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M-22: Quality Challenges in Cellular Therapy: An Examination of Regulatory Compliance in Manufacturing Institutions

Poster Presenter

      Katherine St. Martin

      • Graduate Student, DrSc Regulatory Science Program
      • University of Southern California (USC)
        United States


The objective of this study is to examine the compliance challenges associated with manufacturing the new generation of cellular therapy biologic drug products which must adhere to both current good tissue practice (cGTP) and current good manufacturing practice (cGMP) requirements.



Preliminary analysis of 38 anonymized audits conducted between 2014 and 2017 by the National Marrow Donor Program revealed quality challenges for institutions manufacturing cellular therapy products under IND. Audit findings were categorized by functional area and compared across FDA regulations.


Of the 83 institutions manufacturing product under the NMDP IND, 30 were audited once, 4 were audited twice, and 50 were not audited during the study period. The resulting 38 audit reports, represent 46% of the total manufacturers. The NMDP’s manufacturing institutions are either hospital based (71%), blood center based (28%), or private (1%) cell therapy collection centers. The audited institutions reflect a similar breakdown of hospital based (68%), blood center based (29%), and private (3%) center types. The study indicates that hospital based centers are the primary cellular therapy collection institution type and that 52% of these hospitals are actually affiliated with research universities. During the study audits, auditors identified and described compliance issues as citations within the audit reports. There were 120 total citations. Of the 120 citations, the study found 76% of citations occurred at hospital based institutions, 21% occurred at blood center based institutions, and 3% occurred at private centers. The distribution of citations is proportional to the distribution of manufacturing institution types. The study found that audit citations addressing cGTP requirements represented 64% of total citations whereas citations addressing cGMP requirements represented only 34% of total citations. The cGTP regulations were codified in 2005. Despite a decade of industry familiarity, the study findings point to lasting cGTP compliance challenges. The majority of cGTP and cGMP citations are associated with systematic elements of a quality program and less so with the product and processing elements of manufacturing. Examining the quality program citations further revealed that systems such as personnel and training, document management, and environmental control accounted for 83% of citations. By contrast, only 17% of citations related to product manufacturing processes such as collection, in-process controls, and labeling.


The cellular therapy industry is on the cusp of a new generation of biologic drug products. The recently FDA approved first-in-class Chimeric Antigen Receptor (CAR) T-Cell therapies and the presence of additional products in final development stages indicate that marketed cellular therapies will increase rapidly. Marketed products will increase the need for cellular therapy manufacturing expertise. The cellular collection and processing industry must anticipate the need for rigorous compliance to support this new generation of product development and post-market production. This study implies that differing types of manufacturing institutions are equally compliant with the regulations. The quantity of cGTP citations implies that manufacturers may have lingering gaps in their cGTP implementation. In fact, the nature of the citations indicates that the overarching quality systems are the most challenging areas rather than the product manufacturing processes. These study findings point to the need for reinforcing and expanding the existing quality programs. The manufacturing institutions, many of which are hospitals, are challenged to apply cGTP and cGMP requirements within a health care environment. Hospital’s Quality Control Units are often centralized and focused on quality patient outcomes rather than in-process quality control for manufacturing. The findings support that institutions have extensive knowledge and experience with compliant cellular therapy collection activities. However, the quality program citations indicate an opportunity for growth. Cellular therapy institutions could benefit from additional quality training support. Moving forward, manufacturers may need to resource quality infrastructure improvements in order to support the growing demand for compliant manufacturing.