Simon D. Fraser, PhD, is a researcher at the Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/II, 8010 Graz, Austria.

Simon D. Fraser

In the complex and multi-dimensional environment of modern manufacturing operations, it is a challenge to identify the best manufacturing approach for a specific product, taking into account financial, product, and process related issues, including globalization of manufacturing, regulatory requirements, company-specific strategies and preferences, and a complex process development environment. The authors describe a method based on a techno-economic optimization procedure that supports process development by providing a systematic approach to investigating and comparatively evaluating various manufacturing approaches. The methodology can be applied to both traditional and innovative manufacturing technologies and to both existing and new products.

	Process development in the pharmaceutical manufacturing industry requires the identification and implementation of the best possible manufacturing approach for a specific product. Even more challenging, this task is typically performed in a complex and multidimensional environment with often contradictory technical and economic challenges. Additionally, in pharmaceutical manufacturing, a stringent regulatory framework regarding product quality and patient safety must be considered. Accordingly, new pharmaceutical products are commonly developed and manufactured using standardized recipes and an existing inventory of traditional unit operations. Innovative manufacturing technologies emerging in the process equipment market are often ignored or not considered for a lack of role models, equipment providers, or experience and fear of violating regulatory requirements. Although not all areas of pharmaceutical manufacturing are equally affected, it is certainly the case in the secondary manufacturing of pharmaceutical solid dosage forms. The methodology presented in this article, therefore, was initially developed for this area.

	Interest in innovative manufacturing approaches has grown for a number of reasons. First, cost pressure has been increased by generic-drug companies, the government health system, and the consumers of pharmaceutical treatments. Lean manufacturing concepts have been developed, and supply-chain management has begun to implement concepts, such as just-in-time manufacturing, deployed in other industries. Even more, innovative and continuous manufacturing equipment is gradually penetrating the process equipment market. In process development, concepts and technologies associated with process analytical technology and quality by design are becoming standard. Advanced conceptual approaches, such as real-time release, are slowly becoming a part of operations and appear to deliver their full potential when combined with advanced manufacturing approaches, rather than with traditional batch-based processes.

	In summary, pharmaceutical manufacturing is currently in a situation in which traditional approaches are increasingly questioned and new concepts and technologies are gradually finding their way into manufacturing operations. As such, a holistic evaluation of future manufacturing technologies becomes an increasingly important step in process development.

	The methodology presented here simultaneously considers economic and technological aspects and provides a flexible and holistic platform for the evaluation of pharmaceutical manufacturing processes. The goals were to provide:

		A financial justification of a specific manufacturing approach

		An evaluation of the economic and technological feasibility  of a specific manufacturing approach

		A basis for comparing manufacturing approaches and identifying the best one.

	The manufacturing process evaluation methodology can be applied in three areas, as depicted in 

: Identifying the best of the existing manufacturing approaches. Pharmaceutical products are often produced at different company sites or by different manufacturers. Not all of them may be using the same unit operations or manufacturing approach. For example, a product is manufactured via fluid-bed granulation at one site and high shear or dry granulation at another one. The methodology presented in this paper allows systematic investigation of the different manufacturing approaches to determine the best one among them. This is particularly useful for reducing the number of sites and for centralizing manufacturing.

: Identifying the best manufacturing approach for a new product. Manufacturing technologies are typically chosen at an early stage in product development. Often, the decision is based on the type of equipment used in the early development or the inventory of process equipment available in operations, rather than on a systematic search for the best manufacturing approach. By applying the proposed methodology, a rational selection of future manufacturing technologies can be made.

: Evaluating the feasibility of changing from a traditional to an innovative manufacturing approach. For pharmaceutical products that are already on the market, a periodic assessment of manufacturing approaches may help to identify cost-cutting potential or to increase competitiveness vis-à-vis generic-drug manufacturers after the product’s patent protection expires. In addition, a simple assessment of an existing manufacturing process can eliminate the existing shortcomings or limitations in terms of yield, product quality, or cost of goods by switching to a different manufacturing process. The methodology presented in this paper can help to identify the differences between established and innovative manufacturing technologies.

	Tools traditionally applied for financial analysis can generally be applied for techno-economic manufacturing process evaluation as well. The most relevant ones are briefly discussed as follows

. A cost-benefit analysis is a common technique to assist decision-making that aims at expressing benefits and costs of a project or investment in monetary terms, preferably as the net present value. The most desirable solution within a given set of options can thus be identified. A cost-benefit analysis, however, is ineffective when the benefits cannot be directly expressed in monetary terms, which is often the case in process engineering applications with complex and multidimensional product- and process-related evaluation criteria. Therefore, in process development, a cost-benefit analysis is primarily applied during the final decision-making steps and not in the early or conceptual phase

. A cost-effectiveness analysis relates the cost of a given option to a specific objective or optimization criterion. For example, if an objective were to reduce the overall manufacturing time in days, a cost-effectiveness analysis could be the first step in comparing the various options, followed by a cost-benefit analysis to produce monetary values for the decision-making process.

. A cost-utility analysis relates costs to a multidimensional measure of effectiveness, referred to as “utility” in economic analysis, as a representation of preferences. The utility value is a value assigned to a project or investment based on the anticipated performance. A cost-utility analysis can be used to measure the financial and technological dimensions of various options and generate a combined economic and technical efficiency.

	Because, from the start, a manufacturing process evaluation contains a number of economic and technical performance or compliance parameters, a cost-utility analysis is the tool of choice for an early or conceptual process evaluation. As process development progresses and risks and technical criteria become specified in more detail, a cost-benefit analysis can be applied if necessary.

	The evaluation methodology for a manufacturing process presented here is derived from classical cost-utility analysis and consists of the six consecutive steps described in

: Definition of ranking criteria and risk-profile elements. The first step is to define which ranking criteria to include in the process evaluation. This selection should be made by a team of technical and financial experts and will comprise cost-related and product- as well as process-related ranking criteria.

		Cost-related ranking criteria can include the following:

		Depreciation (e.g., of building, infrastructure, or process and analytical equipment)

		Direct material costs for primary manufacturing (e.g., raw materials) and secondary manufacturing (e.g., API and excipients, primary and secondary packing materials)

		Utility costs (e.g., energy, water, and HVAC)

		Costs of cleaning, preventive maintenance, and repairs

		Production area and factory overhead costs.

		Product-related ranking criteria can include the following:

		Compatibility with the existing dosage form and composition (regulatory product profile of the existing product, if available)

		Dosage form size, shape, and presentation

		Process-related ranking criteria can include the following:

		Commercial availability of process equipment

	If necessary, additional categories can be included in the evaluation procedure. Manufacturing in different countries, including the availability of trained personnel, wage levels, and energy prices, may be considered, for example.

	Risks are economic, technical, or other (e.g., regulatory) aspects not known at the time of the evaluation but potentially affecting the performance of the selected manufacturing approach. Because risks cannot be quantified, and, thus, cannot be directly incorporated into the process evaluation, each process evaluation includes an associated risk profile to indicate potentially critical unknowns that must be further investigated if the respective process option is ranked favorably.

		Risk profile elements may include the following:

		Changes in the solid state of the API vs. the desired state

		Residuals from chemical manufacturing in the product

		Problems with stability that reduce shelf life

		Technical concerns of the evaluation team.

: Definition of quantitative and qualitative ranking criteria. Each ranking criterion can be included in a quantitative or qualitative ranking procedure. If the former is applied, a direct numerical value is assigned as a measure of performance or compliance. Typical quantitative criteria would be available in monetary terms or in technical units (e.g., a footprint of the unit operation in square meters or the maximum output in doses per hour).

	If a quantitative figure cannot be obtained at the time of the evaluation, a qualitative ranking procedure can be used. Instead of actual numerical values, scores are applied to quantify the estimated magnitude of costs or the degree of technical compliance.

	Costs can be ranked qualitatively, for instance, by assigning the following five score levels:

		A score of 2 if a significant (>30%) cost reduction is expected

		A score of 1 if a minor cost (>10 and ≤30%) reduction is expected

Articles

A techno-economic profiling method supports pharmaceutical process development by helping identify the best manufacturing approach.