Stem Cell Medicinal Products cGMP and cGTP

Background

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 is not within the scope of this article.

Code of Federal Regulations

In the US, the 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 to 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 are treated as 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 the 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 more specific and detailed guidelines. 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 follows:

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

General

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:

Facility

Mix up
Area definition
Facility construction

Personnel

Numbers and functions
Responsibilities and background
Training and assessments

Documentation

Document control
Traceability
Good Documentation Practice
Product identification and characterization

Equipment

Operation
Maintenance
Sanitary design
Cleaning
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 is not combined with another article, ancillary products, animal cells, tissues, and in vitro diagnostics.

This guideline includes donor eligibility, current Good tissue Practices, requirements, inspection, and enforcement. 361 and 351 type cell therapy products must comply with the 21 CFR part 1271 requirements. 4.4 Good Tissue Practice (GTP)

GTP scope

cGTP standards were established for communicable disease prevention, introduction, and transmission which can be caused by microorganisms such as bacteria, viruses, fungi, and parasites. cGTP requirements are divided into areas such as facilities, environmental control, equipment, material and reagents, recovery, processing, process controls, labeling, storage, distribution, etc.

GTP Quality System

Quality Systems should include communicable disease Risk Assessment in order to eliminate/reduce the potential risk. Moreover, Quality System should cover the following issues: