The Evolving State of Continuous Processing in Pharmaceutical API

Article pubs.acs.org/OPRD

Cite This: Org. Process Res. Dev. 2018, 22, 1143−1166

The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations J. Christopher McWilliams,*,† Ayman D. Allian,‡ Suzanne M. Opalka,§ Scott A. May,∥ Michel Journet,⊥ and Timothy M. Braden∥

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Chemical Research and Development, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States ‡ Department of Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States § Chemical Process Development, Biogen Idec, 115 Broadway, Cambridge, Massachusetts 02142, United States ∥ Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States ⊥ API Chemistry, GSK, 709 Swedeland Road, UW2810, P.O. Box 1539, King of Prussia, Pennsylvania 19406, United States S Supporting Information *

ABSTRACT: This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes staffing (personnel), chemistry, reaction platforms, postreaction processing, analytical, regulatory, and factors that influence the adoption of continuous manufacturing. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufacturing executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chemistry, while postprocessing and analytical remain in the very early stages of development and implementation. KEYWORDS: continuous process, flow process, pharmaceutical, active pharmaceutical ingredient, contract manufacturing organization, contract research organization, flow chemistry, unit operations, outsourcing, survey

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must take into account not only internal capabilities but also the capabilities and experience available through the third party network. The objective of this survey was to capture a snapshot of the current range of capabilities and experience across representative CMOs and compare that to a representative distribution of Pharma companies: the members of the IQ Consortium.5 In addition, the survey was intended to provide some understanding of the underlying drivers and barriers to implementing CP versus BP from a Pharma and third party network perspective. This survey is anticipated to aid strategic decisions around the feasibility of advancing CP through the external network and internal investments in capital and training. It is not surprising that batch and semibatch processes have long been the preferred mode of manufacturing APIs for pharmaceutical companies, as the versatility of BP equipment toward a variety of reaction types and conditions is an advantage compared to CP platforms, which are designed for optimal performance for a subset of reaction conditions. Additionally, some postreaction processing operations that would occur in a batch reactor, such as extractions, distillations, or crystallizations, require additional equipment

he vast majority of commercial pharmaceutical drugs and New Chemical Entities (NCE) currently in clinical trials continue to be manufactured using Batch Processing (BP) or semi-BP technology.1 However, Continuous Processing (CP) has drawn increasing attention in the Active Pharmaceutical Ingredient (API) manufacturing sector, both from within the pharmaceutical companies (Pharma) as well as the Contract Manufacturing Organizations (CMOs) that support API manufacturing (the third party network).2 Over the last 10−15 years, there has also been a shift in Pharma manufacturing toward broader use of the third party network in the manufacturing of NCEs for clinical trials and commercial APIs. This is largely driven by an increase in cost pressures within the Pharma industry,3 improvements in global manufacturing capabilities, and the emergence of low cost manufacturing in India and China.4 Previously, large pharmaceutical companies typically used internal resources to develop and execute essentially all steps in early phase programs and all Good Manufacturing Practice (GMP) steps in commercial manufacturing. In the current state, most companies have externalized some portion of clinical supply production including, in some cases, the GMP steps. At one end of the spectrum, some companies maintain no internal GMP material production capabilities and rely exclusively on the external network. Thus, a strategic change from BP to CP © 2018 American Chemical Society

Received: May 15, 2018 Published: August 8, 2018 1143

DOI: 10.1021/acs.oprd.8b00160 Org. Process Res. Dev. 2018, 22, 1143−1166

Organic Process Research & Development

Article

budgets are focused on short-term returns or require a returnon-investment (ROI) from a single commercial asset, rather than spread across the portfolio. A CP strategy could take many forms with respect to the types of chemistry, the spectrum of development from preclinical supplies to manufacturing, program specific API quantities ranging from low (e.g., highly potent or acute treatment programs) to high volume (e.g., high dose and chronic treatments), hybrid batch-continuous processes vs multistep and multioperation processes, first generation vs second generation processes, and pre-GMP steps (or preRegulatory Starting Materials for commercial products) vs GMP steps. All of these strategies have varying levels of costs, risks, and benefits. Integrating the third party network into any CP strategies provides an option for Pharma that has the advantage of transferring some or all of the costs associated with CP to the vendor, who may be in a better position to distribute costs across a broader customer base, thereby increasing the rate of, and overall, ROI for those investments. It may also serve to side-step some of the internal cultural or procedural hurdles imbedded within the organization, potentially using successes through the third party network to provide the business justification for internal change. A thorough understanding of the capabilities within the third party network is a prerequisite to consider this approach. From a CMO perspective, the advantages and disadvantages to incorporate CP are similar to that of Pharma, with the ultimate drivers being that of consistent and predictable product quality, while increasing market share and profits by offering unique technology options and cost reductions. The advantages noted previously translate to longer term lower costs to the CMO. In comparison to Pharma, who need to justify an investment based solely on the internal portfolio or even a single product, the broader customer base CMOs enjoy additional demand and cost drivers for CP. This customer base can include other areas of industry, such as the personal care and commodity chemical sectors, where the impact could be more significant due to the generally larger quantities of product.

to run continuously. Batch processing is therefore a convenient approach to cover a portfolio that consists of a diversity of products with limited lifetimes due to attrition in the clinical phases and loss of exclusivity in the commercial market. Additionally, large scale BP equipment is often a direct extension of the small scale lab reactors that are the basis for early scientific training and have been a standard in the laboratory for many years. While multiuse BP equipment has been widely used in commercial manufacturing for decades, this equipment is restricted in terms of operating conditions such as temperature and pressure. Additionally, factors such as heat removal and mixing are often the source of extensive development efforts and can be challenging to transfer to commercial scale reactors. As a result, process chemistry groups must also take into account the BP capabilities which can restrict and limit synthetic approaches. In some cases routes must be redeveloped for that reason alone, an expensive and time-consuming process. Despite practical and historic considerations for BP, CP offers numerous potential benefits. In terms of reaction chemistry, there have been a large number of publications from both academia and industry demonstrating the application and advantages of CP,6 such as improved control of reaction profiles,7 applications of unstable intermediates,8 accessing reactions at temperatures and pressures that exceed those achievable in typical batch reactors,9 safer execution on scale through minimizing the lifetime and quantities of high energy,10 or toxic11 compounds and efficient heat removal from highly exothermic reaction processes,12 application of reaction conditions that would be challenging to engineer efficiently in BP, such as photochemistry11b,13 and electrochemistry.14,15 Along with reactions and reactors, downstream unit operations offer advantages in efficient processing. In general, across both the reaction and the downstream unit operations, CP offers a relatively small equipment footprint, potential for higher equipment utilization, and easier technology transfer. Indeed, there have been recent advances in CP synthesis that link multiple reactions and unit operations, including impressive examples of end-to-end synthesis of API wherein API could be produced “on demand” with space- and cost-efficient platforms.7a,16 Transforming these processes from lab demonstrations to scaled supply chain realities is yet another step change that Pharma and CMOs are engaging in to various degrees. There are practical challenges with implementing CP that slow the uptake of this technology. Continuous processing requires substantial capital investments in new equipment, as both the lab and manufacturing infrastructure in pharmaceutical organizations are designed predominantly for batch chemistry. Additional training of staff is likely to be needed to support design, development, and implementation of CP on scale. Adapting internal procedures to CP and alignment with the Quality organizations could create hurdles to implementation. Perhaps the biggest challenge may be the lack of experience with regulatory interactions. This translates to increased risk for the project teams and scientists, as well as the organization as a whole, especially toward new commercial filings.17,18 This also speaks to another fundamental challenge, the need to change the culture of an organization that is content with BP, despite the potential benefits CP may offer. All of these challenges have an associated cost, and formulating a strong business case to justify those costs is yet another potential impediment for CP implementation, especially if

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METHODOLOGY The survey itself consisted of seven sections, covering the following topics: personnel, equipment, chemistry, postprocessing, analytical, regulatory, and factors impacting adoption of CP. There were 67 questions in total, with several questions containing multiple parts.19 The survey was sent to a representative distribution of 40 CMOs engaged in CP to varying degrees, as well as members of the IQ consortium. A total of 25 CMOs and 10 IQ members responded to the survey. Of the 25 CMO respondents, some did not answer all of the questions.20 We used all the available data that was provided for the analysis that follows and noted the number of respondents for each query.

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PERSONNEL The first section of the survey gathered information on the staff allocated to CP, their educational background, and experience with CP. Within the IQ group’s 10 respondents, 70% indicated they have a team of people dedicating greater than half of their time to pharmaceutical CM.21 The responses revealed that 52% of the CMO group’s 33 respondents have a team of people (chemists and engineers) that dedicate greater than half 1144



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Figure 1. Size of the teams that dedicate greater than 50% of their time to pharmaceutical CM.

Figure 2. Educational background for the members of dedicated IQ and CMO Teams.

Figure 3. Roles and educational background of IQ CM teams.

of their time to pharmaceutical API CM, while 48% of responding companies had no such group. CMOs and IQ Members differed in the size of those teams dedicating >50% of their time on CM (Figure 1). While the majority of CMO teams tended to be either 6−10 (35%) or >10 people (59%), the majority of the IQ Member company teams were smaller, consisting of 1−5 (62%) or 6−10 people

(25%). This likely reflects that CMOs may be focusing a single team on several products, which is not only more efficient but serves to upskill those team members. Some of the IQ teams may be driven by individual products and consist of teams that are built ad hoc as a target product develops. The latter approach would necessitate that some personnel have flexible skills sets, allowing them to work on batch or flow projects as 1145



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Figure 4. Roles and educational background of CMO Member CM teams.

needed. Notably, even among those CMOs who did not have a dedicated group, all but one stated they had at least some chemists or engineers with experience in CM.22 To understand the educational background of the team members for those IQ and CMO respondents who indicated they had dedicated teams, we asked those respondents to provide the typical composition of their teams with regard to most advanced degree (Figure 2). Both the IQ and CMO teams had similar distributions of educational backgrounds, which are heavily skewed toward Doctorate and Master Degrees. The IQ teams had slightly more Ph.D. and less B.S. educated staff compared to the CMO teams. A detailed breakdown of team composition by roles and educational backgrounds is shown in Figure 3 and Figure 4. Process chemists with Ph.D. degrees were the most likely member to be present on either the IQ or CMO continuous processing team. While B.S. and M.S. chemists were less likely to be on an IQ team, they were substantial components making up the CMO teams. The IQ and CMO teams tended to have chemical engineers and analytical chemists with either an M.S. or Ph.D. degree, although the relative distribution of the two was the opposite for the IQ and CMO teams. The IQ teams trended toward more Ph.D. trained chemical engineers and analytical chemists, while the CMOs trended toward M.S. trained members. Automation engineers were almost nonexistent on IQ teams, while they were represented with more frequency on CMO teams, albeit at 1 kg scale were run GMP. From this survey output, it is clear that the chemistry experience of CMOs on >1 kg scale exceeds that of the Pharma industry in general and that most of the 20 reaction types specifically queried in the survey can be externalized to >1 kg scale under GMP conditions. Generally speaking, Pharma tends to be risk adverse, and chemical transformations that are considered a higher safety risk, even if conducted in flow reactors, tend to be avoided. The potential to access these chemical transformations through a CMO with the experience and technology to execute safely on scale could open up new options for Pharma. Experience and capability will not suffice in and of itself, as Pharma companies have EHS requirements for the CMOs they do business with that ensure an overall culture of safety at the CMO sites. Also of note, electrochemistry, although a reaction of recent heightened interest in Pharma and the external network, does not appear ready for scale up in a continuous mode.

Figure 5. Format of survey responses to questions on specific chemistry.

compounds not yet selected for development, small scale batches supporting early pre-GLP studies, or even technology development experience. Overall, this represents chemistry that Pharma is considering as possible enabling opportunities wherein CP may provide value. It is interesting to note that two of the reaction types with the broadest small scale experience within the CMO group, oxidations and reactions with ammonia, have comparatively few IQ members indicating experience on this scale. In contrast, organolithium, organomagnesium, and photochemical reactions had the highest response rate within the IQ Members, albeit not by a great sum. Hydrogenations were prominent in both groups at this scale. The chemistry experience at >1 kg for the IQ and CMO groups is shown in Figure 7 and Figure 8, respectively. For the CMO group, the most common transformations scaled to >1 kg are consistent with the responses for 1 kg scale for all of the reaction types with the exception of electrochemistry. In contrast, the range of experience within the IQ Members is relatively limited (Figure 7). It is important to note that a single company that has experience at both 1−100 kg and >100 kg scale could be counted in both scale categories. Likewise, the same company that indicated experience scaling a reaction type to >100 kg may not have any experience scaling to 1−100 kg (e.g., in the event of a transfer of technology from a customer or another CMO, or the implementation of a second generation route). Thus, while there are clearly six companies with experience scaling oxidations to >100 kg, it is not possible to discern if

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REACTION EQUIPMENT As noted previously, reactions that are best suited for CP are often found at the beginning of a synthesis and are good candidates for outsourcing to the third party network. Understanding the equipment capabilities and experience within the CMO network is critical if one is to plan for this

Figure 6. CMO and IQ Member chemistry CP experience at 50% of the IQ companies indicated they have these same platforms that can support 1−20 kg scale. However, with the exception of heated PFR at 20 kg

IQ

CMO

IQ

CMO

IQ

CMO

500−2,000 3 of 10 200−400 8 of 10

14.5 (1 atm) − 3,000 8 of 19 25−300 12 of 19

200−1,000 3 of 8 150−300 3 of 8

72 (5 bar) − 3,000 7 of 16 150−300 8 of 16

87 (6 bar) − 1,000 1 of 5 150−300 1 of 5

72 (5 bar) − 3,000 6 of 14 150−300 8 of 14

a

P(max) = maximum pressure; T(max) = maximum temperature.

Table 3. Cryogenic Liquid PFR Capabilities of IQ and CMO Equipment Cryogenic Plug Flow Reactor (liquid only)a < 1 kg Range of T(min) limits (°C) Respondents with T(min) ≤ −50 °C

1−20 kg

> 20 kg

IQ

CMO

IQ

CMO

IQ

CMO

−100 − (−30) 9 of 10

−100 − (−40) 12 of 14

−100 − (−30) 6 of 9

−100 − (−20) 10 of 13

−80 − (−20) 3 of 4

−100 − (−15) 9 of 11

a

T(min) = minimum temperature.

100−150 °C for the 2 IQ respondents indicating they have this platform (Table 5). The CMO group has PBRs at all scales with high pressure limits and a wide range of both high and low temperature capabilities. Similar to the gas−liquid PFR responses, the gases used in PBRs by the CMO group cover all those used by the IQ group in addition to other gases. Notably, despite a large number of respondents in both groups indicating capability at 1−20 kg scale, the experience in both groups is very limited (Figure 9 and Figure 10). It appears the 1−2 CMO respondents with extensive experience at >1 kg scale are applying this technology to several reactions based upon the diversity of gases shown in Table 5. A single company in the IQ group indicated extensive experience at >20 kg scale, that experience being entirely with hydrogenation. Thus, it appears that PBR platforms are available, yet underutilized by most of the respondents in both groups. This may be due, in part, to the added complexity of developing these reactions and platforms compared to others, where catalyst deactivation, adsorption variables, complex fluid and vapor dynamics, and continuously changing state of the catalyst bed are all parameters that can vary from reaction to reaction. In addition, the availability of batch capacity for these transformations may also inhibit investment in PBRs. Low pressure CSTRs are platforms in which the IQ group has the most members (4) with extensive experience at the 1− 20 kg scale (Figure 9). Similarly, there are 5 CMO respondents who indicate extensive experience at the 1−20 kg and >20 kg scales (Figure 10). The relatively high utilization of these platforms is partly driven by the challenge to design processes for pharmaceutically relevant molecules that are completely homogeneous, or nearly so, such that a simpler PFR platform could be used. A broad temperature range is available to many in the CMO group, although only a single IQ respondent indicated the ability to achieve temperatures ≤ −50 °C (Table 6). The lowest temperatures are probably needed only for very fast reactions and/or those with unstable intermediates. In both cases, the use of a PFR is likely preferred to a CSTR whenever possible due to the former’s generally superior heat transfer capabilities and ease of configuring for very fast reactions with higher precision (i.e., tighter range of residence time distribution).

are well suited for are nitrations and other highly exothermic reactions due to superior thermal transfer compared to batch reactors.10k,27 The value of this type of platform is evident from the capabilities and experience within both the IQ and CMO groups. The majority of respondents in both groups indicate the ability to reach temperatures of ≤ −50 °C at all scales, including 9 of the 11 CMOs having these platforms at >20 kg scale (Table 3). In cases where a reaction contains too much solid to flow in a PFR, low pressure CSTRs are a potential option, albeit with some compromise in thermal transfer efficiency (vide infra). Transformations in gas−liquid PFRs include ozonolysis, reactions with ammonia gas, and a variety of reactions with hydrogen, oxygen, carbon monoxide, syngas, ethylene, and other gaseous reagents using homogeneous catalysis. On 20 kg scale. A broad range of gaseous reagents have been used at 1 kg scale, with only one IQ respondent indicating extensive experience at >1 kg scale (Figure 9). A comparatively larger number of CMO respondents have this platform with a wide range of temperature and pressure limits at all scales. In addition, the experience (Figure 10) and diversity of gases employed within the CMO group at all scales is more extensive. Packed Bed Reactors (PBRs) offer several potential advantages over homogeneous catalysis systems, including creating a reaction environment of effectively high catalyst concentrations, the potential for recycling and overall reduction in amount of catalyst required, and the elimination of catalyst impurities in the reaction mixture that may require additional purification steps later in the synthesis.29 Given the abundance of hydrogenations and hydrogenolysis in API syntheses, one would expect this to be a commonly utilized platform. Indeed, both the IQ and CMO groups have capabilities for high pressure and temperatures with the exception of >20 kg scale for the IQ group, wherein pressures are limited to ∼150 psi and the upper temperature limits are 1151


7 of 10

−78−25

1 of 1

ambient (no lower T limit indicated) 0 of 1

H2, syn gas

−78−25

H2, O2, O3, CO, Cl2, SF4, NH3, phosgene

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POSTREACTION, PURIFICATION PLATFORMS In order to get an understanding of continuous platforms deployed in downstream operations, the survey asked participants about five common postreaction, purification platforms, namely: separation and extraction, continuous distillation, packed column scavenging, continuous crystallization, and Simulated Moving Bed (SMB) chromatography. Using the same query format as for reaction platforms, each participant was asked to indicate if any of the following conditions were true for each of the 5 platforms at 3 different scales (20 kg): (1) do not have the capability (2) have the capability (3) have used the technology extensively (extensively was defined as having used the tool in at least two applications in the last three years) (4) have GMP qualified capability In general, few of the 10 IQ respondents indicated capability across all 5 platforms, with only 1−2 of those having extensive experience at any scale larger than 1 kg (Table 8). Within the CMO group, all platforms are available at all scales from at least 3 respondents. The least available technologies are SMB at >1 kg scale, and continuous crystallization at >20 kg scale. At small scale (1 kg (vide supra). Consistent with this observation is the dearth of experience within the IQ group. Heterogeneous reactions that require high pressure containment and are not amenable to PFR reactors represent relatively complex reaction types for CP and are a reaction type for which most pharmaceutical companies probably use high-pressure autoclaves and similar batch reactors. Due to the specialized equipment required, and the absence of commercially available, off-the-shelf hardware from continuous manufacturing suppliers, it is a platform that is not readily amenable to develop on small scale in a standard lab, which can also contribute to slow uptake. Even on small scale (20 kg). Given the limited experience in continuous postreaction processing unit operations (vide supra), it is not surprising to see that the maximum number of operations in series is relatively low. Responses from the CMO group show that the uptake of integrating a large number of unit operations in a continuous processing train is also low, with only 14 total respondents within the larger group, and of those, only three with experience connecting more than two operations at scales ≥1 kg. The open text comments indicated most of the shorter sequences consisted of linked reactions, quenches, and some with phase separations (extractions). With that said, those three standouts have achieved from 6 to 20 consecutive operations and clearly perceive value in this approach.

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connection is convenient but carries the risk that a disturbance in the upper stream can significantly affect the downstream operations. Surge tanks provide a means of derisking upset scenarios by providing an intermediate zone that can decouple material at an intermediate point in the process from downstream processes and the material that has previously passed through that unit step in the process. The deployment of surge tanks requires complex analysis, their size introducing an additional residence time for material, and thus stability and impact of their deployment on residence time distribution, quality, and throughput can require additional development resources that can impede uptake. To understand the extent of surge tank utilization, the IQ and CMO groups were asked “What is your strategy on the use of surge tanks at stable hold points?” and “What is the desired surge tank capacity (24 h, 12 h, Less, None)?” The respondents were provided an openended text format for their response. Of the 9 IQ respondents, 3 indicated they used surge tanks, with a range in process time for surge tank capacity depending upon the process (1, 12, or 24 h). The remaining 5 indicated they either did not use them or collected the entire run in a single tank. Some respondents indicated the scale or phase of development (Discovery) had not justified the use of surge tanks. For one IQ respondent, they indicated regular use of surge tanks and have deployed two parallel 12/24 h surge tanks. Not surprisingly, this member

SURGE TANKS

Both IQ and CMO groups have invested in connecting processes to varying extent. When it comes to connecting multiple unit operations in series, operations can be connected directly, or through an intermediate surge tank.31 The direct 1157



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Focused Beam Reflectance Measurement FBRM tools, wherein the capability in the CMO group is lower than the IQ group as a percent of the totals. These tools are typically used for developing and monitoring of API crystal form and particle size. While these are a core tool used by the majority of large pharmaceutical companies, outsourcing this aspect of process development to external vendors is likely less frequent than other steps in the route due to the importance this step has on the API and drug product attributes. HPLC/UPLC, GC, NMR, and IR have been used extensively for ≥50% of the IQ group, while only HPLC/ UPLC and GC for the CMO group. Less than 50% of the IQ and CMO respondents indicated that any of the analytical methods are GMP qualified. With the exception of pH measurement, a larger percentage of the IQ group indicated having analytical capabilities for online or in-line analysis compared to the CMO group. Of those capabilities, only infrared spectroscopy (IR) was used extensively by greater than 50% of the IQ respondents. Although IR does not provide the level of detail that HPLC/ UPLC, GC, and NMR can, it is one that is often needed when monitoring intermediates that are not amenable to off-line/atline tools (e.g., temperature, water, and/or air sensitive intermediates). It is also a technology that can be employed over a wide range of temperatures, and the technology for flow processes is readily available from commercial sources. Not surprisingly, the number of respondents with GMP qualified analytical capabilities for online/in-line analysis was very low across both groups. Process temperature and process pressure were the only two GMP capabilities present in >25% of the CMO respondents, and this may be due to the installation of these capabilities into the equipment design as a necessary means of equipment process control and is less likely to be an add-on capability, although enhanced capabilities in both categories may be added later to provide better equipment and process understanding. The final question in the analytical section of the survey asked how analytical methods were integrated into processes, whether for information only, to approve forward processing, for feedback control, and/or for real time release testing (RTRT). The responses are tabulated in Table 12. With the exception of 75% are highlighted in yellow with bolded, blue font. Cells with values between 50 and 74% are highlighted in light blue with bolded, black font.

identify process upsets so as to discontinue the process until the issue is identified and resolved and/or divert out-ofspecification material to a separate collection vessel.33,18,34 Using analytical tools to enable RTRT can allow for coupling continuous drug substance (API) manufacture to continuous drug product manufacture, reduce time and costs associated with batch testing, and longer term, the potential for API on demand, which would have large benefits that arise from the ability to rapidly adjust drug product supply as market demand changes. This would reduce costs associated with excess supply stock maintenance and losses due to API and drug product expiry. The benefits of incorporating analytical methods into a process must be weighed against the costs of doing so. Implementing online or in-line analytical methods as a means of process control increases the process complexity on scale. This additional level of complexity may not be warranted for a process supplying clinical trial API with an uncertain future. It is typically more practical to enable a process and set process conditions such that there is high confidence the process will be successful (e.g., set the residence time to a value much larger than is required to complete a reaction), and to limit the number of sequential operations where possible such that testing of intermediates can occur prior to committing the material to the next step. While the efficiencies gained from reduced operations are not fully realized under these conditions, it can greatly simplify the resources and time needed to develop a process. As confidence in a product reaching market increases, the scale of the deliverable and/or the number of campaigns with the same process increase, complexity can be incorporated with a higher return on investment. Even under these conditions, the most costeffective means to monitor a process will be the simple ones, such as process temperature and pressure. 1159



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is now predominantly BP to CP, at least not in the next 15 years. Each of the groups were asked if the barriers to implementing continuous were primarily business or technical challenges. The vast majority of responses from both groups were business challenges (100% and 71% of IQ and CMO responses, respectively), although in the open ended write in comments, both business and technical challenges were cited, and in some cases, it was noted that there were cultural barriers to implementation as well (Table 14). Many of the challenges are the same for both the IQ and CMO groups. It is interesting to note the perspectives of the IQ and CMO response to the added development time for a CP at a CMO. The IQ group cites that a barrier to implementation is the additional development costs invoked by the CMO vendors, while the CMO group cites that Pharma does not accept the additional development time. This is a point that seems ripe for discussion between the two groups to better understand costs and benefits with a goal of aligning perspectives. Reductions in development time and costs may also come as the industry gains experience, although it is not clear if CP development times will ever be as fast as the development of BP. Also of note is the challenge of alignment with the quality groups, another barrier that should dissipate with more experience across the industry and with regulatory agencies. Each of the groups was asked what factors influenced their decision to select a CP approach versus a BP approach. We have consolidated the open-ended responses into major and minor categories, although some overlap between categories is inevitable (Figure 14). Despite some overlap in categorization, this provides a list of the primary considerations that go into a decision for a batch or CP. Interestingly, the trend for primary drivers emphasized by the most to the least number of respondents is very similar, with the exception of the scalability and process fit category. For both IQ and CMO groups, safety was the number one driver, with 89% and 72% of IQ and CMO respondents providing this as a primary factor, respectively. Safety was placed in the same Reaction Properties category as responses that were focused on unique properties of a particular process that render it more amenable to CP equipment compared to BP equipment, such as those requiring very high temperature and pressures, or requisite mass and heat transfer rates that may exceed typical BP equipment limitations. The scalability and process fit was a major consideration for the CMOs but not mentioned in any of the IQ responses. This, perhaps, represents a greater focus on fitting in existing processing equipment for the CMO group, whereas IQ respondents may consider continuous processes that exceed their internal

required additional time to install but that reusing existing continuous processing equipment can result in reduced transfer time compared to batch.

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FACTORS AND ISSUES RELATED TO THE ADOPTION OF CONTINUOUS PROCESSES In the final section of the survey, we asked questions of both groups that would help understand what drives the change from BP to CP for their company, and the barriers they perceive in making that change. The two groups were asked to provide an estimate of the shift from batch to continuous processes as a percent of the total portfolio, then to provide an estimate of expected shift that will occur over the next 15 years (Figure 13). While only

Figure 13. Shift in percent of total portfolio from batch to continuous processes that occurred in the last 5 years, and projected percent shift to occur in the next 15 years for the IQ and CMO groups.

33% (3 of 9) of IQ respondents indicated a >5% shift from BP to CP over the last 5 years, all of the respondents projected an increase of >5% in CP over the next 15 years (Figure 13). Similarly, 47% (8 of 17) CMO respondents indicated a >5% shift from BP to CP over the last 5 years, while all projected an increase of >5% over the next 15 years. The majority of respondents in both groups (66% of Pharma and 71% of CMO group) speculate the shift from BP to CP to be no more than 25% of their portfolio over the next 15 years. Only 1 company from each group that had not already observed a >50% shift over the last 5 years projected a shift of >50% over the next 15 years.36 This implies that most companies from both Pharma and CMO groups do not foresee a wholesale change from what Table 14. Barriers to Implementing CPs (IQ and CMO groups) IQ Group • Compelling business case and internal sponsorship, especially when existing batch capacity is available • Cost of equipment and training • Time to make the transition from batch to continuous • Cultural - scientists have batch design mindset, continuous perceived as higher risk • Higher initial costs to outsource - vendors charge additional development costs • Alignment with Quality function

CMO Group • Existing batch capacity weakens business case, less compelling if only a small portion of the process is continuous • Cost of equipment and training • Lab development tools are lacking • Risk averse nature of pharmaceutical companies • Requires additional time to develop, not widely accepted by Pharma customers

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Figure 14. Factors that influence the selection of continuous vs batch process for IQ and CMO groups.

Table 15. Learnings from the Surveya • Both the Pharma industry and CMOs that support Pharma have been increasing, and will continue to increase, their investment in CP. However, only a minority of companies in both groups have observed a >5% change over the last 5 years, and most companies do not forecast >25% shift over the next 15 years. • The perceived value and focus of CP applications thus far have been on enabling reaction chemistry. A large variety of reactors are available in the CMO network, with diverse reaction experience at all scales. However, capabilities for postreaction processing and real time analytical methods are further behind in both groups. • With notable exceptions, sequencing unit operations has been limited. In the absence of large investments supported by strong business case analysis and sponsored initiatives, end-to-end CP for most of the IQ and CMO groups appears to be much further behind the relatively recent academic demonstrations that have been published in the literature. • The CMO network as a whole has advanced CP further than the Pharma group with regard to implementation on scale. • There is limited regulatory experience with CP. a

These are generalized based upon the collective survey results, exceptions can be found within the respondents.

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CONCLUSIONS One can draw some general conclusions based upon the collective survey responses (Table 15). The results of this survey show that both the IQ and CMO groups have begun moving toward increasing the applications of CP, with a corresponding decrease in BP, and are projected to continue to do so in the future. However, most participants in both groups indicated 0−5% shift to CP over the last 5 years, so the shift has been slow despite the large majority of participants anticipating a larger increase in CP over the next 15 years. With the majority of Pharma and CMOs that participated in this survey, the shift to CP is expected to be modest over the next 15 years (≤25%), with BP remaining as the predominant approach. The barriers to implementation are primarily business issues related to costs and ROI, along with some changes that are needed to address culture, training, and perception of regulatory risk. It will likely take large investments and company initiatives to accelerate the transition from BP to CP. Consequently, sharing of business case analysis and case study successes among Pharma and CMOs is a potential accelerator of CP across the industry. There is a wide range of experience with different chemical transformations, as well as the availability of platforms to support different types of chemistry in both groups. This appears to be where most of the CP value has been realized to

capabilities by externalizing or developing those capabilities internally. Process control was among the more common factors cited by both groups. This category included control of quality, which can encompass control through reaction selectivity and working with unstable intermediates. Control of reaction selectivity and unstable intermediates may also be a business driver in that yield and overall process efficiency could increase as a consequence and could be a primary driver from this perspective in some cases. Business drivers were a key concern for nearly all respondents. This major category was broken down into subcategories based upon response, but most have a similar meaningdoes the cost to invest in CP versus BP provide a sufficient return on that investment? This can be particularly challenging if the cost of purchasing or developing new technology must be weighed against not only the current project but also the uncertainty of future projects that may utilize the technology and contribute to the ROI. Judging by the responses to the anticipated shift to continuous over the next 15 years (vide supra), it seems that most of the respondents from both groups are projecting substantial return on those investments. 1161



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Table 16. Gaps and Opportunities • Clarity of business case rationale. Sharing of business case studies and examples of ROI could help accelerate buy-up of CP across the industry, especially where organization support is lacking. • CP platforms for the scale up of single electron chemistry, such as photochemistry and electrochemistry, are a current gap. • Platforms for, and knowledge of, certain postprocessing unit operations, such as continuous crystallization, filtration, and drying is a gap. There is an opportunity to collectively develop these platforms. • Standardization of CP equipment to enable more rapid uptake and lower costs. Collaborations and sharing of experience and goals can be an accelerator. • There is an opportunity to leverage knowledge from other industries that are further advanced in the implementation of CP. • Limited understanding of, and experience with, regulatory expectations is a barrier to implementation. Communication of perspectives by regulatory agencies, harmonization across regulatory authorities, and open communication of regulatory experiences are all potential accelerators. • Integration of API CP to drug product CP is not occurring within this survey group. • Mutual understanding of CP development costs between Pharma and the CMO network is a gap. Identifying and harmonizing on development expectations for CP between the two groups could set common expectations and lower costs by focusing the industry on acquiring standardized data sets in the most efficient manner possible.

manufacturing conditions. In addition, CMOs generally have larger teams dedicated to CP development compared to the Pharma group. There are some companies that have had regulatory experience, including NDA and ANDA filings. However, that number is still relatively small, and the uncertainty surrounding regulatory expectations not only in the major markets, but worldwide, will act as a barrier to implementation, as will lack of alignment with the internal Quality Organizations noted in the survey. There are a number of actions Pharma and the CMO third party network could take to help advance the technology and accelerate the implementation of CP (Table 16). Sharing learnings, technology development, and process development approaches (including harmonizing technology transfer packages) could be effective means of accelerating CP. The very fact that a survey was needed to understand the scope of CP within the industry is an indication that there is a lack of awareness of all the activities that are occurring in this field and the experience that is available. The results of the survey show that there is broad interest in the technology, yet literature reports and discussions within the community indicate most companies appear to be going it alone when it comes to developing or implementing CP technology. This inherently means a relatively slow growth of knowledge and technology, where sporadic learnings are shared through common venues such as publications, conferences, and vendor information events. One could envision precompetitive collaborations wherein learnings are shared in real time, and resources can be distributed across a larger group, accessing a larger pool of expertise. Funding to support sharing learnings and collaboratively developing technology may not be needed, but for those cases that it is, the costs can also be minimized through collective funding. The IQ Consortium and the Non-Precious Metal Catalysis Alliance38 are examples wherein Pharma companies are sharing precompetitive learnings in real time, with minimal or no required monetary contributions. Another example of sharing resources to advance technology is the Enabling Technologies Consortium, where Pharma and Biopharma collaborate to identify, improve, and develop new technologies with commercial and academic entities.39 Expertise in continuous processing in food, oil, and gas industries could be leveraged to advance continuous processing in pharmaceutical applications. The CMO group, with a more diverse portfolio spanning different industries, may be best positioned to do just that. The challenge may be in identifying the value statements for those more experienced industries in supporting such collaborations. Some of the comments from the CMO group indicate that they are already transferring

date, and/or that the business case is easier to make, with rapid realization of ROI. This is consistent with many of the primary drivers indicated by the respondents, such as safety and process control, especially for reactions that BP cannot compete well with CP. The focus on reactions would also help to explain why the survey results indicated process chemists were more likely to be on dedicated CP teams than engineers were at this time. As postreaction processing and linking sequential unit operations become a larger part of the CP applications, one would expect engineering skills will become increasingly prominent (vide infra). Despite a broad range of reaction experience, some of the rapidly growing synthetic transformations in Pharma and academia, such as fluorination37 and single electron transfer chemistry (photoredox and electrochemistry), still appear to be in a very early phase within these groups. CP for photoredox and electrochemical processes, in particular, will likely be critical for efficient scale up, and these appear to be gaps that are in need of rapid development. In contrast to reaction chemistry, postreaction CP has not advanced to the same extent across the industry as a whole, nor has the use of real-time analytical tools. There are significant gaps in some fundamental technology, such as continuous crystallization, filtration, and drying. This is indicative of an industry that is primarily enabling single step transformations or processes that telescope continuous reactions with little or no postreaction processing between telescoped reactions. This is consistent with the responses to the maximum number of sequential unit operations and the relatively small number of companies that have automation engineers as a part of their dedicated CP teams. Postreaction CP will become critical if one is considering linking many steps in a process, and while it is clear this is occurring for some smaller number of companies further advanced in CP, it is not common across the industry. It is likely that postreaction CP and real-time analytical tools will become more prominent as more experience in the development and implementation of CP is gained and the equipment becomes better established and harmonized. As a whole, the CMO group has advanced further in CP compared to the IQ group, although there are companies within both groups that are very advanced in the use of CP, as evidenced by the experience on large scale and the complexity of processes implicated by the examples of the largest sequential CP unit operations. Also consistent with this conclusion is the range of chemistry experience within and breadth of reaction platforms available at all scales to the third party network compared to that of the IQ group. In general, most of the IQ group chemistry experience is at the smaller scales (50% of their portfolio will shift to CP in 15 years were the same that indicated a >50% shift over the last 5 years. In the free text, one company noted that they were already 100% continuous. Thus, it is likely some interpreted this question as “How much of your total portfolio will be CP” rather than “how much is shifting from BP to CP”. Despite this potential ambiguity, the trends remain the same. (37) (a) Dilman, A. D.; Levin, V. V. Difluorocarbene as a Building Block for Consecutive Bond-Forming Reactions. Acc. Chem. Res. 2018, 51 (5), 1272−1280. (b) Bos, M.; Poisson, T.; Pannecoucke, X.; Charette, A. B.; Jubault, P. Recent Progress Toward the Synthesis of Trifluoromethyl- and Difluoromethyl-Substituted Cyclopropanes. Chem. - Eur. J. 2017, 23 (21), 4950−4961. (c) Rehm, T. H. Photochemical Fluorination Reactions - A Promising Research Field for Continuous-Flow Synthesis. Chem. Eng. Technol. 2016, 39 (1), 66−80. (d) Shah, P.; Westwell, A. D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem. 2007, 22 (5), 527−40. (38) The Non-Precious Metal Catalysis Alliance is a collaboration between AbbVie, Boehringer-Ingelheim, and Pfizer to share knowledge and advance the technology for the use of nonprecious metals, such as the replacement of iron for palladium in cross-coupling. The collaborators are not required to provide any monetary input. (39) According to their website: “The Enabling Technologies Consortium is comprised of pharmaceutical and biotechnology companies collaborating on issues related to pharmaceutical chemistry, manufacturing, and control with the goal of identifying, evaluating, developing, and improving scientific tools and techniques that support the efficient development and manufacturing of pharmaceuticals.” http://www.etconsortium.org.

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The Evolving State of Continuous Processing in Pharmaceutical API

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