Standard Manufacturing Process Research Articles

Virus Filtration and Flow Variation: An Approach To Evaluate Any Potential Impact on Virus Retention.

Virus removal by filtration has improved safety margins of plasma-derived medicinal products and recombinant proteins. However, low or no flow (stop) situations during virus filtration may potentially affect virus removal. Transforming filtrate flow versus time data into histograms generates intuitively understandable visuals that provide a powerful tool to investigate the equivalence of manufacturing scale processes and down-scaled virus-spiked study runs, and thus to understand the robustness of virus removal for this parameter. With this tool at hand, lower mean flow rates during small-scale experiments are an elegant approach to support the robustness of virus filtration with respect to this parameter at manufacturing scale.

Antibody Therapeutics in Oncology

One of the newer classes of targeted cancer therapeutics is monoclonal antibodies. Monoclonal antibody therapeutics are a successful and rapidly expanding drug class due to their high specificity, activity, favourable pharmacokinetics, and standardized manufacturing processes. Antibodies are capable of recruiting the immune system to attack cancer cells through complement-dependent cytotoxicity or antibody dependent cellular cytotoxicity. In an ideal scenario the initial tumor cell destruction induced by administration of a therapeutic antibody can result in uptake of tumor associated antigens by antigen-presenting cells, establishing a prolonged memory effect. Mechanisms of direct tumor cell killing by antibodies include antibody recognition of cell surface bound enzymes to neutralize enzyme activity and signaling, or induction of receptor agonist or antagonist activity. Both approaches result in cellular apoptosis. In another and very direct approach, antibodies are used to deliver drugs to target cells and cause cell death. Such antibody drug conjugates (ADCs) direct cytotoxic compounds to tumor cells, after selective binding to cell surface antigens, internalization, and intracellular drug release. Efficacy and safety of ADCs for cancer therapy has recently been greatly advanced based on innovative approaches for site-specific drug conjugation to the antibody structure. This technology enabled rational optimization of function and pharmacokinetics of the resulting conjugates, and is now beginning to yield therapeutics with defined, uniform molecular characteristics, and unprecedented promise to advance cancer treatment.

Investigation on the thermo-oxidative stability of carbon fiber sizings for application in thermoplastic composites

The stability of the surface chemical composition of different polymer sizings on carbon fibers, designed as a reinforcing material for thermoplastic composites, was investigated in detail under conditions closely related to the standard processing ones, i.e. high temperature, short periods of processing time and presence of an oxidative atmosphere. X-ray photoelectron spectroscopy and contact angle measurements were used to characterize the surface properties of the sizings in dependence of treatment time and temperature. The obtained results clearly show a rapid thermo-oxidative altering of the initial surface functionalities, in particular of the polyether based component, which was found to be the major surface constituent of all types of investigated sizing systems. Moreover, the observed degradation of surface functionalities leads to significant changes in the surface free energies of the sizings determined by contact angle measurements. Finally, the surface analysis of single fibers, which were pulled out during fracture of model composite specimens, confirmed that the revealed surface degradation of the sizing also takes place during a standard polymer composite manufacturing process.

A flexible-dose dispenser for immediate and extended release 3D printed tablets

The advances in personalised medicine increased the demand for a fast, accurate and reliable production method of tablets that can be digitally controlled by healthcare staff. A flexible dose tablet system is presented in this study that proved to be suitable for immediate and extended release tablets with a realistic drug loading and an easy-to-swallow tablet design. The method bridges the affordable and digitally controlled Fused Deposition Modelling (FDM) 3D printing with a standard pharmaceutical manufacturing process, Hot Melt Extrusion (HME). The reported method was compatible with three methacrylic polymers (Eudragit RL, RS and E) as well as a cellulose-based one (hydroxypropyl cellulose, HPC SSL). The use of a HME based pharmaceutical filament preserved the linear relationship between the mass and printed volume and was utilized to digitally control the dose via an input from computer software with dose accuracy in the range of 91–95%. Higher resolution printing quality doubled the printing time, but showed a little effect on in vitro release pattern of theophylline and weight accuracy. Physical characterization studies indicated that the majority of the model drug (theophylline) in the 3D printed tablet exists in a crystal form. Owing to the small size, ease of use and the highly adjustable nature of FDM 3D printers, the method holds promise for future individualised treatment.

Low-Cost Chemical Sensing Platform With Organic Polymer Functionalization

The characteristics of an inexpensive transistor-based chemical sensing platforms with organic polymer, polyaniline (PANI), was investigated in terms of tranconductance, pH sensitivity, and drift properties. The platform consists of a printed circuit board manufactured in a standard manufacturing process and commercial discrete MOSFETs. The platform is funtionalized with PANI by a simple low-cost drop casting. The platform shows low average pH sensitivity of 9.1 mV/pH in the range 4–7 where physiological recognition events take place and as such is a promising candidate for intrinsic charge-based biosensing since PANI is able to directly interact with charged macromolecules such as proteins and DNA. In addition, the PANI functionalized sensors show low nonmonotonic drift and only slightly reduced transconductance compared with the MOSFET counterpart.

Abstract 2481: CEA TCB, a novel T-cell bispecific antibody with potent in vitro and in vivo antitumor activity against solid tumors

Abstract T cell bispecific antibodies (TCBs) are potent molecules that upon simultaneous binding to tumor cells and T cells trigger strong T cell activation resulting in the killing of tumor cells. CEA TCB (RG7813) is a novel bispecific antibody targeting carcinoembryonic antigen (CEA), often overexpressed on solid tumors (e.g. colorectal, gastric, pancreatic, lung carcinoma etc.), and the CD3 epsilon chain present on T cells. CEA TCB bears several innovative technological features that distinguish it from other bispecific antibodies currently in (pre-)clinical development: (a) bivalency for tumor antigen translating into higher avidity, superior potency and better differentiation between high and low antigen-expressing cells; (b) head-to-tail fusion geometry for anti-tumor and CD3-binding domains, resulting in higher potency compared to conventional IgG-based TCBs; (c) extended half-life compared to non-Fc-based TCBs; (d) fully silent Fc ensuring lower risk of FcgR-mediated infusion reactions; and (e) robust production using standard manufacturing processes (enabled by “CrossMAb” and knob-into-hole bispecific antibody technologies). In vitro, CEA TCB mediates potent target-dependent T cell cytotoxicity, T cell activation, proliferation, and cytokine release in killing assays, exclusively in the presence of CEA-expressing target-cells. CEA TCB activity correlates with CEA expression level, showing higher potency against tumor cells with high expression of CEA. In vivo, CEA TCB induces dose- and time-dependent regression of CEA-expressing tumors with variable amounts of immune cell infiltrate. In fully humanized NOG mice, CEA TCB is efficacious in poorly-infiltrated tumors and converts non-inflamed into highly-inflamed tumors. Histological and FACS analyses revealed that CEA TCB recruits new T cells into tumors and/or expands pre-existing ones and is able to induce T cell re-localization from the tumor periphery into the tumor bed. Surprisingly, CEA TCB treatment also qualitatively alters the composition of intratumoral T cells resulting in an increased frequency of activated (CD69, CD25), proliferating (Ki67) and differentiated T cells (having effector memory phenotype) that are ready to kill (express high levels of Granzyme B). Taken together, these preclinical data show that CEA TCB is a novel tumor-targeted T cell bispecific antibody with promising anti-tumor activity and the novel ability to modify the tumor microenvironment. Phase 1 clinical trials with CEA TCB are currently ongoing. Future studies will focus on identification of combination partners that inhibit T cell suppression and unleash the full potential of T cell activity. Citation Format: Marina Bacac, Tanja Fauti, Sara Colombetti, Johannes Sam, Valeria Nicolini, Nathalie Steinhoff, Oliver Ast, Peter Bruenker, Ralf Hosse, Thomas Hofer, Ekkehard Moessner, Christiane Jaeger, Jose Saro, Vaios Karanikas, Christian Klein, Pablo Umana. CEA TCB, a novel T-cell bispecific antibody with potent in vitro and in vivo antitumor activity against solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2481. doi:10.1158/1538-7445.AM2015-2481

Adhesion energy of printed circuit board materials using four-point-bending validated with finite element simulations

Modern printed circuit boards (PCB) are high performance products consisting of metal and dielectric materials in a multi-layered structure. Due to this build-up different failures, such as cracking or delamination, may occur during manufacturing and use leading to failure of the entire electronic device. The mismatch in the thermal expansion coefficients leads to stresses in the structure during temperature change, e.g., during the reflow process. To improve device reliability, it is critical to understand the delamination between different layers and to know the adhesion energy of the interfaces in a PCB. The adhesion energy in test PCBs was determined using four point bending (4PB) experiments before and after 15 reflow cycles. The investigations show that 4PB is applicable for determining the adhesion energy in samples made of halogen free pre-pregs and copper sheets with standard manufacturing processes. Furthermore, the applicability of the analytical adhesion energy calculation in the presence of non-linearities was examined by finite element simulations. It was found that friction between the sample and the pins of the loading device has an influence on the reaction force used for the calculation of the critical energy release rate. Plastic deformation of the 4PB sample, especially in the ductile copper layers, also will affect the analytically determined critical energy release rate. The role of both factors on the analytical approach to measure adhesion energies of PCB interfaces with 4PB will be shown and discussed.

An Analytical Study on Evaluating the Performance of Developed Cultivator Mounted Seed Metering Mechanism

Prototype cultivator-cum-seed drill was designed, fabricated and tested for sowing of paddy. The machine consisted of cultivator frame, tines, seed box, seed tubes, metering mechanism, power transmission unit, furrow opener and hitching attachments. The selection of materials and fabrication was done following the standard manufacturing process. The cultivator-cum-seed drill with shovel type furrow openers was tested for sowing of the paddy. The performance of the machine was evaluated considering the effect of field capacity, field efficiency, energy requirement and cost of operation in relation with conventional seed drill in the laboratory as well as in the field. The seed rate of cultivator-cum-seed drill was found to be 80.87 kg/ha and that of conventional seed drill was found to be 80.26 kg/ha.when seed drill was half filled and flute exposure was 14.9 mm & 13.8 mm. The standard deviation for inter row variation for sowing paddy with cultivator-cum-seed drill was 0.46 with CV of 1.8 % and that for conventional seed drill was 0.41 and 1.5 % respectively.The effective field capacity of the cultivator-cum seed drill was 0.537 ha/h with field efficiency of 82.8 % as compared to conventional seed drill which was 0.596 ha/h and 82.32 %. The cost of operation for cultivator-cum-seed drill was 591.08 Rs/ha and that for conventional seed drill was 535.016 Rs/ha. The Energy requirement for cultivator-cum-seed drill was found to be 454.18 MJ/ha and that for conventional seed drill was found to be 416 MJ/ha.

High-cycle fatigue behavior of thin-walled CoCr tubes

Thin-walled tubes made of the biocompatible Cobalt–Chromium alloy L605 are being used as the starting material for manufacturing of stents with fine struts of about 100μm due to their excellent mechanical properties. The required long-term reliability of these medical implants is endurance of 4·108 loading cycles without failure. Knowledge of the high-cycle fatigue properties of the tubing material used for the stent fabrication is a prerequisite for optimization of these high quality products during the stages of design and fabrication. In the present study, the high-cycle fatigue behavior of thin-walled tubes of CoCr L605 was studied by using an ultrasonic resonance fatigue testing system. Laser cutting technique was used to introduce holes in the midsection of the tubes followed by electro-polishing and passive coating processes. Standard stent manufacturing processes were applied for preparation of the tube samples, ensuring representative microstructures and mechanical properties to final stent products. Vibrometry measurements and finite element simulations were conducted to analyze the overall modal response of the tubes during the vibrational loading and to calculate the stress–strain distribution in the periphery of the holes. A lifetime prediction model covering the low- and high-cycle fatigue regime is proposed, based on the experimentally obtained high-cycle fatigue curves in combination with the literature data and finite element modeling.

ITOC2 – 037. CEA TCB, A novel T-cell bispecific antibody with potent in vitro and in vivo antitumour activity against solid tumours

T cell bispecific antibodies (TCBs) are potent molecules that upon simultaneous binding to tumour cells and T cells trigger strong T cell activation resulting in the killing of tumour cells. CEA TCB (RG7813) is a novel bispecific antibody targeting carcinoembryonic antigen (CEA), often overexpressed on solid tumours (e.g. colorectal, gastric, pancreatic, lung carcinoma etc.), and the CD3 epsilon chain present on T cells. CEA TCB bears several innovative technological features that distinguish it from other bispecific antibodies currently in (pre-)clinical development: (a) bivalency for tumour antigen translating into higher avidity, superior potency and better differentiation between high and low antigen-expressing cells; (b) head-to-tail fusion geometry for anti-tumour and CD3-binding domains, resulting in higher potency compared to conventional IgG-based TCBs; (c) extended half-life compared to non-Fc-based TCBs; (d) fully silent Fc ensuring lower risk of FcgR-mediated infusion reactions; and (e) robust production using standard manufacturing processes (enabled by “CrossMAb” and knob-into-hole bispecific antibody technologies). In vitro , CEA TCB mediates potent target-dependent T cell cytotoxicity, T cell activation, proliferation, and cytokine release in killing assays, exclusively in the presence of CEA-expressing target-cells. CEA TCB activity correlates with CEA expression level, showing higher potency against tumour cells with high expression of CEA. In vivo , CEA TCB induces dose- and time-dependent regression of CEA-expressing tumours with variable amounts of immune cell infiltrate. In fully humanised NOG mice, CEA TCB is efficacious in poorly-infiltrated tumours and converts non-inflamed into highly-inflamed tumours. Histological and FACS analyses revealed that CEA TCB recruits new T cells into tumours and/or expands pre-existing ones and is able to induce T cell re-localisation from the tumour periphery into the tumour bed. Surprisingly, CEA TCB treatment also qualitatively alters the composition of intratumoural T cells resulting in an increased frequency of activated (CD69, CD25), proliferating (Ki67) and differentiated T cells (having effector memory phenotype) that are ready to kill (express high levels of Granzyme B). Taken together, these preclinical data show that CEA TCB is a novel tumour-targeted T cell bispecific antibody with promising anti-tumour activity and the novel ability to modify the tumour microenvironment. Phase 1 clinical trials with CEA TCB are currently ongoing. Future studies will focus on identification of combination partners that inhibit T cell suppression and unleash the full potential of T cell activity. Presented in Plenary Session 4 : Immunomodulatory agents.

전통 발효음청류 계장의 기호도 우수 발효조건

Kyejang is a Korean traditional beverage manufactured from medicinal plants and fruits using honey, sugar, or starch in cold water. In this study, cinnamon-containing kyejang, which is a type of beverage Jang, was reproduced based on Imwonsibyukji’s method published in 1827 in the Korean literature. Kyejang made by nuruk, cinnamon, and medicinal plants was prepared at various temperatures and periods. Kyejang was assayed for physiochemical properties (pH and acidity), contents of metabolites (organic acids, sugars, and amino acids), and sensory characteristics (aroma and taste). During fermentation, content of organic acids (e.g. lactic acid, acetic acid, and shikimic acid) increased, which lowered pH, increased acidity, and increased intensity of sour taste. In the case of free sugars, fructose and maltose levels decreased while glucose and mannitol levels increased during fermentation periods, and sweetness decreased. The main amino acid in kyejang was tryptophan, followed by asparagine, proline, and arginine. The sensory evaluation score of overall preference was highest for kyejang which was fermented at 20°C for 3 days. The results will be provide the basic data of fermentation conditions for standardized manufacturing process of kyejang.

Pharmaceutical standardization of Apamarga kshara.

Standardization of herbal drugs is essential to certify their quality and purity. Kshara (alkaline substance) of Apamarga (Achyranthes aspera Linn.) is an important constituent in many Ayurvedic formulations, but its standard manufacturing process (SMP) is not attempted till date. This study is aimed to establish SMP for Apamarga kshara. In pharmaceutical process; generally the sediments of ash obtained at the end of washes will be discarded. However, in the study, we attempted to wash the sediments repeatedly by adding water to extract more Kshara. Apamarga was collected from the local area and authenticated. Kshara was prepared by following standard methods and the preliminary physicochemical profile was developed. It is observed that the ash yields Kshara even in the consecutive washes. First wash yielded 21.23% w/w Kshara, while the second and third washes yielded 9.38% w/w and 4.76% w/w, respectively. Repeated washes yield more Kshara. Hence, it is advocated to wash the ashes repeatedly. As the findings are encouraging, similar experiments can be extended to all other Kshara preparations.

Engineering high charge transfer n-doping of graphene electrodes and its application to organic electronics.

Using thermally evaporated cesium carbonate (Cs2CO3) in an organic matrix, we present a novel strategy for efficient n-doping of monolayer graphene and a ∼90% reduction in its sheet resistance to ∼250 Ohm sq(-1). Photoemission spectroscopy confirms the presence of a large interface dipole of ∼0.9 eV between graphene and the Cs2CO3/organic matrix. This leads to a strong charge transfer based doping of graphene with a Fermi level shift of ∼1.0 eV. Using this approach we demonstrate efficient, standard industrial manufacturing process compatible graphene-based inverted organic light emitting diodes on glass and flexible substrates with efficiencies comparable to those of state-of-the-art ITO based devices.

Understanding transferable supply chain lessons and practices to a "high-tech" industry using guidelines from a primary sector industry: a case study in the food industry supply chain.

Flexibility and innovation at creating shapes, adapting processes, and modifying materials characterize composites materials, a “high-tech” industry. However, the absence of standard manufacturing processes and the selection of materials with defined properties hinder the configuration of the composites materials supply chain. An interesting alternative for a “high-tech” industry such as composite materials would be to review supply chain lessons and practices in “low-tech” industries such as food. The main motivation of this study is to identify lessons and practices that comprise innovations in the supply chain of a firm in a perceived “low-tech” industry that can be used to provide guidelines in the design of the supply chain of a “high-tech” industry, in this case composite materials. This work uses the case study/site visit with analogy methodology to collect data from a Spanish leading producer of fresh fruit juice which is sold in major European markets and makes use of a cold chain. The study highlights supply base management and visibility/traceability as two elements of the supply chain in a “low-tech” industry that can provide guidelines that can be used in the configuration of the supply chain of the composite materials industry.

Manufacture of immunoglobulin products for patients with primary antibody deficiencies - the effect of processing conditions on product safety and efficacy.

Early preparations of immunoglobulin (Ig) manufactured from human plasma by ethanol (Cohn) fractionation were limited in their usefulness for substitution therapy in patients with primary antibody deficiencies (PAD), as Ig aggregates formed during manufacture resulted in severe systemic reactions in patients when given intravenously. Developments in manufacturing technology obviated this problem through the capacity to produce concentrated solutions of intact monomeric Ig, revolutionizing PAD treatment and improving patient life expectancy and quality of life. As the need for Ig has grown, manufacturers have refined further manufacturing technologies to improve yield from plasma and produce therapies, which are easier and less expensive to deliver. This has led to the substitution, partly or wholly, of ethanol precipitation by other techniques such as chromatography, and has also stimulated the production of highly concentrated solutions capable of rapid infusion. Ig products have been associated, since their inception, with certain adverse events, including infectious disease transmission, hemolysis, and thromboembolism. The introduction of standardized manufacturing processes and dedicated pathogen elimination steps has removed the risk of infectious disease, and the focus of attention has shifted to other problems, which appear to have increased over the past 5 years. These include hemolysis and thromboembolism, both the cause for substantial concern and the subject of recent regulatory scrutiny and actions. We review the development of manufacturing technology and the emerging evidence that changes for the optimization of yield and convenience has contributed to the recent incidents in certain adverse events. Industry measures under development will be discussed in terms of their potential to improve safety and optimize care for patients with PAD.

Cool products for building envelope – Part I: Development and lab scale testing

The paper describes the methodology followed for the development of new cool products in order to widen the range of existing solutions both including coloured (even dark) materials and extending the application also to building vertical components. Cool coloured ceramic tiles and acrylic paints for façades and roof membranes have been developed and tested at lab scale. Spectral reflectance measurements have been performed demonstrating a significant improvement of reflectance in the Near InfraRed (NIR) range (up to+0.40) while keeping dark colour and high absorbance in the visible. The development of new products has been also oriented to the improvement of durability properties, being this aspect of relevance for high reflecting materials that have to keep their cooling properties over the time. While ceramic tiles naturally offer superior resistance to outdoor ageing, a significant increase of biological growth resistance has been achieved also for roof membranes by including ZnO nanoparticles. The approach followed by the authors aimed at delivering products, that besides having higher NIR reflectance, were capable of satisfying industrial and market requirements being compatible with standard manufacturing processes and offering additional functionalities. A complementary paper will be dedicated to the extensive experimental and numerical evaluation of new materials’ thermal performances.

Special issue on modeling and simulation of advanced manufacturing processes

This special issue’s objective was to explore and illustrate the development of cutting-edge modeling techniques and computational methods for advanced manufacturing processes. The special issue investigated nontraditional, scalable, manufacturing methods, exemplified by, for example, additive manufacturing processes. It is important to emphasize that we did not seek papers that simply apply well-established computational techniques and commercial codes to standard manufacturing processes. One of the primary objectives was to provide scientific and engineering foundations for many emerging new technologies that are being used or proposed to be used in industry. As we have witnessed over the last 20 years, many of the modern breakthroughs in science and technology are a result of the development of innovative research tools and new materials that can be processed and inexpensively manufactured rapidly, in large amounts, and in a “green” manner.

Fabrication and application of temperature triggered MEMS switch for active cooling control in Solid State Lighting system

As the power of Solid State Lighting (SSL) system continuously rising and consequently high temperature occurred in the light source, active cooling solutions with controlling were widely used and smart controlling was indispensable for less energy consuming. In this work, a micro–electro-mechanical-system (MEMS) based, temperature triggered, switch was developed as a cost-effective solution for smart cooling control in SSL systems. The switch (1.0×0.4mm2) was embedded in a silicon substrate and fabricated with a single-mask 3D micro-machining process. The device switched on at a designed temperature threshold with a contact resistance less than 2ohm, and switched off when the temperature dropped below that limit. In this way, this device can enhance the automatic control of a cooling system without any need of additional electronic components and the used standard semiconductor manufacturing process gives highly possibility for integration and fabrication for future silicon based SSL systems.

Standardization and characterization of ATIR cell therapy product: applying QbD to both process and assay development

Kiadis Pharma is developing ATIR, a T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host alloreactive T-cells to reduce risks and improve outcomes of haploidentical stem cell transplantation for blood cancer patients. Laboratory evaluations of ATIR have shown photodepletion of recipient-reactive cells and immune reactivity retention. ATIR product demonstrated favorable anti-infection and anti-leukemia properties without causing severe graft-versus-host disease in a Phase I clinical trial. In 2011, the company terminated a next-phase clinical trial, because the product did not resemble ATIR, but contained dead and apoptotic cells. A root cause failure investigation confirmed that the process should be re-engineered. A Quality-by-Design (QbD) approach was taken towards both process and assay development, aiming at (i) development of a standardized manufacturing process for a phase II clinical study, and (ii) development of new cellular potency assays that accurately measure critical process and product attributes. Experiments were designed to test single modifications in full ATIR runs. Ultimately, comparability of the new process/product to the original process/ product was demonstrated in a head-to-head comparison, using the fixed and qualified assays, currently used for release testing in ongoing clinical study CRAIR-007. This approach has resulted in a set of qualified assays fulfilling predefined requirements, enabling methodical process characterization during development. The knowledge gained about critical process parameters will be highly valuable during next phase development steps. The standardized, robust and transferable process resulting from the QbD approach is currently used for manufacturing ATIR at CMO’s in North America and Europe for ongoing clinical studies.

Mechanically coupled laminates with balanced plain weave

Abstract Definitive listings of laminate stacking sequences are derived for balanced plain weave laminated materials, assuming each layer is composed of the same material with constant thickness throughout and that standard ply angle orientations 0, 90, and ±45° are adopted; consistent with industrial design practice. A single layer of balanced plain weave material is shown to be immune to thermal distortion following a standard high temperature manufacturing process, which implies that all laminates constructed of this material possess what is commonly referred to as the hygro-thermally curvature-stable or warp-free condition, irrespective of the individual ply orientations used or the laminate stacking sequence definition. A single uncoupled parent laminate class is shown to contain sub-groups with extensionally isotropic and fully isotropic properties that are invariant with off-axis orientation of the principal material axes with respect to the system or structural axes. By contrast a single mechanically coupled parent laminate class is shown to give rise to seven unique forms of coupled laminate through judicious off-axis orientation. Invariant off-axis properties are also identified in coupled laminate designs. Finally, example calculations, abridged stacking sequence listings and design data are presented.