Application of Neural Computing in Pharmaceutical Product Development: Computer Aided Formulation Design

Most pharmaceutical products are complex systems designed to meet several compendial or other performance standards simultaneously. Ideal or 'optimum' product composition and the manufacturing process variables are generally established after extensive experimentation. Artificial Neural Networks are pattern recognition tools that allow the development of 'expert' systems without having to write computer programs. With this technology it may be possible to develop formulation 'expert' systems to predict the formulation composition and the manufacturing process conditions necessary to achieve the desired performance standards. This report introduces the concept of a formulation expert system to predict the in vitro drug release profile from hydrophilic matrix tablets. Formulation expert systems or Computer Aided Formulation Design has the potential to reduce the time and cost of the product development process.     

Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools

Abstract

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a ‘One factor at a time (OFAT)’ approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.     

Fast-Cycle Product Development

ABSTRACT

In today's highly competitive industrial environment, those who are slow in bringing new products to market often lose out to those with a more agile development process. Developing products quickly while maintaining cost and quality demands a distinctive management approach that integrates marketing, engineering, manufacturing, and other activities. This article discusses the importance of development speed relative to the product's cost, performance, and development expense, and it suggests ways in which a company can cut development time. Topics covered include top management involvement; product objectives and complexity, team composition and leadership; communication vehicles, including the product specification; prototyping and testing; and control systems, such as design reviews.     

Standardised product development for technology integration of additive manufacturing

ABSTRACT

The implementation of additive manufacturing (AM) as an industrial production process poses extraordinary challenges to companies due to the far-reaching differences to conventional processes. In addition, there are hardly any standards and guidelines or methodical process models for the relatively new technologies that enable the reproducible and target-oriented use of AM. In order to solve this problem, five industrial companies together with the Paderborn University are researching as part of the ‘OptiAMix’ research project funded by the Federal Ministry of Education and Research (BMBF). This paper focuses on the development of an ideal process chain. Reference processes of the OptiAMix partners were analysed, norms and standards from conventional production were adapted and implemented and procedure models developed OptiAMix were integrated. The resulting AM Product Development Process was then applied and validated with the aid of a previously developed integration methodology using an example component from the automotive industry.     

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization

Objective: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.

Methods: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.

Results: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product’s disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5?seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600?g load).

Conclusions: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.     

“Monitoring Punch Forces and Punch Movements as an AID to Developing Robust Tablet Formulations”

Abstract

The benefits of commencing the pharmaceutical development program for a new drug entity as soon as practical are obvious. However, the ability to do so is controlled by many factors including limited availability of drug substance and very little information on pharmaceutically relevant properties. It is this data which the formulator must begin to collect as soon as any material becomes available. Establishing the physico-chemical characteristics (often referred to as ‘preformulation’) covers a wide range of attributes. This paper only considers those which can be investigated by use of instrumented compaction equipment

The first experiments should include establishing the intrinsic compactibility of the compound by preparation of simple compacts of drug substance under controlled conditions and with essentially no additives except die wall lubrication. Irrespective of whether compacts are formed or not, the raw data collected from the instrumentation may be used to give an initial reading of this important property of the material

On completion of these tests on drug substance, the development process then follows a pattern of making simple tablets and testing them for dissolution, strength, content uniformity, etc. Instrumentation can improve the efficiency of this process in several ways by providing information on predominant compaction mechanisms, a predictive capability of strength and maybe even dissolution. It will also create a data base of ‘normal’ results and a rapid, easy screen for variability

If the work is being carried out on a sophisticated test instrument or simulator, the formulations may be subjected to high speed tabletting cycles in order to obtain a measure of the strain rate sensitivity. Several reports have now shown the effect of strain rate on properties such as tensile strength of tablets and their disintegration time

As more drug substance becomes available a set of experiments designed to identify a commercializable formulation is carried out. This is also an appropriate point to transfer the processing to a rotary tablet press (if not already done), but the conditions must be controllable and precisely known. From these experiments a primary and at least one back-up formulation are identified, including processing conditions as well as composition

The first clinical material, using the preferred formula and manufacturing instructions, can now be made. During the ensuing development phases the emphasis on utilisation of the instrumentation changes, but many of the measurements already referred to, are still useful. Much of the data resulting from the overall program described, can provide an impressive addition to the “Formulation Development” section of any submission!     

Pharmaceutical Development of (Investigational) Anticancer Agents for Parenteral Use-A Review

Abstract

Due to the high mortality rate, the therapy of cancer has been and still is under vigorous investigation. Traditional approaches to new drug development have led to the discovery of several chemotherapeutic agents, which are now routinely used in the clinic. The objective of this review is to evaluate the current status of the pharmaceutical formulation of antineoplastic drugs from 1986 onwards. Among the aspects of the pharmaceutical development of antineoplastic drugs discussed are the following: formulation development process, solubilization techniques, the application of several colloidal systems, the use of prodrugs, and lyophilized (freeze-dried) formulations. Formulation procedures, the advantages and disadvantages of the different strategies, and the toxicity risk are described and illustrated with examples from the literature.     

Systems thinking and SEA

Abstract

Systems thinking seeks ‘how things work’ in an explicit way, considering not only the elements of systems (or processes) but most importantly the relationships between them. Its suggested contribution to SEA is that practitioners and researchers who are either (a) not entirely satisfied by reductionistic approaches based on behaviour or statistics (e.g. ‘black boxes’ or ‘composite points’), or (b) pro-active enough to seek understanding about the SEA process, SEA systems (e.g. per country), as well as the ‘object systems’ of SEA (physical and social structures) will be able to fulfil their curiosity or need for unequivocal and transparent documentation in what respects structure and function.     

Process and dosage form controlts: Formulation factors

Abstract

During the last decades, there have been considerable developments in the field of pharmaceutics, pharmaceutical technology and product manufacture.

The trend of the pharmaceutical industry is, like in most of the sophisticated industries, to produce, day after day, a better product, and as final goal, to manufacture continueously a perfect drug dosage form.

A few years ago, the defaults were counted in “percent”. After that, it was in per “thousand”. Now it is often expressed in “per million”, or even for very high series (for example empty hard gelatine capsules) the trend is “per billion”. Such an evaluation can only be achieved with a complete control of the whole manufacturing process.

The requirement for pharmaceutical dosage form are numerous (1): adequate biopharmaceutical profile, ease of manufacture, quality assurance (the dosage form must contain the correct quantity of the correct drug, and liberate it at the correct place, at the correct time, and in the correct quantity, with the correct speed), stability, …

These requirements can only be fulfilled with a perfect knowledge of the drug and the dosage form, from the beginning of the development of the dosage form (formulation) to the end of the manufacturing process (production and final product control).

It is the aim of the present lecture to show how important are the formulation factors and what is their influence on the processing and the dosage form control.     

Distributed intelligent control of exceptions in reconfigurable manufacturing systems

In order to react to the continuous and unpredictable changes in product demand, in product variety, and in process technologies, reconfigurable manufacturing systems allow quick adjustment of production capacity and functionality by rearranging or changing their modular components. In this kind of system, operation management issues, such as exception handling policies, become more complex since correct reconfiguration strategies have to be selected. This paper explores the potential of the reconfigurability feature to be a basis for the development of new strategies to handle out-of-the-ordinary events in the production process; in particular, maintaining production flow when machine breakdowns occur. Decisions regarding how to deal with exceptions to the production process are complex and depend on the manufacturing system configuration and on many performance and economic variables. The authors propose agent-based manufacturing control for exception handling because of its ability to be very agile, as well as being reactive and efficient. Manufacturing agents, while working to pursue their specific goals, achieve the global target of the system. Complex decisions can be made due to the synergy arising from the agents' internal reasoning and the negotiation process among these agents. The adopted negotiation mechanism is based on the contract-net protocol, while different strategies have been designed for the internal reasoning. The authors demonstrate that, under certain conditions, an agent's internal strategies based on fuzzy reasoning improve the global performance of the system. The proposed control model has been tested on a discrete event simulation test-bed.     

Using multi-axis material extrusion to improve mechanical properties through surface reinforcement

ABSTRACT

Due to the layer stacking inherent in traditional three-axis material extrusion (ME) additive manufacturing processes, a part's mechanical strength is limited in the print direction due to weaker interlayer bond strength. Often, this requires compromise in part design through either adding material in critical areas of the part, reducing end-use loads or forgoing ME as a manufacturing option. To address this limitation, the authors propose a multi-axis deposition technique that deposits material along a part's surface to improve mechanical performance. Specifically, the authors employ a custom 6 degree of freedom robotic arm ME system to create a surface reinforcing ‘skin’, similar to composite layup, in a single manufacturing process. In this paper, vertical tensile bars are fabricated through stacked XY layers, followed by depositing material directly onto the printed surface to evaluate the effect of the skinning approach on mechanical properties. Experimental results demonstrate that surface-reinforced interlayer bonds provide increased yield strength.     

Evaluation of Product and Process Design Robustness

Critical design decisions are commonly made throughout the product development process assuming known material and process behavior. However, stochastic variation during manufacture can inadvertently result in inferior or unacceptable product performance and reduced production yields. Stochastic simulations have been developed to estimate the end-use performance distribution prior to the commitment of hard tooling. This article proposes a definition for integrated product and process robustness, and extends existing stochastic methods to model the important role of the manufacturing flexibility in elimination of defects and product optimization. The goal is to enable the designer to understand and account for not only the negative effects of manufacturing variation, but also the positive impact of manufacturing flexibility wherein instantaneous corrections in the manufacturing process can frequently improve the product quality and eliminate flaws in the product design. Then, a methodology is introduced and contrasted with conventional development methods in the evaluation of best practices for development of a molded plastic component.     

Some comments on Malakooti et al. ‘Integrated group technology,cell formation,process planning,and production planning with application to the emergency room’

In this technical note, we suggest an alternative to the cellular layout for the emergency room problem discussed in Malakooti et al. (Malakooti, B., Malakooti, N.R. and Yang, Z., Integrated group technology, cell formation, process planning, and production planning with application to the emergency room. Int. J. Prod. Res., 2004, 42(9), 1769–1786). The alternative layout—hybrid flowshop layout—belongs to a class of hybrid cellular layouts that can be designed using the integrated suite of algorithms available in the production flow analysis and simplification toolkit (PFAST) software (Irani, S.A., Zhang, H., Zhou, J., Huang, H., Tennati, K.U. and Subramanian, S., Production flow analysis and simplification toolkit (PFAST). Int. J. Prod. Res., 2000, 38(8), 1855–1874). These layouts are intermediate between the traditional layout extremes—process layout and cellular layout—for a high-variety low-volume (HVLV) manufacturing facility. Our results indicate that the hybrid flowshop layout is superior to the cellular layout since it eliminates/reduces the duplication of procedures1 ¹?A ‘procedure’ and a ‘patient’ in the emergency room layout problem are analogous to ‘machines (or work centres)’ and ‘parts (or products)’, respectively, in a typical manufacturing facility layout problem. , backtrack flows between non-adjacent procedures and by-pass flows between procedures.     

Production and quality control of superalloy forging-quality billet

Abstract

During the past forty years, a range of forged nickel–base alloys with progressively increasing strength and alloying complexity has been developed. They are used in a variety of arduous applications which demand the highest standards of billet integrity. Some of the possible manufacturing techniques are reviewed in this paper, along with the control of various defect types. To ensure quality and consistency of product integrity, a system of review and verification of process control data is outlined, along with the usual inspection and product testing techniques.

MST/256     

Fatigue life predictions for notch geometries in particle reinforced metal matrix composites

Abstract

The potential use of particle reinforced metal matrix composites (MMCs) for demanding structural applications highlights the need for an effective method to predict the fatigue performance of notched components. The present paper evaluates the ‘critical strain’ technique and its suitability with respect to particle reinforced MMC alloys. Strain controlled fatigue data generated on the aluminium alloy 2124 reinforced by two different fractions of 2–3 μm SiC particles are used to predict the lives of a ‘pseudocomponent’ representative of engineering situations. It is demonstrated that both alloys are essentially cyclically stable compared with monotonic work hardening curves and, where available, data from tension and torsion modes superimpose on a Von Mises effective stress-strain criterion. The implications of the fatigue life analysis are discussed.     

The planning of a manufacturing system: a dynamic model

The paper studies a dynamical model of a manufacturing process taking into account:

the purchase of raw materials;

the scheduling of production;

the planning of sales.

We particularly deal with the planning of the production rate and of sales.

The basic hypotheses are:

the orders of each finished product are known over a given period of time

T;

the inventory levels are the state variables of the process;

the control variables are the purchase, productiqn and sale rates.

The goal of the ‘controller’ is to determine a policy which allows him to minimize at the time T the ‘capital’. As ‘capital’ we consider both the financial means and the technological resources employed in the process. Bilateral constraints in state and control variables have been introduced in our model.

The Maximum Principle has been used to formulate the problem and to obtain a solution.     

Dry powder nasal drug delivery: challenges,opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation

Purpose: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development.

Methods: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction).

Results: Teijin Rhinocort^® (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (D_v50?=_?98?±?1.3?µm). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2?±?4.78%), while 4.64?±?1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E.

Conclusions: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.     

CAE FOR THE MANUFACTURING ENGINEER: THE ROLE OF PROCESS SIMULATION IN CONCURRENT ENGINEERING

As America refocuses its attention on the factory, design and manufacturing engineers must work together closely to design the appropriate products, and matching production process in a team effort. By building off the designer's CAE tools that predict product performance, the manufacturing engineer is today able to simulate the proposed production process. Process simulations for the following manufacturing processes are available or being developed:

▪Forging, ▪Machining, ▪Injection Molding, ▪Die Casting, ▪Investment Casting, ▪Metal Forming, ▪Heat Treating, ▪Assembly Tolerancing

By utilizing the same 3-D solid model and finite element modeling tools used by the designer, coupled to powerful analysis simulation tools to predict the transient nonlinear heat transfer and plastic material flow found in many manufacturing processes, the manufacturing engineer is able to explore alternative processing plans, evaluate trade-offs and even influence the design to produce superior products.

Process simulation brings a science to support the manufacturing engineers experience for reduced lead time, lower cost, increase product quality and better understanding of the process. The next step will be to directly link the process simulation to an expert system.

This paper describes the current state of technology in the area of manufacturing process computer simulation for a number of manufacturing operations and suggests how these tools can be used “up-front” and lead to concurrent engineering.     

What hampers green product innovation: the effect of experience

ABSTRACT

Based on representative firm-level survey data for Austria, Germany, and Switzerland, this study systematically analyses the relevance and drivers of barriers to green product innovation using the example of green energy technologies. ‘Low willingness to pay’, ‘high development costs’, ‘high commercial uncertainty’, and ‘lack of favourable political framework’ are identified as the most important barriers. Moreover, we find that the firms’ innovation experience is an important driver of the level of green innovation barriers. Green innovation barriers are more accentuated for firms with green innovation activity than for firms with no green innovation activity. However, experience from different fields of green innovation and experience from non-green innovation activities help to limit these barriers.     

Strategies for Formulation and Evaluation of Emulsions and Suspensions: Some thermodynamic Considerations

Abstract

The difficulties in the development of reasonably stable emulsions and suspensions and the problems associated with the evaluation of such products are, for the most part, related to their non-equilibrium state. A conceptual understanding of the thermodynamics of these dispersions, particularly their surface and/or interfacial free energy, will facilitate successful formulation of such disperse systems. A strategy that fails to utilize surface behavior to stabilize thermodynamically unstable formulations is unlikely to be productive whereas a strategy based on an appreciation of the surface properties of the system is much more likely to succeed. Stability testing of liquid disperse systems is one of the most difficult problems faced by pharmaceutical and cosmetic chemists. The scientist is often asked to predict the shelf-life of a product or choose between experimental formulations based on estimates of how well they will hold up with time. While there are no standardized tests available to determine stability, a conceptual understanding of the thermodynamics of these systems, particularly their interfacial properties, can provide some insight into the expected types of instability, and equally important into the most sensible tests for predicting shelf-life.