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Quantification of biological variation in blood ‐ based therapy – a summary of a meta ‐ analysis to inform manufacturing in the clinic

View Article: PubMed Central - PubMed

ABSTRACT

Background and objectives: Biological raw materials, the basis for cellular therapies such as stem cells, have a significantly greater degree of complexity than their traditional pharmaceutical counterparts. This can be attributed to the inherent variation of its source – human beings. Currently, cell therapies are made in small, ad hoc batches, but larger scale production is a prerequisite to meeting future demand and will require a quality‐by‐design approach to manufacturing that will be designed around, or be robust to this variation. Quantification of variation will require understanding of the current baseline and stratification of its sources.

Materials and methods: Haematopoietic stem cell therapy was chosen as a case study to explore this variation, and a PRISMA‐guided (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) systematic meta‐analysis was carried out for a number of predetermined cell measurements.

Results: From this data set, it appears that the extent of variation in therapeutic dose (in terms of transplanted total nucleated cells and CD34+ cells per kilogram) for HSCT is between one and four orders of magnitude of the median.

Conclusions: This is tolerated under the practice of medicine but would be unmanageable from a biomanufacturing perspective and raises concerns about comparable levels of efficacy and treatment. A number of sources that will contribute towards this variation are also reported, as is the direction of travel for 4 greater clarity of the scale of this challenge.

No MeSH data available.


Pareto analyses of meta‐analysis database by geographical location and patient indication.
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vox12288-fig-0002: Pareto analyses of meta‐analysis database by geographical location and patient indication.

Mentions: Data drawn from this meta‐analysis originated from multiple global sources, clinical centres, clinicians/surgical teams, addressing different indications and derived from different patient and donor demographics. Stratification into each of these subsets was not possible due to the limitations of the literature; however, the data set was scrutinized using Pareto analysis as a factor of location and indication of study. Pareto analyses are one of the seven tools of quality in the manufacturing sector, the Pareto rule being commonly referred to as the 80/20 rule – the observation that 20% of the causes determines 80% of the problems. In this case, each variable (indication/country) is plotted in descending order from highest to lowest contribution with an overlay of percentage cumulative contributions (Fig. 2).


Quantification of biological variation in blood ‐ based therapy – a summary of a meta ‐ analysis to inform manufacturing in the clinic
Pareto analyses of meta‐analysis database by geographical location and patient indication.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016773&req=5

vox12288-fig-0002: Pareto analyses of meta‐analysis database by geographical location and patient indication.
Mentions: Data drawn from this meta‐analysis originated from multiple global sources, clinical centres, clinicians/surgical teams, addressing different indications and derived from different patient and donor demographics. Stratification into each of these subsets was not possible due to the limitations of the literature; however, the data set was scrutinized using Pareto analysis as a factor of location and indication of study. Pareto analyses are one of the seven tools of quality in the manufacturing sector, the Pareto rule being commonly referred to as the 80/20 rule – the observation that 20% of the causes determines 80% of the problems. In this case, each variable (indication/country) is plotted in descending order from highest to lowest contribution with an overlay of percentage cumulative contributions (Fig. 2).

View Article: PubMed Central - PubMed

ABSTRACT

Background and objectives: Biological raw materials, the basis for cellular therapies such as stem cells, have a significantly greater degree of complexity than their traditional pharmaceutical counterparts. This can be attributed to the inherent variation of its source – human beings. Currently, cell therapies are made in small, ad hoc batches, but larger scale production is a prerequisite to meeting future demand and will require a quality‐by‐design approach to manufacturing that will be designed around, or be robust to this variation. Quantification of variation will require understanding of the current baseline and stratification of its sources.

Materials and methods: Haematopoietic stem cell therapy was chosen as a case study to explore this variation, and a PRISMA‐guided (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) systematic meta‐analysis was carried out for a number of predetermined cell measurements.

Results: From this data set, it appears that the extent of variation in therapeutic dose (in terms of transplanted total nucleated cells and CD34+ cells per kilogram) for HSCT is between one and four orders of magnitude of the median.

Conclusions: This is tolerated under the practice of medicine but would be unmanageable from a biomanufacturing perspective and raises concerns about comparable levels of efficacy and treatment. A number of sources that will contribute towards this variation are also reported, as is the direction of travel for 4 greater clarity of the scale of this challenge.

No MeSH data available.