Control of starting material and final product administration of cellular therapies

The manufacture of cellular therapies involves the challenge of maintaining critical characteristics of starting materials and the final product which contain living cells. In order to ensure that the cellular product administered is viable and therapeutically active, there is a need to define and control the starting cell collection and final product administration processes that take place outside of the manufacturing facility. First, it is necessary to understand and define the characteristics of suitable cellular starting materials, such as patient’s autologous leukapheresis or blood draw collection or allogeneic placental tissue. In order to do so, collection parameters have been set based on industry known standards for these starting materials and data are being continually collected and analyzed to further drive controls that need to be established. An understanding of the collection parameters that affect the critical attributes of the starting material will further drive the development of a manufacturing process that is robust to the variability inherent in a biological starting material. Additionally, it is necessary to control the manipulations such as thawing and dilution of the final cellular product at the patient interface. In order to establish a design space for the thawing and dilution at clinical site of our cellular products, studies were executed to establish limits for the time and temperature of the product thaw, stability of the thawed and diluted product prior to administration, and infusion rates and procedures that are tolerable for the living product and the patient. The characterization of failure limits for each processing step has further motivated the simplification of a number of steps in the preparation procedure to reduce the risk of working outside the design space. Once such simplification is the design and implementation of a thaw device that is simpler, lower risk, and more user-friendly than a water bath. The characterization of and requirement to control both the collection parameters for our starting material and the cellular product preparation and administration procedure has broadened our scope of responsibilities. These responsibilities include identifying a design space for steps in the starting material collection and product preparation procedures, creating simplified and user-friendly cellular preparation procedures, providing training and technical support for our clinical counterparts, and creating systems that allow traceability from collection to administration. This collaboration of engineers and the clinical research groups will be crucial in the cellular therapeutic industry moving forward

Establishing successful commercial CAR T manufacturing on a short timeline: A process development and planning perspective

The transformational impact of CAR T cell therapies on serious diseases enables a rapid path to licensure. Although many challenges of reliably delivering autologous CAR T therapies have been managed at clinical scale and quality, the transition to commercial scale and widespread availability to desperate patients presents many additional challenges. The process development contribution of pragmatic and engineering-based operations science with respect to facility fit, scale-out, and patient variability is essential to the success of this transition. Whether adapting an existing facility or constructing a new one, GMP workspace design requires detailed process evaluation. In addition to maximizing efficient use of space, equipment, and labor, addressing facility impact on process is critical. For example, the scale or layout of a large commercial facility can increase the time necessary to perform a process step. As a result, the process runs within a different range of the parameter space within the facility. We describe time-related process characterization data and closed-system solutions to facility fit challenges along with the process expertise which contributes to successful technology transfer to new facilities. The task of facility fitting becomes increasingly complex as multiple facilities are implemented, as it is desirable to minimize facility-to-facility process variation. A dramatic increase in scale (number of patient-batches) is associated with establishment of commercial manufacturing. Due to an individual batch being performed for each patient, an increase in the necessary facilities, equipment, and staff accompanies the scale increase. As new manufacturing, QC, and QA talent ramps up the workforce, a robust training program that imparts both process instruction and understanding is critical. Further, process design and batch record clarity must be improved to minimize process variability. We describe process and batch record improvements that address rapid workforce expansion and training. Autologous cell therapies present patient variability, which results in variable process performance and product characteristics. As the number of patient-batches increases, the number of occurrences uncommon process phenotypes also increases. This requires extensive instructions on how to consistently adjust the process for patient variability as well as process design that minimizes the effect of patient variability on performance while ensuring a consistent, high quality product. In addition, process performance data must be monitored to assess process performance and variability. We discuss examples of patient variability, troubleshooting, and batch history data

La calibración de la escala de distancias cósmicas : distancias exactas de estrellas cefeidas en la galaxia, las nubes de Magallanes y en varias galaxias del Grupo Local

IP 1101-05-217-89ARTICULO(S) EN REVISTA: On the binary status of the cepheid SVpersei / Wolfgang P. Gieren, E. Brieva. --;and 2257 / Wolfgang P. Gieren. -- En: Monthly notices of the Royal Astronomical Society. -- Vol. 265 (1993);En: Astronomy and Astrophysics. -- Vol. 253 (1992); p. 126-130.'-- a distance to the cepheid HV 829 in the;small magellanic cloud / Wolfgang P. Gieren. ... [et. al].--En: The Astrophysical Journal. -- Vol. 405 (Mar;1993); p. 51-53. -- The cepheid period-luminosity relationfromindependent distances of 100 galactic;variables / Wolfgang P. Gieren. ... [et. al]. -- En: The Astrophysical Journal. -- Vol. 418 (Nov 1993); p.;135-146. -- Surface brightness distance determinations tothelarge magellanic cloud cepheid variables HV 899;distance determinations to milky way cepheids in open clustersand associations II. Cf cas in NGC 7790 /;Wolfgang P. Gieren. ... [et. al]. -- En: The AstronomicalJournal. -- Vol.110, no. 5 (Nov 1995); p.;2280-2287. -- Independent distance determinations to milkywaycepheids inopen clusters and associations III.;Cv mon in anon van den bergh / Wolfgang P. Gieren. ... [et. al].'-- en: The Astronomical Journal. -- Vol. 111,;no. 5 (May 1996); p. 2059-2065. -- Comparison of the opencluster and surface-brightness distance scales for;galactic classical cepheids / Wolfgang P. Gieren, Pascal Fouque.'-- en: The Astronomical Journal. -- Vol. 106,;no. 2 (Aug 1993); p. 734-739.;184-188. -- The distance to the large magellanic cloud clusterNGC 1866 from ITS cepheid members / Wolfgang P.;Gieren. ... [et. al]. -- En: The Astrophysical Journal. --Vol.433 (Oct 1994); p. 73-76. -- Independen