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

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.

Deformation-phase measurement of diffuse objects that have started nonrepeatable dynamic deformation.

We have developed what we believe is a new technique for obtaining a whole-field image representing the deforming amounts of a diffuse object. The object is supposedly continuously deforming and does not stop deforming during the measurement. This technique uses arccosine operations to extract the absolute, not signed, value of the phase. We assume that a right-phase change retains almost the same value in a small local area. This retention determines the sign of the phase and consequently the value of the phase change. The deformation phase during any term of the deforming process is shown as a map through the temporal-phase unwrapping of the calculated phase.

Measurement of transient deformations with dual-pulse addition electronic speckle-pattern interferometry.

We describe an electronic speckle-pattern interferometry system for analyzing addition fringes generated by the transient deformation of a test object. The system is based on a frequency-doubled twin Nd:YAG laser emitting dual pulses at a TV camera field rate (50 Hz). The main advance has been the automatic, quantitative analysis of dual-pulse addition electronic speckle-pattern interferometry data by the introduction of carrier fringes and the application of Fourier methods. The carrier fringes are introduced between dual pulses by a rotating mirror that tilts the reference beam. The resulting deformation-modulated addition fringes are enhanced with a deviation filter, giving fringe visibility close to that of subtraction fringes. The phase distribution is evaluated with a Fourier-transform method with bandpass filtering. From the wrapped phase distribution, a continuous phase map is reconstructed with an iterative weighted least-squares unwrapper. Preliminary results for a thin plate excited by an acoustic shock show the suitability of the system for the quantitative evaluation of transient deformation fields.