The use of stem cells for therapeutic and clinical applications is a fast growing area in Biotech research and development. Stem cells have the potential to differentiate into specific cell types which can be used to repair or replace damaged cells, tissues and organs.
This vast field of research, the potential therapeutic treatments, the rapid expansion of new technologies (such as human cell bio-reactors) and the blurring of the boundary between research and clinical therapy requires a broad and comprehensive regulatory framework in order to deal with the unique hazards and limitations of production, manufacturing and distribution of cell therapy based products.
This article summarizes US regulations and guidelines regarding cells, tissues and cellular & tissue based products (HCT/Ps). Regulation of stem cell therapy and products in the EU according to the EMA directives are not within scope of this article.
Code of Federal Regulations
In the US, use of cell therapy products is codified within the following sections of the Code of Federal Regulations:
- IND regulations (21 CFR 312)
- Biologics regulations (21 CFR 600)
- cGMP (21 CFR 211)
- cGTP (21 CFR 1271)
351 and 361 Cell Therapy Products
US federal regulation on cellular therapy is divided into two sections of the Public Health Service Act (PHSA), referred as “351 products” and “361 products”.
- “351 products”
“351 products” are manipulated and gene-modified cell based products (cultured cells, CTLs, tumor vaccines etc.) that are used in a non-homologous way for a different function in comparison to their original purpose, such as bone marrow cells used for heart disease treatment and/or a non-autologous use on a different individual/s than the cell donor.
As such, 351 products are considered a higher risk, are regulated and registered as an Investigational New Drug (IND) and treated as a biological products under cGMP guidelines. In addition, these products are required to comply with sub parts B (Procedures for Registration and Listing), C (Donor Eligibility) & D (Current Good Tissue Practice) of 21 CFR 1271.
- “361 products”
“361 products” are traditional blood and bone marrow progenitor cells as well as other cells, minimally manipulated for transplantation. These products are intended for homologous use, with no combinations of cells/tissues and intended for autologous treatment (or allogenic use in first degree relatives).
Minimal manipulation is defined as processing that does not alter cell-/tissue-relevant biological characteristics. These products may or may not have a systemic effect but are for analogous use. 361 products are considered a lower risk (compared to 351 products) and as such do not require FDA pre-market review.
Since not directly covered under the current good manufacturing practice (cGMP) guidelines, 361 products are regulated under title 21 CFR 1271 for current good tissue practice (cGTP). Specified guidelines concerning 361 products mainly deal with prevention of communicable diseases, infection and donor eligibility requirements.
Products such as blood and blood components, minimally manipulated bone marrow, organs for transplant and secreted products are not considered HCT/Ps and are not regulated under cGMP or cGTP guidelines. All human cell based products, in addition to being regulated under the broader cGMP guidelines, are regulated under Title 21 CFR 1271 covering the cGTP guidelines.
As a rule, a conflict between regulations will be resolved by adhering to the more specific and detailed guideline. Title 21 CFR 1271, “Human Cells, Tissues, and Cellular & Tissue-Based Products”, is categorized as follows:
- Subpart A-General Provisions
- Subpart B-Procedures for Registration and Listing
- Subpart C-Donor Eligibility
- Subpart D-Current Good Tissue Practice (cGTP)
- Subpart E-Additional Requirements for Establishments is described in 1271.10
- Subpart F-Inspection and Enforcement of Establishments is described in 1271.10
cGTP guidelines core requirements (1271, subpart D) are categorized as follow:
- Exemptions/alternatives [1271.155]
- Quality Program [1271.160]
- Personnel [1271.170]
- Procedures [1271.180]
- Facilities [1271.190 (a) and (b)]
- Environmental control [1271.195 (a)]
- Environmental monitoring [1271.195 (c) through (h)]
- Equipment [1271.200 (a)]
- Supplies and reagents [1271.210 (a) and (b)]
- Recovery [1271.215]
- Processing/process controls [1271.220]
- Process changes [1271.225]
- Process Validation [1271.230]
- Labeling controls [1271.250 (a) and (b)]
- Storage [1271.260]
- Receipt, pre-distribution shipment, and distribution [1271.265 (a) through (d)]
- Records [1271.270 (e)]
- Tracking [1271.290 (a) through (g)]
- Complaint file [1271.320]
Cell Therapy Products Good Manufacturing Practice/Good Tissue Practice
For cell therapy basic research purposes, Good Laboratory Practice (GLP) can be sufficient for this specific stage. On the other hand, for cell therapy clinical trials, good clinical practice (GCP) is required. For cell therapy products manufacturing, Good manufacturing Practice (GMP) and Good Tissue Practice (GTP) are both required.
In general, GMP guidelines cover areas such as documentation, validation, facilities, equipment & systems, personnel, training, controlled documentation management, manufacturing, process control, labeling, packaging, storage, distribution etc. The title 21 code of federal regulations (CFR) includes GMP guidelines that cover the various GMP areas detailed below:
- Part 210- cGMP for manufacturing, processing, packaging and storage of drug products.
- Part 211- cGMP for finished pharmaceutical products.
- Part 225- cGMP for medicated feed.
- Part 226- cGMP for type A medicated articles.
- Part 606- cGMP for blood and blood components.
Cell therapy products GMP
Cell therapy medicinal products are covered under cGMP regulation for finished pharmaceutical products. The GMP requirements are divided into the following areas:
- Mix up
- Area definition
- Facility construction
- Numbers and functions
- Responsibilities and background
- Training and assessments
- Document control
- Trace ability
- Good Documentation Practice
- Product identification and characterization
- Sanitary design
- Qualification and Validation
- Software verification and validation
Production and process controls
- Standard Operation Procedures (SOPs)
- Donor suitability criteria
- Sterile collection methods validation
- Product-donor relation methods
- Collection procedures
- Product preparation
- In process and final product testing
- Final product storage and distribution
- Product administration methods
21 CFR Part 1271 Regulations
In May 2005, 21 CFR part 1271 regulations were published in order to close this gap, related to human cells, tissues and cellular tissue based products (HCT/Ps). HCT/Ps do not include “vascularized organs” for transplant, blood components, secreted/extracted products, minimally manipulated bone marrow which are not combined with another article, ancillary products, animal cells, tissues and in vitro diagnostics.
These guideline includes donor eligibility, current Good tissue Practices, requirements, inspection and enforcement. 361 and 351 type cell therapy products must comply the 21 CFR part 1271 requirements. 4.4 Good Tissue Practice (GTP)
cGTP standards were established for communicable disease prevention, introduction and transmission which can be caused by microorganisms such as bacteria, virus, fungi and parasites. cGTP requirements are divided into areas such as facilities, environmental control, equipment, material and reagents, covery, processing, process controls, labeling, storage and distribution etc.
GTP Quality System
Quality System should include communicable disease Risk Assessment in order to eliminate/reduce the potential risk. Moreover, Quality System should cover the following issues:
- Deviations documentation and investigations (including root cause analysis)
- Corrective And Preventive Actions (CAPA)
- Change Control
- Complaint handling
- Control and monitoring for critical parameters
- Personnel education, training and qualification
- Facility and clean room design, maintenance, cleaning
- Environmental controls
- HVAC/clean room validation
- Equipment design, operation, maintenance, cleaning and validation
- Computerized System and Software Validation
- Contamination, cross contamination and mix-up
- Process Performance Qualification (PPQ)
- Pathogen inactivation validation
- Labeling controls
- Storage controls
- Distribution controls