CGMP and cell processing

Abstract

Over the past 20 years cell processing has changed. What an under statement! The types of cells processed, the complexity of the procedures, the addition of gene therapy and ex vivo cell expansion protocols together challenge the laboratory scientist. In the early days, as cell manipulation techniques were being developed, both research and clinical laboratories performed cell-processing procedures. Some cell manipulations yielded products which were associated with successful clinical outcomes; others failed to produce positive results and the methods were abandoned. In the 1970s and 80s, regulations and standards were not in place for bone-marrow processing laboratories. Most groups adapted general clinical laboratory operating standards and equipment quality-control programs to meet their unique needs. The focus was on ‘the cells’—which cells were important, were they altered during the processing procedure, how could specific cell types be identified and did assays exist to define the biological activity of the cells of interest? There were more questions than answers. However, with the success of bone-marrow transplantation as a treatment for hematologic malignancies, the shift of cell processing from a handful of academic hospitals to a multitude of hospitals and centralized processing laboratories became a reality. The need for standards and regulation became apparent to both laboratory professionals and the Food and Drug Administration (FDA). The goal was to balance patient safety with medical research. At the same time, the regulation of blood establishments was undergoing a change. In 1975, current Good Manufacturing Practice (cGMP) regulations for human blood, blood components and products were published in the 21 Code of Federal Regulations (CFR) Part 606 [1]. These regulations stated that the way in which blood was collected and processed would be regulated using the same manufacturing standards as those that the FDA used to regulate the pharmaceutical industry. cGMP is defined by the FDA in the CFR for drugs, biologics and devices as a systematic approach to reduce the risk of variability in product purity, potency and efficacy. Clarification was further provided in 1995 when the FDA released the Guideline for Quality Assurance in Blood Establishments [2]. The purpose of this document was to assist the manufacturers of blood and blood components in developing a quality assurance program, in their efforts to be consistent with recognized principles of quality assurance and cGMP. The publication in 1991 of Points to Consider in Human Somatic Cell Therapy and Gene Therapy added cGMP to the vocabulary of cellprocessing staff [3]. In 1998, the FDA published the Guidance for Human Somatic Cell Therapy and Gene Therapy [4] and, by the end of this year, may publish the draft proposed rule—Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products: Inspection and Enforcement. So, how should cell-processing laboratories integrate cGMP into their daily activities? This question was the basis for the ISHAGE sponsored GMP workshop for cell processing laboratories, held in April 1999. The purpose of the meeting was to introduce GMP concepts (for example, environmental and personnel monitoring, facility design, equipment and process validation) and discuss how these could be integrated into cell-processing laboratories. Presentations included the implementation of GMP in laboratories that prepared minimally-manipulated products and in facilities that genetically altered, or expanded cell products. This issue of Cytotherapy contains excerpts from the workshop. Carlos Lee spoke on personnel training and competency, and provided an assortment of documentation related to the topic in the workshop binder. The subject is a familiar one to most individuals trained in clinical laboratories and can be easily integrated into a GMP program. Robert Preti introduced process validation, using as an example a