procedures is achieved by validation and alert limits must be set that trigger remedial actions.
Validation:
Validation is an important component of a new procedure and provides evidence that the procedure is routinely capable of achieving the required and expected results. In the case of manufacturing of cellular products, the validation process can be more complex, due to variability’s of biological materials and processes. Those specified in the Certificate of Analysis can simplify selection of the criteria for acceptability. These studies should be designed in collaboration with quality/assurance control personnel (QA.QC), who will ultimately be responsible for signing off on the validation. CBER has recently published a Guidance document titled “Validation of Procedures for Processing Human Tissues for Transplantation”, which discusses validation measures intended to prevent contamination during processing (CBER, 2002). In some cases, procedures have been in use
for a long time without formal validation. In these cases a retrospective validation should be performed. This can be accomplished by collecting historical results and comparing them to the published literature, and/or by the manufacturer of the equipment used.
Documentation;
Efficient documentation is at the core of the cGMP and provides evidence that the facility is in routine compliance with the regulations. A user-friendly system is necessary for recording the required data during manufacturing, and direct linkage to other associated data, and manufacturing data are usually assembled in the form of a batch record.
Good Tissue Practices:
The FDA published a proposed rule “Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue Based Products; Inspection and Enforcement” The cGTP would provide the requisite applicable to all human cellular and tissue based products, regardless of their regulation category. Facilities preparing products that require an IND or IDE application would, in addition, be subject to the provisions of cGTP, which are considered a supplement and do not supersede existing cGMP regs.
Gene Therapy:
The controversies surrounding cellular therapies pale in comparison to those swirling around gene therapy in the United States, with more stringent regulations, oversight and implementations. Vector products facilities will be expected to comply with cGMP and the expectation is likely to be maintained and held to a pharmaceutical manufacturing level.
Testing of Cellular Products for Cardiac Repair:
Regardless of the type of product and the manufacturing process, a variety of parameters must be evaluated by adequate and appropriate testing to ensure administration of a safe product.
Infectious disease testing:
Although most cellular products currently used in clinical trials and therapies are autologous and taken from subject donor and then returned to the same patient; other cellular products are also being intensely studied and developed. Allogenic donors, including mothers of umbilical cord blood donors, must be tested and screened for communicable diseases. Testing and screening of autologous donors for infectious diseases, although not required, is recommended, particularly if there is a risk of expanding any infectious disease into any source material.
Microbiological safety:
Although many of the cellular preparations used in clinical trials for cardiac repair are collected, processed, and administrated in a matter of hours, processes should be designed to minimize the risk of microbial contamination. Appropriate product testing should be performed on each lot of cellular products to ensure its safety for clinical use. Those products collected in systems that are open to the environment or partially open to the environment are at the greatest risk for contamination with microbial agents. Whenever possible, manufacturing steps should be performed in a closed system protected from sources of contamination. Devices are available that provide sterile welds of transfer tubing so that cellular products may be transferred safely from container to container.
Because many of these products are stored for a few hours, at most, between preparations and administration, it is not possible to complete conventional 14-day microbial safety testing. Therefore, gram staining or newer and more rapid sensitive tests for microbial detection should be performed as negative before infusing the product. In addition, sterility cultures should be performed on samples. Cryopreservation and storage of products for at least 14 days permits availability of final sterility culture results. Even without contamination of the final product with live bacteria, endotoxin can be introduced into the product in various ways and pose a serious risk to the recipient. Ancillary materials that are used in the collection, processing, or formulation of cells should be documented to be free of endotoxin and pyrogens. Cellular products that are expanded or cultured should be tested for mycoplasma, at the end of the culture period.
Cell dose and viability:
The cell dose of each lot should be accurately measured and its viability measured for product safety and consistency. The most popular viability assays make use of the live cells’ ability to exhibit a nuclear dye or stain and this enables factual determination of living and dead cells. Detection systems are available using bright light and fluorescent microscopy as well as flow cytometry. The FDA generally recommends the process maintain at least 70% viability of total cells, unless available data supports lower criteria. In addition, testing should show that transinjection catheters do not significantly reduce initial cell numbers and viability.
Product characterization:
Few if any of the products currently used in clinical trials and therapies are a pure population of well-characterized cells. Even those preparations processed by immunoselection with CD34 or CD133 monoclonal antibodies may contain as many as 50% contaminating cells
of various phenotypes. Some or all of these other cell populations may be important to the success of failure of a particular cellular therapy, and investigators of cardiac repair should explore new methods of identifying and quantifying the various cell populations in each type of product. As we reported infra, in cryopreservation sections; currently there are serious drawbacks to exact assays of cellular dose, viability, and characterizations, using current testing protocols.
Product identity:
Because most of the cellular products in development for cardiac therapy are prepared for a specific recipient, it is critical that the identity of the product be confirmed before it is released or administered. Whether autologous or allogenic, the product may undergo a variety of processes, some performed by different personnel at different facilities. Cellular products from various patients may be in various stages of processing and the cellular product must be tested by an assay that will distinguish it from other products as well as adequately identify that the product on the container label is; in fact, contained within. Immunophenotyping and molecular histocompatibility typing are some of the techniques used in identity testing.
Product potency:
As product development progresses and cellular products used in cardiac protocols become better defined and characterized, an assay or combination of assays will be implemented that determine the product potency. An assay should demonstrate that the cellular product possesses biologic activity, which shows possible intended medical potential.
Product purity:
The types of purity testing that should be developed and performed on cellular products for cardiac repair will depend on the nature of the product, the manufacturing process, and the ancillary materials used.
Catheter testing:
FDA expects data from bench testing for each unique cellular product/catheter combination prior to proceeding with clinical trials. Quantification of the changes in viability and cell count of cellular subpopulations by passage through various specific catheters can provide insight into potential problematic situations that may occur with the catheter and the prepared cellular products. In addition to bench, testing the various committees of the FDA recommended in vivo testing of cellular products with experimental catheters and catheters cleared for other indications.
Several routes of administration are presently under experimentation.
1. Direct, syringe-and-needle injection of cellular products through the exposed epicardial surface into the subjacent myocardium during comitant thoracic surgery.
2. Infusion of cellular products into coronary arteries.
3. Intramyocardial injection of cell suspensions through cardiac catheters.
Each of these possibilities presents a different spectrum of pharmacological opportunity, toxicology, and regulatory challenges.
Cell handling systems:
Culture systems have to be very flexible for products. In contrast to hematopoietic progenitor cell processing, where a large number of cells is processed, immunotherapy-starting materials can come in a variety of forms, ranging from a small volume of blood, to a large tissue sample. In many cases the practice is to start with a relatively small sample, from which the target cell population must be isolated, manipulated, and expanded. While there has been considerable progress in the development of closed handling systems for larger cell numbers, small numbers often start out of petri dishes, cluster plates, or 96 well plates,
and progress through progressively larger open culture systems until sufficient cells have been grown to permit transfer into a bag. Overexpansion at an early stage can result in decreased viability or loss of the culture.
The use of open systems obviously increases the risk of contamination, and requires particular attention to aseptic technique and sterility monitoring Also there are incidences where a starting product is received contaminated. Antibiotic decontamination should be used with care under these circumstances.
Each stage of cell manipulation is recorded on worksheets that provide systematic step-by-step documentation of cell culture processes. An Activity Report accompanies each worksheet. This lists all the reagents used, the manufacturer, lot number, and expiration date. It also provides a listing of equipment used, the serial number, and the date of calibration. Although such data can be recorded manually, one may have it encoded into barcodes that are scanned during the manufacturing process. Barcodes are also applied to reagents at the time of receipt and accessioning into cGMP storage. Reagents also must have a certificate of analysis from the manufacturer or supplier on file, to be admitted into storage.
Each worksheet and activity report is signed by the technologist and reviewed by a second staff member. Testing is documented by inclusion of the test request form, the confirmatory email from the test lab that provides an accessioning number for tracking the results, and eventually by a summary sheet listing the results generated by the QA/QC Laboratory database system. Labeling during processing is computer-generated in-house, and copies of labels are attached to the work sheets and crosschecked by a second staff member before use. These checks are documented. At the time of cryopreservation and storage, an inventory form is completed listing the products to be stored and the storage locations and providing a copy of the labels used on the storage containers. A designated individual transcribes this data into computer-based inventory system. This system has features that prevent double
entry into the same location and also track and archive all entries, changes and identity of the person making the entries.
Testing and test selection:
Testing protocols during, and at the end, of manufacturing can be problematic for some cell therapy products. Often total cell numbers are relatively small and the entire product could be consumed in performing the required tests for release. Under such circumstances, it is possible to develop alternative tests systems, in consultation with the FDA.
Viability testing can also be problematic. A routine practice has been to test cell viability prior to freezing, rather than attempting to monitor the thawed product, which is routinely impossible, due to the critical time sensitive protocols involved in reinfusion of cellular products because of the cryopreservant. In addition, cells lose their viability if they sit for extended periods in cryoprotectant. Many hospitals use automated sterility testing systems that finalize test results in 4-5 days.
Release for use:
When the cells are required for administration to a patient, a prescription for infusion is generated. This lists the products that are available for that patient. A copy of the flowchart, which provides specific dosing information, usually accompanies it. The prescription is reviewed by QA, who will also print out an inventory sheet that confirms the existence and location of the stored products. The patient’s physician reviews and selects the specific components that are to be administered and sign the prescription.
Concluding comments and conflicts of law:
Collecting and reinjecting a patients own cells is not regulated by the FDA, if those cells are considered minimally manipulated and if the providers do not make therapeutic claims that would cause it to be regulated as a drug.
This procedure is considered the practice of medicine and has not been regulated by federal statutes. The physicians are licensed by their respective state medical boards. Outpatient surgery settings present a unique opportunity for physicians in the State of California because of various legal possibilities. A review of various non-traditional medical ambulatory clinics sites has determined that two unique jurisdictional possibilities are possible. These plans only involve reinfusion clinics and do not relate to cell processing facilities, which will be held to these standards.
With heart disease at unprecedented and incurable levels, what are the rights of the dying patients that need immediate and viable intervention right now? Each year the numbers of medical tourists, to offshore hell holes are escalating as desperate dying people, are willing to try anything that may extend their lives.
The basic legal question remains. Does an individual have a basic legal, personal, and constitutionally protected right to have investigational elective medical procedures? The resounding answer must be yes, much as, the right of women to have abortions, pushed legal frontiers decades past.
Certainly autologous stem cells present a unique biomedical legal possibility. Your cells- your body- your right too decide may become the credo of millions of medically challenged individuals, who simply cannot wait anymore for lifesaving “stem cell rescue”.
The Future:
Advances in knowledge have spurred the development of cellular based therapies at a rate that could not have been imagined even 5 years ago. Cells from many sources are being purified, cultured, genetically modified, frozen, thawed, and infused to treat a host of diseases. These types of treatments have been regarded by many simply as the practice of medicine that should not be subject to regulatory oversight. This notion has been abused by a minority of practitioners and has caused the FDA to re-examine its regulatory approach. This moves cell processing facilities clearly into the classification of product manufacturers, and in the case of products covered under IND’s, the expectation is that manufacturing will resemble that of pharmaceuticals.
There is, however, a major difference between current types of cell therapy products and pharmaceuticals. In complete contrast to drugs, the vast majority of cellular therapies are currently prepared for a single recipient, where administration is under informed consent and the potential risks and benefits have been explained. Most of these therapies are in phase I or II clinical trials, and although the FDA has held that full compliance and product characterization will not be required until phase III; the problem is the degree of compliance required at earlier stages has not been fully elaborated.
Global Regulatory Considerations:
International regulatory strategies must be implemented. It is necessary to think about the potential to standardize the format of regulatory submissions that will facilitate access across jurisdictions that are accepted worldwide. As we know, the regulatory procedures in the EU/CAT is a centralized procedure, whereby companies submit one authorization application, to the EMEA and a single evaluation is carried out through the Committee for Medicinal Products for Human Use (CHMP). The EMEA will only be accepting electronic submissions of cCTD as of 2010.
In today's global environment, multi-center international trials are becoming a necessity. Top quality multinational research requires experienced medical and regulatory support: pre-trial assessments of the regulatory environment, familiarity with the timelines, an understanding of the issues surrounding the shipment of products, GCP expertise, mechanisms for safety reporting, and many other details.
The need to develop all required data as early as possible and to meet the various requirements in all markets; a global regulatory strategy needs to be prepared early and updated continuously. Using a best practices approach, companies need to understand pre-clinical and clinical parameters, as well as intellectual property, legal, business, local health care, reimbursement, and other issues for successful global filings.

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