Comparing Manufacturing Process Options

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.

Evaluation method applications

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 Figure 1 and discussed as follows.

Application 1: 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.

Application 2: 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.

Application 3: 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.

Techno-economic analysis tools

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

Cost-benefit analysis. 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

Cost-effectiveness analysis. 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.

Cost-utility analysis. 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.

Process evaluation method

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 Figure 2.

Step 1: 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)

• Direct labor costs

• Costs of cleaning, preventive maintenance, and repairs

• Material handling and storage costs

• 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

• Solid state of the API

• Stability and shelf life

• In-vitro profile and bioavailability.

• Process-related ranking criteria can include the following:

• Number of unit operations

• Overall manufacturing time

• Product yield or efficiency

• Commercial availability of process equipment

• Footprint

• Scalability

• Robustness.

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:

• Thermal degradation of the API

• 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

• Infringing patent rights of others

• Technical concerns of the evaluation team.

Step 2: 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

• A score of 0 if no change in costs (±10%) is expected

• A score of -1 if a minor increase in cost (>10 and ≤30%) is expected

• A score of -2 if a significant increase in cost (>30%) is expected.

Technical criteria can be ranked qualitatively, for instance, by applying the following three score levels:

• A score of 2 indicates good compliance with the ranking criterion

• A score of 1 indicates fair compliance with the ranking criterion

• A score of 0 indicates poor compliance with the ranking criterion.

In previous studies, the authors combined a quantitative approach with specific cost-related ranking criteria and a qualitative approach with technical ranking criteria. The information was merged by automatically converting the quantitative data into scores as described above. Risk elements were only considered using a binary value indicating the presence or absence of a specific risk.

Step 3: Definition of weighting factors. Because not every ranking criterion is equally important for the evaluation, a weighting factor is assigned to each one, with its relevance directly proportional to the relative magnitude of the weighting factor. If, for example, a total of 100 points is distributed between individual ranking criteria, a more important ranking criterion will receive a weighting factor of 25 or higher, whereas a less important or “nice to have” ranking criterion may only receive 5 points or less. Weighting factors are assigned to the ranking criteria and not to the risks elements.

Step 4: Evaluation of manufacturing process options. When a manufacturing process option is evaluated, the quantitative and/or qualitative information is entered into a spreadsheet and the risk profile is completed.

Step 5: Computation of the weighted ranking scores. The goal of step 5 is to consolidate the information into a small number of key performance indicators rather than use a large number of individual scores to compare different manufacturing process options. This consolidation can be achieved by multiplying each score by the respective weighting factor and summing up the weighed scores in the cost-, product- and process-related categories and a total process score comprising all three categories. The result is three consolidated category-specific scores and one total process score as key performance indicators for each manufacturing process option.

Step 6: Interpretation of the results. Comparing category-specific and total process scores concludes the comparative evaluation procedure and provides a straight-forward ranking of process options. Risk profiles indicate which additional information should be investigated (e.g., via laboratory-based analysis or experimental trials) before making the final decision regarding a specific manufacturing process option.

Application example

In general, the techno-economic profiling methodology can be applied with all sorts of drug products (e.g., solid as well as liquid products) and manufacturing operations (e.g., with single-unit operations and process chains as well as with primary and secondary manufacturing). Implementation of the methodology is always application-specific, and therefore, has to be made according to product- and process-related requirements on a case-by-case basis.

A simplified example application is presented and discussed in the following. The purpose of this example is to provide the reader with an idea of how such a methodology can be implemented, but without implying that such a simple approach would be sufficient to investigate an actual application in industrial manufacturing process evaluation. Real-world applications will be significantly more complex to consider all relevant product- and process-related dimensions involved in choosing the best possible manufacturing strategy for a specific drug product.

The simplified example application presented in the following discusses a hypothetical solid oral-dosage form. The product is assumed to have already been on the market for a number of years and is manufactured by an established manufacturing process consisting of a sequence of traditional batch-based unit operations including fluid-bed technology for granulation and filling the granular material into hard gelatin capsules. This process is referred to as a “fluid-bed granulation” or “reference” process. The goal is to evaluate if another manufacturing approach may provide a better combined economical and technical performance than this reference process.

For the purposes of this demonstration, the process evaluation included only two other process technologies: wet and hot-melt extrusion, both of which produce nearly spherical pellets for direct filling into capsules using a spheronizer and a dryer in case of wet extrusion, and a hot die-face cutting system in case of hot-melt extrusion, as depicted in Figure 3.

Structure and results of the evaluation procedure are summarized in Table I and discussed in the following:

Cost-related process evaluation. Two cost-related ranking criteria were considered: investment into process equipment and direct material costs. Both cost-related ranking criteria received weighting factors of 15, meaning that each one constituted 15% of the total process score. The existing fluid-bed granulation process received a score of zero because it represented the current cost structure. Considering the investigated equipment prices, wet and hot-melt extrusions were assumed to be more cost-efficient with regard to the equipment investment. Hot-melt extrusion was particularly favorable and received a score of 2, because drying occurs in the processing section of the extruder using a vacuum system, as opposed to wet extrusion, which received a score of 1 because it requires a downstream drying system. As for direct material costs, hot-melt extrusion was slightly less advantageous because the quantity of a certain excipient had to be increased and/or a new excipient added. The total cost-related score, which was derived by summing up the individual scores and multiplying the result by the respective weighting factors, was the same for both extrusion technologies.

Product-related process evaluation. Two product-related ranking criteria were considered: compatibility with the existing dosage form and composition, which indicates if a change in the formulation is required, and the size of the hard gelatin capsule. With regard to the first, the existing process received the highest score, as it was clearly suitable for the formulation. For the purpose of this study, wet extrusion was considered to require a minor change in the formulation. Hot-melt extrusion, which called for a significant change in the formulation (i.e., increasing the amount of current excipients and/or adding a new excipient), received the lowest ranking score. Because it was likely to significantly affect patient compliance, the second product-related criterion (the size of the hard gelatin capsule) was assigned a high weighting factor of 20. Wet and hot-melt technologies were each assigned a score of 1, meaning that a capsule size #3 had to be used instead of #4 due to changes in the formulation (i.e., the increase in the volume of material to be filled into each capsule).

Process-related process evaluation. The process-related ranking included two criteria. The first one was the number of unit operations, which is an important factor with regard to investment, intermediate product handling and storage, cleaning, maintenance and repair, machine operator, and control-room operations. As such, it was assigned a high weighting factor of 30. The current process had a score of zero, indicating no reduction in the number of unit operations. Melt extrusion, a highly integrated process that replaces many formerly independent unit operations, received the highest score of 2. Wet extrusion that requires downstream spheronisation and drying received a score of 1.

The second criterion was footprint reduction (i.e., reducing the GMP area). Because it is generally desirable but not crucial, it only received a low weighting factor of 5. Both process-related ranking criteria clearly show how the proposed methodology supports the multidimensional analysis.

The results of the comparative process evaluation are plotted in Figure 4. The current fluid-bed granulation process received the lowest total process score and was the least favorable of the cost- and process-related ranking criteria. Because the product was on the market, the current manufacturing approach evidently performed well with regard to the product-specific ranking criteria and received the highest product-related scores. In total, both extrusion approaches received higher total process scores than the existing process and were further considered as future manufacturing technologies.

Risk profile. Table II shows a simple risk profile established for the purpose of the example. The current fluid-bed granulation process is not associated with any risks, as it is currently used in production. However, for wet and hot-melt extrusion technologies, the risks associated with the API’s thermal degradation and post-processing solid-state profile were identified for further evaluation using laboratory-based analysis and experimental trials.

Results of the comparative process evaluation. Applying the techno-economic profiling methodology in this simplified example indicates that, given the ranking scheme applied, both extrusion processes are more favorable than the current fluid-bed granulation process. Aside from the fact that the strongly simplified selection of ranking criteria does not cover all aspects of relevance to the choice of process technologies, risks have been identified with both extrusion approaches. These risks might eventually prevent a successful implementation of an otherwise favorable manufacturing approach and thus must be further investigated.

In general, the results of a qualitative techno-economic profiling will not directly justify choosing a specific manufacturing approach. This kind of early-stage profiling will normally rather be applied to identify which options are particularly promising and thus interesting. The most promising options can then be further investigated with experimental trials or by conducting a market or patent analysis, for instance. Thus, the risks present with the early-stage profiling can be gradually transferred into reliable technical and financial data and directly included into the evaluation procedure.

In practice, techno-economic profiling will thus often start with a qualitative cost-utility analysis aiming at identifying promising manufacturing approaches and ultimately end up with a cost-benefit analysis in which the implications of using the different process options are expressed in monetary terms; at this level, the results are perfectly suited for deciding which process technologies to choose for a specific manufacturing application.

Discussion

With regard to the reliability and clarity of the results of the process evaluation procedure, the following aspects should be considered.

Process evaluation team. Because the results of a comparative manufacturing process evaluation depend on the experience and judgment of the individuals involved, it should be performed by a team that has enough technical, regulatory, and economic expertise to establish a holistic view of the investigated process options. Testing our methodology in an industrial setting confirmed that the best results were delivered when an individual from an external--and preferably independent--organization guided the company team through the evaluation process, taking all relevant dimensions of the problem into account and minimizing the effect of the company employees’ bias.

Reliability of results. A big difference in the total process score indicates that one process option is significantly better or worse than others. Tweaking ranking criteria, individual scores, and weighting factors will normally have no impact on the general outcome if a big difference in the total process score is present and will thus only affect the relative magnitude of the preference. Typically, a significant relative difference in the total process score is thus a solid basis for selecting a particular manufacturing technology. When the differences between manufacturing process options are minor, however, the results are less reliable. Defining the evaluation parameters and assigning the scores subjectively results in a certain variability and should always be considered when interpreting the results and using them for decision-making.

Dealing with risk factors. Risks identified in otherwise favorable process options should be investigated further. For example, depending on the results of a laboratory-based analysis or experimental trials, a risk may be re-evaluated to be rather a problem to be considered during the process evaluation or a limiting factor in the manufacturing of a specific product using the investigated process.

Preference of traditional processes. Comparing new (continuous) and traditional (batch-based) manufacturing technologies is likely to result in the former having significantly higher process-related and significantly lower product-related scores than the latter. This trend can be due to the advantages of modern continuous manufacturing equipment (e.g., smaller footprint, and increased flexibility in scale-up, batch size, and throughput) and to a lack of experience in using it for pharmaceutical processing. By carefully considering which criteria to evaluate and which to categorize as a risk, the tendency of assigning “bad” scores to potentially critical aspects can be reduced and the analysis can be objectified.  

Process evaluation as a dynamic process. A cost-utility analysis is not necessarily static and, in practice, can be performed in stages. The first stage may be a theoretical evaluation of a wide range of technologies. The second stage may include lessons learned from testing the most favorable technologies identified in stage one. The third stage may be a comparative evaluation of various configurations or unit operations of the same manufacturing approach. Once the technological solution is narrowed down, the cost-utility analysis may be transformed into a cost-benefit analysis to provide monetary terms for decision making.

Conclusion

The methodology presented in this paper offers a systematic approach to comparing pharmaceutical manufacturing process options. Its unique advantage is the flexibility of including and weighting economic-, product- and process-specific ranking criteria or, if desired, site-, country- or company-specific factors. Compiling all the information into a small number of category-specific and one total process scores is a straightforward and convenient way of interpreting the evaluation results. In addition, the methodology is versatile enough to be applied at different stages, from an early conceptual investigation to the actual choice of equipment. As such, a well-implemented comparative manufacturing process evaluation is a convenient way of systematically investigating relevant process technologies and identifying the best one for the manufacturing of a specific product.

About the Authors

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

Diana Dujmovic is a researcher at the Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/II, 8010 Graz, Austria.

Johannes G. Khinast, PhD, is a researcher at the Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/II, 8010 Graz, Austria, and a professor at the Institute for Process and Particle Engineering, Graz University of Technology.

Peer-review paper submitted: Oct. 25, 2013. Accepted: Dec. 12, 2013.

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.

Evaluation method applications
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 Figure 1 and discussed as follows.

Application 1: 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.

Application 2: 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.

Application 3: 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.

Techno-economic analysis tools
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

Cost-benefit analysis. 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

Cost-effectiveness analysis. 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.

Cost-utility analysis. 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.

Process evaluation method
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 Figure 2.

Step 1: 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)

• Direct labor costs

• Costs of cleaning, preventive maintenance, and repairs

• Material handling and storage costs

• 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

• Solid state of the API

• Stability and shelf life

• In-vitro profile and bioavailability.

• Process-related ranking criteria can include the following:

• Number of unit operations

• Overall manufacturing time

• Product yield or efficiency

• Commercial availability of process equipment

• Footprint

• Scalability

• Robustness.

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:

• Thermal degradation of the API

• 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

• Infringing patent rights of others

• Technical concerns of the evaluation team.

Step 2: 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

• A score of 0 if no change in costs (±10%) is expected

• A score of -1 if a minor increase in cost (>10 and ≤30%) is expected

• A score of -2 if a significant increase in cost (>30%) is expected.

Technical criteria can be ranked qualitatively, for instance, by applying the following three score levels:

• A score of 2 indicates good compliance with the ranking criterion

• A score of 1 indicates fair compliance with the ranking criterion

• A score of 0 indicates poor compliance with the ranking criterion.

In previous studies, the authors combined a quantitative approach with specific cost-related ranking criteria and a qualitative approach with technical ranking criteria. The information was merged by automatically converting the quantitative data into scores as described above. Risk elements were only considered using a binary value indicating the presence or absence of a specific risk.

Step 3: Definition of weighting factors. Because not every ranking criterion is equally important for the evaluation, a weighting factor is assigned to each one, with its relevance directly proportional to the relative magnitude of the weighting factor. If, for example, a total of 100 points is distributed between individual ranking criteria, a more important ranking criterion will receive a weighting factor of 25 or higher, whereas a less important or “nice to have” ranking criterion may only receive 5 points or less. Weighting factors are assigned to the ranking criteria and not to the risks elements.

Step 4: Evaluation of manufacturing process options. When a manufacturing process option is evaluated, the quantitative and/or qualitative information is entered into a spreadsheet and the risk profile is completed.

Step 5: Computation of the weighted ranking scores. The goal of step 5 is to consolidate the information into a small number of key performance indicators rather than use a large number of individual scores to compare different manufacturing process options. This consolidation can be achieved by multiplying each score by the respective weighting factor and summing up the weighed scores in the cost-, product- and process-related categories and a total process score comprising all three categories. The result is three consolidated category-specific scores and one total process score as key performance indicators for each manufacturing process option.

Step 6: Interpretation of the results. Comparing category-specific and total process scores concludes the comparative evaluation procedure and provides a straight-forward ranking of process options. Risk profiles indicate which additional information should be investigated (e.g., via laboratory-based analysis or experimental trials) before making the final decision regarding a specific manufacturing process option.

Application example
In general, the techno-economic profiling methodology can be applied with all sorts of drug products (e.g., solid as well as liquid products) and manufacturing operations (e.g., with single-unit operations and process chains as well as with primary and secondary manufacturing). Implementation of the methodology is always application-specific, and therefore, has to be made according to product- and process-related requirements on a case-by-case basis.

A simplified example application is presented and discussed in the following. The purpose of this example is to provide the reader with an idea of how such a methodology can be implemented, but without implying that such a simple approach would be sufficient to investigate an actual application in industrial manufacturing process evaluation. Real-world applications will be significantly more complex to consider all relevant product- and process-related dimensions involved in choosing the best possible manufacturing strategy for a specific drug product.

The simplified example application presented in the following discusses a hypothetical solid oral-dosage form. The product is assumed to have already been on the market for a number of years and is manufactured by an established manufacturing process consisting of a sequence of traditional batch-based unit operations including fluid-bed technology for granulation and filling the granular material into hard gelatin capsules. This process is referred to as a “fluid-bed granulation” or “reference” process. The goal is to evaluate if another manufacturing approach may provide a better combined economical and technical performance than this reference process.

For the purposes of this demonstration, the process evaluation included only two other process technologies: wet and hot-melt extrusion, both of which produce nearly spherical pellets for direct filling into capsules using a spheronizer and a dryer in case of wet extrusion, and a hot die-face cutting system in case of hot-melt extrusion, as depicted in Figure 3.

Structure and results of the evaluation procedure are summarized in Table I and discussed in the following.

Cost-related process evaluation. Two cost-related ranking criteria were considered: investment into process equipment and direct material costs. Both cost-related ranking criteria received weighting factors of 15, meaning that each one constituted 15% of the total process score. The existing fluid-bed granulation process received a score of zero because it represented the current cost structure. Considering the investigated equipment prices, wet and hot-melt extrusions were assumed to be more cost-efficient with regard to the equipment investment. Hot-melt extrusion was particularly favorable and received a score of 2, because drying occurs in the processing section of the extruder using a vacuum system, as opposed to wet extrusion, which received a score of 1 because it requires a downstream drying system. As for direct material costs, hot-melt extrusion was slightly less advantageous because the quantity of a certain excipient had to be increased and/or a new excipient added. The total cost-related score, which was derived by summing up the individual scores and multiplying the result by the respective weighting factors, was the same for both extrusion technologies.

Product-related process evaluation. Two product-related ranking criteria were considered: compatibility with the existing dosage form and composition, which indicates if a change in the formulation is required, and the size of the hard gelatin capsule. With regard to the first, the existing process received the highest score, as it was clearly suitable for the formulation. For the purpose of this study, wet extrusion was considered to require a minor change in the formulation. Hot-melt extrusion, which called for a significant change in the formulation (i.e., increasing the amount of current excipients and/or adding a new excipient), received the lowest ranking score. Because it was likely to significantly affect patient compliance, the second product-related criterion (the size of the hard gelatin capsule) was assigned a high weighting factor of 20. Wet and hot-melt technologies were each assigned a score of 1, meaning that a capsule size #3 had to be used instead of #4 due to changes in the formulation (i.e., the increase in the volume of material to be filled into each capsule).

Process-related process evaluation. The process-related ranking included two criteria. The first one was the number of unit operations, which is an important factor with regard to investment, intermediate product handling and storage, cleaning, maintenance and repair, machine operator, and control-room operations. As such, it was assigned a high weighting factor of 30. The current process had a score of zero, indicating no reduction in the number of unit operations. Melt extrusion, a highly integrated process that replaces many formerly independent unit operations, received the highest score of 2. Wet extrusion that requires downstream spheronisation and drying received a score of 1.

The second criterion was footprint reduction (i.e., reducing the GMP area). Because it is generally desirable but not crucial, it only received a low weighting factor of 5. Both process-related ranking criteria clearly show how the proposed methodology supports the multidimensional analysis.

The results of the comparative process evaluation are plotted in Figure 4. The current fluid-bed granulation process received the lowest total process score and was the least favorable of the cost- and process-related ranking criteria. Because the product was on the market, the current manufacturing approach evidently performed well with regard to the product-specific ranking criteria and received the highest product-related scores. In total, both extrusion approaches received higher total process scores than the existing process and were further considered as future manufacturing technologies.

Risk profile. Table II shows a simple risk profile established for the purpose of the example. The current fluid-bed granulation process is not associated with any risks, as it is currently used in production. However, for wet and hot-melt extrusion technologies, the risks associated with the API’s thermal degradation and post-processing solid-state profile were identified for further evaluation using laboratory-based analysis and experimental trials.

Results of the comparative process evaluation. Applying the techno-economic profiling methodology in this simplified example indicates that, given the ranking scheme applied, both extrusion processes are more favorable than the current fluid-bed granulation process. Aside from the fact that the strongly simplified selection of ranking criteria does not cover all aspects of relevance to the choice of process technologies, risks have been identified with both extrusion approaches. These risks might eventually prevent a successful implementation of an otherwise favorable manufacturing approach and thus must be further investigated.

In general, the results of a qualitative techno-economic profiling will not directly justify choosing a specific manufacturing approach. This kind of early-stage profiling will normally rather be applied to identify which options are particularly promising and thus interesting. The most promising options can then be further investigated with experimental trials or by conducting a market or patent analysis, for instance. Thus, the risks present with the early-stage profiling can be gradually transferred into reliable technical and financial data and directly included into the evaluation procedure.

In practice, techno-economic profiling will thus often start with a qualitative cost-utility analysis aiming at identifying promising manufacturing approaches and ultimately end up with a cost-benefit analysis in which the implications of using the different process options are expressed in monetary terms; at this level, the results are perfectly suited for deciding which process technologies to choose for a specific manufacturing application.

Discussion
With regard to the reliability and clarity of the results of the process evaluation procedure, the following aspects should be considered.

Process evaluation team. Because the results of a comparative manufacturing process evaluation depend on the experience and judgment of the individuals involved, it should be performed by a team that has enough technical, regulatory, and economic expertise to establish a holistic view of the investigated process options. Testing our methodology in an industrial setting confirmed that the best results were delivered when an individual from an external--and preferably independent--organization guided the company team through the evaluation process, taking all relevant dimensions of the problem into account and minimizing the effect of the company employees’ bias.

Reliability of results. A big difference in the total process score indicates that one process option is significantly better or worse than others. Tweaking ranking criteria, individual scores, and weighting factors will normally have no impact on the general outcome if a big difference in the total process score is present and will thus only affect the relative magnitude of the preference. Typically, a significant relative difference in the total process score is thus a solid basis for selecting a particular manufacturing technology. When the differences between manufacturing process options are minor, however, the results are less reliable. Defining the evaluation parameters and assigning the scores subjectively results in a certain variability and should always be considered when interpreting the results and using them for decision-making.

Dealing with risk factors. Risks identified in otherwise favorable process options should be investigated further. For example, depending on the results of a laboratory-based analysis or experimental trials, a risk may be re-evaluated to be rather a problem to be considered during the process evaluation or a limiting factor in the manufacturing of a specific product using the investigated process.

Preference of traditional processes. Comparing new (continuous) and traditional (batch-based) manufacturing technologies is likely to result in the former having significantly higher process-related and significantly lower product-related scores than the latter. This trend can be due to the advantages of modern continuous manufacturing equipment (e.g., smaller footprint, and increased flexibility in scale-up, batch size, and throughput) and to a lack of experience in using it for pharmaceutical processing. By carefully considering which criteria to evaluate and which to categorize as a risk, the tendency of assigning “bad” scores to potentially critical aspects can be reduced and the analysis can be objectified.  

Process evaluation as a dynamic process. A cost-utility analysis is not necessarily static and, in practice, can be performed in stages. The first stage may be a theoretical evaluation of a wide range of technologies. The second stage may include lessons learned from testing the most favorable technologies identified in stage one. The third stage may be a comparative evaluation of various configurations or unit operations of the same manufacturing approach. Once the technological solution is narrowed down, the cost-utility analysis may be transformed into a cost-benefit analysis to provide monetary terms for decision making.

Conclusion
The methodology presented in this paper offers a systematic approach to comparing pharmaceutical manufacturing process options. Its unique advantage is the flexibility of including and weighting economic-, product- and process-specific ranking criteria or, if desired, site-, country- or company-specific factors. Compiling all the information into a small number of category-specific and one total process scores is a straightforward and convenient way of interpreting the evaluation results. In addition, the methodology is versatile enough to be applied at different stages, from an early conceptual investigation to the actual choice of equipment. As such, a well-implemented comparative manufacturing process evaluation is a convenient way of systematically investigating relevant process technologies and identifying the best one for the manufacturing of a specific product.

About the Authors
Simon D. Fraser, PhD, is a researcher at the Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/II, 8010 Graz, Austria.
Diana Dujmovic is a researcher at the Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/II, 8010 Graz, Austria.
Johannes G. Khinast, PhD, is a researcher at the Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/II, 8010 Graz, Austria, and a professor at the Institute for Process and Particle Engineering, Graz University of Technology.

Peer-review paper submitted: Oct. 25, 2013. Accepted: Dec. 12, 2013.