The Evolving State of Continuous Processing in Pharmaceutical API

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The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations James Christopher McWilliams, Ayman D Allian, Suzanne M Opalka, Scott A May, Michel Journet, and Timothy M. Braden Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00160 • Publication Date (Web): 08 Aug 2018 Downloaded from http://pubs.acs.org on August 8, 2018

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Organic Process Research & Development

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,ǁ Michel Journet,┴ Timothy M. Bradenǁ †

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, CA 91320, United States §

ǁ

Chemical Process Development, Biogen Idec, 115 Broadway, Cambridge, MA 02142, United States

Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United

States ┴

API Chemistry, GSK, 709 Swedeland Rd, UW2810, P.O. Box 1539, King of Prussia, PA 19406,

United States

ACS Paragon Plus Environment

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Table of Contents Graphic


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KEYWORDS: continuous process, flow process, pharmaceutical, active pharmaceutical ingredient, contract manufacturing organization, contract research organization, flow chemistry, unit operations, outsourcing, survey

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, post-reaction 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 post-processing and analytical remain in the very early stages of development and implementation.


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The 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 increased 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 3rd party network).2 Over the last 10-15 years, there has also been a shift in Pharma manufacturing towards broader use of the 3rd 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 batch to CP must take into account not only internal capabilities, but also the capabilities and experience available through the 3rd 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 3rd 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.


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It is not surprising that batch and semi-batch processes have long been the preferred mode of manufacturing APIs for pharmaceutical companies, as the versatility of BP equipment towards 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 post-reaction processing operations that would occur in a batch reactor, such as extractions, distillations, or crystallizations, require additional, equipment 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 energy10 or toxic11 compounds and efficient heat removal from highly exothermic reaction processes,12 application of reaction conditions that would be challenging to engineer efficiently


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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-toend 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 towards 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 budgets are focused on short term returns or require a return-oninvestment (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 pre-clinical supplies to manufacturing, program specific API quantities ranging from


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low (e.g. highly potent or acute treatment programs) to high volume (e.g. high dose and chronic treatments), hybrid batch-continuous processes vs. multi-step and multi-operation processes, first generation vs. second generation processes, and pre-GMP steps (or pre-Regulatory Starting Materials for commercial products) vs. GMP steps. All of these strategies have varying levels of costs, risks, and benefits. Integrating the 3rd 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 3rd party network to provide the business justification for internal change. A thorough understanding of the capabilities within the 3rd party network is a pre-requisite 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. Methodology The survey itself consisted of seven sections, covering the following topics: personnel, equipment, chemistry, post-processing, analytical, regulatory, and factors impacting adoption of CP. There were 67


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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. 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 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 needed. Notably, even amongst those CMOs who did not have a dedicated group, all but one


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stated they had at least some chemists or engineers with experience in CM.22

Figure 1. Size of the teams that dedicate greater than 50% of their time to pharmaceutical CM? 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 towards Doctorate and Master Degrees. The IQ teams had slightly more Ph.D and less B.S. educated staff compared to the CMO teams.


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Figure 2. Educational Background for the members of dedicated IQ and 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 towards more Ph.D. trained chemical engineers and analytical chemists, while the CMOs trended towards M.S trained members. Automation engineers were almost non-existent on IQ teams, while represented with more frequency on CMO teams, albeit at 100 kg

GMP Experience

Photochemical Reactions

Figure 5. Format of survey responses to questions on specific chemistry For every reaction type, at least three CMOs and one IQ Member indicated experience at < 1 kg scale (Figure 6). For the IQ Members, these reactions can represent programs moving toward larger scale, but also represent: early preclinical programs wherein the chemistry supports the synthesis of new 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.


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Figure 6. CMO and IQ Member chemistry CP experience at < 1 kg scale ordered by IQ member experience (high to low). The chemistry experience at >1 kg for the IQ and CMO groups are 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


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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 2nd generation route). Thus, while there are clearly six companies with experience scaling oxidations to >100 kg, it is not possible to discern if those same six companies make up six of the ten companies with experience scaling to 1-100 kg.


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Figure 7. Scale up chemistry experience of the IQ members group


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Figure 8. Scale up chemistry experience of the CMO group

The IQ and CMO groups were provided open text entries to add any additional chemistry experience they have had and at what scale, the results of which are shown in Table 1. Some of the chemistry categories have some overlap, such as thermal deprotection, thermal rearrangement and N-Boc deprotection (thermal), as well as cross-coupling and Kumada categories. In some cases the descriptions provided were general reaction types, and in others, more specific transformations. There is quite a diverse range of chemistry experience within both groups. Of the 7 reaction types with experience at > 1


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kg scale, 5 were run GMP within the IQ group. Within the CMO group, 3 of 10 reaction types at >1 kg scale were run GMP. Table 1. Additional IQ and CMO continuous chemistry experience provided in free text responses.

Alkylation

1

Acrylonitrile

1

Me2SO4

1

Carbene chemistry w/ethyl diazoacetate

1

Amide bond formation

1

1

Diazonium salt formation

1

1

Cadogan cyclization

1

Condensation Reactions

Carboxylation

1

Decarboxylation

Cross-Coupling

2

Cyclization Dehydration (high T) Bromination Chlorination (radical)

2 2

1 1

1

2 1

Cross-Coupling

1

1

1

Friedal-Crafts Halogenation (Br2, Cl2, I2) Curtius Rearangement

1 2

1

Kumada coupling

Enzymatic transformation

1

Enzymatic transformation 1

Epimerization

1

1

Nitration

1 2

Polymer synthesis

Lithiation

1

Propoxylation

1

Ritter reaction

Nitrile hydration w/MnO2

1

TEMPO oxidation

Reductive Amination

1

Wittig reaction

1

Staudinger reaction

2

1

> 100 1 1

1

1 1

Reactive Crystallization

1

Mitsunobu

SNAr

1 1

N-Boc deprotection

1

Mesylate formation

1

1

Formylation

1

1

Epichlorohydrin reaction

Diels-Alder N-Boc deprotection (thermal)

2

1

1 1

100

1 kg scale exceeds that of the Pharma industry in general, and that most of the twenty 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 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. 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 3rd party network. Understanding the equipment capabilities and experience within the CMO network is critical if one is to plan for this option. Pharma companies can use the knowledge of CMO equipment capabilities to develop processes targeted towards those capabilities, to purchase internal equipment that will make technology transfer more consistent and facile, and/or to use the external network to fill gaps in internal capabilities. Each IQ and CMO participant was asked to indicate if any of the following conditions were true for each of the 6 reaction platforms at 3 different scales (20 kg): 1) do not have the capability


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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 Further, we asked each respondent to respond to each statement in the context of the scale of material that could be reasonably prepared in the equipment, either 20 kg (typically supplies for phase 2 through to commercial manufacturing). The results from the IQ and CMO groups are shown in Figure 9 and Figure 10, respectively. The results follow the expected trend that as scale increases, the number of companies with each of the six platforms decrease, as does the extent of use. At the smallest scale (80% of the IQ companies had capabilities across all platforms with the exception of the high-pressure Continuous Stirred Tank Reactor (CSTR) platform, and >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

Range of P(max) limits (psi)

500 - 2,000

14.5 (1 atm) 3,000

200 - 1,000

72 (5 bar) 3,000

87 (6 bar) 1,000

72 (5 bar) 3,000

Respondents with P(max) ≥ 1,000 psi

3 of 10

8 of 19

3 of 8

7 of 16

1 of 5

6 of 14

Range of T(max) limits (°C)

200 - 400

25 - 300

150 - 300

150 - 300

150 - 300

150 - 300

Respondents with T(max) ≥ 250 °C

8 of 10

12 of 19

3 of 8

8 of 16

1 of 5

8 of 14

a

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

Cryogenic liquid PFRs can have significant benefits relative to batch reactors when running reactions that proceed through thermally unstable intermediates, a common occurrence with reactive organolithium species, for example. Intermediates or products that undergo rapid decomposition at or near ambient temperature can render some transformations unsuitable for batch processing, yet can be robust processes in a temperature and time controlled cryogenic PFR. These reactions run as continuous processes can often be conducted at significantly higher temperature compared to batch processing with equal or better outcomes due to precise control of reactive species lifetimes, which can be limited to just seconds or less if needed.26 Other transformations that cryogenic PFR platforms 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


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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).

Table 3. Cryogenic liquid PFR capabilities of IQ and CMO equipment

Cryogenic Plug Flow Reactor (liquid only)a < 1 kg

1 - 20 kg

> 20 kg

IQ

CMO

IQ

CMO

IQ

CMO

Range of T(min) limits (°C)

-100 - (-30)

-100 - (-40)

-100 - (-30)

-100 - (-20)

-80 - (-20)

-100 - (-15)

Respondents with T(min) ≤ - 50 °C

9 of 10

12 of 14

6 of 9

10 of 13

3 of 4

9 of 11

a

T(min) = minimum temperature

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.


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Table 4. Gas-Liquid PFR parameter ranges for IQ and CMO equipment

Plug Flow Reactor (gas - liquid)a < 1 kg Range of P(max) limits (psi) Respondents with P(max) ≥ 1,000 psi Range of T(max) limits (°C) Respondents with T(max) ≥ 150 °C Range of T(min) limits (°C) Respondents with T(min) ≤ - 50 °C

Gases used

a

1 - 20 kg

> 20 kg

IQ

CMO

IQ

CMO

IQ

CMO

290 (20 bar) 2,000

15 - 3,000

150 - 1,500

15 - 3,000

1,000

50 - 1450 (100 atm)

5 of 8

8 of 14

3 of 4

6 of 13

1 of 1

5 of 10

50 - 400

100 - 300

150

100 - 300

150

100 - 300

6 of 8

12 of 14

4 of 4

11 of 13

1 of 1

7 of 10

-78 - ambient

-78 - 25

-78 - (-40)

-78 - 25

ambient (no lower T limit indicated)

-78 - 25

1 of 8

4 of 14

1 of 4

4 of 13

0 of 1

4 of 10

H2, CO, O2/N2 blend, NH3, CO2, CH2N2, syn gas, ethylene

H2, O2, air, O3, CO, Cl2, SF4, HCl, NH3, CH2N2, ethylene, allene, phosgene

H 2, O 2, O 3, syn gas, ethylene

H 2, O 2, O 3, CO, Cl2, SF4, NH3, phosgene

H2, syn gas

H 2, O 2, O 3, CO, Cl2, NH3, HCl, phosgene

P(max) = maximum pressure; T(max) = maximum temperature; T(min) = minimum temperature

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 100-150 °C for the 2 IQ respondents indicating they have


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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 under-utilized 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.

Table 5. Solid-liquid or solid-liquid-gas packed bed reactor parameter ranges for IQ and CMO equipment

Packed-Bed Reactor (solid - liquid or solid - liquid - gas) < 1 kg Range of P(max) limits (psi) Respondents with P(max) ≥ 1,000 psi Range of T(max) limits (°C) Respondents with T(max) ≥ 250 °C

1 - 20 kg

> 20 kg

IQ

CMO

IQ

CMO

IQ

CMO

800 - 2900 (200 bar)

100 (7 bar) 3,000

800 - 2900 (200 bar)

300 - 3,000 psi

145 (10 bar) 150

300 - 1450 (100 bar)

8 of 9

4 of 11

5 of 6

6 of 8

0 of 2

3 of 5

100 - 300

100 - 300

150 - 300

250 - 300

100 - 150

100 - 300

3 of 9

8 of 11

2 of 6

8 of 8

0 of 2

4 of 5


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Range of T(min) limits (°C) Respondents with T(min) ≤ - 20 °C Gases used

a

-30 - ambient

-78 - 20

-40 - ambient

-70 - 20

ambient

-78 - 20

1 of 9

3 of 11

2 of 6

3 of 8

0 of 2

2 of 5

H2, O2/N2 blend, CO, CO2, syngas

H 2, O 2, O 3, CO, Cl2, SF4, HCl, NH3, CH2N2, phosgene

H2, O2/N2 blend, CO, CO2, syngas

H 2, O 2, O 3, CO, Cl2, SF4, HCl, NH3, CH2N2, phosgene

H2

H 2, O 2, O 3, CO, Cl2, HCl, NH3, CH2N2, phosgene


Low pressure CSTRs are platforms in which the IQ group have 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 (Table 6). 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. 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). Table 6. Low pressure CSTR parameter ranges for IQ and CMO equipment Continuous Stirred Tank Reactor (low pressure)a < 1 kg Range of P(max) limts (psi)

1 - 20 kg

> 20 kg

IQ

CMO

IQ

CMO

IQ

CMO

14.5 (1 bar)

15 - 72 (5 bar)

14.5 (1 bar)

15 - 72 (5 bar)

1 bar

10 - 435 (3 Mpa)


27


Range of T(max) limits (°C) Respondents with T(max) ≥ 150 °C Range of T(min) limits (°C) Respondents with T(min) ≤ - 50 °C a

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150 - 180

50 - 300

150 - 180

ambient - 300

150

ambient - 300

5 of 6

5 of 12

3 of 4

5 of 11

2 of 2

5 of 11

-50 - (-20)

-78 - ambient

-50 - (-20)

-78 - ambient

-50 - (-20)

-78 - 0

1 of 6

7 of 12

1 of 6

7 of 12

1 of 2

7 of 11


High pressure CSTRs are the least available platform in the IQ and CMO groups at any 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 is 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 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 IQ 1000

CMO 435 (30 bar) 1450 (10 MPa)


28

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Respondents with P(max) ≥ 1,000 psi Range of T(max) limits (°C) Respondents with T(max ≥ 150 °C Range of T(min) limits (°C) Respondents with T(min) ≤ - 50 °C a

2 of 2

4 of 8

1 of 2

3 of 5

1 of 1

3 of 5

140 - 250

100 - 300

230 - 250

100 - 300

250

100 - 300

1 of 2

5 of 8

2 of 2

4 of 5

1 of 1

4

-40

-78 - 0

-65

-78 - (-50)

none specified

-78 - (-50)

0 of 2

3 of 8

1 of 2

3 of 5

0 of 1

3 of 5


Post-Reaction, Purification Platforms In order to get an understanding of continuous platforms deployed in downstream operations, the survey asked participants about five common post-reaction, 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 of those having extensive experience at any scale larger than 1 kg (Table 8). Within the CMO group, all ACS Paragon Plus Environment

29


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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.


30

Table 8. Continuous post-reaction processing platform capabilities and experience of the IQ (10 respondents) and CMO (24 respondents) groups.

Scale

Extensive Use

GMP Qualified

Have capability

Extensive Use

GMP Qualified

CMO

Have capability

Packed Column Scavenging

Continuous Distillation

Separation And Extraction

Continuous Post-Reaction Purification Technology

IQ

Continuous Crystallization

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Simulated Moving Bed (SMB)

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< 1 kg

7

3

2

11

7

5

1 – 20 kg

3

1

1

14

6

5

> 20 kg

0

1

1

12

4

7

< 1 kg

4

1

0

15

6

5

1 – 20 kg

3

1

1

14

5

5

> 20 kg

2

1

1

12

4

5

< 1 kg

5

2

2

11

3

5

1 – 20 kg

2

1

1

9

2

5

> 20 kg

2

2

2

8

2

4

< 1 kg

3

2

0

10

4

1

1 – 20 kg

2

1

1

9

2

1

> 20 kg

1

1

0

3

1

1

< 1 kg

2

1

0

5

2

2

1 – 20 kg

2

0

1

3

2

2

> 20 kg

1

0

1

3

2

1


31


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At small scale ( 20 kg

1

1

1

< 1 kg

1

1

1 – 20 kg

1

1

< 1 kg

1

1

1 – 20 kg

1

1

< 1 kg

2

1

1 – 20 kg

2

1

> 20 kg

2

1

> 20 kg

> 20 kg


35


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a

In addition, 1 IQ member indicated having capacity for a flip filter and a membrane-and-separator at 1 kg scale. One CMO respondent indicated they had a proprietary platform for continuous filtration that was similar to an agitated filterdryer. A GMP qualified belt filter was available on 1-20 kg and >20 kg scales at one of the CMOs who also had extensive experience with this technology at those scales. Continuous Drying For continuous drying, the survey asked IQ members to provide up to three platforms that might be available for continuous drying. Only one respondent from the IQ group indicated they had continuous drying capability in the form of a rotary drum dryer, albeit at small scale (Table 10). In a rotary drum dryer, wet materials enter one end of the drum from the higher section of the drum and come in contact with preheated (inert) gas. With the rotation of the cylinder, the material is driven by gravity to flow down to the lower end of the drum, moving laterally across the drum, and ultimately discharging as a dried solid at the end of the drum.30 Sometimes the dryer is fitted with rotating paddles to draw the solids back to the top of the drum. It is worth mentioning that rotary drum dryers are commonly used in drug product processing, and thus, investing in this technology for API drying could be a means of transferring established knowledge and bridging drug substance and drug product processes.


36

Table 10. Continuous drying capabilities and experience within the IQ (10 respondents) and CMO (24 respondents) groups.

Have capability

Extensive Use

GMP Qualified

1 1

1 1

1 1

< 1 kg

1

1

1 – 20 kg

1

1

> 20 kg

1

1

< 1 kg 1 – 20 kg

1 1

GMP Qualified

< 1 kg 1 – 20 kg > 20 kg

Extensive Use

Have capability

Continuous Drying Platforms Rotary Drum Dryer

< 1 kg 1 – 20 kg > 20 kg

Spray Dryer

Scale

Rotary Cone Dryer

CMO

Vacuum Drum Dryer

IQ

Fluidized Bed Dryer

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Parallel Dryer

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1

> 20 kg < 1 kg 1 – 20 kg > 20 kg

1

< 1 kg

1

1

1

1 – 20 kg > 20 kg

Five of the 24 CMO respondents described continuous drying capabilities, including: rotary cone dryer, vacuum drum dryer, spray dryer, fluidized bed dryer, and a parallel dryer. Extensive experience was limited to a single respondent with rotary cone dryer experience at ≤20 kg scale, and another respondent with experience with fluidized bed drying at >20 kg. Spray drying is available within other


37


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CMO companies, and our survey likely doesn’t capture some companies with specialized capabilities such as this. Interestingly, the respondent with vacuum drum drying capabilities indicated this platform could dry dilute suspensions to free flowing powders with 20 kg scale. In addition, the open-ended text entries were provided so the respondent can include additional information. Responses from both IQ and CMO groups are shown in Figure 11 and Figure 12, respectively. All nine IQ respondents indicated that they have run at least two consecutive continuous unit operations at one of the three scale ranges. At small scale, one IQ member (IQ(1)), managed to successfully connect fourteen continuous unit operations. IQ(1) also indicated on the survey that the fourteen steps consisted of four telescoped chemical transformations and associated separation unit operations. IQ(1) also led the pack at 1-20 kg scale with eight connected unit operations, which consisted of multiple reactions, extractions, distillations, crystallizations, and filtrations (after filtration, solids were dissolved on the filter and used directly in subsequent steps). Other than these two responses from IQ(1), all other IQ members ranged from 0-5 consecutive unit operations, with no more than three consecutive operations at the largest scale (>20 kg). Given the limited experience in continuous post-reaction 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 fourteen 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,


39


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quenches, and some with phase separations (extractions). With that said, those three standouts have achieved from 6-20 consecutive operations, and clearly perceive value in this approach.

Figure 11. The largest number of continuous (unit) operations run consecutively within IQ member companies (9 respondents) at three scales.


40

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Figure 12. The largest number of continuous (unit) operations run consecutively within CMO companies (14 respondents) at three scales. 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 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


41


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unit step in the process. The deployment of surge tanks require complex analysis, their size introducing an addition 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 hours, 12 hours, Less, None)?” The respondents were provided an open-ended 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 is IQ(1) from Figure 11, wherein up to 14 steps had been connected, and the value of surge tanks is clear given the higher potential for, and great impact of, unplanned events. Only 13 CMOs responded to the question on the use of surge tanks. Of these, 7 indicated that use depended upon the process with a range of processing time capacity similar to the IQ respondents (1-24 h). At least one respondent stated that the deployment of parallel surge tanks is critical for quality, robustness, and flexibility, and targeted a 1 h capacity. Another respondent stated they used surge tanks in pairs, operating in an alternating manner (i.e. not in parallel). Similar to the IQ responses, the duration of capacity, if not 1 h, was either 12 or 24 h, the latter time intervals implying the duration may be structured around plant personnel shift changes. Integration with Drug Product


42

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The final question in the section focused on connected processing was on integration of drug substance (API) with drug product, wherein an open-ended response could be provided. One IQ respondent indicated they were investigating the possibility, and one CMO respondent indicated they prefer to integrate upstream and downstream processes, although it was not clear if an actual active project has been demonstrated by this respondent. Other than these two respondents, the remaining respondents (22 in total from both groups) indicated no integration, although some had capabilities for both working independently. It appears that more of the fundamental applications and developments within continuous API processing will need to advance further before the coupling with drug product manufacturing becomes commonplace.

Analytical Capabilities The analytical section of the survey consisted of three questions. The first and second questions provided a list of analytical tools and asked the respondent to select from one or more of the following if: 1)

they do not have the capability

2)

they have the capability

3)

they have used the tool extensively (extensively was defined as having used the tool in at least

two applications in the last three years) 4)

they have a GMP qualified tool

The first question asked the respondent to answer in the context of using the tool for off-line or at-line applications (not coupled to process with manual retrieval of the sample). Question number two asked the respondent to answer the question in the context of using the tool for on-line or in-line applications (coupled to process). The survey results, shown as percentage of total responders answering in the affirmative, are shown in Table 11. Notably, while the following discussion will be based upon the


43


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percent of total responses in the affirmative, a single affirmative response from the IQ or CMO respondents represents 10% and ~5% of the total from each group, respectively. Thus, in absolute numbers, the same percentage from the CMO and IQ groups indicates twice the number of CMO companies responding in the affirmative compared to the IQ companies. In general, the survey results show that the off-line/at-line analytical capabilities of both the IQ members and CMO respondents are similar as a percentage of total respondents. Where there is a notable difference is in the use of Raman and 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 control and monitoring of API crystal form and particle size during development. 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 on-line 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 doesn’t provide the level of detail that HPLC/UPLC, GC, and NMR can, it is one that is often needed when monitoring intermediates that aren’t amenable to off-line/at-line 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.


44

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Not surprisingly, the number of respondents with GMP qualified analytical capabilities for on-line/inline 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 are 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.

Table 11. IQ and CMO analytical capabilities supporting CP (percent of IQ respondents (out of 10) and CMO respondents (out of 21) that indicated they had this capability).a

Off-Line or At-Line ( Not Coupled to Process )

Extensive Use

GMP Qualified

Have capability

Extensive Use

GMP Qualified

Have capability

Extensive Use

GMP Qualified

CMO

Have capability

IQ

GMP Qualified

CMO

Extensive Use

IQ

In-Line or On-line ( Coupled to Process )

Have capability

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


HPLC/UPLC

100

70

40

95

57

38

40

30

0

29

10

5

Gas Chromatography

90

60

30

95

57

38

10

10

0

24

5

0

Mass Spectrometry

70

40

20

62

33

19

30

10

10

10

0

0

NMR

90

60

10

76

29

19

20

0

0

14

0

5

Infrared

90

50

20

90

38

24

80

70

0

38

19

5

UV or Visible Spectroscopy

80

30

10

81

33

24

60

10

0

29

10

10

Raman

80

20

10

38

5

5

70

20

0

24

5

0

FBRMb

70

30

10

43

19

19

60

20

0

29

14

10

Refractive Index

60

30

10

67

24

14

50

20

0

19

10

0

Camera

50

20

0

57

19

14

40

10

0

24

10

5

pH Measurement

90

40

30

90

43

19

50

30

20

62

38

14

80

50

20

67

43

29

90

50

20

71

48

33

Process Temperature

Not applicable

Process Pressure


45


XRF, Dissolved O2 probes

Other Capabilities

PVM, TGA, DSC, pXRD, Density, NIR

Page 46 of 75

XRF, Dissolved O2 sensor

Conductance probe, Density, PVM, NIR Spectroscopy

Values represent percent of responses in the affirmative relative to the total IQ respondents (10) or CMO respondents (21). Cells containing values >75% are highlighted in yellow with blue font. Cells with values between 50-74% are highlighted in light blue with bolded, black font. bFocused Beam Reflectance Measurement

a

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 100 kg

20

38

GMP

10

33


46

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Approval for Forward Process

Feedback Control

Real time Release Testing

< 1 kg

10

29

1 - 100 kg

30

33

> 100 kg

10

33

GMP

0

24

< 1 kg

0

24

1 - 100 kg

20

29

> 100 kg

0

29

GMP

0

10

< 1 kg

0

10

1 - 100 kg

0

14

> 100 kg

0

19

GMP 0 10 Cells containing values >75% are highlighted in yellow with bolded, blue font. Cells with values between 5074% are highlighted in light blue with bolded, black font.

a

Incorporating analytical methods into continuous processes has many potential benefits. The data can provide scale-up knowledge of the process to improve the understanding of both the process and the equipment the process is run in, which translates to better design and control. Real time analytical data, especially if coupled to feedback control, provide an opportunity to modify parameters in real time, either to obviate a deviation or to further optimize the conditions of the process in real time, resulting in greater process control and the potential for a consistently higher quality product.32 For processes that have multiple, consecutive continuous operations, real-time data may be critical to 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.


47


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The benefits of incorporating analytical methods into a process must be weighed against the costs of doing so. Implementing on-line 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 cost effective means to monitor a process will be the simple ones, such as process temperature and pressure. Clearly the full potential of incorporating analytical methods into CP has not been realized in the pharmaceutical industry and 3rd party network in general. Regulatory The IQ and CMO groups were asked if they contributed to a continuous process that was part of a regulatory filing or interaction (Table 13). Continuous processes have advanced to NDA filings for at least two NCEs within the IQ group. Interestingly, the CMO group responded with 3 NDA filings and 3 ANDA filings, implying that the generics market is also advancing in continuous manufacturing. This is encouraging given the uncertainties surrounding regulatory filing of CP. The number of EOP2 meeting contributions implies that companies planning to file continuous processes are notifying the regulatory agencies of these plans in order to receive early agency feedback.


48

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Table 13. IQ and CMO regulatory experience with continuous processes EOP2 IND NDA ANDA Meetinga IQb

2

3

2

0

CMOc

3

4

3

3

a

EOP2 = End of Phase 2; b10 respondents; c20 respondents

The two groups were asked a series of questions related to the definition of batches, process excursions, and cleaning procedures in an open-ended response format. When asked how a batch was defined, the respondents used one or more of three approaches. In one approach, the process stream is consolidated into a single tank for final BP, thereby defining the batch. In those cases wherein a CP stream required more than one iteration of consolidation (e.g. new vessel or separate collection in the same vessel), each iteration would constitute a new batch. A second approach was to define a batch by time of processing. The third approach was to define a batch by lot of raw material.35 When asked how batch history was accounted for if feed materials changed in the midst of a CP, most respondents indicated they did not handle it differently than a typical BP, wherein all lots of feed materials were added to the batch record. One respondent indicated the batch history would be defined based upon time and residence time distribution. This latter approach seems to increase complexity, but may be needed when numerous raw material lots are used over a long period of continuous processing, and multiple batches are produced. When an excursion in the process occurs, all those that responded indicated they divert to another vessel and send to waste if not within specifications.


49


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Cleaning of pumps and process hoses were handled similarly to batch, wherein a standard cleaning procedure was in place, followed by an analytical verification (e.g. UV analysis of test sample). When the respondents were asked if they had participated in a technology transfer of a CP to a pharmaceutical GMP facility, only one company from each group indicated having this experience. As a follow-up, those that responded in the affirmative were asked to note any differences compared to transferring a BP. The CMO respondent indicated they had only transferred CPs, so did not have a comparison with BP transfers. The IQ respondent indicated that new technologies required additional time to install, but that re-using existing continuous processing equipment can result in reduced transfer time compared to batch. 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 33% (3 of 9) 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


50

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implies that most companies from both Pharma and CMO groups do not foresee a wholesale change from what is now predominantly BP to CP, at least not in the next 15 years.

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 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 sited, 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 doesn’t 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


51


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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.

Table 14. Barriers to implementing CPs (IQ and CMO groups)

IQ Group

CMO Group

•

Compelling business case and internal sponsorship, especially when existing batch capacity is available

•

Existing batch capacity weakens business case, less compelling if only a small portion of the process is continuous

•

Cost of equipment and training

•

Cost of equipment and training

•

Time to make the transition from batch to continuous

•

Lab development tools are lacking

•

Risk averse nature of pharmaceutical companies

•

Cultural - scientists have batch design mindset, continuous perceived as higher risk

•

Requires additional time to develop, not widely accepted by Pharma customers

•

Higher initial costs to outsource - vendors charge additional development costs

•

Alignment with Quality function

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, and there are clearly some categories that overlap with others (Figure 14). However, this provides a snapshot 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


52

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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 capabilities by externalizing or developing those capabilities internally. Process control was amongst 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 sub-categories 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.


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

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 towards 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.


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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 amongst 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 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 post-reaction 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 electrochemistry 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, post-reaction 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 post-reaction processing between telescoped reactions. This is consistent with


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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. Post-reaction 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 post-reaction 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 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 3rd party network compared to that of the IQ group. In general, most of the IQ group chemistry experience is at the smaller scales (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 post-reaction 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. There are a number of actions Pharma and the CMO 3rd 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 pre-competitive collaborations wherein learnings are shared in real time, and resources can be distributed across a larger group, accessing a ACS Paragon Plus Environment

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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 pre-competitive 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 knowledge learned on applications to products in other industries, albeit within the confines of their own portfolio. Another opportunity to accelerate the uptake and use of CP is to develop standardized, commercially available platforms. One could envision CP platforms for reactions and unit operations to be interchangeable with plug-and-play designs to reduce capital investment and development time. However, this vision has not been realized, in part due to the lack of standardization across the industry. Publications of new CP tools for organic synthetic chemistry are becoming commonplace, and some Pharma companies are developing their own, in-house technology. This approach continues to advance the science, but may not always be the best approach to advancing the use of CP in industry as a whole. The absence of harmonized, commercial platforms for both development and manufacturing will result in slower uptake and higher costs for equipment purchases, equipment maintenance, and technology transfer from one platform to another. Some platforms may be ready for standardization now, while


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other technology still needs more basic research. Collaborative approaches to standardization where possible and basic research where needed could benefit both the individual companies and the industry as a whole.

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 post-processing 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.

Despite significant gap areas within CP, and a strategy of advancing the technology that is inherently slow and costly, and existence of barriers such as cost, culture, training and perceived regulatory risk, the results of this survey indicate that the technology has moved forward and is expected to continue


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advancing within Pharma and the CMOs 3rd party network. There have been some early adopters that have pushed forward to an advanced state of practice, with large portions of their portfolio and processes committed to CP. Some IQ and CMO companies have regulatory experience with applications that have contributed to INDs, NDAs, and ANDAs. The survey also shows a level of broader CP uptake across the industry, and it appears that we are in a phase wherein “fast followers” have begun to buy up as well. Currently, there is sufficient CP experience and capabilities for reaction chemistry across a range of CMOs such that Pharma should have reasonable confidence that externalization options for chemical transformations are available even if internal capabilities are lacking. However, sequencing multiple CP unit operations is far more limited in the CMO network and while the breadth of CP experience is broad, it is still spread across the network. Therefore, Request for Information (RFI) approaches to obtain detailed understanding of individual CMO capabilities will be important to making strategic decisions around which chemical transformations and processes will be amenable to a range of suppliers at different scales, and which suppliers will be able to implement CP processes with multiple linked operations versus hybrid CP-BP approaches. This survey has provided details of the CP landscape across representative Pharma and CMO companies. It will be interesting to see how that landscape changes over the next several years, and we plan to conduct a follow-up survey in the future to assess how the industry has progressed in CP since this survey was taken. Supporting Information. A complete list of the survey questions (PDF). Corresponding Author *Email: [email protected] Author Contributions


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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources The authors declare no competing financial interests. ACKNOWLEDGMENTS This manuscript was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community. We would like to gratefully thank all the companies that took the time to answer the questionnaire. We would also like to thank Drinkler Biddle and Reath staff, especially Maja Leah Marshall for her support of the project. Finally, we thank the reviewers for their helpful suggestions. REFERENCES 1.

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Lee, D. S.; Amara, Z.; Clark, C. A.; Xu, Z.; Kakimpa, B.; Morvan, H. P.; Pickering, S. J.; Poliakoff, M.; George, M. W., Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory. Org. Proc. Res. Dev. 2017, 21 (7), 1042-1050; (c) Lehmann, H., A scalable and safe continuous flow procedure for in-line generation of diazomethane and its precursor MNU. Green Chem. 2017, 19 (6), 1449-1453; (d) Chen, Y.; Gutmann, B.; Kappe, C. O., Continuous-Flow Electrophilic Amination of Arenes and Schmidt Reaction of Carboxylic Acids Utilizing the Superacidic Trimethylsilyl Azide/Triflic Acid Reagent System. J. Org. Chem. 2016, 81 (19), 9372-9380; (e) White, T. D.; Berglund, K. D.; Groh, J. M.; Johnson, M. D.; Miller, R. D.; Yates, M. H., Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide. Org. Proc. Res. Dev. 2012, 16 (5), 939957. 12. Movsisyan, M.; Delbeke, E. I.; Berton, J. K.; Battilocchio, C.; Ley, S. V.; Stevens, C. V., Taming hazardous chemistry by continuous flow technology. Chem. Soc. Rev. 2016, 45 (18), 4892-928. 13. (a) Triemer, S.; Gilmore, K.; Vu, G. T.; Seeberger, P. H.; Seidel-Morgenstern, A., Literally Green Chemical Synthesis of Artemisinin from Plant Extracts. Angew. Chem. Int. Ed. 2018, 57 (19), 5525-5528; (b) Hsieh, H.-W.; Coley, C. W.; Baumgartner, L. M.; Jensen, K. F.; Robinson, R. I., Photoredox Iridium–Nickel Dual-Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor. Org. Proc. Res. Dev. 2018, 22 (4), 542550; (c) Otake, Y.; Nakamura, H.; Fuse, S., Recent advances in the integrated micro-flow synthesis containing photochemical reactions. Tetrahedron Lett. 2018, 59 (18), 1691-1697; (d) Lisiecki, K.; Czarnocki, Z., Flow Photochemistry as a Tool for the Total Synthesis of (+)-Epigalcatin. Org. Lett. 2018, 20 (3), 605-607; (e) Kong, C. J.; Fisher, D.; Desai, B. K.; Yang, Y.; Ahmad, S.; Belecki, K.; Gupton, B. F., High throughput photo-oxidations in a packed bed reactor system. Bioorgan. Med. Chem. 2017, 25 (23), 6203-6208; (f) Fabry, D. C.; Ho, Y. A.; Zapf, R.; Tremel, W.; Panthöfer, M.; Rueping,


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M.; Rehm, T. H., Blue light mediated C–H arylation of heteroarenes using TiO2 as an immobilized photocatalyst in a continuous-flow microreactor. Green Chem. 2017, 19 (8), 1911-1918; (g) Photochemical Processes in Continuous-Flow Reactors: From Engineering Principles to Chemical Applications. World Scientific: 2017; p 284; (h) Jackl, M. K.; Legnani, L.; Morandi, B.; Bode, J. W., Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis. Org. Lett. 2017, 19 (17), 4696-4699; (i) Emmanuel, N.; Mendoza, C.; Winter, M.; Horn, C. R.; Vizza, A.; Dreesen, L.; Heinrichs, B.; Monbaliu, J.-C. M., Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow Conditions. Org. Proc. Res. Dev. 2017, 21 (9), 1435-1438; (j) Douglas, J. J.; Sevrin, M. J.; Cole, K. P.; Stephenson, C. R. J., Preparative Scale Demonstration and Mechanistic Investigation of a Visible Light-Mediated Radical Smiles Rearrangement. Org. Proc. Res. Dev. 2016, 20 (7), 1148-1155; (k) Douglas, J. J.; Sevrin, M. J.; Stephenson, C. R. J., Visible Light Photocatalysis: Applications and New Disconnections in the Synthesis of Pharmaceutical Agents. Org. Proc. Res. Dev. 2016, 20 (7), 1134-1147; (l) Lima, F.; Kabeshov, M. A.; Tran, D. N.; Battilocchio, C.; Sedelmeier, J.; Sedelmeier, G.; Schenkel, B.; Ley, S. V., Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp(2) )-C(sp(3) ) CrossCouplings in Flow. Angew. Chem. Int. Ed. 2016, 55 (45), 14085-14089; (m) Cambie, D.; Bottecchia, C.; Straathof, N. J.; Hessel, V.; Noel, T., Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116 (17), 10276-341. 14. (a) Li, H.; Breen, C. P.; Seo, H.; Jamison, T. F.; Fang, Y. Q.; Bio, M. M., Ni-Catalyzed Electrochemical Decarboxylative C-C Couplings in Batch and Continuous Flow. Org. Lett. 2018, 20 (5), 1338-1341; (b) Atobe, M.; Tateno, H.; Matsumura, Y., Applications of Flow Microreactors in Electrosynthetic Processes. Chem. Rev. 2018, 118 (9), 4541-4572; (c) Pletcher, D.; Green, R. A.; Brown,


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R. C. D., Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev. 2018, 118 (9), 4573-4591. 15. This is not intended to be a comprehensive list. 16. (a) Ziegler, R. E.; Desai, B. K.; Jee, J. A.; Gupton, B. F.; Roper, T. D.; Jamison, T. F., 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. Angew. Chem. Int. Ed. 2018, 57 (24), 71817185; (b) Britton, J.; Raston, C. L., Multi-step continuous-flow synthesis. Chem. Soc. Rev. 2017, 46 (5), 1250-1271; (c) Cole, K. P.; Groh, J. M.; Johnson, M. D.; Burcham, C. L.; Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J. R.; Kallman, N. J.; Koenig, T. M.; May, S. A.; Miller, R. D.; Mitchell, D.; Myers, D. P.; Myers, S. S.; Phillips, J. L.; Polster, C. S.; White, T. D.; Cashman, J.; Hurley, D.; Moylan, R.; Sheehan, P.; Spencer, R. D.; Desmond, K.; Desmond, P.; Gowran, O., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science 2017, 356 (6343), 1144-1150; (d) Bana, P.; Orkenyi, R.; Lovei, K.; Lako, A.; Turos, G. I.; Eles, J.; Faigl, F.; Greiner, I., The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds. Bioorg. Med. Chem. Lett. 2017, 25 (23), 6180-6189; (e) Britton, J.; Jamison, T. F., Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules. Eur. J. Org. Chem. 2017, 2017 (44), 6566-6574; (f) Verghese, J.; Kong, C. J.; Rivalti, D.; Yu, E. C.; Krack, R.; Alcázar, J.; Manley, J. B.; McQuade, D. T.; Ahmad, S.; Belecki, K.; Gupton, B. F., Increasing global access to the high-volume HIV drug nevirapine through process intensification. Green Chem. 2017, 19 (13), 2986-2991; (g) Lin, H.; Dai, C.; Jamison, T. F.; Jensen, K. F., A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in Continuous Flow. Angew. Chem. Int. Ed. 2017, 56 (30), 8870-8873; (h) Britton, J.; Jamison, T. F., A Unified Continuous Flow Assembly-Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines. Angew. Chem. Int. Ed. 2017, 56 (30), 88238827; (i) Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu,


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J. C.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P., On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 2016, 352 (6281), 61-7; (j) Porta, R.; Benaglia, M.; Puglisi, A., Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products. Org. Proc. Res. Dev. 2015, 20 (1), 2-25; (k) Tsubogo, T.; Oyamada, H.; Kobayashi, S., Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts. Nature 2015, 520, 329; (l) Ghislieri, D.; Gilmore, K.; Seeberger, P. H., Chemical assembly systems: layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 2015, 54 (2), 678-82; (m) Mascia, S.; Heider, P. L.; Zhang, H.; Lakerveld, R.; Benyahia, B.; Barton, P. I.; Braatz, R. D.; Cooney, C. L.; Evans, J. M.; Jamison, T. F.; Jensen, K. F.; Myerson, A. S.; Trout, B. L., End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. Angew. Chem. Int. Ed. 2013, 52 (47), 12359-63. 17. At the time of writing, there are no journal publications describing a commercial CP actively used in the GMP production of commercial API. 18. (a) Nasr, M. M.; Krumme, M.; Matsuda, Y.; Trout, B. L.; Badman, C.; Mascia, S.; Cooney, C. L.; Jensen, K. D.; Florence, A.; Johnston, C.; Konstantinov, K.; Lee, S. L., Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals. J Pharm Sci 2017, 106 (11), 3199-3206; (b) Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M. V.; Yu, L. X.; Woodcock, J., Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. J. Pharm. Innov. 2015, 10 (3), 191-199. 19. The complete survey is included in the Supporting Information.


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20. CMO Group: Almac, Alphora Research Inc, AMPAC Fine Chemicals, APC Ltd, Ash Stevens Inc., Asymchem Inc., CARBOGEN AMCIS, Continuus, CSIRO Manufacturing, Dottikon Exclusive Synthesis, DSM, Euticals, Lonza, Microinnova GmbH, Minakem SAS, Patheon, Piramal Enterprises, Porton Fine Chemicals Ltd, Sai Life Sciences Ltd., Siegfried, SK Biotek, Snapdragon Chemistry, Inc, Syngene International Ltd, SynTheAll (Wuxi AppTec), Takasago International Corporation. Notably, some of the vendors are more accurately classified as Contract Research Organizations (CROs). To simplify the text, the entire group was refered to as the CMO Group. IQ Member Group: AbbVie Inc, Amgen,

Biogen,

Bristol-Myers

Squibb,

Boehringer

Ingelheim,

Eli

Lilly

and

Company,

GlaxoSmithKline, Novartis, Pfizer, Takeda Pharmaceutical Company. 21. Drug Product CP is not considered as part of this survey. 22. A chemist or engineer with experience was defined as one having developed at least two continuous processes. 23. The responses do not indicate how much of the platform capability is available to the Pharma sector, as some companies may have CP platforms designed for use supplying other markets, and an organizational structure may not be optimal to capture opportunities between internal business lines. 24. N-Boc = a primary or secondary amine protected with a tert-butoxycarbonyl group. Provide references 25. Choy, J.; Jaime-Figueroa, S.; Jiang, L.; Wagner, P., Novel Practical Deprotection of N-Boc Compounds Using Fluorinated Alcohols. Synth. Commun. 2008, 38 (21), 3840-3853. 26. (a) Usutani, H.; Nihei, T.; Papageorgiou, C. D.; Cork, D. G., Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material. Org. Proc. Res.


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Dev. 2017, 21 (4), 669-673; (b) Feng, R.; Ramchandani, S.; Ramalingam, B.; Tan, S. W. B.; Li, C.; Teoh, S. K.; Boodhoo, K.; Sharratt, P., Intensification of Continuous Ortho-Lithiation at Ambient Conditions—Process Understanding and Assessment of Sustainability Benefits. Org. Proc. Res. Dev. 2017, 21 (9), 1259-1271; (c) Grongsaard, P.; Bulger, P. G.; Wallace, D. J.; Tan, L.; Chen, Q.; Dolman, S. J.; Nyrop, J.; Hoerrner, R. S.; Weisel, M.; Arredondo, J.; Itoh, T.; Xie, C.; Wen, X.; Zhao, D.; Muzzio, D. J.; Bassan, E. M.; Shultz, C. S., Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor. Org. Proc. Res. Dev. 2012, 16 (5), 1069-1081. 27. Yu, Z.; Lv, Y.; Yu, C.; Su, W., A High-Output, Continuous Selective and Heterogeneous Nitration of p-Difluorobenzene. Org. Proc. Res. Dev. 2013, 17 (3), 438-442. 28. Some of the respondents did not specify a lower temperature limit. For the purposes of this analysis, these were assumed to be ambient unless otherwise indicated. It is possible that the number of respondents having gas-liquid PFRs with lower temperature limits of T ≤ -20 °C is higher than what is noted in the table. 29. Amara, Z.; Poliakoff, M.; Duque, R.; Geier, D.; Franciò, G.; Gordon, C. M.; Meadows, R. E.; Woodward, R.; Leitner, W., Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis. Org. Proc. Res. Dev. 2016, 20 (7), 1321-1327. 30. Hamawand, I.; Yusaf, T., Particles motion in a cascading rotary drum dryer. Can. J. Chem. Eng. 2014, 92 (4), 648-662. 31. Faanes, A.; Skogestad, S., Buffer Tank Design for Acceptable Control Performance. Ind. Eng. Chem. Res. 2003, 42 (10), 2198-2208.


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32. Sans, V.; Cronin, L., Towards dial-a-molecule by integrating continuous flow, analytics and selfoptimisation. Chem. Soc. Rev. 2016, 45 (8), 2032-43. 33. This would also be applicable to single unit operations. All responses to the question on what is the fate of material that is not in specifications indicated they divert this material to waste (vide infra). 34. Allison, G.; Cain, Y. T.; Cooney, C.; Garcia, T.; Bizjak, T. G.; Holte, O.; Jagota, N.; Komas, B.; Korakianiti, E.; Kourti, D.; Madurawe, R.; Morefield, E.; Montgomery, F.; Nasr, M.; Randolph, W.; Robert, J. L.; Rudd, D.; Zezza, D., Regulatory and Quality Considerations for Continuous Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci 2015, 104 (3), 803-812. 35. It is not clear how the third approach meets the ICH Q7A definition of a batch, but may imply that each lot (or lots) of raw material is used in a discrete continuous run producing a single lot of API. 36. Noteably, 3 of the 5 companies that indicated >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". Dispite this potential ambiguity, the trends remain the same. 37. (a) Dilman, A. D.; Levin, V. V., Difluorocarbene as a Building Block for Consecutive BondForming 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.


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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, BoehringerIngelheim, and Pfizer to share knowledge and advance the technology for the use of non-precious 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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