Toward a New Mathematical Definition of Datums in Standards to Support Advanced Manufacturing.

Recent advances in the digitization of manufacturing have prompted ASME and International Organization for Standardization (ISO) standards committees to reexamine the definition of datums. Any new definition of datums considered by the standards committees should cover all datum feature types used in design and support both traditional metrological methods and new digital measurement techniques. This is a challenging task that requires some careful compromise. This paper describes and analyzes various alternatives considered by the standards committees. Among them is a new mathematical definition of datums based on constrained least-squares fitting. It seems to provide the best compromise and has the potential to support advanced manufacturing that is increasingly dependent on digital technologies.

Measurement of Aerodynamic Particle Size Distribution of Orally Inhaled Products by Cascade Impactor: How to Let the Product Specification Drive the Quality Requirements of the Cascade Impactor.

The multi-stage inertial cascade impactor is used to determine the mass-weighted aerodynamic particle size distribution (APSD) as a critical quality attribute for orally inhaled products (OIPs). These apparatuses progressively size-fractionate the aerosol passing through a series of stages containing one or more nozzles, by increasing particle velocity. Nozzle sizes for a given multi-nozzle stage can be described collectively by effective diameter ([Formula: see text]), related to the cut-point size, providing the link to aerodynamic diameter. Users undertake stage mensuration periodically to assure that each stage [Formula: see text] remains within the manufacturer's tolerance, but there is no guidance on how frequently such checks should be made. We examine the philosophy that particle size-related specifications of the OIP should determine when an impactor is mensurated. Taking an example of a dry powder inhaler-generated aerosol sampled via a Next Generation Impactor with pre-separator, we find that there are only three critical stages that could have a material effect on the measured APSD specified as four groupings of stages following current regulatory practice. Furthermore, [Formula: see text] for the most critical stage having the smallest nozzle sizes could be relaxed by a factor of four or more before risking an inability to measure the mass fraction of API in the group containing the finest particles to a specification within ± 10% of nominal. We therefore conclude that users should consider letting the specification for APSD performance of an OIP in terms of accepted stage groupings drive the impactor quality requirements and frequency that stage mensuration is undertaken.

Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation.

The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients' stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.

Advice to the US FDA to Allow US Pharmacopeia to Create Biological Product Specifications (BPS) to Remove Side-by-Side Analytical Comparisons of Biosimilars with Reference Products.

Pharmacopeia monographs are not intended to establish biosimilarity. However, the US Food and Drug Administration (FDA) has stopped the US Pharmacopeia (USP) from creating monographs for biological drugs due to the need for side-by-side comparisons with the reference products. The USP can create Biological Product Specifications (BPS), not to be labeled as monographs, based on the analytical testing of reference products and validated test methods that will remove the need for side-by-side analytical testing of biosimilars with reference products. Scientific arguments confirm that this plan is logical and capable of creating global quality standards for biosimilars to allow their interchangeability with other biosimilars. While the regulatory agencies have waived many high-cost biosimilar tests, analytical assessment is the most sensitive test; reducing its cost will further enhance the entry of biosimilars with no clinically meaningful difference.

The study of the roundness and cylindricity deviations of parts produced with the use of the additive manufacturing.

The paper is dedicated to the evaluation of the accuracy of rotary parts produced with the use of advanced manufacturing technology. The authors investigated the impact of the layer thickness of the applied material and the orientation of the model when printing using the PolyJet method™ on the geometrical quality of manufactured products. To analyze the influence of the assumed factors on the geometrical quality of the holes, a novel evaluation method has been developed. The proposed method takes into account parameters such as roundness deviation, profile irregularity coefficient, dominant harmonic component of the roundness profile, cylindricity deviation, diameter error, and surface topography parameters. The study presented in this paper had two main objectives. The former was to analyze the impact of the layer thickness of the applied material and the orientation of the model when printing using the PolyJet method™ on the geometrical quality of rotary parts. The latter objective was to test a novel, multi-parametric method of evaluation of the accuracy of produced parts in practice. The results obtained by the authors prove that the new evaluation method can be useful in the assessment of the accuracy of manufactured products.

Expert consensus on an open-access United Nations International Multiple Micronutrient Antenatal Preparation-multiple micronutrient supplement product specification.

The multiple micronutrient supplement (MMS) based on the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) formula provides women and their offspring with a healthy start to life in an efficacious, safe, and cost-effective way. To date, however, no precise and transparent specifications exist to support the manufacturing and distribution of UNIMMAP-MMS globally. To palliate for this need, the MMS Technical Advisory Group at the New York Academy of Sciences and the Micronutrient Forum convened a technical consultation to develop an open access UNIMMAP-MMS Product Specification for the manufacturing of this product. The specifications offered in this paper cover: ingredients, excipients, and processing aids used in the manufacturing of UNIMMAP-MMS; stability studies recommended under different testing conditions and climatic zones; packaging considerations; manufacturing standards, including pharmacopeia standards, manufacturing practices, certificates of analysis, change control, and quality agreement; finished product specifications, including tablet characterization and purity, potency assay; analytical test methods; and storage and transportation requirements.

Justification of disintegration testing beyond current FDA criteria using in vitro and in silico models.

Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations. A mechanistic approach, which is beyond the current FDA criteria, is presented. Dissolution testing via United States Pharmacopeial Convention Apparatus II at various paddle speeds was performed for immediate and extended release formulations of metronidazole. Dissolution profile fitting via DDSolver and dissolution profile predictions via DDDPlus™ were performed. The results showed that Fickian diffusion and drug particle properties (DPP) were responsible for the dissolution of the IR tablets, and that formulation factors (eg, coning) impacted dissolution only at lower rotation speeds. Dissolution was completely formulation controlled if extended release tablets were tested and DPP were not important. To demonstrate that disintegration is the most important dosage form attribute when dissolution is DPP controlled, disintegration, intrinsic dissolution and dissolution testing were performed in conventional and disintegration impacting media (DIM). Tablet disintegration was affected by DIM and model fitting to the Korsmeyer-Peppas equation showed a growing effect of the formulation in DIM. DDDPlus was able to predict tablet dissolution and the intrinsic dissolution profiles in conventional media and DIM. The study showed that disintegration has to occur before DPP-dependent dissolution can happen. The study suggests that disintegration can be used as performance test of rapidly disintegrating tablets beyond the FDA criteria. The scientific criteria and justification is that dissolution has to be DPP dependent, originated from active pharmaceutical ingredient characteristics and formulations factors have to be negligible.