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Kimberly JohnsonSite Head Quality Assurance

Small molecules:2020 visionExpert insights from the small molecule company

Robert MatthiesonMFG Chemist II

Part 2 of 2

2015 - 20192016 - 2019

https://www.cambrex.com

Steven KloskPresident andChief Executive Officer

The successful integration of Halo Pharma and Avista Pharma Solutions has transformed Cambrex into a true end-to-end CDMO. The past year has been a busy one with our global teams focused on the strategic transformation and the expansion of our capabilities and services across the entire small molecule lifecycle.

Industry growth

The pharmaceutical industry continues to grow and is estimated to be worth $1.5 trillion by 2021, driven by positive industry trends — many of which our experts commented on in Part 1. Market data shows just how big the small molecule pharmaceutical market is, making up 65% of the total clinical pipeline and growing at the fastest rate seen in more than a decade.

Investing to stay ahead

As a CDMO, our success lies in the ability to serve our diverse customer base and evolve with the industry, while

striving to stay one step ahead. We are continually adapting and enhancing our approach and resources to offer the most appropriate outsourcing solutions in terms of capacity, expertise and technologies on a global basis. This enables us to handle a wider variety of drug substance and drug product projects and chemistries with greater flexibility than ever before.

From lab-scale to commercial manufacturing, adapting to the dynamic demands of the marketplace is crucial. Our commitment to investing in technologies such as continuous flow, solid-state chemistry and high potency manufacturing facilities will benefit us and, most importantly, our customers.

Enjoy Part 2 of our latest Cambrex insights.

Steven Klosk

President and Chief Executive Officer

Cambrex leads the way

https://www.cambrex.com/wp-content/uploads/Cambrex_eBook_2019_Part1.pdf

Praveen SuryadevaraSenior Research Scientist

Contents

Process optimization by design

Outsourcing analytical testing: The gateway to drug manufacturing

Utilizing spectral analysis in HPLC diode array to discover impurities

Considerations for replacing deuterium lamps in HPLC systems

Select suppliers with demonstrated expertise to avoid sourcing “bad” APIs

Off the drawing board

Overcoming limitations to achieve uniform dosing

The complexities of developing pediatric oral doses

Combo drugs require a complex design approach

An interview with Anthony Qu, PhD

Uncovering hidden risks in solid-state API properties

Peak identification by LC/MS: Automation versus analyst

The economic advantages of continuous flow chemistry

Successful technology transfer

Technical advantages of continuous flow chemical synthesis

Cambrex updates integration of Halo Pharma and Avista Pharma; expands small molecule API manufacturing

Small molecules still big at DCAT Week

Outsourcing formulation development and manufacturing

The economic benefits of continuous flow

HPAPI capacity challenges

Handling and assessing HPAPIs

The right pieces for a quality program

Development of continuous flow — Updating the toolbox

Five minutes with Shawn Cavanagh

Five minutes with Joe Nettleton

Award winning

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Pediatric dosage form development: Challenges and opportunities

De-risking the solid form landscape of an API: How predictable stability and solubility can minimize development timelines and cost

75Future focus: Our 2020 vision

Experts you’ll enjoy working with

Manufacturing & Investments

Elaine JenningsDirector, Process Improvements

Josh TiptonProcess Technician I


However, economic advantages are taking continuous flow out of the realm of a niche technology for high energy, hazardous reactions to become an essential part of the small molecule manufacturing toolkit.

Using continuous flow chemistry to safely handle these high-energy products and reagents has removed the need for batch operations to be done in bunkered production facilities that are expensive to set up and maintain. The efficient use of continuous flow can also show marked cost savings through a smaller footprint and overall process simplification.

As a result, continuous flow can lead to a capital expenditure reduction of approximately 50%, although the savings can be even more dramatic in some instances. It is feasible to convert a batch process into a very compact, designated flow production workspace.

Figure 1 shows a developmental phase process involving a Grignard reaction, a formulation coupling, a reduction, quench and, finally, the addition of a cosolvent that was set up using five reactors coupled with multiple recirculating temperature controllers, scales and pumps. The entire process fitted within a double-sided, walk-through hood with a total footprint of approximately 50 sq. ft..

Further cost benefits can be achieved from the reduction of inputs. Energy consumption can be cut by up to 30%, whereas solvent usage will also be reduced significantly — or in some cases eliminated entirely — as a result of enhanced process control. In addition, less waste solvent will be produced, which

reduces the costs associated with its disposal and drastically improves the process intensity for the final product.

Typically, operating costs are also significantly reduced; studies have estimated total operational savings to be in the region of 20%, and possibly as much as 50%, compared with traditional batch operations. Some of this comes about as a result of lower labour requirements and the need for fewer

Batch production has been the traditional workhorse of the pharmaceutical manufacturing sector.



Figure 1: A developmental phase process involving a Grignard reaction, a formulation coupling, a reduction, quench and the addition of a cosolvent that was set up using five reactors coupled with multiple recirculating temperature controllers, scales and pumps


analytical procedures, but process efficiencies that are gained from yield and quality improvements also play a key role.

Frequently in a batch process, infrastructure constraints such as achievable pressures, temperatures, addition rates or equipment availability within a plant will force a process chemist or engineer to accept a less than ideal synthetic route, which can generate impurities that must be removed. In some instances, continuous flow can avoid these impurities, or at least reduce them significantly, by designing the process to avoid or minimise their formation, whereas analysis can be integrated into the process rather than functioning as a separate operation, resulting in major savings in both time and cost.

As a result, optimising the chemical synthesis in flow can reduce lengthy reaction times and extensive work-ups, drastically lowering occupancy requirements and reducing the plant time required for a given process. This not only cuts the cost of a project, but can also free up capacity for additional production and revenue.

Developmental and scale-up implications

Another key advantage of continuous flow is that the overall development phase can be shortened considerably. Depending on the required volumes for a process as it moves through the different clinical phases, the same equipment used for early development can remain with that process through to the later phase batches and, possibly, even into commercialization.

Streamlining this traditional workflow could even eliminate the scale-up phases of the development cycle entirely, saving not only the costs of those batches, but also reducing the time to market by months or even years and enabling development investment costs to be recovered sooner.

Even in the most controlled scenarios, scale-up is inherently non-linear, and this is exacerbated by the variations in equipment design that are often found between facilities or in the different phases of process development. Equipment geometry, material quantities and resulting addition rates, agitator design, heat transfer capability and efficiency all influence scale-up and impact the core attributes of a chemical process.

A common and significant scale-up challenge with conventional batch reactors is agitation, especially at larger volumes. Predicting the differences in mixing profiles between vessels is a complicated process with many variables. Even with constant aspect ratios, the characteristic mixing time within a vessel can increase by an order of magnitude with a simple increase in scale from one to 50 litres. Ultimately, the impact of agitation manifests itself by an inability to maintain consistency.

Perturbations in concentration can directly affect chemical synthesis as the availability of reagents can limit a desired reaction or potentially cause an undesired one. Extending reaction times to ensure full, or at least acceptable, conversion can not only have an adverse effect on product quality but can also extend processing times, thereby decreasing throughput and ultimately increasing the cost.

These are only a few examples to illustrate why scale-up can be one of the most difficult aspects of the traditional batch manufacturing process, but continuous flow chemistry can address some of the major challenges. One powerful

alternative is that rather than having to transfer a process from a small reactor to incrementally larger ones — with the validation requirement that each step entails — scaling-up a continuous flow process can simply require the addition of another reactor of the same size to run in parallel (scaling out), thereby reducing validation costs significantly.

Alternatively, depending on the volume demands of a process as it moves through the development phases, continuous flow technology can achieve volume increases or batch size demands by increasing the run times rather than necessitating an increase in scale: one day to make 10kg, two days to make 20kg, four to make 40kg, etc. Scale-up can be effectively eliminated just by utilising throughput.

Risk management

The use of continuous flow technologies has important implications for process control and analytics. With most batch processes, critical process parameters are developed and tested throughout the development and validation stages, but quality decisions and material dispositions are often based on offline representative testing. Using this approach, it is possible that an entire production batch can be processed... only to fall out of specification and require reprocessing or disposal.

In contrast, continuous flow allows for the implementation of real-time feedback so that measured values are available instantly and potential disruptions can be realised, captured and solved with an appropriate control strategy, avoiding a scenario in which an entire batch is put at risk. Constant monitoring of the flow rate and other critical process parameters mean that small changes can be made in real-time to account for fluctuations.

For a process that is well understood and tightly defined, control can be maintained with simplified measurements. In such cases, the process analytical technology (PAT) required is generally easier than that of batch production — often with only temperature probes and flow meters being required to ensure that the process remains within the acceptable parameters to deliver product of a known quality.

"Even in the most controlled scenarios, scale-up is inherently non-linear."

If necessary, sophisticated PAT probes can be easily integrated into a flow process to allow for the rapid detection of deviations, as well as providing nearly continuous monitoring of quality, as opposed to waiting on a single batch sample and corresponding measurement.

Introducing additional PAT can provide an extra level of process performance assurance and product quality. Layering in measurements to track key parameters, such as reaction conversion, can be utilised to make real-time adjustments to correct raw material variations or drift that may be happening within the process itself.

In situ spectroscopic techniques, such as Fourier-transfer infrared (FTIR) or Raman spectroscopy, can be used to map reaction kinetics, and then subsequently incorporated into flow streams for the real-time monitoring of conversion. Peak depletion or peak growth can be used during development to define optimal conditions, allowing for peak intensity to be tracked online during campaigns to monitor for deviations and to develop a process control response.



Case study: Commercial-scale nitration

A batch operated nitration process was converted into a commercial-scale continuous flow process with an annual capacity of more than 50 tonnes, with a view to meet growing demand from the customer and also to free up capacity and reduce operational costs. The project presented a number of major challenges.

First, the intermediate itself was highly energetic and to transfer it from a bunkered facility into a regular manufacturing facility involved rigorous safety assessments and precautions. Additionally, the nitration reaction is exothermic and requires a high cooling capacity to strictly control the temperatures during the reaction.

The process was a heterogeneous liquid/solid slurry system, carrying more than 30% of the solid throughout the process from the raw material feed into the nitration reaction, followed by a quench step and isolation. This meant that both heat and mass transfer had to be managed carefully to achieve a safe and predictable process. A further requirement was to keep the purity profile unchanged; any variation could affect both capacity and quality in the downstream processes.

Commissioning of the new continuous flow nitration production train began within seven months of the start of the project. The equipment was first tested using water to verify the functionality, after which 14 pilot batches of varying size were produced to optimise the process parameters during start-up, steady state and batch end.

All 14 batches met the quality specifications, proving the robustness of the continuous flow process. During commissioning, another reactor was added, which doubled the capacity of the production train for a relatively modest 10% additional investment.

The upgraded production train now consists of two nitration reactors working in parallel and with one confined post-reaction vessel. Capacity has been increased significantly and the bottleneck has been moved downstream in the process to product isolation and waste handling.

The project met all its target objectives. The annual capacity of the new continuous flow production train is in excess of 80 tonnes — well above the original target of 50 tonnes — and capacity has been freed up in the bunkered high-energy pilot plant.

All of the batches produced have been within specification and had the same purity profile as product made in batch mode. Furthermore, the improved repeatability in the continuous process generates product with a much more consistent quality between batches compared with the previous process.

The safety of the process has been maintained and even improved, enabling operation in the regular production facility. This consolidation has, in turn, significantly reduced the overall cost of production and improved internal logistics. The currently installed API manufacturing infrastructure means that batch operation will continue to be the predominant production method for the foreseeable future.

However, the interest from large pharmaceutical companies in becoming increasingly engaged with continuous flow technologies, in both API manufacture and formulation, indicates that demand for continuous flow is set to increase. Vertex and Johnson & Johnson have

the first two FDA-approved continuous flow processes for drug products, whereas Eli Lilly, GSK and Novartis, among others, have invested significantly in development and production capabilities.

Every unit operation associated with traditional batch processing has a flow counterpart, and throughputs achievable with continuous flow can rival batch capacities and often even outperform them for small-volume molecules. Continuous flow should therefore be regarded as a truly enabling technology and a powerful development tool.

First published: Manufacturing Chemist

Title: The economic advantages of continuous

flow chemistry

Date: April 2, 2019

About the author

Dr Shawn Conway,

Director, Engineering Research

and Development,

Cambrex



Preparing for a tech transfer

Question (Q): What are the first steps that should be taken when starting the process of tech transfer?

Dan Bowles and Kurt Kiewel (DB & KK): The early transfer of information between companies is critical to a successful process transfer. At the RFP [request for proposal] stage, the receiving site should review the information provided and set up a teleconference to fully define the goals of the transfer and discuss the information provided in detail. The discussion between the technical staff on both sides helps to fill in any gaps in the information and to eliminate any ambiguities in the RFP and assumptions in the proposal. Early alignment between parties allows a proposal to be tailored to the precise goals of the program and reduces unnecessary back-and-forth during the proposal generation process. When possible, representatives from the receiving site should travel to the sending site in order to witness key operations first-hand.

Q: Should both entities be involved in developing the tech transfer process?

DB & KK: The receiving site should drive the transfer process, as it will ultimately be responsible for adherence to internal SOPs [standard operating procedures] and the final outcome of the transfer. The manner of transferring a specific technology or process from site to site should not be developed in an ad-hoc manner, but instead by following a clear, well-defined,

SOP-driven method, regardless of whether the transfer is within a company or between a sponsor and CDMO.

Inter-company transfers should start at the early development stage with an understanding that the process is being developed for transfer to a known inter-company site, and unit operations should be developed with the full knowledge of both sites’ capabilities. Additionally, analytical methods should be developed for instrumentation which has been harmonized between sites in order to streamline method transfer.

Best practices and challenges

Q: What are some best practices and challenges in technology transfer, and how are these addressed? Are there specific considerations when it comes to large-molecule products/processes versus small molecule?

DB & KK: One of the key challenges facing technology transfer for manufacturing is the difference between equipment and specific reactors at different facilities. For internal transfers within a company, standard practice should be that the development work done at the developing/sending site is carried out with careful consideration for the equipment capabilities of the receiving site — a true one-company approach.

An interview with Daniel Bowles, Senior Director, Chemical Development, at Cambrex; and Kurt Kiewel, Director, Research and Development, also at Cambrex, about best practices for a successful technology transfer.




About the authors

Dan Bowles,

Senior Director, Chemical Development,

Cambrex

Title: Successful technology transfer

Date: April 2, 2019

Kurt Kiewel,

Director, Research and Development,

Cambrex



Continuous flow chemistry has traditionally been used as a safer and more efficient way of handling high-energy products and reagents when batch operations were deemed too dangerous. To undertake these in batch mode often requires bunkered production facilities away from main manufacturing areas, while vessel sizes and inventories would be kept low so that in an uncontrolled event, any damage could be easily contained and the risk to personnel and the surrounding area would be limited. However, constructing and maintaining these facilities, together with the small scale of the reactions, can be prohibitively costly.

Continuous flow processing reduces the effective volume of a unit operation, enhances control and minimizes the exposure and risk so that energetic chemistries or hazardous reagents can be handled safely. It does not eliminate safety concerns entirely, but does reduce the risk factors to levels that are easier to manage and mitigate. Furthermore, by enabling these operations to take place in a regular manufacturing plant, they can be linked directly to other downstream processes, giving the advantage of integration of operations.

Chemical syntheses which have benefited from continuous flow on a commercial level include nitration, where the rapid reaction can be monitored and controlled to ensure the process is efficient and yields high-quality product.

Case study: Conversion of batch nitration to continuous flow process

A nitration process that Cambrex converted from batch to continuous processing demonstrates the safety benefits that the technology affords at its Karlskoga, Sweden facility, the company developed a commercial scale continuous flow process with an annual capacity of more than 50 tons within its regular production facility.

The intermediate in the reaction itself is highly energetic (more than 2,000 kJ per kilogram), so the process to transfer it into a regular manufacturing facility involved rigorous safety assessments and precautions. Additionally, the nitration reaction is exothermic and requires high cooling capacity to strictly control the temperatures during the reaction.

Based on the risk profile, a focus of process development was carefully managing both heat and mass transfer to achieve a safe and predictable operation of the process. A formal Design of Experiments (DoE) study was carried out to investigate the impact of key parameters, such as residence time and reaction temperature, on yield and purity to ensure the process can not only be conducted safely but also without sacrificing efficiency or quality.

Based on the DoE results in conjunction with early development work in the laboratory, the effort to design the nitration reactors began, again with the focus being on

Continuous flow chemistry is known for its ability to handle hazardous reactions safely, but can also unlock many other technological benefits.




maximizing heat and mass transfer. Two continuous stirred tank reactors (CSTRs) were chosen, each with a volume of 15L so that at any single time in the process, the amount of material in each reactor was limited to 5kg. The arrangement also offered a relatively high surface to volume ratio, which is of course beneficial for the heat transfer. To minimize the risk of any pressure build-up in the event of a runaway reaction, the design of the pressure relief on the reactors was oversized.

The reaction vessels by design allow high cooling capacity, and the use of small reactors in series limits the amount of product present in each reactor, and thereby the amount of energy stored at any one time.

To further minimize the risk of explosion, the stoichiometric ratio between the substrate, the solvent and the nitrating agent had to be controlled by monitoring and controlling the ratio between the two feed streams into the nitration reaction, and by interlocking the control system. In an event where the temperature could not be controlled, an emergency quench system was incorporated, utilizing a pre-pressurized tank that could release water into the nitration vessel. As yet another level of process safety, the equipment was also designed to withstand the gas evolution associated with a complete decomposition of the reactants in the vessel.

Development of continuous flow processes: Overcoming challenging conditions

The previous case study is an excellent example of the importance of both heat transfer and mass transfer (mixing) for chemical processes, with respect to both quality and process safety. It also illustrates the enabling power that continuous flow can provide in managing or even enhancing these key process attributes. Looking into this further, controlling temperature is critical to a successful scale-up within a process development or commercialization cycle, and this is particularly true when dealing with exotherms within a reaction. The impact of scale is seen when looking at the ratio of heat transfer surface area to the overall reactor volume. In general, the ratio drops by at least an order of magnitude when a process is scaled up from a laboratory or pilot demonstration batch to a modestly sized production run.

This drop in the ratio hinders the ability to remove the excess heat from the reaction mixture, possibly putting the material at risk as it reaches a temperature limit. It can also lead to localized hot spots within the mixture, which can cause inconsistency and non-homogeneity.

The reduction in the surface area to volume ratio is still present in the scale-up of a flow process, however that ratio is considerably larger for a tube reactor. For example, a 4-inch diameter tube has approximately the same ratio as a typical 0.5L laboratory reactor; while more typical tube or pipe reactor diameters will have considerably higher values, ensuring that temperature control and exotherm management can be handled in a straightforward manner.

In some cases, it may be advantageous to purposely increase the process temperature. With regard to reaction kinetics, in general, the reaction rate doubles for every increase in 10 degrees of absolute temperature, but at larger scale in batch processing there are several pitfalls to elevated temperatures. Firstly, as with elevated process pressure, elevated process temperatures often require a much more expensive

infrastructure which will be exacerbated by inefficient mixing in large reactors, extending reaction times and negating any process time gains resulting from the accelerated kinetics of a higher temperature.

Secondly, after a reaction is completed at elevated conditions, the process is typically returned to ambient or near-ambient conditions for quenches, work-ups and subsequent process steps. The large thermal mass in a batch reactor takes a considerable amount of time to adjust, which not only further erodes process time gains but also exposes the reaction mixture to extreme conditions for an extended period of time.

Finally, higher temperatures may have undesirable effects on reaction selectivity, while also significantly increasing the risk profile and potential dangers with solvents being raised to or above flashpoints and reaction mixtures purposely being raised to the point where runaway conditions or over-pressure conditions are a real possibility.

Continuous flow reactions, using smaller, instantaneous volumes drastically minimize mixing impacts and concentration or temperature gradients, and also bring the amount of material that has an elevated risk status to a much more manageable level. Furthermore, the reduced thermal mass makes the process of temperature quenching orders of magnitude quicker, allowing for a rapid introduction to elevated conditions to drive kinetics, followed by a rapid return to ambient conditions for further processing or to protect the integrity of the products or intermediates that are being formed.

At the other end of the spectrum, traditional batch equipment is limited when cryogenic conditions are necessary, for example when stereoselectivity needs to be controlled, or to protect unstable intermediates. Maintaining cryogenic temperatures efficiently and consistently is difficult and multiple low temperature thermal cycles can have a detrimental impact on the equipment itself and lead to stress cracking and premature equipment failure. Using a liquid nitrogen injection as an alternative to drive cryogenic conditions is difficult to control and can become very costly at scale.

An example of an industrially relevant process that typically requires cryogenic conditions is lithiation chemistry. The previously discussed advantages of continuous flow can certainly be utilized to improve the performance of lithiations, but another alternative is replacement by Grignard reactions to avoid the problems of maintaining low temperatures. However, these bring different challenges as they are energetic and extremely air and moisture sensitive, and often necessitate the use of pyrophoric and short shelf-life reagents. Converting Grignard reactions to a continuous process allows much more efficient and safe synthesis, as the reagents can be manufactured in a just-in-time manner.

Just as with temperature, pressure can also be a powerful process parameter that can be harnessed with continuous flow processes. Hydrogenation is a widely used synthetic tool that’s use can be limited by batch processing and restrictions of standard plant equipment. The pressure requirements for hydrogenations can typically be 100-150psig (although pressures higher than 300psig are not uncommon), and often involve expensive catalysts and lengthy reaction times.

Flow hydrogenation has become an increasingly investigated and accepted technology to solve these issues, and strategies and technologies are available allowing for both homogeneous and heterogeneous catalyst processes.

Tube reactors and packed bed columns are readily adaptable



to much higher processing conditions, easily achieving pressures 10 times that of standard batch reactors. Strategies also exist for replenishing supported catalysts that are consumed over the course of a process, utilizing multiple columns with diverters or automating a semi-batch/semi-continuous process with multiple catalyst charges. By these means, a throughput of several kilograms in a day is readily achievable with a modest equipment footprint.

Improved product quality

While the case study focused on process safety concerns, the need to maintain quality standards was also a key consideration. Certainly, consistent quality performance during a transition from a batch to a continuous process must be maintained, at a minimum. However, an important benefit that continuous flow can afford in some situations is improved quality of the final product. Frequently, a process chemist or engineer is forced to accept a less than ideal synthetic route due to infrastructure constraints, such as achievable pressures, temperatures, addition rates or equipment availability within a plant. These processes can generate impurities that must be removed, and in some situations the majority of an industrial process may be more focused on removing impurities rather than actually making the desired product.

In some cases, flow chemistry can avoid these impurities, or at least reduce them significantly, as the process can be designed to minimize their formation, and analysis can be integrated into the process rather than functioning as a separate operation.

In a continuous flow process, introducing process analytical technology (PAT) for more sophisticated analysis is generally easier than for batch production: often only temperature probes and flow meters are required to ensure that the process remains within the acceptable parameters to afford product of a known quality. Sophisticated PAT probes can be easily integrated into a flow process to allow for rapid detection of deviations, in addition to nearly continuous monitoring of instantaneous quality, as opposed to waiting on a single batch sample and corresponding measurement.

These PAT probes can be used to monitor process performance attributes, such as reaction conversion, with the data being utilized to make real-time adjustments, correcting for process variations. Fourier-transform infrared (FTIR) spectroscopy can be used to map reaction kinetics during process development, and then subsequently incorporated into flow streams for real-time monitoring of conversion. Peak depletion or peak growth can be used during development to define optimal conditions, with standardized peak intensity, then being used online during campaigns to monitor for deviations and to develop an online process control response. Similarly, with Raman spectroscopy, tracking wave numbers can be used to monitor reaction conditions; however, it adds an intriguing functionality, as different polymorphs of a substance have unique spectra, enabling its use in a crystallization or precipitation process to ensure that the desired form is produced.

However, chromatographic analysis remains the standard for analytical measurements, and as a result, equipment has been developed to perform these analyses as close to real-time as possible. An added feature is that when a sample is pulled, it is typically representative of the entire flow stream, which, by

definition is a complete representation of the reaction mixture in that instantaneous moment, eliminating potential concerns over a sample being truly representative.

The PAT data can be used to ensure the process is operating within its targeted window and often allows for a process incorporating a single flow step to be embedded in a larger process, while still fitting comfortably within well-established quality systems that exist in most manufacturers.

Although it might not be applicable for all reactions and all conditions, for continuous flow to achieve successful widespread implementation, it must be seen as a technology of choice and not just a niche problem-solving option for energetic reactions. Along those lines, a number of pharmaceutical companies have invested in, and are actively investigating the use of continuous flow. Moving forward, as products come to market that have utilized the technology, undoubtedly there will be greater adoption to leverage the advantages that it brings.

First published: Contract Pharma

Title: Technical advantages of continuous flow

chemical synthesis

Date: April 5, 2019

About the author

Dr Shawn Conway,


and Development,

Cambrex



Cavanagh explained that the acquisition of Halo Pharma added drug development and drug product manufacturing capabilities to Cambrex, a provider of small molecule active pharmaceutical ingredient (API) development and manufacturing services. The addition of Avista Pharma Solutions brought early-stage development and discovery services, standalone analytical services, solid-state sciences capabilities, and microbiology testing to the company’s portfolio of services.

Cambrex is now organized into three main business units: drug substance, drug product, and early-stage development and testing. The drug substance business unit incorporates the majority of the company’s existing API business. It includes services for the development and manufacturing of innovator and generic APIs, scale-up, technical transfer and related analytical development as well as specialist capabilities, such as the handling of controlled and highly potent substances, continuous flow chemistry, biocatalysis, and solid-state science.

The drug product business unit consists of two sites in Whippany, New Jersey, and Mirabel, Canada (outside of Montreal), which were the facilities gained in the Halo Pharma acquisition, which was completed in September 2018. The business has expertise in formulation and development of conventional dosage forms, including oral solids, liquids, creams, sterile and non-sterile ointments, and specialist drug product capabilities, including developing and manufacturing complex and difficult-to-produce formulations, products for pediatric indications, and controlled substances.

The third business unit includes capabilities gained from Cambrex’s acquisition of Avista Pharma Solutions, which the company completed in January 2019. The new business unit consists of early-stage discovery and testing services and

provides early clinical-phase support to customers requiring smaller quantities of drug substance and drug product supply as well as standalone analytical services, such as microbiology, compendial, and drug-release testing and cleanroom validation.

The two acquisitions added over 800 employees and six new facilities to Cambrex. Its workforce now numbers over 2,000 at 13 locations across North America and Europe.

In addition to the acquisitions, Cavanagh outlined investments made by the company in its core API development and manufacturing business. Cambrex made several key investments in 2018 in its US facilities. These investments included the purchase of a new 45,000 sq. ft. building in High Point, North Carolina, to expand the company’s clinical supply and process-development capacity. At Charles City, Iowa, a new $24 million, 4,500 sq. ft. facility for the manufacture of highly potent APIs is due to open in May 2019.

Shawn Cavanagh, President and Chief Operating Officer, Cambrex, provided an update on the integration of the company’s $425-million acquisition of Halo Pharma and $252-million acquisition of Avista Pharma Solutions at the DCAT Week ’19.



First published: DCAT Value Chain Insights

Title: Cambrex updates integration of Halo Pharma and

Avista Pharma; expands small molecule API manufacturing

Date: April 9, 2019

About the author

Shawn Cavanagh,

President and Chief Operating Officer,

Cambrex


DCAT Week ’19 took place in New York on 18-21 March, organised by the Drug, Chemical & Associated Technologies Association (DCAT), a not-for-profit, member-supported, global business development association, whose members include innovator and generic drug manufacturers and suppliers of ingredients, development and manufacturing services, and related technologies.

The event opened as usual with the member company announcement forum. These are checked for real news content and come from DCAT members with substantial investments and expansions to announce; many more wanted to be present but were rejected. All the same, there was a strongly positive tone from those who were there.

Cambrex, said President and Chief Operating Officer Shawn Cavanagh, has invested $262 million across six facilities since acquiring PharmaCore in 2016. The company had completed a new 150m2 R&D facility at its intermediates and generic API site near Milan in the week before DCAT Week and had also recently installed a new 12,000L reactor at one of its cGMP facilities there, as part of a $3 million upgrade and improvement plan.

Recent acquisitions have been Halo Pharma, a finished dosage form (FDF) CDMO with facilities in New Jersey and Canada, and Avista Pharma Solutions, which offers early stage contract development of APIs and FDFs, plus analytical and microbial testing, from three sites in the US and one in the UK. These cost a combined $677 million and brought assets with a combined pro forma additional value of $160-170 million/year. Of Halo’s 70 customers, 50 are new to Cambrex, Cavanagh said.

Having historically been active mainly in late-stage API development and manufacturing, Cambrex now also has drug product and early stage services, operating across 12 sites in North America and Europe. The company announced subsequently that it would double the liquid packaging capacity from 600,000 to 1.2 million bottles/month at its site in Mirabel, Québec with a new cGMP packaging line and a new filler on the existing packaging line. This will also enable XP and non-XP fillers to work in parallel throughout the process. “I believe we are well on the way to creating the small molecule company,” Cavanagh said. “Small molecules are big again: there is robust funding, a strong number of approvals, a growing clinical pipeline and an increasing trend to outsourcing as Big Pharma shuts plants and moves from fixed to variable costs, while accessing technologies from CDMOs like us.”

Announcements of new and ongoing investment in New York in March.



First published: Speciality Chemicals

Title: Small molecules still big at DCAT Week

Date: May, 2019

About the author

Shawn Cavanagh,


Cambrex


As drug products become more complex, there is increasing customer demand for relationships with contract development and manufacturing organizations (CDMOs) that have core competencies in highly specialized formulation and process technology areas.

One of these specialty areas is complex molecules. Biotech companies developing novel biologics are increasing in the market, thus there is an increase in outsourcing development services to BioCDMOs.

Another area of expertise where pharma is relying on CDMOs is in cell and gene therapy. Industry insiders expect gene therapy manufacturing market to boom and grow at rates ranging from 15 to 20%1. Benefits of partnering with a cell or gene therapy CDMO include scalability, speed to market, access to technical expertise without overhead costs, and cost efficiencies. Demand for specialized manufacturing and clinical trial support for cell and gene therapies has resulted in more than 40 companies offering these services2. And the market continues to expand.

No matter the area of specialty, CDMOs find they must shift toward providing value-added services by establishing themselves as a one-stop shop for pharma clients.

Working with a one-stop shop means that everything is done in one place, removing time and risk mitigation concerns. This is a particularly critical issue when transferring between late-phase clinical to commercial.

In this exclusive Drug Development & Delivery magazine annual report, several CDMOs discuss their formulation development and manufacturing capabilities for bio/pharma companies of all sizes.

Cambrex: Responding to formulation trends and regulatory changes

As a full-service CDMO, Cambrex is witness to many industry trends. First, as the market evolves, new products are being developed in smaller batch sizes than in the past, due in part to the increasing number of drugs being developed for selectively niche patient populations, explains Maryse Laliberté, Vice President and General Manager, Cambrex. “This is a change from the previous paradigm where historically drugs were developed with multiple indications in mind. We are currently seeing many new drugs in the pipeline being developed with a focus on very specific and orphan diseases.” She adds that more targeted, smaller patient populations have driven demand for a niche type of support, which can mean a more complex manufacturing process.

“As companies work on drugs for smaller patient populations, the reduced quantities of drug material required during the clinical trial process potentially means a more simplified supply chain and the sponsor company no longer has to manage multiple CDMOs as in the past,” adds James E. Cherry, Vice

CDMOs shift to offer more specialized services.




President, General Manager, Cambrex Whippany. “Additionally, developing for smaller populations reduces clinical trial costs and can help expedite the approval process for the product.”

When it comes to regulatory approval, Mr. Cherry says it is critical to understand that companies are looking for full support. This has caused a growing use of third-party consultants, as well as heavy reliance on the expertise of CDMOs. He says: “Particularly true is that smaller or virtual companies bringing new molecules to market are looking to work with a CDMO much earlier in the process — sometimes starting at clinical phases — and more often are keeping the product in-house for longer, rather than the historical notion of licensing or divesting to Big Pharma after Phase 2. Drug complexity aside, two-thirds of new drug approvals in the clinical pipeline is coming from small and emerging pharma companies who are leaner than the traditional pharma companies in terms of support functions such as regulatory affairs.”

New regulations are coming into play with respect to pediatric dosage and formulation development. This is of particular importance to drug manufacturers seeking to create alternative formulations for younger patients. “The industry, and in particular Big Pharma, is placing a stronger focus on developing pediatric formulas as they look to extend their current patent on their existing adult formulas,” says Mr. Cherry.

References/Sources

1Gene therapy manufacturing partnership to support

‘booming’ market.

Date: December 3, 2018

2Contract manufacturing for cell and gene

therapies, bioinformant.

Article: Click here


First published: Drug Development & Delivery

Title: Outsourcing formulation development

and manufacturing

Date: June 1, 2019

About the authors

Maryse Laliberté,

Vice President and General Manager,

Cambrex Mirabel

James Cherry (Jim),

Vice President and General Manager,

Cambrex Whippany

https://bioinformant.com/product/cell-gene-therapy-cdmo/


The economic and safety benefits of implementing continuous flow retrospectively on a commercial scale for a single process step are widely known and have been well documented, with the replacement of traditional batch-based manufacturing by continuous flow chemistry continuing apace. Many major pharmaceutical corporations, including Eli Lilly, GSK and Novartis, are actively investigating and investing significant sums in the use of continuous flow.

There is also an emerging use of continuous flow processes in early clinical development, where the need is to manufacture enough of a drug compound so that the development process can begin.

Introducing continuous flow at this point enables the use of specific types of reactions that are very difficult to accommodate with the traditional batch process. This means that a compound can typically be obtained in a quicker, cleaner manner; it also makes it possible to start building a process that can be commercially viable from the outset, reducing the potential multiple iterations of a development cycle as the compound progresses from phase to phase.

The ability to optimise the process from the outset is a major advantage as it means that the best route can be used, rather than one best suited to a batch operation. Commercial scale batch processing imposes limitations in terms of the types of equipment that may be available and the processes that could be used. With continuous flow, all routes can be explored to find the most appropriate synthesis that can then be progressed through all the different stages of development.

In general, continuous flow offers a process that is scalable from the beginning, allowing the manufacture of a few hundred grams or perhaps a kilogram of a compound, and this can be quickly increased to larger quantities of material for a later phase, by increasing the scale of the equipment, or by extending the processing time. This scale-up can be done multiple times through to commercial quantities, as opposed to batch manufacturing, where process optimisation would have to be carried out each time production is scaled up.

Applying continuous flow in early phase development also allows greater control over the reaction. A batch reaction can introduce significant variations within the vessel that can lead to incomplete conversion, side reactions and degradation, whereas with continuous flow, parameters such as residence time, temperatures, pressures, concentration and pH, can all be tightly controlled resulting in a high degree of consistency. Avoiding these impurities gives a more streamlined process that is easier to take on to subsequent phases.

Similarly, the increased monitoring of the process and the ability to take samples in real time increases the understanding of what is happening during the synthesis. Monitoring the process across a range of time points creates a much better picture of the reaction compared with leaving a batch to process for 12 or 16 hours and then sampling the result.

Although cost savings cannot be quantified precisely, making an intermediate sized batch of product could be in the region of hundreds of thousands of dollars, so any technology that can streamline this process and reduce or remove this

The rising trend of continuous flow is bringing economic and safety benefits to manufacturers, says Dr Shawn Conway, Engineering Research and Development Director for Cambrex.




spend is obviously advantageous. Furthermore, reducing the development timeline and shortening the development phases can mean that a compound reaches the market faster, bringing forward the time when a drug gets to the patient and the company starts to make a return on its investment.

There is increasing demand for drug substances with higher potencies which require smaller doses and, therefore, potentially smaller manufacturing campaigns. Smaller volume batches can be relatively expensive using traditional batch production, due largely to the overhead costs of the facility, so lend themselves well to continuous flow technology where capital costs tend to be much lower. Rather than converting a batch process into a continuous flow-based analogue, exploring flow synthesis in the early development stages allows for the subsequent steps to be streamlined, saving time and money in the long run, as previously noted.

Multiple process steps in flow, such as reactions, work-up, extractions, crystallizations and distillations with different equipment requirements can be developed and connected in a small footprint facility as opposed to over several large assets in a production facility with the associated handling challenges and costs.

Eli Lilly's highly potent oncology drug Prexasertib demonstrates the practice of employing continuous flow in early phase development, where the technology was adopted for the final four steps of the synthesis throughout clinical scale manufacture, and now on to commercial production at a rate of three kilograms a day. Specific challenges that needed to be addressed, that have been published and discussed, included the use of hydrazine at elevated reaction conditions to drive purity and performance, as well as avoiding issues surrounding isolation and handling of potent toxic intermediates. Concurrent analytical monitoring also enabled rapid trouble-shooting during the manufacturing process.

The recognised benefits of this process were numerous and allowed eight continuous operations to take place in series, within small continuous reactors, extractors, evaporators, crystallisers and filters. A continuous reactor type was developed and utilised, as was a method for in-process filtration and redissolution. The process included the ability to operate at high temperature in a low-boiling solvent, afforded improved safety for a hazardous reaction, better yield and an improved impurity profile. The containment of highly potent materials was achieved through the use of dedicated and disposable equipment; and synthetic efficiencies were seen with enhanced product stability, the elimination of one isolation step, and the elimination of solids handling in another isolation step.

The advantages described above and illustrated in the example from Eli Lilly demonstrate that continuous flow drastically minimises, if not eliminates, safety and quality complications that arise from inhomogeneity and it should therefore be regarded as a truly enabling technology and a powerful development tool.

First published: European Pharmaceutical Manufacturer

(EPM)

Title: The economic benefits of continuous flow

Date: August 6, 2019

About the author

Dr Shawn Conway,

Director, Engineering Research and

Development,

Cambrex



The pharmaceutical industry has been experiencing an increase in demand for drug products that contain highly potent APIs (HPAPIs), both in the United States and in Europe. According to Adam Bradbury, associate analyst at PharmSource, a GlobalData product, the number of innovative pharma product approvals requiring containment has been increasing since 2008 (see Figure 1). A majority of these products have been in the oncology and pain treatment areas. “The most commonly approved US product types requiring containment were (highest to lowest) controlled drugs, cytotoxics, steroids, immuno suppressants, kinase inhibitors, and nucleotides, which is indicative that many of these treatments are for oncology or pain relief,” says Bradbury.

Global Data’s Drugs by Manufacturer database reports that 532 novel approved drugs approved in the US and the EU require containment. “There is a tendency for both high potency drugs’ API and dose manufacture to be outsourced rather than manufactured in-house, although some of these products will also be dual sourced (both manufactured in-house and outsourced),” says Bradbury.

Global Data’s research supports that statement; API manufacturing is outsourced for 255 of those drugs; 317 drug products are produced by contract manufacturers. In-house production is used for 201 highly potent drug substances and 295 HPAPI-based drug products.

Does the pharmaceutical industry have adequate access to contained equipment, facilities, and infrastructure for the manufacture of highly potent APIs?



14

12

10

8

6

4

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0

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

EU approvals of contained novel products

Source: GlobalData PharmSource drugs by manufacturer database (Accessed date: June 7, 2019)

3 32

87

98

10 10

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7

Figure 1: Number of innovative pharma product approvals in the European Union and United States from 2008–20181

910

7

14

19

1416

22 23

37 36

40

35

30

25

20

15

10

5

0

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

US approvals of contained novel products

Source: GlobalData PharmSource drugs by manufacturer database (Accessed date: June 7, 2019)


Approximately 60% of HPAPIs in development are for oncology drugs (see Figure 2), which, according to Bradbury, points to an increase in demand for HPAPI manufacturing capacity. Because HPAPIs have special requirements for handling and containment, those companies looking to outsource HPAPI production may encounter challenges locating a contract development and manufacturing organization (CDMO) to develop and manufacture these hazardous materials.

Projecting capacity supply and demand

According to Bradbury, there are 209 facilities across 148 companies in the US that offer containment capabilities. Europe has 403 facilities in 247 companies. “All of the evidence indicates that containment facilities are in high demand, and this trend will increase as the oncology pipeline continues to flourish,” says Bradbury. “CDMOs with containment capabilities are likely to be at an advantage compared to those without, as the number of marketed HPAPIs tends to increase over time as more HPAPI drugs gain approval,” says Bradbury.

To meet this demand, CDMOs may need to tailor services and facilities for specific clients and add facilities, equipment, and services to meet demand. These organizations may also have to balance manufacture of HPAPIs alongside non-potent APIs. Being flexible and tailoring manufacturing techniques, equipment, and containment options to a molecule’s properties and synthesis requirements may result in increased safety, a reduction in cost, and enhanced capacity for HPAPIs3.

Expansion and investment

Contract manufacturing organizations (CMOs) that offer containment capabilities have an advantage over those that do not and may also see an increase in revenue, Bradbury says.“There is a direct correlation between CMOs that offer HPAPI capabilities and generation of high revenues; as those facilities/capabilities are very expensive to build or acquire, only the largest CMOs can afford them, allowing those CMOs to take on projects that others cannot, therefore boosting revenues,”says Bradbury. Many CDMOs and CMOs, as a result of the increase in demand, have been making investments in the HPAPI area.

In April 2019, Cambrex completed construction of a $24 million HPAPI manufacturing facility in Charles City, IA4. “The production area will operate to an OEL down to 0.1μg/m3 and contain four reactors ranging from 200 to 1000 gallon capacity,” according to the company. The facility will be capable of manufacturing batch sizes up to 300kg.

“Across our sites, Cambrex has a strong reputation in the handling and supply of potent molecules, and this investment allows us to increase the capacity we can offer our customers,”said John Andrews, Vice President, Operations and Site Director, Cambrex Charles City, in a press release. “We have seen an increased number of molecules in the clinical pipeline being designated as potent and highly potent, so having the flexibility within our manufacturing network to scale up with existing customers as projects progress, as well as accommodate new projects, is crucial to meet those market needs.”

Conclusion

It’s apparent that the contract manufacturing industry is recognizing the increased demand for HPAPI containment capabilities, and companies are making investments and adjusting their services to meet that demand. As the pharmaceutical industry continues to develop complex treatments requiring complex ingredients, the industry will soon know if these adjustments are enough.

References/Sources

1GlobalData PharmaSource drugs by

manufacturer database.

Date: June 7, 2019

2GlobalData drugs database.

Date: July 1, 2019

3J. Pavlovich, “Classifying potent and highly

potent molecules.”


4Cambrex, “Cambrex completes highly potent API

manufacturing facility at Charles City, IA.”

Date: April 10, 2019


Oncology drugs in development

2000

1800

1600

1400

1200

1000

800

600

400

200

0

Source: GlobalData Drugs Database (Accessed date: July 1, 2019)

Nu

mb

er

of

dru

gs

in p

ipelin

e

Phase I

1159

692

Phase II

972

620

191

183

36

40

Phase III Pre-registration

Small molecule

Other molecule types

Figure 2: Oncology drugs in development2

Title: HPAPI capacity challenges

Date: August, 2019

About the author

John Andrews,

Vice President, Operations and

Site Director,

Cambrex Charles City


The containment and handling precautions that are required when manufacturing active pharmaceutical ingredients (APIs) and their intermediates vary according to the hazards posed by the individual materials. Clearly, those that pose greater risk to human health must be handled much more cautiously than those that are less likely to cause problems. A current trend in the small molecule API market is the growth of the oncology pipeline, which is at about twice that of other indications, and various market data suggest as being between 30 and 40 percent of preclinical and clinical small molecules. Because of the real clinical data available about developmental compounds, many oncology drugs are classed as “highly potent” and although by no means is this the only therapeutic class of compounds that are classified as such, these highly potent molecules require careful handling and specific containment facilities.

Handling and assessment of highly potent materials

Handling chemicals considered hazardous is more time-consuming and expensive than working with those that are not, and for contract development and manufacturing organizations (CDMOs), simply treating every project as if it were highly dangerous is not appropriate. Instead, to ensure projects can be managed cost-effectively, a careful risk assessment should be carried out before any API manufacturing project is embarked upon.

The risk assessment weighs up all the information that is available, both about the API itself, and any raw materials or intermediates that are used in its manufacture, and this is particularly important for highly potent APIs (HPAPIs). Where there is a paucity of information at the outset for development compounds and scale-up projects, the risk assessment will take on board whatever data are available, and use it to determine an exposure limit that is likely to be safe for the operators, and the containment that will be required. However, the risk of being overly conservative and imposing far more controls than are truly needed can cause costs to escalate, so needs to be avoided whenever possible.

Different companies use their own classification systems in which the numbers of compound classes and their criteria vary, and at Cambrex we use a five-category exposure control band (ECB) system to determine the handling requirements. ECB 1 includes chemicals that have a relatively high occupational exposure limit above 100µg/m3. In ECB 2, the products will have exposure ranges at a level of 10–100µg/m3. Containment will be required for these materials, but local ventilation will typically suffice, and open handling will remain acceptable.

Those compounds that fall into ECB 3 and ECB 4 have substantially higher risk levels, and HPAPIs will always be placed in one of these categories. For ECB 3, where the allowable exposure limit is 1–10µg/m3, containment with no open handling will be necessary. If it falls into ECB 4, where the allowable exposure limit is 0.1-1µg/m3, full containment in an isolator will be essential. Although very small quantities of

As oncology pipelines grow, so too is the demand for highly potent materials, which require careful handling and containment.




ECB 3 and ECB 4 may be handled outside of containment in certain situations.

The greatest level of risk is posed by those chemicals that we place in ECB 4+ with allowable exposure limits at 0.01-0.1µg/m3. No open handling whatsoever of such materials is permitted, even if they are in solution, and they must remain within barrier isolation at all times. This group will include products such as API warheads for antibody–drug conjugates.

There is also an additional sub-category. ECB 2* will include any compound that otherwise sits in ECB 1 or ECB 2 because of its toxicity levels, but which has a special hazard associated with it. It might be a mutagen, carcinogen, sensitizer, or a chemical that poses developmental or reproductive risks. It might also be prone to dermal absorption, pose an inhalation hazard, or have an adrenergic effect. In these cases, additional training, and physical or administrative controls, will be required.

The project safety dossier

The risk assessment is used to inform the creation of a project safety dossier (PSD) for each product. This will include every chemical substance involved in the process, other than common reagents, catalysts and solvents. It will provide the chemist or operator with occupational exposure bands (OEBs), and the rationale behind their determination. It is important to include the reasoning behind the classification because it will give workers an insight into the reasoning behind the handling requirements, and therefore increase buy-in within the whole project team.

Importantly, the PSD will also include presumptive or demonstrated destruction procedures for any ECB 3, ECB 4, or ECB 4+ chemicals. Presumptive procedures are acceptable for development activities, while demonstrated procedures will be required before the project moves into pilot and commercial manufacturing.

The dossier will identify special hazards and especially hazardous reagents. Administrative controls and personal protective equipment (PPE) will be provided, along with ECB procedures.

The PSD uses a color-coded procedure on the front page for ease of identification, and this front page will be affixed to the door of the lab or suite where the product is being handled. In a multi-purpose facility where projects are undertaken for multiple different customers, this color coding highlights hazards without disclosing any confidential client or chemical structure information.

The second part of the dossier is a single page that highlights the top-line hazard information, including chemical-specific information. Part 3 includes more detailed information, such as chemical structures of all raw materials, intermediates and final products, along with their OEB range, and ECB control procedures.

In part 4, the detailed information from the chemical-by-chemical risk assessment is laid out. This is where we feel Cambrex differentiates itself, including the justification for each chemical’s OEB rating and ECB strategy in a fashion that is easily understood by all co-workers all the way to the operator level to achieve buy-in. Co-workers end up with a high level of respect for the chemicals they are handling and the controls/procedures to keep them safe. Finally, in part 5, there will be a list of references.

For high ECB category projects, employee training takes place as the scale of manufacture increases to ensure operators and chemists are aware of specific risks prior to working with the materials. It is valuable to involve toxicology specialists in training sessions to allow discussions to take place and for affected employees to raise any queries, or clarify any specific protocols.

Building and designing a containment facility

For CDMOs looking to design a multipurpose facility, there are a number of challenges in the process. Cambrex has just completed the building of a HPAPI manufacturing facility at its site in Charles City, Iowa. Reviewing the project highlights the following considerations were taken into account in the design and construction:

1. Cross-functional design team

The project design team should be set up to ensure that existing knowledge about HPAPIs of both internal experts and external partners are leveraged. These should include project engineers, maintenance, equipment vendors, experienced operators, and representatives from environmental health and safety (EH&S) and operations functions, as well as engineering design specialists, and the general building contractor.

The design team can then develop the equipment sizing, the layout of the facility and the equipment within it, as well as the unit operation capability, based on both prior API experience and customer input. Engineering partners can assist in ensuring that the building codes and regulatory requirements — which are constantly evolving — are met, and can offer up-to-date information and experience about these.

2. Future needs

For a CDMO, a facility is built on specifications and matches the needs of current demands, with no knowledge of what will be made within it in coming years. Substantial assumptions about the future capability needs have to be made, informed by past experience. Projections about previous requirements and demands against actual experience can ensure that a facility does not become obsolete or in need of further expansion as soon as it is completed.

3. Scale and containment capabilities

Understanding the market influences the design criteria for a facility. Considering the target batch size for materials being manufactured is important as this affects the level of containment that is economic to achieve. To have appropriate containment below an OEL of 0.1µg/m3 becomes very difficult and expensive to achieve, particularly for the mid-scale to large batch sizes (100-300kg). Few batches this large are likely to be so potent that they are below that OEL, because such minuscule doses are required that no more than a few kg may ever need to be made.

As with any plant design, the target batch size dictates the equipment size such as filters for isolation steps. Reactor choice is influenced by the types of chemistries being performed, and the concentrations needed — so it may be that various sizes and material of construction (Glass Lined / Hastelloy) are considered.



4. Isolator technology

In terms of the isolator technology, there are advantages and disadvantages for both rigid and flexible alternatives. With a fixed or rigid isolator, the capital cost will be high, there will be a long lead time, and it will be difficult to modify for different operations, but the operating costs could be lower and it will generally be more robust and easier for the operators to manipulate. In contrast, flexible containment or isolator alternatives will have a lower initial cost and shorter lead time, but operating costs might be higher and more delicate operator technique will be necessary. Furthermore, no modifications are possible; any changes must be made by purchasing a different item from the vendor.

It may be appropriate to have a mixed approach, depending on the needs of the facility and assumptions about volumes being handled. If the end product is likely to be low OEL and high volume, a fixed isolator may be appropriate for final product packaging and sampling, with a flexible approach for material charging that can handle a wide variety of OELs, volumes, reactor destinations and methods.

There are more drugs and therapies being developed and coming to the market that are classified as “highly potent,” as well as a number of commercial products reaching patent expiry. For CDMOs wishing to capitalize on this market opportunity, having appropriate assets to manufacture the molecules effectively and efficiently is crucial, as is the level of expertise to handle the projects safely.

First published: Contract Pharma

Title: Handling and assessing HPAPIs

Date: September 16, 2019

About the author

Jason Korbel,

Technical Services Manager,

Cambrex



The safety and efficacy of pharmaceutical products is of utmost importance. Regulations in the United States require that pharmaceutical companies establish a quality control unit to perform quality functions to ensure their products meet specifications and are safe for use. This unit also has the task of assuring regulators that good manufacturing practices (GMPs) are being followed. Regulators in Europe and other parts of the world have similar but varied requirements.

The consequences of failing to ensure the quality of drug products range from the most egregious — adverse effects on patients — to potential regulatory actions, such as consent decrees, import bans, and seizure of product. Regulatory responses can include reports such as FDA Form 483 observations, inspection findings from the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, or requests for urgent actions such as FDA warning letters. In addition to regulatory actions, an ineffective quality system may also affect a pharmaceutical company’s success. “Ultimately the consequences are reduced profitability, as scrap, rework, and downtime are increased,” says Karen Ginsbury, CEO of PCI Pharmaceutical Consulting Israel Ltd.

Warning letters issued by FDA to various pharmaceutical companies located in the US and around the world in 2019, however, seem to have a common theme: a lack of a properly functioning quality control (QC) unit1–4. The agency has cited companies for everything from failure to establish an adequate QC unit to QC units not performing their duties properly.

“Many FDA 483 observations have been issued for quality units failing to fulfill all their responsibilities. If a firm releases product (or other material) in the absence of a quality unit, this is even more egregious,” says Mary Oates, Vice President Compliance Services, at Lachman Consultant Services, Inc. “There may also be consequences for patients. If there is no quality unit, in all probability there will be significant gaps in the pharmaceutical quality system, potentially presenting risk to patients if processes and controls are not in place to ensure product quality.”

Pharmaceutical companies are responsible for ensuring the standards of all drug components, including excipients, APIs, and packaging materials, says Susan J. Schniepp, Executive Vice President of Post-approval Pharma and distinguished fellow at Regulatory Compliance Associates, and it is the QC unit’s responsibility to investigate why any of these components fails to meet those standards. “The quality control unit plays a huge part in making sure that products meet the proper applicable standards before they are released,” says Schniepp. “It’s interesting to note that the quality control unit is the only functional unit required by law. This is not to imply that the quality unit works in a vacuum, but rather that it facilitates the investigation into any failures. [The QC unit] has the sole responsibility of releasing product. No other department in an organization has this authority, and it cannot be delegated. Bottom line; we rely on the quality unit to make sure that product released to the market is safe and effective.”

An effective quality control unit is independent from manufacturing and ensures current standards are followed.




With quality being so imperative, how is it that pharmaceutical companies are improperly maintaining such a vital part of their operations? One could argue that a failure to create a quality culture in the organization from the top to bottom may be a cause for this failure. The following discusses why companies may be faltering in this area and what a company can do to maintain a more effective quality control unit.

What is a quality control unit?

One of the challenges in ensuring quality may be the varied regulations and requirements pharmaceutical companies must follow. When it comes to the QC unit, there seems to be some confusion and debate about what exactly a QC unit is and what duties it performs. This confusion can be somewhat blamed on different names for the quality department itself and the language in the US and EU regulations.

According to Ginsbury, the message in the GMP regulations is unclear and possibly misleading. “Based on the definitions in the GMPs, we can conclude that in the United States and the European Union, the QC unit apparently has a rather narrow role, limited to sampling, testing, and making judgements as to product quality (or lack thereof, i.e., release/reject). This is not necessarily, nor ever was, the intent of the regulator,” insists Ginsbury. The GMP regulations are more product than process focused, says Ginsbury, “which can result in executives mistakenly believing that product meeting all release specifications may be released even when there are some serious GMP deviations related to the batch or other batches of product, or equipment or facility.

“Under QC unit roles, there is not much to be found at all about establishing, maintaining, and continuously improving the quality system, measuring (quality metrics), and reporting to management as to how well the system is doing,” Ginsbury continues. “The QC unit is perceived as a sort of judge, who with unusual wisdom can ‘decide’ if faulty/flawed product produced with a deviation or non-conformity is ‘impacted’ or not impacted by the non-conformity. The concept of zero defects and prevention of defects, which is the basis for any true quality system, and the Plan-Do-Check-Act process-based cycle, are absent [in the written GMP regulations].”

Russell Madsen, President of The Williamsburg Group, LLC, argues that, in the US, the QC unit has “sweeping responsibilities specified in 21 Code of Federal Regulations (CFR) §211.22, including ‘the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product’”5.

So, what is a QC unit? US 21 CFR 210.3(15) defines the quality control unit as “any person or organizational element designated by the firm to be responsible for the duties relating to quality control”6.

According to Oates, the QC unit includes both quality assurance (QA) and quality control functions and should be involved in the approval of the drug product, testing results, production records, procedures, and all materials that might affect the final drug product whether that product is produced in-house or “manufactured, processed, packed, or held under contract by another company,” says Oates.

Both Schniepp and Ginsbury state it is important to understand the difference between QA and QC. Ginsbury further states that neither of these on their own are what the regulator intended regarding the QC unit. “The quality unit should be […] preventing defects and non-conformities from

happening by planning (including proactive risk assessment/management during design of processes, checking [validation]), monitoring, and continuous improvement,” says Ginsbury. “This needs to be real time and not as current Product Quality Reviews are performed — annually with a lag of up to 18 months from when the data [were] collected.”

Need for independence

The QC unit should be independent from manufacturing and should serve as oversight for the overall quality system and set the quality culture within the company. “The [QC] unit can be seen to have two tasks: quality testing and the decision to pass or fail on the basis of the results. These two functions are usually separated into a quality control laboratory (testing) and quality assurance (release and documents administration). There is a good reason for this because it takes the release decision away from the testing group and keeps it independent,” says Chris Moreton, Partner at FinnBrit Consulting. Oates agrees, “The quality unit itself manufactures nothing. It is responsible for oversight.”

This independence contributes to overall product quality, says Oates, especially when it comes to quality decisions and the commitment to delivering quality products. “All firms in the pharmaceutical industry, no matter the size, must have robust processes and systems to enable right-first-time manufacturing (inclusive of all GMP activities along the supply chain) and, perhaps most critically, a culture that puts the interests of patients first. Only then will product quality be assured,” says Oates.

In Europe, the batch release/reject decision falls to the role of a Qualified Person (QP) as defined in the European guidelines7, 8. Europe Directive 2001/83/EC9 states, “Member States shall take all appropriate measures to ensure that the qualified person referred to in Article 48, without prejudice to his relationship with the holder of the manufacturing authorization, is responsible, in the context of the procedures referred to in Article 52, for securing: (a) in the case of medicinal products manufactured within the Member States concerned, that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization.”

Setting up a quality control unit

An understanding of the role of the QC unit is the first step in creating and maintaining the QC unit. A company’s standard operating procedures (SOPs) must clearly define the role of the QC unit, says Oates. Processes that are clear and easy to follow in repetition should be implemented, agrees Bo Henry, director of quality control at Catalent. Documentation should be standardized, and staff should be trained to ensure the integrity of data. “Finally, build a culture focused on the patient. With an effective training program and a culture of quality, the entire organization will be able to approach decision-making effectively,” says Henry.

The make-up of the unit is the next important step. The QC unit should be comprised of personnel with knowledge of the products and processes they oversee, says Madsen, and should be familiar with the GMP regulations. Oates agrees, “They must understand the processes and systems for which they have oversight. For example, an employee in



QA responsible for oversight of aseptic media fills must fully understand the critical aspects of aseptic manufacturing, grasping the ‘why’ as well as the ‘what.’ Ideally, a quality control unit would include some employees who have prior experience in manufacturing. This deeper understanding of the production processes and systems enhances their ability to provide appropriate oversight,” says Oates. According to Ginsbury, in Europe, these requirements are stated in the EU GMP guidelines10.

According to Mark TePaske, Senior Director, Global Regulatory Affairs, Quality and Compliance at Cambrex, the nature of pharmaceutical products requires more stringent controls than other industries. QC personnel operate complex analytical instruments and must follow approved written procedures, says TePaske. “QC needs metrology resources (often contractors) to qualify and maintain instruments; analysts to set-up and operate instruments and perform tests methods; persons to qualify/validate test methods; technically competent persons to draft procedures; personnel to perform peer review of data and supervisors (as required by the FDA out of specification guidance document11, support investigations and troubleshoot; and persons to approve and report results. All personnel need to be suitably trained by qualified trainers with training documented. This list assumes that QC relies on [the quality assurance department] for document control, issuance, and retention,” says TePaske.

A QC unit should consist of personnel from quality assurance, quality control, validation, and sterility assurance departments, according to Henry. It may also include personnel from document management and quality engineering. All personnel must understand how their role ultimately affects patients, says Henry. “It is also critical to align with all applicable regulations and guidance for the product. Start by creating a quality manual, then build foundational standard operating procedures. Performing an initial process map of the quality and operational processes prior to generating quality management system policies and procedures is a very useful exercise,” says Henry.

Best practices for quality control units

The key aspects of an effective QC unit include well-written SOPs, well-informed personnel, and a clear understanding of roles and responsibilities of everyone involved. The development of a quality culture throughout the organization is also important. Ginsbury stresses that developing this quality culture is only possible if executive management is brought on board.

To ensure continued quality and uninterrupted supply of pharmaceutical products that are distributed to patients, the QC unit must stay apprised with changing GMPs, says Oates. Procedures that at one point were compliant with the regulations may no longer be. “This is often seen in the areas of validation and aseptic manufacturing. Regulatory expectations are increasing, and some firms are not remaining current,” says Oates.

Procedures and personnel

Written procedures must be developed and followed according to the regulations. These procedures should be

thorough and complete, says Oates. “For example, validation for a manufacturing process may not have been completed or the responsibilities of the quality unit may not be defined in a procedure.” Procedures that lack sufficient detail can lead to quality problems, says TePaske. “The most common problems here are that some procedures lack enough detail to ensure control, other procedures omit required information (e.g., the FDA out-of-specification guidance document includes an extensive list of considerations), and some procedures contain too many or contradictory details and are impossible to accurately follow.”

Each individual’s role within the QC unit and the organization must also be clearly defined, says Henry. “The plan should outline which individuals need to be informed of a deviation, and who can make the decision on next steps if the next steps are not captured already in the procedure. As an organization grows, it can become difficult to maintain clarity on written procedures as more people are trained and asked to execute the procedure with a reproducible result. It is extremely important to revisit the procedure at an established frequency to revise it as needed for clarity.”

Failure to develop and follow such procedures may lead to regulatory actions. “When a firm receives a finding regarding the quality unit, it must look more holistically at its controls than perhaps is evident from the observation itself,” says Oates.

There is also the problem of a “misalignment” of practices and written procedures, according to Oates. “Operators may execute a manufacturing process in one way while the SOP indicates it should be done differently. Additionally, it is possible that the validation document may not be aligned with either the actual or written practice,” says Oates.

Rapid and thorough response

Ensuring that deviations are properly investigated is also imperative for the QC unit. Oates stresses that it is the QC unit’s responsibility to define what constitutes a deviation and that this definition must be clearly communicated to the rest of the organization. “Training with examples must be provided so that the understanding of what is a deviation is fully calibrated across the organization,” says Oates.

The QC unit must have a system of “escalating” the investigation and resolution of deviations. Root cause must be identified and corrective actions and preventive actions (CAPAs) should be established. Henry states that investigations should remove human performance from the equation. “Most importantly, the product strength, identity, safety, purity, and quality should be considered when determining the impact of the deviation and ultimately the overall integrity of the batch by the quality control unit.”

“Firms can fall into a trap of being more focused on product release than on completing a holistic investigation, and the quality unit has the obligation to ensure the investigation is complete and appropriately supports any decisions being taken,” says Oates. Any trends found across multiple investigations should also have CAPAs implemented, and the QC unit should look for common themes. “Continuous improvement must be an objective of the quality unit and the firm as a whole,” says Oates. “Attention must also be given as to whether regulatory notification is required in a prescribed time frame.”



“Top management and the QC unit must work in harmony to ensure there are adequate resources to investigate and correct situations that result in deviations. The importance of finding and correcting root causes cannot be overemphasized, so that deviations do not recur and overwhelm the organization,” stresses Madsen.

Establishing a quality culture throughout the organization is an important way to ensure that these steps are being taken. “It all comes down to training and motivation. Everybody, from the most junior to the most senior members of the organization, should be thinking ‘Quality’. This [quality culture] is obviously important in manufacturing and quality groups, but it is also important in finance, marketing, sales, etc,” says Moreton. “For example, there are always pressures to contain costs, but this should not be to the extent that people tend to gloss over things because there is not time or resources to deal with it properly. There are pressures to get the medicinal products into the supply chain as quickly and efficiently as possible, but this should not compromise patient safety,” says Moreton.

Conclusion

An effective QC unit must be independent of the manufacturing unit, says Oates, and the QC unit’s final decision on the release of product must be respected. “It is never appropriate to pressure the quality unit to release product to meet business needs if the product is not acceptable for release,” says Oates. “The quality unit must have a single, final decision-maker who is ultimately responsible for quality decisions.”

Pharma company executives should be aware that the quality of their products is a responsibility of many components of the organization and not the sole responsibility of the QC unit. “Perhaps the biggest mistake is for the firm to assume that the quality unit is responsible for quality. Manufacturing is responsible for product quality. The quality unit provides the framework in which GMP activities occur and subsequent, ongoing oversight and support for continuous improvement,” says Oates.

Ultimately, a successful quality control system requires a dedication to quality and investigating problems. “Small issues have a way of snowballing. Additionally, quality units cannot ensure product quality. Product quality can only be ensured when all company organizational units work in harmony, with product quality and patient safety as their primary goals,” says Madsen.

References/Sources

1FDA, Warning letter to NingBo Huize Commodity Co., Ltd.


2FDA, Warning letter to Spectrum Laboratory Products.

Date: June 4, 2019

3FDA, Warning letter to Kingston Pharma LLC.

Date: May 14, 2019

4FDA, Warning letter to Pharmasol Corporation.

Date: March 14, 2019

5FDA, Responsibilities of quality control unit, 21 CFR

§211.22.

6FDA, Current good manufacturing practice In

manufacturing, processing, packing, or holding of drugs;

general, definitions, 21 CFR §210.3 (15).

7EC, EudraLex–Volume 4–Good Manufacturing Practice

(GMP) guidelines.

8EMA, Directive 2001/83/EC of The European Parliament

and of the Council of 6 November 2001 on the community

code relating to medicinal products for human use.

Date: November 28, 2004

9Directive 2001/83/EC of The European Parliament and of

the Council of 6 November 2001 on the community code

relating to medicinal products for human use.


10EC, EudraLex-Volume 4–Good Manufacturing Practice

(GMP) guidelines, Annex 16.

11FDA, Guidance for industry, investigating out-of-

specification test results for pharmaceutical production.

Date: October, 2006

Title: The right pieces for a quality program


About the author

Mark TePaske,

Senior Director, Global Regulatory Affairs,

Cambrex



However, the economic and technological advantages of continuous flow chemistry are driving many API manufacturers to add it to their toolbox, according to Jonathan Knight, Director, Market Intelligence, and Dr Shawn Conway, Engineering Research and Development Director, at Cambrex.

Historically, continuous flow chemistry has been reserved primarily for highly energetic and/or hazardous reactions. In batch mode, these reactions have been limited to small vessels and minimal inventories to produce small quantities in facilities that may require bunkers and isolation in a location away from main manufacturing areas. In this way, if an uncontrollable event should occur during a reaction, the risk to personnel and the surrounding area could be minimized and any damage would be contained. Unfortunately, these facilities are expensive to build and maintain, and the small scale of the reactions limits their cost-effectiveness, with their remoteness adding additional logistical complexity, increasing headcount, time and ultimately cost.

For example, Cambrex has a long history of manufacturing and handling energetic compounds and reagents. The inherent explosive nature of these compounds and reagents meant that large-scale production needed to be carried out in bunkered production facilities at its site in Karlskoga, Sweden, dating back to when the site was founded by Alfred Nobel in 1896.

In the pharmaceutical industry, continuous flow chemistry has traditionally been limited to a specific subset of reactions and synthetic processes, driven by efficiency and cost savings,

with nitrations being among one of the most common processes undertaken. One of the biggest obstacles for companies looking to expand development capabilities in continuous flow has been the lack of suitable commercially available equipment, however in recent years this has changed. Driven by the availability of new technologies and equipment, as well as the need to develop drugs faster, more cost-effectively and for smaller patient populations, there has been a growing movement towards replacing batch production with continuous flow operations. A number of large pharmaceutical companies have invested in continuous flow operations for API production, as well as formulation, or both. For example, GSK has invested in continuous flow API development capabilities at its facilities in the UK, US and Singapore; while Vertex, MSD and Johnson & Johnson have invested in continuous flow formulation technology. Novartis, in collaboration with Massachusetts Institute of Technology (MIT), has also spoken of its plans to combine continuous flow synthesis and continuous flow formulation.

Safety remains, and will continue to be, a key advantage of continuous flow technology, but there are also economic benefits of converting energetic and hazardous reactions from batch to continuous flow. It reduces the effective volume of a unit operation, enhances control and minimizes exposure and risk, so that energetic chemistries or hazardous reagents can be handled safely as a feasible process option. By enabling these operations to take place in a regular manufacturing plant, they can be linked more directly to other downstream processes giving the advantage of operational integration.

Batch production has traditionally been — and still is — the mainstay of the pharmaceutical manufacturing sector.




In terms of cost, the most striking difference between continuous flow and batch production is the comparative investment cost of a new plant, with the rebuild of a batch facility costing up to four times more than a comparable continuous flow facility. A smaller equipment footprint, which could be less than half that required by a traditional batch operation, and associated infrastructure can also drive capital expenditure down significantly.

Handling smaller reaction volumes also means that energy consumption can be cut by implementing continuous flow synthesis, with solvent usage and associated process intensity also being significantly reduced. Additionally, continuous flow requires less labor and may lead to fewer analytical procedures, representing a significant reduction in operating expenditure.

Efficiencies gained from yield and quality improvements can make a further contribution to reducing operating costs. Optimizing the process can reduce lengthy reaction times and extensive work-ups, drastically lowering occupancy requirements and reducing the plant time required for a given process. Continuous flow chemistry can often replace the use of low temperature (-70°C) chemistry, where it is used to reduce the formation of unwanted by-products. As well as reducing the cost of a project, this can also free up capacity for additional production and revenue.

Aside from the obvious advantages of continuous flow that are realized once a compound reaches commercial phases, it should also be pointed out that the overall development phase may also be shortened considerably. Depending on the required volumes for a process as it moves through the different clinical phases, the same equipment used for early development can move through later phase batches, and potentially even into commercialization. Streamlining the traditional batch-based workflow could even eliminate the scale-up phases of the development cycle entirely, saving not only the cost of those batches, but also reducing the time to market by months or even years, enabling development investment costs to be recovered sooner.

Even if scale-up phases cannot be eliminated, continuous flow often allows for easier and more cost-effective scale-up. Scaling up a continuous flow process typically does not require the same magnitude of scale increase, and for some compounds, increased throughput can be achieved by simply running longer, or the addition of another reactor of the same size to run in parallel alongside (“scaling out”), thereby reducing validation and investment costs significantly.

When discussing scale-up, controlling temperature is critical to success, and this is particularly true when dealing with exotherms within a reaction. In general, the ratio of heat transfer surface area — commonly the jacket surface area — to the overall reactor volume drops by at least an order of magnitude when a process is scaled up from a laboratory or pilot demonstration batch to a modestly sized production run.

This drop in the ratio hinders the ability to remove the excess heat from the reaction mixture, possibly putting the material at risk as it reaches a temperature limit. It can also lead to localized hot spots within the mixture, which can cause inconsistency and non-homogeneity. The practical solution is frequently a reduction in the addition rate of a key reagent. However, this can lead to extended times at reaction conditions that can result in degradation, side reactions or even potentially runaway conditions.

In the scale-up of a flow process, the reduction in the surface area to volume ratio is less significant. For example, a 4-inch diameter tube reactor has approximately the same ratio

as a typical 0.5L laboratory reactor; more typical tube or pipe reactor diameters will have considerably higher values, ensuring that temperature control and exotherm management can be handled in a straightforward manner. For a flow process that uses stirred vessels or continuous stirred tank reactors (CSTRs) instead of tube reactors, the exotherm impact can also be managed by using smaller reactors in parallel, leveraging throughput and providing the necessary production while also minimizing the scale-up impact.

Similarly, continuous flow can overcome the effects on accelerated reaction kinetics of inefficient mixing in large batch reactors, which can extend reaction times and degrade any process time gains resulting from the accelerated kinetics.

Furthermore, after a reaction is completed at elevated conditions the process is typically returned to ambient or near-ambient conditions for quenches, work-ups and subsequent process steps. The large thermal mass in a batch reactor takes a considerable amount of time to adjust, which not only further erodes process time gains but also exposes the reaction mixture to extreme conditions for an extended period of time.

Finally, higher temperatures may have undesired effects on reaction selectivity, while also significantly increasing the risk profile and potential dangers with solvents being raised to, or above, flashpoints and reaction mixtures purposely being raised to the point where runaway conditions or over-pressure conditions are a real possibility.

Continuous flow offers a scalable solution to these pitfalls. Smaller instantaneous volumes drastically minimize mixing impacts, and concentration or temperature gradients, and also bring the amount of material that is in an elevated risk status to a much more palatable level. The reduced thermal mass makes the process of temperature quenching orders of magnitude quicker, allowing for a rapid introduction to elevated conditions to drive kinetics, followed by a rapid return to ambient conditions for further processing or to protect the integrity of the products or intermediates that are being formed.

While overcoming these challenges of scale-up is a major benefit of continuous flow, an even more powerful advantage is its ability to not just simplify a process but to break through traditional process limitations and constraints.

Frequently, a process chemist or engineer is forced to accept a less than ideal synthetic route due to infrastructure constraints, resulting in processes that can generate impurities which must be removed. In some cases, flow chemistry can provide an optimized process that reduces these impurities significantly or even avoids them altogether.

The quality of the final product can also be enhanced in a continuous flow process because there is greater opportunity to control the process by using real-time analysis to monitor quality instantaneously, rather than waiting to measure a single batch sample. Applying process analytical technology (PAT) is generally easier in flow than with batch production, as often only temperature probes and flow meters will be needed to ensure that the process remains within the acceptable parameters to achieve product of a known quality. Where necessary, sophisticated PAT probes can be easily integrated into a flow process to allow for rapid detection of deviations. For example, layering in an additional measurement, such as Fourier-transform infrared (FTIR) or Raman spectroscopy, to track a parameter such as reaction conversion can allow real-time adjustments to correct raw material variations or drift that may be happening within the process.



Continuous flow also now makes it possible to use technologies that are technically challenging on a large scale due to infrastructure constraints, such as cryogenic conditions, Grignard reactions, and hydrogenations. Meanwhile, other technologies that are of great interest throughout the industry, notably photochemistry, are not suitable for use in a large batch reactor as a light source cannot fully penetrate into the reaction mix with consistency or efficacy. However, with continuous flow this can be achieved very easily, meaning that this technology can now be scaled up and no longer needs to be regarded as a purely academic exercise.

Every unit operation associated with traditional batch processing has a continuous flow counterpart, and the throughputs and capacities achievable with continuous flow can rival, or often even outperform, traditional batch processes. Viewed until recently mainly as a niche problem-solving technology, the use of continuous flow should now be seen as an option when assessing a synthetic route, and where applicable, can be a powerful development tool and a process of choice.


First published: The Small Molecule Manufacturer

Title: Development of continuous flow — Updating

the toolbox

Date: November, 2019

About the authors

Dr Shawn Conway,


and Development,

Cambrex

Jonathan Knight,

Director, Market Intelligence,

Cambrex


Science & Technology

Dipti PatelSenior Inspector

Brian BarlowHiPO Operator


Design of experiments (DoE) is becoming increasingly accepted in the pharmaceutical sector by manufacturers and regulators alike. The strategy involves a series of experiments that are designed to give statistically relevant information about multiple factors involved in the process at the same time, rather than relying on a large number of individual experiments.

Not only does it have the potential to save significant time and costs in the short-term, DoE allows the optimum conditions to be established rapidly, moving a project into the manufacturing plant more quickly.

Applying statistical tools and changing multiple factors simultaneously in premanufacturing experiments removes the need to run every permutation and combination of all the factors at different levels to determine the optimal conditions for production. DoE provides insight regarding individual factors, or a combination of factors, and how they affect the process.

DoE also highlights potential interactions between factors that might not normally be observed with a conventional one-variable-at-a-time (OVAT) approach. Synergistic effects — whether positive or negative — could otherwise be missed. By exploring different combinations of high, low and midpoints of all the relevant factors, it is possible to establish their interactions and how these can affect the experimental results.

There are three distinct phases of the DoE process: the screening model; the optimization model; and robustness evaluation. The screening model is designed to identify which factors are statistically relevant to the process, whereas the

optimization model takes these factors and looks to improve the process by determining the best combination of conditions.

The robustness evaluation may be used to assess any sensitivity to small changes near the set points. A focus of efforts on the first two phases may provide a design space for regulatory filings.

The screening design

The screening design provides an assessment environment in which all the potential experimental variables are studied to determine whether they directly impact a quality attribute of the process.

Although the nature of these factors will always be process-specific, the list is likely to include inputs such as temperature, pressure, time, concentration, solvent, equivalents of reagents and the nature and degree of mixing in the vessel. Other relevant variables include those based on scale and the type of equipment being used.

Various different experimental designs can be applied, such as full factorial or fractional factorial, many of which employ a linear regression model. The selection of the appropriate screening design is driven by the number of relevant factors, the number of levels of each factor, the power of the design, process-specific details and the ease of performing the experiments.

Establishing a design space allows the full range of outcome-specific parameters to be examined and identifies the edges of failure for a given process.




The primary objective is to identify variables that are not statistically relevant to the experimental result to reduce the complexity of the models. If a particular variable is deemed not to affect the outcome of the process, it is set and no further development will be required for that variable. This allows the other identified variables to be changed around it.

Risk-based analysis

Every company has its own approach to the risk-based analysis that underpins its DoE strategy. The method developed at Cambrex starts with a multidisciplinary brainstorming session to identify different factors and the quality attributes that may be important to the process.

The brainstorming group of five to seven people includes both those who have an intimate knowledge of the process to be studied and those with expertise in the implementation of DoE methodology. The initial list will almost certainly include too many factors; therefore, the next step is to reduce the design space to the most relevant factors for a screening study.

Each individual in the group will rank all the factors in the list in terms of how they may affect the various quality attributes on a scale of one to five. Any factors that rank above three are deemed important, with those four and above being the most important.

The quality attributes are similarly ranked, which can provide insight into which are critical quality attributes (CQAs). These subjective rankings are averaged across the group, with the average values for factor contribution multiplied by the average values for quality attributes. The result is a consensus list that’s used to recommend which factors and quality attributes ought to be included in the DoE.

For this strategy to work, it is important that there is already some process knowledge regarding potential factors and CQAs. This might be from initial scouting runs in the laboratory or a report describing the work already undertaken. In the example highlighted in Table 1, the summary of weighted factor responses for two CQAs indicates the relative importance of the factors.

The most important, highlighted in red, should be included in the screening DoE study. Careful consideration should also be given to those deemed to be of intermediate importance, coloured yellow, and whether they should also be included.

Prior to starting the screening experiments, additional factors may be added to the screening study. Once the screening

design has been set, further controlled factors may not be added to the same study. Uncontrolled factors can be added later, as long as the data are collected at the time of experimentation. Examples of uncontrolled factors are the potency of commercial reagents or advantageous water levels in a hygroscopic reaction mixture.

The next step is to utilise the selected factors and quality attributes to generate an experimental design for the screening study. This considers both the number of factors and the type of design that is required. For example, a full factorial design will require many more experiments, whereas a fractional factorial design pulls out some of them to give a statistically relevant model with a reduced number of experiments.

Once the screening study is completed, the data gleaned produce a model for each response (CQA) to identify those factors for which changes are likely to be relevant. This should significantly narrow the list of factors included in the subsequent optimization study.

Figure 1 shows the coefficients plot for the example screening model. The magnitude of the factor influence on the response (conversion or purity) is represented by the bar graph.

Comparing the bar graph with the standard error bar allows the determination of statistically relevant factors. In this screening study, reagent 1 (R1) and temperature were both deemed significant for conversion and purity, whereas reagent 2 (R2) was not. Thus, the study moved into the optimization phase with just two factors.

During data analysis, it was also noted that a square term, shown in the figure as Temp*Temp, also contributed to the responses. Interaction terms (such as R1*R2 or R1*Temp) were evaluated but not significant in this case.

Optimization design

The aim of the optimization design stage is to look in greater depth at the factors to give a better understanding of the whole design space and set the optimal conditions for the process in the manufacturing plant. Compared with screening studies, the optimization study uses a quadratic regression model to provide much more detail by allowing full characterisation of the potential square terms and cross terms.

Instead of simply identifying that a factor is relevant for a given response, insight is gained into the nature of that relevance.

In-processreaction

conversion

Reagent 1 mol equiv

Reagent 2 mol equiv

Reagent temperature

Factor 4

Factor 5

Factor 6

15.0

16.3

20.9

9.8

8.5

9.1

In-processreactionpurity

14.3

14.3

18.2

6.1

10.5

8.8

Table 1: Summary of weighted factor responses for two CQAs

Conversion (N=11; DF=5; R2=0.98), Purity (N=11; DF=4; R2=0.98), Confidence=0.95

Coefficients (scaled and centered) - Example FF (MLR)

Conversion ~

Pu

rity

~ [

%]

0.8

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

R2

R1*

Tem

p

Co

nvers

ion

~ [

%]

R1

Tem

p

Tem

p*T

em

p

0.5

0.4

0.3

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

R1

R2

Tem

p

Tem

p*T

em

p

R1*

Tem

p

R1*

R2

Purity ~


Figure 1: A coefficients plot for an experimental screening model


The procedure then takes each of the relevant factors identified in the screening study into the optimization design to quantify acceptable ranges. Importantly, they will also be included in the filings that will ultimately be submitted to regulatory agencies. If it is possible to quantify how the factors affect the quality attributes of the process, then it will allow definition of the design space, critical process parameters (CPPs) and proven acceptable ranges (PARs) that will give predictable results.

The software, again, will generate the experiments that should be run in the optimization study. This takes both the number of factors and the type of design that is required into account. Often, Central Composite Designs (CCDs) are employed; this second model is much more in-depth than the initial screening model, allowing for additional statistical analysis. It becomes possible to predict what is likely to occur in future experiments and removes any presumption when setting reaction conditions.

The software will generate the likelihood that target quality attributes will be met with various combinations of factors and gives the probability of failure. This information cannot be gleaned from the screening studies, owing to the use of simplified regression models. After generating an optimization model, reaction conditions can be identified to obtain the desired quality attributes and reduce the risk of failure.

Figure 2 shows the coefficients plot for the example optimization model. In this example, the quadratic regression model showed that reagent 1 (R1) has a smaller impact on the studied attributes than temperature, including a non-linear contribution of temperature.

The generated model is predictive and therefore capable of extrapolating outside the factor ranges that were studied experimentally. The software gives the option to optimise factor set points based on quality attributes (maximum, minimum or target).

Optimization DoE models also allow a design space plot to be generated. In the example, Figure 3 shows the optimal working ranges across a temperature range of 18–28°C and quantities of reagent 1, ranging from 65–135 mole equivalents, with a minimum purity of 97.5% and a minimum conversion of 98.5%.

The greyed-out areas at the edges of the plot are predictive, whereas the green zone shows factor combinations wherein the risk of failure to meet criteria is lower than 0.5%. As the risk increases, indicated by the contour lines, the colour transitions

from green to red. Based on the design space and optimiser, it was recommended that the reaction should be run at 24 ± 2°C, and with 115 ± 10 mole equivalents of reagent 1.

At this point, it can be the end of the DoE process, with conditions being implemented in the manufacturing plant. However, potential follow-up work may include verification trials, single variable experiments for factors that do not fit a DoE model or robustness evaluations.

DoE advantages

DoE has multiple advantages above and beyond simple time and cost savings. It gives an insight into how changes to one variable might affect the optimal point for other variables. Synergies are not always obvious from traditional/single experiments and it’s easy to miss how different factors affect each other.

It also makes non-linear effects clearer. Development efforts can be focused on those parts of the process that are actually important, without wasting time and resources on studying something with little or no impact. The statistical analysis can then be used to justify to regulators why a factor was deemed unimportant.

By establishing a proven acceptable range, it will become clear whether the material is likely to be compromised if the process goes outside the target operating window.

Establishing a design space allows the full range of outcome-specific parameters to be optimised and identifies the edges of failure for the process. The result will be a more predictable manufacturing process with significant savings in both cost and time.

About the author

Michael Tracey,

Principal Scientist,

New Product Development,

Cambrex


Title: Process optimization by design

Date: January 25, 2019


Conversion (N=10; DF=6; R2=0.98), Purity (N= 1; DF=7; R2=0.84), Confidence=0.95

Coefficients (scaled and centered) - Example CCF (MLR)

1

0.6

0.5

0.4

0.3

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

R1

Tem

p

Tem

p*T

em

p

Conversion

Co

nvers

ion

[%

]

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

-1

R1

Tem

p

Tem

p*T

em

p

Purity

Pu

rity

[%

]

Figure 2: A coefficients plot for an optimization model

No disruption on factors, Interval=Prediction, Acceptance limit=1%

Temp [°C]

Design space - Example CCF (MLR)

Probability of failure (%) for purity and conversion

130

120

110

100

90

80

70

18 19 20

50

%

10

5

2

1

0.521 22 23 24 25 26 27 28

Reag

en

t 1

[mo

l eq

]

Figure 3: An example design space plot


But they also expect that CDMOs will be challenged by more rigorous requirements put forth by pharma customers.

Cambrex: Navigating R&D and regulatory pathways

Cambrex’s facility in High Point, NC, specializes in clinical phase active pharmaceutical ingredients (APIs), mainly in the pre-investigational new drug application (IND) through Phase 2. The company provides analytical R&D support, QC release, and stability capabilities to small virtual companies and large pharmaceutical multinationals.

The High Point site follows ICH Q7 guidelines, as well as other regulatory guidances, and is fully cGMP compliant. “Changes to the analytical landscape over the past 10 years have included the replacement of USP<231> Heavy Metals with the new USP<233> Elemental Impurities testing, and the growing interest in the determination of potential genotoxic impurities (PGI),” says Mark Shapiro, Director, Analytical Research and Development Cambrex. “In the PGI field, we have successfully developed methods capable of quantitation at very low level (sub-parts per million).”

Cambrex has addressed these industry changes through straightforward approaches, including the installation and qualification of triple quad mass spectrometers, as well as ICP-MS instrumentation. Additionally, Cambrex expanded

capabilities in identifying unknowns, installing electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) sources to triple quad LC-MS instruments, as well as GC-MS instruments with both electrospray ionization (EI) and chemical ionization (CI) capabilities.

Relying on its technical knowledge and testing capabilities, Cambrex High Point recently manufactured drug material for a customer for which an HPLC assay and impurity testing method had been developed and qualified at another CMO lab, and for which QC release and stability were performed. “Our studies and work showed the HPLC method to be

Pharma’s reliance on Contract Development and Manufacturing Organizations (CDMOs) to provide method development, process validation and stability storage testing has experts predicting the global analytical testing outsourcing market will reach $9.6 billion by 20251.



Cambrex High Point's quality control laboratory follows strict guidelines in performing testing held to the highest standards


insufficient to determine a positional isomer of the drug compound that very closely co-eluted with the main compound,” explains Mr. Shapiro.

A new, more specific test method had to be developed and qualified. This process was fairly straightforward, but, as the material underwent stability storage, the assay values for the main compound were observed to be rising over time. Mr. Shapiro says this was because of the previously unrecognized hygroscopic nature of the material (both standard and sample), which was not accounted for in the assay calculations. Upon discovery of this, appropriate changes to the method, including determination of water content of the standard at time of use, as well as modifications to the assay calculations, provided sufficient course correction to the stability, and allowed the material to successfully continue on an extended stability regimen.

From a regulatory standpoint, Cambrex mentors clients by helping them navigate the complex waters of regulations, while meeting the phase-appropriate needs of the drug compound. Cambrex has recently announced an expansion program for the High Point site, and, Mr. Shapiro says, the challenge will be to ensure this growth aligns with the continuing changes to the regulatory landscape for the analytical demands of the earlier phases of the pharmaceutical lifecycle as well as more broadly across the API field.

References/Sources

1Pharmaceuticals analytical testing outsourcing market

worth $9.6 billion by 2025, Grand View research.

Date: January, 2017


First published: Drug Development & Delivery

Title: Outsourcing analytical testing: The gateway to

drug manufacturing

Date: January/February, 2019

About the author

Mark Shapiro,

Director, Analytical Research and

Development,

Cambrex


Spectral analysis, including three-dimensional modelling, was used to characterize the peak, leading to the development of a new HPLC method for analysing impurity content.

Analytical scientists in the pharmaceutical industry are tasked with ensuring the high performance liquid chromatography (HPLC) purity methods that they develop and validate provide complete separation of compounds, and this work can yield unexpected findings that lead to improvements in methods and manufacturing processes.

In the following case study, peak spectral analysis was used as an analytical tool to determine the cause of peak purity failure during HPLC method validation. This analysis resulted in the separation and identification of a previously unknown impurity, and the development and validation of a new HPLC method that allowed this impurity to be separated and independently determined.

Case study

Early phase HPLC purity/assay validations typically include the following components, based on International Council for Harmonization (ICH) Q2(R1) guidelines1:

• Specificity — the ability of a method to separate the analyte, or compound of interest, from other components expected to be present in the sample

• Linearity — the ability of a method to provide results

within a specified concentration range that are directly proportional to concentration of the analyte

• Accuracy — the ability of a method to produce assay results near the true value

• Precision — the ability of a method to give consistently reproducible results

• Detection limit — the lowest concentration of analyte that can be detected

• Quantitation limit — the lowest concentration of analyte that can be consistently measured

• Forced degradation — exposing the drug substance to severe environmental and chemical stresses to rapidly evaluate material stability.

This final component is performed according to the ICH guideline Q1A(R2), Section 2.1.2, and will demonstrate that a method is stability-indicating2.

During a recent validation on an API that was being manufactured for a client, forced degradation studies were performed on the API using the client-supplied method. During the study, the HPLC-diode array detector (DAD) peak purity analysis of the analyte peak failed for all conditions, including the control. Failure was not observed during pre-validation exercises, which were performed on a different, previous batch of API. This indicated that a new, unknown impurity could be co-eluting with the analyte peak.

Investigation of peak purity failure during HPLC method validation led to discovery of a co-eluting impurity under the main peak.




Using Chemstation software (Agilent), the ultraviolet (UV) spectra of the analyte peak collected by the diode array are analysed for spectral purity, giving the purity factor. A purity factor of ≥990 generally indicates a peak is pure and suggests no other peaks co-elute.

Peak purity analysis results for an older lot are shown in Figure 1, where the upper-left quadrant shows the chromatogram, with its baseline enlarged for detail. The green bar under the peak indicates the peak has a purity factor above the threshold of 990, with an observed result of 999.433, which is shown in the upper-right quadrant. The lower-right quadrant shows the analysis of spectral purity within the peak, as indicated by the wide line that remains within the green bar, and the lower-left quadrant includes the peak spectral results taken from five points across the peak.

The results in Figure 2 show the new, failing, lot of API, which has a purity factor of 835.895. The wide line beneath the peak in the lower-right quadrant indicates the presence of a spectral impurity on the tail of the peak. A careful review of the spectra in the lower-left quadrant indicates that one of the spectral plots differs from the others, as it is shifted to the right, and this corresponds to the co-eluting impurity. This shift pattern would be useful in developing a method for the new impurity, as it implied that the impurity responded better than the analyte at a wavelength of about 290nm.

The three-dimensional spectral results of the analyte peak were also modelled, and the area around the baseline enlarged for detail. The spectral map of the pure analyte peak obtained from the older lot is shown in Figure 3, which plots wavelengths between 240 and 310nm against time (11.6 minutes to 10.9 minutes, right to left). Note that the peak is reversed from the normal chromatogram to allow the spectral details to be observed. The spectral map of analyte peak from the impure lot is shown in Figure 4 (using the same axis scale), and the impurity shows up as a ‘bulge’ on the main peak.

The method that was being validated was performed at a wavelength of 260nm, but when the impure analyte peak was evaluated at 290nm, it became clear that there were two distinct compounds. Overlays of the impure analyte peak at 260nm and 290nm wavelengths were created, as

shown in Figure 5. The later peak (right, red, 290nm) shows the location of the bulge in the three-dimensional model in Figure 4.

The information from Figure 5 indicated that it might be possible to separate the later-eluting new compound from the analyte, based on the differences in properties of the two molecules. As the identity of the new impurity was unknown, data from the manufacturing campaign of the impure batch were reviewed to check for information that might point to the source of the impurity. HPLC data from the manufacturing batch record indicated that the impurity was introduced early in the manufacturing. The data also revealed that the method used for in-process checks was able to separate out the impurity from an intermediate material with the use of a different column and mobile phase.

Isolated intermediate material from the manufacturing campaign that produced the impurity containing API was analysed using the in-process HPLC method, column, and mobile phase. Although the method was not optimized for this separation, the impurity appeared as a peak before the main intermediate peak, and was resolved from the intermediate peak. Additional analysis showed a spectral profile similar to the impurity in the final compound. The HPLC results are

Figure 1: Peak purity analysis of control lot

Figure 2: Peak purity analysis of new lot

Figure 3: UV spectral three-dimensional map of pure analyte peak

Figure 4: UV spectral three-dimensional map of impure analyte peak


Figure 5: Overlay (normalized) of analyte peak with 260nm (left, in blue) and 290nm (right, in red). Time shown on x-axis


shown in Figures 6 (expanded scale) and 7. Spectral results are shown in an overlay in Figure 8, where the impurity has a spectral maximum of approximately 274nm, compared with the intermediate, which has a spectral maximum of 260nm.

Additional method development was performed on the API, leading to a final set of conditions that successfully separated out the impurity. Although the intermediate and the API have a similar structure (the intermediate molecule contributes a significant structural fragment to the API), the API is less polar, and elutes much later than the intermediate shown in the previous figures. Using the final method conditions, the impurity elutes first, as shown in the example chromatogram in Figure 9, and the API peak was determined to be spectrally pure.

Spectral results from the peaks in the example chromatogram are shown in Figure 10, where the impurity peak has a spectral maximum at 274nm. Because the impurity’s spectral maximum was different from the API’s maximum at 260nm, a response factor correction for the impurity was empirically determined and added to the new method. This new method was subsequently validated and implemented prior to release of the next batch (a clean-up of the impure batch of API), demonstrating the versatility and utility of spectral analysis as an analytical tool.

References/Sources

1ICH, Q2 (R1) Validation of analytical procedures: Text and

methodology, (ICH).

Date: November, 2005

2ICH, Q1A (R2) Stability testing of new drug substances

and products, (ICH).

Date: February, 2003

mAU

70

60

50

40

30

20

10

0

DAD1 A, Sig = 260,4 Ref= 400, 100 (LC4625-2016-12-20-16-24-22\2EB-0301.D)

2.0

83

2.4

46

1 1.5 2 2.5 3 3.5 min

DAD1 A, Sig = 260,4 Ref= 400, 100 (LC4625-2017-10-14-17-13-25\1DI-0901.D)

12.4

71

11.3

26

mAU

25

20

15

10

5

0

5 10 15 min

Figure 9: HPLC results (using final method conditions) of the impure API. Time shown on x-axis

Figure 6: HPLC results of the intermediate using the in-process method. Time shown on x-axis (expanded scale)


Nom

400

350

300

250

200

150

100

50

0

220 240 260 280 300 320 340 360 380

DAD1, 12.471 (424 mAU, - ) Ref=12.092 & 13.332 of 1DI-0901.D

DAD1, 11.326 (26.9 mAU, - ) Ref=11.139 & 11.885 of 1DI-0901.D

Figure 10: Spectral overlay of HPLC results of API and API impurity (Impurity spectrum shifted right, orange)

DAD1 A, Sig = 260,4 Ref= 400, 100 (LC4625-2016-12-20-16-24-22\2EB-0301.D)

mAU

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1000

800

600

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Figure 7: HHPLC results of the intermediate using the in-process method. Time shown on x-axis (full scale)

Nom

1200

1000

800

600

400

200

0

DAD1, 2.446 (1454 mAU, - ) Ref = 1.983 & 3.413 of 2EB-0301.D

DAD1, 2.094 (55.5 mAU, - ) Ref = 1.983 & 3.413 of 2EB-0301.D

220 240 260 280 300 320 340 360 380 nm

Figure 8: Spectral overlay of HPLC results of intermediate and impurity (Impurity spectrum shifted right, orange)

Title: Utilizing spectral analysis in HPLC diode array to

discover impurities

Date: March 1, 2019

About the author

Daniel Hayes,

Associate Principal Scientist, Analytical,

Cambrex


Light with a wavelength below 190nm is not readily transmitted, as it is absorbed by the lamp’s quartz envelope.

These lamps, as is the case for any light bulb, have a finite lifespan. The operating life can be defined as the total number of hours for which the lamp can be used for meaningful work. This useful lifetime for a trace-level analysis is likely to be shorter than the lifetime for routine analysis because of the lower level of quantitation required.

What affects lamp life?

However carefully it is used, the lamp will always be subject to normal degradation. Its metal coatings will evaporate, and there is a filament coating reaction with the quartz envelope. Furthermore, solarization of the transparent sheath material occurs, with shadowing from intense radiation.

Some degradation is related to the way the lamp is used. The number of times the lamp is ignited increases stress on the lamp filament and is inversely proportional to its operating life. However, leaving it on continuously will tend to decrease its useful life by about threefold, assuming the instrument is used eight hours a day. It is advisable to shut the detector lamp off when not being used for extended periods of time.

Touching the lamp with bare fingers can reduce its lifespan by creating hot spots on the outer envelope from oily residues. Physical shock also has an effect, whether it is caused by moving or jarring the detector while the lamp is on or

powering down the detector and not allowing the hot lamp to cool down before it is turned on again.

Lamps also have a limited shelf-life before installation, so it is important to check the date of manufacture before installing the instrument. Additionally, it is important to condition the incoming voltage to an instrument to prevent spikes or swings that may also damage the lamp.

Indicators of lamp problems

An experienced analyst will recognize the signs that a lamp might not be performing perfectly, including baselines that feature irregular, high, or periodic noise. There are several reasons why this may be the case, but, if other factors —including air bubbles in the system, temperature swings or pump pulses, a contaminated flow cell, or if immiscible solvents are being used — then an aging lamp may be the cause.

Another indicator is that the peak response is lower than expected. Again, the flow cell might have been contaminated, or the injection volume might be insufficient; but it may also be indicative of the lamp’s diminishing performance.

Characteristics of the lamp itself can also have an impact. The lower the wavelength, the more degradation in output can be expected. This may mean that an aging lamp that works almost perfectly at 340nm and is acceptable at 280nm could be next to useless at 210nm.

Deuterium lamps produce intense ultraviolet (UV) radiation at wavelengths between 190 and 400nm via plasma discharge in an atmosphere of deuterium.




Of course, if the signal from the analyte is sufficiently large, then, in reality, the substandard energy output from the lamp may not be a problem. Lamp energy becomes important if the signal is small. If the signal-to-noise ratio is low, then the greater impact of the baseline noise may alter the detectability of trace analytes due to the compromised output from the lamp.

When to replace a lamp

Clearly, if the lamp does not illuminate when the power is switched on, it must be replaced. It may still be emitting UV light, but the analytical results will be obviously atypical. But it is rarely that clear-cut, and a strategy to determine its replacement is important.

If the peaks of interest have a strong signal, in other words, in excess of 100mAU/mV, then it is reasonable to wait until the lamp fails to ignite until it is replaced. This will typically be 4,000–8,000 hours. However, if trace analyses or impurity checks are being performed, a procedure should be in place to evaluate the signal-to-noise ratio of the instrument at the set wavelength. If this is suboptimal, then it is likely that a new lamp will need to be purchased as a consumable if its warranty has expired, and the unit would then need to be recalibrated and qualified.

Another option is to monitor the lamp’s performance on a regular basis. This approach may provide some indication of an impending lamp failure if the checks are sufficiently frequent. The problem with this strategy, however, is that once the lamp starts to fail, its output will decrease exponentially and the failure will occur extremely rapidly.

Some instrument systems include an early maintenance feedback feature that tracks the hours of use. For an analyst, it is probably not feasible to rely solely upon this, given the unpredictable nature of the operational life of the lamps.

Alternatively, an intensity test can be performed to monitor the status of the detector lamp, although this is not always conclusive without further confirmation testing. If it does fail this intensity test, the first step is to rule out all other common causes, such as solvents, bubbles, dirty flow cells, or optical issues.

To differentiate detector problems from flow cell issues, and to perform a detector cell test, a test cartridge would need to be purchased, which can be expensive. If the lamp is pinpointed as the cause of the intensity test failure and is replaced, then it will need to be recalibrated and qualified.

Another approach, although more expensive, is to replace the lamps at regular intervals, even if the equipment is working properly. For example, UV lamps could be replaced after a certain number of hours in use — say, 4,000 hours. The lamp hours would need to be monitored, and there would still be no guarantee that failures would not occur before the lamp is replaced.

Alternatively, the lamps could be replaced on a regular cycle, for example, every three months, which represents about 2,000 hours of continuous use. Again, there is no guarantee that lamp failures would not occur before the new lamp is installed, but it would be under warranty.

The material cost of exchanging lamps on a quarterly cycle is substantial. Carrying out three additional changes a year, on top of the periodic maintenance replacement for 25

instruments with long-life deuterium lamps, would be close to $100,000 per year. In addition to the consumable costs, each change would require the detectors to be recalibrated and qualified, adding greatly to the cost incurred in both dollars and time.

Selecting the right strategy

When considering the lamp replacement strategy, the first question to ask is: How many HPLC system failures can truly be attributed to the failure of a deuterium lamp in any given year? Additionally, can these lamp failures be substantiated through vendor service reports or logbook entries? Do guidelines exist for shutting lamps off when not in use, and which has the greater impact on lamp life — ignition frequency or continual operation?

The decision will also depend on whether the instrument is typically used for trace and impurity analyses, where background noise has a greater impact on accuracy. Are signal-to-noise, limit of detection, and limit of quantitation determinations performed, monitored, and documented? Are detector optimization parameters such as bandwidth, slit width, reference settings, and response times reviewed or changed when new methods are brought online?

Ultimately, the strategy will depend on the evidence and the risk-to-reward ratio. A large company may be less concerned about the cost of replacing a $600 lamp every quarter, but a smaller one may choose to take the risk of replacing on a less frequent basis.


First published: American Laboratory

Title: Considerations for replacing deuterium lamps in

HPLC systems

Date: April 2019

About the authors

Robert Pritchard,

Analytical Instrumentation Specialist,

Cambrex

Mark Shapiro,

Director, Analytical Research

and Development,

Cambrex


The presence of the probable carcinogens N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) found in APIs used for the production of a number of generic versions of angiotensin II receptor blocker (ARB) medicines has raised concerns about how manufacturers and regulatory bodies address the potential for production of undesirable impurities1. The products in question complied with regulations yet contained genotoxic compounds. FDA has taken several steps to address this particular issue2,3. Drug makers also clearly need to consider what approaches they should be taking to ensure their API suppliers are supplying high-quality material that is safe for use in final drug formulations.

“Despite the fact that manufacturers have the process knowledge and experience that regulatory bodies do not have, we are still dealing with massive recalls of very important medications, the scope of which just keeps increasing,” observes Macniell Esua, chief compliance officer at CordenPharma International.

In this particular case, Esua points out that it appears that a trace impurity in a solvent reacted with a process reagent used, resulting in a genotoxic impurity. “Surprising levels of the impurity are being found in the drug that exceed the levels one might have predicted and that are allowed. One guess is that recycled solvents may be a contributing factor,” he notes. Esua adds that it is critical that the full investigation findings be shared with the industry in an open fashion, so everyone can learn from this potentially tragic situation.

Looking specifically at the issues concerning valsartan, it is also important to note that after the initial recall of drug product containing an API manufactured by Zhejiang Huahai China, additional API manufacturers in China and India had their approvals recalled for the same reason. “The presence of nitrosamines is not only a ‘variation’ problem but has also been shown to be a GMP cross-contamination problem at some of the manufacturing sites involved,” says Rolf Arndt, Senior Quality Assurance and Regulatory Affairs Specialist with Cambrex.

He adds that the fact that different nitrosamines were identified for both APIs and drug products makes the problem more challenging, because the required maximum specification limits of nitrosamines are substantially lower than for normal impurities.

“The issue is not a simple question of ‘approval systems,’ but more a combination of better evaluation of the risks of formation of nitrosamines as well as better analytical techniques; but most importantly, that API manufacturers have sufficient controls within their GMP procedures to avoid cross-contamination,” Rolf asserts. “Furthermore,” he states, “because this field is so fast moving, it is not enough to merely comply with the regulations; it is important to be ahead of them.”

Confidence in the quality systems and scientific competence of the API manufacturing team is essential.




Value of fate and purge studies

During a process validation exercise related to an investigational new drug, a full fate and purge study should normally be conducted, according to Esua. In the current situation with valsartan and related products, Esua suggests a fate and purge study would have correctly identified NDMA as a potential impurity in the process. “As a result, work would have been conducted to identify the potential risk of introduction of NDMA in the final product and to develop mitigation strategies. Through the change control process, full consideration should have been given to the change in solvent, the potential impurities that the change was introducing, and the downstream implications,” he says. He also points out that this issue is again related to the scientific competence aspect — and whether the study was conducted with sufficient rigor or paid “mere lip service.”

Risk assessments essential

Any process change must involve a risk assessment that includes a judgement of whether the proposed changes have the potential to result in the production of new or additional impurities, according to Arndt. The assessment should also identify whether there is a risk of formation of impurities that may fall under International Council for Harmonisation M7 guidelines.

“If there is a risk of formation of so-called ‘M7 impurities,’ further investigation must be performed, and the basis to exclude any process change must rest fully on supportive analytical data,” Arndt states. “These types of impurities cannot normally be detected by simple chromatographic methods that are used for ‘related substances’ — substances similar to the API, so more advanced techniques must be used, for example, [tandem mass spectrometry] MS/MS,” he adds.

Burden rests with the manufacturer

When considering drug process changes, the burden resides rightfully with the manufacturer, according to Esua. It is also the manufacturers’ responsibility to complete a comprehensive scientific review of the proposed changes, with thorough consideration of all possible implications, and a detailed impact assessment as part of the change control process.

“In the case of the NDMA contamination of valsartan, is it known that dimethylamine could be an impurity in the solvent [drug master file] DMF? Yes. Is it known that dimethylamine would react under the reaction conditions to give NDMA? Yes. Where, then, did the manufacturer go wrong? Were dimethylamine levels higher than anticipated in the DMF (since it’s not a typical impurity that would be screened during a DMF solvent release), or was the combination of these two factors (the presence of dimethyl amine and reactivity in the reaction) simply not considered?” Esua asks.

What is important to remember, according to Esua, is that although a regulatory inspection is a tool to measure compliance against current manufacturing regulations, it does not, nor can it, dictate a certain level of scientific competence on the part of the manufacturers, or unfortunately, the regulatory agencies themselves.

Know your API supplier

So how can drug makers be sure they are selecting API suppliers with the appropriate level of scientific competency? “It is imperative that pharma/biotech companies understand the partners they choose to do business with,” asserts Stephen Houldsworth, Director of Global Small Molecules and Antibiotics Platforms at Corden Pharma International. “They must have confidence in the company’s quality systems and its manufacturing team, as well as the team’s scientific competence and ability to make the correct decisions,” he explains.

Houldsworth points out that there are suppliers in the marketplace today that perhaps make decisions based on incorrect assumptions or poor science, the consequences of which are often not discovered until much later, as in the case of valsartan and similar drugs. “Unfortunately, price drives a lot of purchasing decisions — especially in the generic API business — but this cannot be the only priority. Considerations such as quality controls, process development, project management, and scientific expertise must also be factored into these decisions,” he stresses.

The first and most important step is to evaluate and audit the API manufacturer to ensure that it has a sufficient standard of GMP protocols and procedures in place to minimize the risk for cross-contamination, according to Jonathan Knight, Director of Marketing Intelligence for Cambrex. The second step is to ensure further evaluation where necessary, such as for potential toxic elemental impurities originating from the environment, the raw materials used for manufacturing, and/or corrosion of manufacturing equipment. “Confirmation is needed that these types of impurities are not present in the API and thus do not impact the product quality,” Knight observes.

In addition, Cambrex suggests reviewing the company’s regulatory history and its corrective actions around observations and GMP compliance and training. Additionally, Knight notes, it is important to assess the company’s experience in developing new chemical entities, and the proficiency and experience of its chemical development, analytical development, and quality assurance departments. That includes checking the investment history of a manufacturer, especially with respect to the acquisition of the most up-to-date analytical equipment.

“Having a good understanding of what the potential risks are can be determined by the development of good design of experiments. In addition, ensuring openness between parties and clear documentation can avoid problems,” Knight adds.

The success of a company’s outsourcing efforts is driven by the quality of their vendor qualification and management systems, according to Houldsworth. “They need to be robust, structured, and detailed to provide a high level of confidence that the API suppliers in question are reliable and competent,” he concludes.

Reasonable responses needed

Esua cautions that regulatory agencies should not respond to the valsartan contamination issue with a simple knee-jerk reaction and demand that all process changes must be approved by regulatory agencies before implementation. “Apart from crippling both the manufacturers (via delays in change approvals) and the regulatory agencies (by drastically



increased burden of work), this approach would lead to rising costs in an industry that is already under intense pressure from a costing point of view, without any guarantee that problems will be avoided in the future,” he states.

References/Sources

1A. Shanley, “After valsartan recalls, regulators grapple with

nitrosamine contamination in APIs.”


2FDA, “Statement from FDA Commissioner Scott Gottlieb,

M.D., and Janet Woodcock, M.D., Director of the Center

for Drug Evaluation and Research on the FDA’s ongoing

investigation into valsartan and ARB-class impurities

and the agency’s steps to address the root causes of the

safety issues.”

Date: January 25, 2019

Article: fda.gov

3FDA, “Zhejiang Huahai Pharmaceutical 11/29/18,”

warning letter.


Article: fda.gov

Title: Select suppliers with demonstrated expertise to avoid

sourcing “bad” APIs

Date: April 2, 2019

About the author

Rolf Arndt,

Senior Quality Assurance and Regulatory

Affairs Specialist,

Cambrex


https://www.fda.gov

https://www.fda.gov


While most industries have employed continuous manufacturing processes for decades, if not centuries, the pharmaceutical industry has remained staunchly committed to batch operations. Drugmakers have steered clear of making major changes to validated processes, despite the advantages to be gained in cost, process time, and quality. But new drugs coming to market — chemically complex and targeted therapies — call for just the benefits that continuous processes offer. With the US Food and Drug Administration’s blessing, drug companies are finally implementing technologies that have been in development for 20 years.

"It’s called a BHAG,” says Hayden Thomas, divulging a term popular among chemical engineers at Vertex Pharmaceuticals, where Thomas is Vice President of Formulation Development. “A big, hairy, audacious goal.” In his case it was committing to continuous process manufacturing for all new products in development.

As Thomas prepared in 2011 to pitch the idea to the top brass at Vertex, he knew it would be a long shot. After all, the pharmaceutical industry has resisted continuous processes, even though virtually all other industries have replaced step-by-step batch manufacturing over the past two centuries.

Highly profitable and ultraconservative, the drug industry has traditionally held back on investing in any transformative production or information technology despite solid evidence of benefits. In the case of continuous process manufacturing, benefits include lower costs, lower waste, higher yield, and higher quality. Such processes also allow ready application of

complex and hazardous chemistries and much smaller — often bench top — facilities than those traditionally employed to make drugs.

Thomas had a sense that the timing was right. Concerns about regulatory validation of continuous processes have slowly evaporated since the US Food and Drug Administration began encouraging them 15 years ago. And the industry has been experimenting with continuous techniques in engineering research for at least that long; Vertex began in 2005.

“I was kind of nervous leading up to the event,” Thomas recalls about his meeting with management. “We were making a pitch for a lot of money and commitment of resources. But they looked at it and said, ‘This is where Vertex needs to be.’ ”

Vertex’s commitment to the project paid off in 2015 when the FDA approved a continuous process for Orkambi, its cystic fibrosis drug. It was the first time the agency approved a finished-dose drug — called a drug product in industry parlance — made on an entirely continuous basis. Since then, the company scored a second time with a tableting plant for Symdeko, also for cystic fibrosis.

Janssen, Eli Lilly and Company, and Pfizer subsequently received approvals for drug products employing continuous production. Janssen’s Prezista treats HIV, Lilly’s Verzenio treats breast cancer, and Pfizer’s Daurismo treats acute myeloid leukemia. Indeed, every major drug company is either testing continuous technologies or beginning to use them to produce pharmaceutical chemicals and finished-dose drugs. Several have made aspirational statements

New drugs pull continuous process manufacturing into the batch-dominated world of pharmaceuticals.




regarding implementation of continuous techniques. GlaxoSmithKline’s manufacturing technology road map, a manifesto against traditional batch manufacturing, looks toward widespread use of continuous techniques. Janssen has said it expects to manufacture 70% of its drug product via continuous processes.

Yet most of the drug industry’s progress has been in the continuous manufacture of finished-dose tablets. To date, no active pharmaceutical ingredient — also known as the API or drug substance — has been fully synthesized in a continuous process in a facility that conforms to the FDA’s current good manufacturing practice (cGMP) standards. At best, proponents can point to hybrid processes involving both batch and continuous systems.

Small first steps

Drug companies and the contract development and manufacturing organizations (CDMOs) that serve them insist that continuous manufacturing of APIs will happen, though they acknowledge that the delay, coming after decades of development, is frustrating.

Alessandra Vizza, Commercial Manager of Corning’s reactor technologies unit, which launched continuous flow reactors in 2007, notes an irony in the current interest among pharmaceutical makers. “When we started the business, our only focus was on pharma,” she says. But pharma lagged. “We decided we had to cover other markets that might go a bit quicker to industrial steps.”

Another irony is noted by Bernhardt L. Trout, a Professor of Chemical Engineering at the Massachusetts Institute of Technology and director of the Novartis-MIT Center for Continuous Manufacturing, a partnership launched to develop continuous technology. “What is kind of ironic is that the major benefit of continuous manufacturing is with drug substance,” he says. “It’s best in terms of streamlined processes, cost savings, footprint savings, and quality improvement.”

Designing continuous processes for drug substance is technically more challenging, however, than designing them for drug product, Trout says. And the industry moves slowly. “It tends to start with the low-hanging fruit,” he says, “but drug substance is coming.”

The center, in fact, has proved it can be achieved, having built the first end-to-end continuously automated drug manufacturing process in 2012. In the second phase of the 12-year partnership, which ends next month, the center developed a range of continuous process technologies — including flow chemistry, crystallization, and dosage manufacturing — transferring several to Novartis.

The project also spawned a systems integration firm, Continuus Pharmaceuticals, headed by Salvatore Mascia, a former project manager at the Novartis-MIT center.

Snapdragon Chemistry, a process design and consulting firm spun out separately from MIT, is focused on API manufacturing, using flow-based retrosynthetic analysis and design techniques in areas such as photochemistry, liquid-gas reactions, high-temperature and high-pressure reactions, and electrochemistry. The company was formed in 2014 in response to drug companies’ requests for MIT’s assistance designing continuous processes.

As Snapdragon CEO Matthew M. Bio acknowledges, one of batch manufacturing’s advantages is that it is not dedicated

to a particular product, whereas continuous systems are. Batch plants can switch from one chemistry to another when compounds fail after a short time in the clinic, or they can remain workhorses for drugs that are commercialized.

But the technical demands of producing emerging therapies has upset the manufacturing status quo.

“Some of the molecular complexity coming forward from the discovery groups has kind of focused people on putting together molecules and technologies that don’t scale very well in batch production because they were hazardous,” Bio says. “You could look at the antibody conjugates or the protein conjugates that were relying on azide click chemistry. Making the azides, a high-energy material — nobody wants to do that in a big batch reactor.”

Photochemistry is another growing application for continuous systems. “Light doesn’t penetrate reactors very far,” Bio says. “Only a few millimeters before it’s fully absorbed. It doesn’t make sense to put a lamp in a big batch reactor.” Snapdragon develops technologies for customers, mostly drug companies, that have molecules they want to make continuously. “We develop the technology and build the reactor system,” Bio says, noting that the company recently shipped systems to North Carolina and Milan. “These are full-scale reactor systems that do one or more steps on the order of a kilo per hour of material.”

He expects Snapdragon to have its own manufacturing capability by the end of the year.

Snapdragon has also partnered with nearby Johnson Matthey, one of many CDMOs moving into continuous process manufacturing services in response to growing customer demand.

Service sector innovations

The addition of continuous process services — for both drug product and drug substance — at CDMOs reflects increased interest among the drug companies that are their customers. Hovione, for example, moved quickly to establish a unit at its R&D and manufacturing center in East Windsor, New Jersey, after landing a contract with Vertex to produce Orkambi tablets. The company plans to put similar assets in place at its headquarters in Portugal. Italian CDMO Flamma says it is experimenting with a continuous unit at its plant in Chignolo d’Isola near Milan.

Others have been at it much longer. Thermo Fisher Scientific, for example, has continuous process experience dating back to DSM’s introduction of micro flow reactors in 2004. DSM’s drug substance unit merged with the drug product firm Patheon in 2013; Thermo Fisher acquired the combination in 2017.

“We started to develop continuous processes for active pharmaceutical ingredients in DSM’s custom pharma manufacturing division,” recalls Peter Pöchlauer, now head of innovation management for Thermo Fisher’s pharma services group. “That dates back to the early 2000s when we did our first experiment in small-structured flow rectors in nondrug applications.”

In 2007 DSM took on its first drug project: an intermediate that could only be made using a flow process. “It was a nitrate ester formation,” Pöchlauer says, “that simply couldn’t be done in batches at the scale we wanted to run it.”

As DSM got started in the area, the FDA was beginning to



push continuous processes, Pöchlauer says, noting that the agency began recommending them in 2004. The agency further advocated continuous processing in its 21st Century Cures Act, signed by President Barack Obama in 2016, before issuing formal guidance in February of this year.

Cambrex also moved continuous flow chemistry know-how from Europe to the US. Drawing on expertise at its facility in Karlskoga, Sweden, the firm has invested over $1 million to develop flow chemistry services in High Point, North Carolina. The company, like Thermo Fisher, is responding to a “pull from the market,” says Dr Shawn Conway, Director of Engineering Research and Development at Cambrex High Point.

“A number of drug companies have expressed an interest in flow chemistry and want to know about our capabilities,” Conway says. “Their thinking is that if the industry is moving in this direction, starting to pursue this type of technology, there needs to be a network of providers able to work with them in developing process and manufacturing material as well.”

Cambrex is positioning High Point to provide flow chemistry services through late-stage clinical trials, with the goal of expanding operations to commercial scale. The Karlskoga site already offers commercial-scale continuous flow manufacturing.

SK Biotek began developing flow chemistry for pharmaceuticals in the mid-1980s, according to Seongho “Ryan” Oh, head of R&D. The firm used know-how from its parent company, SK Group, which owns the largest refining and petrochemical firm in South Korea. SK Biotek has offered flow chemistry at the pilot scale for nearly 20 years, Oh says. Its latest R&D development is a continuous triazole process.

“These days customers are accumulating knowledge and come by asking if we can develop a continuous process on the basis of their ideas,” Oh says. SK Biotek is currently applying continuous techniques at its plant in Daejeon, South Korea, to an AstraZeneca diabetes drug being developed at SK Biotek’s Swords, Ireland, facility, he adds. The Korean plant was approved for ton-scale advanced intermediates production in 2014.

Lonza also has a history of developing continuous processes. “We have done a lot of work in microreactors over the years, but more recently we have been focusing on different types of flow reactor,” says Lee Newton, head of the company’s API business. “We now have a couple of operational units big enough to produce ton scales in our non-cGMP plant in flow reactors, and we want to move that into cGMP very soon.”

Newton cites major drug companies’ broad statements of intent to convert large swaths of manufacturing to flow and other continuous technologies as the incentive for expanding contract services. The industry as a whole is following pioneers like Novartis and Lilly, he says. It is also looking ahead at the nature of new drugs, the cost of producing them, and the feasibility of doing so in traditional batch operations. “Today, it’s very much an economic driver,” he says.

But there are competing economic arguments, Newton observes. Some industry watchers insist that batch operations are less expensive over time given that vessels can easily be cleaned and repurposed, as they have been for decades.

“And then there is this kind of mythical Lego set,” he says, referring to modular design in flow chemistry. “The idea that you can take all these bits and pieces, build a plant, run it for a few weeks, take it apart, clean it, put it back together, and make a few molecules. But all these reactions have to be fast enough to work in flow. Not all reactions are.”

And regulatory considerations persist, despite the FDA’s encouragement of continuous process techniques, Newton says. “You can build it, but if it takes six weeks to qualify it, you’ve lost another advantage.”

Other CDMOs are holding back altogether. “Companies have been talking about it for a long time,” says Vivek Sharma, CEO of Piramal Pharma Solutions. “For us it’s early. We are talking to customers, exploring, seeing how it fits into new investments — whether it makes sense.” Although customers have inquired about Piramal’s capabilities, none have said they require continuous process manufacturing, Sharma says.

“If we invest the capital, we have to find the right buyer,” he says. “I think current processes are good enough to service customers for the near future.”

And views diverge on how continuous processes should be approached. Ian Shott, who has been advocating for process acceleration centered on continuous methods for more than 20 years, is critical of much of the current activity.

“Over the last two decades, the high ground on continuous process has been taken by what I call the gadget makers rather than the process owners,” says Shott, who is now CEO of the British CDMO Arcinova. “What I am trying to do is get back to fundamentals and design processes based on thermodynamics and kinetics, not picking up a particular continuous reactor and trying to force fit the process.”

Shott describes an approach that takes modular engineering a step beyond configuring flow reactor plates and tubes like Lego pieces. He advocates mixing technologies and in some cases using batch-oriented gear in a continuous process.

For example, as an alternative to conventional flow manufacturing, Arcinova has modeled a cascade of continuous stir-tank reactors. The advantage, Shott contends, is that the stir tanks can be typical glass reactors used for batch chemistry. “You put them together in a string.”

The ideal approach is a mix of technologies determined by reaction modeling. Shott says Arcinova has developed a process for one of its clients that turned a 55-batch campaign into a five-batch campaign, employing continuous techniques at some of the stages.

Big change for Big Pharma

As a relatively new company without large fixed assets, Shott says, Arcinova is well positioned to bring continuous process manufacturing to bear on the high-tech, low-volume drugs that are taking up an increasing amount of the development pipeline.

Big drug companies have lots of fixed assets, though, dampening the incentive to embrace the new. Still, several of them have established centers for the development of continuous technologies.

Lilly and GlaxoSmithKline invested $40 million and $50 million, respectively, in plants dedicated to continuous manufacturing. Lilly opened its site in Kinsale, Ireland, in 2016 and expanded it the following year with a plant producing clinical-scale cGMP material. The company also has continuous capability at facilities in Indianapolis and Puerto Rico.

GSK declared its commitment to continuous processing in 2013 with the announcement of a plant in Singapore where it will develop continuous technologies. Then-CEO Andrew



Witty hailed the move as “a really significant technology leap for the company.” He said the firm was undertaking a “shift from synthetic chemical reactions to enzymatic reactions and a whole reframing of how we do analytical testing in all of our facilities.”

GSK says it has a filing pending with the FDA for commercialization of a drug substance manufactured with a mix of continuous and batch processing at the plant. And the company is building an additional continuous manufacturing facility in Singapore, where it plans to produce a potential new treatment that would be the first new chemical entity developed at the Singapore site with continuous chemistry.

In 2011, Novartis opened a center for continuous manufacturing in Basel, Switzerland, where it has established an end-to-end process based on work done at the Novartis-MIT center. Though it is operational, it has yet to find practical application, largely because of the difficulty of converting API production to an entirely continuous process.

“We have a road map but no end-to-end production for a molecule at this time,” says Markus Krumme, head of continuous manufacturing.

Pfizer, meanwhile, has incorporated continuous processing into its pharmaceutical chemical plant in Freiburg, Germany. Kevin Nepveux, Vice President of Manufacturing, defines the company’s approach as hybrid. Rather than strive for end-to-end processes, the company looks for individual reactions where continuous production offers a significant advantage over batch, he says.

For those reactions where continuous manufacturing makes sense, Pfizer prefers to employ standard technologies with minimum customization, Nepveux explains. Off-the-shelf technology is more effective than custom designs in achieving cost and time savings, he says. “Our real competitive advantage, as with other innovative pharmaceutical companies, is our molecules.”

If the quest for that advantage is tipping the balance toward continuous processes, it is also vindicating early efforts and bold moves in engineering that entailed a high level of the industry’s greatest aversion: risk. Even if continuous drug substance manufacturing still hasn’t truly arrived, the fear of it is gone.

“We were not the first drug company studying continuous processes when we started our initiative with MIT,” Novartis’s Krumme says. “But we were taking a very brave approach. We decided to forget almost everything we knew about making drugs and conceive a different approach.”


About the author

Rick Mullin, C&EN Senior Editor, Chemical & Engineering News

Dr Shawn Conway,

Director, Engineering

Research

and Development,

Cambrex

First published: Chemical & Engineering News

ISSN 0009-2347. Copyright © 2019 American Chemical Society

Title: Off the drawing board


Contributor


Formulations of low-dose drugs require a careful balance of several factors to ensure that each dose has an acceptable blend and content uniformity. Determining the right methods and equipment specifications to pair with the selected material requires expertise across multiple areas of the development process.

When at this critical step in the drug development process, companies are faced with the question of whether to complete these activities in-house with purpose-built facilities that can be capital intensive, or to outsource the work to a contract developing and manufacturing organization (CDMO). Further complicating the choice is the wide selection of CDMO providers in the market, making it important that a customer fully understands their needs and seeks a supplier that is able to meet those requirements.

In this article, two cases are reviewed where customers had an immediate need for lower dose capsules in the clinic, which posed several challenges in blend formulation with very tight timelines for delivery, and needed to ensure greater uniformity of a pharmaceutical product. Optimized equipment and targeted modifications were applied to the formulations to solve the clients’ needs, and the analytical team aligned to deliver qualified methods to support release testing of batches of the new formulation. Working with a CDMO that has strong formulation expertise, and the best interests of the customer and end patients in mind, can bring added value in cases such as this.

Case study: A chemical solution to a physical problem

Pharmaceutical formulation is the process where the active pharmaceutical ingredient (API) and different chemical substances are mixed to create an end-user drug product. The amount of active drug in the product varies depending on the format and expected end users of the product. Formulation studies are carried out for new drug products to verify the activity of a drug and what combination of chemical substances is needed to reach the appropriate format and dosage. The dosage should not only have a uniform amount, it should also have uniform appearance.

Low-dose drugs can pose challenges during filling due to physical limitations of the equipment being used and the ability to achieve blend homogeneity. When doses are low, transfer accuracy can be compromised and lead to a higher reject rate. Here, the challenge was to add components to the formulation that would not alter the potency or safety profile of the drug substance, while improving the flowability of the product during capsule filling. The use of automated equipment to maximize throughput capabilities offers flexibility in transferring specific doses to capsules, but there are some limitations.

An existing method for the neat powder in capsule was used as a starting point, but recovery using that method was not adequate. The team theorized that the sample diluent was not breaking up the blend sufficiently. One of

The experts at Cambrex outline the difficulties in achieving uniformity in pharmaceutical blends and dosing, and review two case studies in which outsourcing provided solutions with optimized equipment and targeted modifications.




the excipients, methyl crystalline cellulose (MCC), may have accounted for this by creating a complex with the API that filtered out during sample preparation. A key deliverable for the client was the development of a validated method for maintaining content uniformity using a new diluent to disrupt the complex formation. By selecting a new diluent during method development and using a ‘flood fill’ encapsulation method to accommodate the increased bulk of the formulated material, accurate content uniformity testing was achieved for the drug substance.

It takes expert knowledge of the chemical process in order to trace a physical limitation during manufacturing back to its chemical origin. Here, the limitations of the ProFiller ‘flood fill encapsulator’ during the filling operations were addressed by adding the glidant silicon dioxide to improve the flowability of the drug substance. This allowed the equipment to produce reliable low-dose capsules to meet the clinical demand.

Case study: Blending to ensure uniformity

Uniformity is a critical attribute in drug product formulation because it will ultimately impact the clinical effect on the patient by affecting drug dissolution, absorption and bioavailability. Achieving uniformity in formulation development not only has an impact on the product, it helps manufacturers to satisfy regulatory requirements and reduce lost revenue caused by insufficient or rejected product.

To verify that the critical attributes of uniformity have been achieved, thorough testing of formulations is critical. This helps to determine the uniformity after blending and after encapsulation with the goal of assessing the potency of the material. It also serves to demonstrate to regulatory authorities that the process is controlled to ensure the same amount of drug substance in each dosage.

Rather than relying on a single form of analysis, several methods were applied to ensure quality, including Karl Fisher (KF) water content and related substances methods. These methods can be redeveloped as needed according to the unique attributes of the drug substance. For example, after adding the excipients to the formulation in this case study, the water content increased dramatically. The existing KF method for the neat powder had to be modified for a different level of standard and melting temperature in order to yield valid results for the new blend formulation.

Chromatography was used to measure content and blend uniformity across several samples, and to quantify potency when performing the assay method. When the team detected excipient interference using the original method, they adjusted the wavelength to isolate the API.

In this case, the experts also developed a dissolution method for the material from scratch. Samples of the acidic media were pulled across various time points to assess the timing of drug product release while the dosage form disintegrates in the dissolution batch. Dissolution methods can be especially powerful because they mimic the drug activity in vivo.

All four of these methods were developed in parallel to dramatically compress the timeline and speed up time to market for the customers. With validated methods available, batch release testing was able to take place as product came off the manufacturing line, and the team was able to deliver the low-dose capsule formulation on time and on budget.

Drivers for outsourcing formulation

Every drug producer must evaluate the value of carrying out operations internally versus outsourcing to an experienced supplier. For formulation of small molecule drugs, the right CDMO can have a deep impact on the success of a drug manufacturer's process, so choosing the right supplier is critical. A proper CDMO will apply expert knowledge of the root causes to address both chemical and physical challenges that customers come against during product development, and in key final phases, like formulation.

Beyond expertise, there are other advantages to working with a CDMO, including a drastic decrease in capital investment, elimination of transfer and scale barriers, and access to the newest technologies and methods. Where an individual company may not be able to take advantage of the latest equipment and advances, a CDMO has a vested interest in staying ahead of the curve to ensure that their capacity continues to book.

Early-stage impact

Not only is the choice of a supplier critical, but an often-overlooked element is the stage when outsourcing is engaged, which is more impactful than it may first seem. In today’s market, interest is starting to be expressed in supplier support from earlier and earlier in the process, which reflects the continued drive for quality by design in the industry. Smart design from the start matters, and it has become common to see companies engage CDMOs for process development in discovery phase, as well as for meeting milestones, including regulatory filing and scale-up efforts and specific needs in the clinic. This earlier engagement ultimately improves the drug product formulation process.

Additionally, regulatory compliance has become a more important CDMO offering because discovery-based companies often do not maintain their own regulatory affairs departments. And it remains challenging to get into early-stage manufacturing without enormous commitments in personnel, training and recruitment. Consequently, regulatory affairs are an expense that these firms do not necessarily fund in-house any longer.

Cambrex leverages top analytical and formulation expertise with customer support to overcome challenges and meet or exceed aggressive timelines and regulatory considerations. Leadership is focused on business decisions that advance the level of support available to customers from discovery to commercial development. A global network of facilities with optimized technologies and flexible capacity helps to secure the supply chain and offer the reliability customers need for the life of a drug product.


First published: Chemicals Knowledge Hub

Title: Overcoming limitations to achieve uniform dosing

Date: May 17, 2019

About the author

Dr Anthony Qu,

Vice President, Scientific Affairs,

Cambrex


Infants, children and adolescents require different oral dosage forms depending on their swallowing abilities, taste preferences and dosage requirements. The development of tailored solutions that are practical to manufacture increases medication adherence and provides a competitive advantage.

Growing pediatric market

Currently there are nearly 1,300 pediatric clinical trials under way investigating the safety and efficacy of over 600 drug substances for the treatment of various cancers, central nervous system disorders, infectious diseases and other ailments.

In the US, pediatric drugs based on new molecular entities (NMEs) must be evaluated in pediatric clinical trials. Existing drugs marketed for adults only can, if proven safe and effective for children, receive approval from the FDA as pediatric medications with six months of marketing exclusivity. Similarly, existing drugs proven safe and effective as pediatric medications for different indications can also benefit from marketing exclusivity.

Need for age-appropriate dosage forms

Consequently, developing pediatric dosage forms for both new and existing drug substances provides an effective

means for expanding market reach and improving the lifecycle management of many different products. The pediatric population includes children ranging from infants to teenagers, and each age subgroup has different pharmacokinetic responses, dosage requirements, swallowing abilities and taste preferences. Therefore age-appropriate formulations are essential.

Liquids are ideal for newborns, infants and toddlers. They are also effective for pre-school children, along with mini-tablets. Chewable tablets may be the best solution for schoolchildren, but traditional capsules and tablets work as well, as do liquid dosage forms. Adolescents prefer capsules, chewable tablets and mini tabs. For all children, the palatability of medication can have a direct impact on treatment success. For many younger children, easy-to-swallow formulations are equally necessary.

Choosing the right dosage form

Once the age-appropriate dosage form options are identified, the next step is to determine the most appropriate dosage form for the specific API in question. The first consideration is whether a measurable dosage form is required, such as dosing based on milligram (mg) of drug per kilogram (kg) of body weight. If yes, then liquid formulation will be suitable. Tablets and capsules would not be suitable in this case. Next, it is important to consider whether taste masking is needed and effective in the drug products. If it is not effective, then sprinkle powders or granules, tablets or capsules are the best

Dr Anthony Qu, Vice President of Scientific Affairs at Cambrex, and Dr Yanjun Zhao, Market Intelligence Manager, examine the complexities of developing oral doses for the pediatric market.




choice because taste masking can be effective and achieved via coating technology in solid dosage forms. For liquid formulations, drug products must be chemically stable over a two-year period.

Formulation design requirements

Overall design requirements for pediatric oral dosage forms are primarily based on the age, body size and swallowing ability of the target population. In addition to liquid and solid forms such as tablets and capsules, multiparticulate formulations like granules and mini-tabs, and alternative oral delivery pathways such as dose-sipping technology are available.

Liquid dosage forms are ideal for patients with trouble swallowing, allow for flexible dosing and are more rapidly absorbed than solid dosage forms, but they often have shorter expiration periods; require special storage conditions (i.e., refrigeration); require careful dosage measurement; have unpleasant tastes and can be difficult to administer.

Traditional oral solid dosage forms leverage the most established manufacturing technologies with control costs, have long-term stability, do not require dosage measurement and are relatively easy and effective to taste mask via coating. They can, however, be difficult for young children to swallow and do not afford and dose flexibility.

Fast-dissolving tablets allow absorption of the tablets in 60 seconds or less. They are appropriate for smaller molecule weight of APIs with no bitter taste that are delivered at doses of less than 20mg and can diffuse into the epithelium of the upper GI tract and permeate oral mucosal tissues. However, they do not work for APIs that have a bitter taste, short half-lives and for formulations requiring sustained or controlled release.

Chewable tablets provide fast absorption and better bioavailability through bypass disintegration and tend to have high pediatric patient acceptance. They also offer convenience to caregivers because no water is required for swallowing. On the other hand, these formulations contain sorbitol, which can cause diarrhea and flatulence. Due to their hygroscopicity, they must be kept dry and may require specialised packaging and storage conditions. The formulation must also have the right flow, lubrication, disintegration organoleptic and compressibility properties.

Multiparticulate formulations are popular for pediatric populations because as a solid dosage form they have long-term stability; several options are available; they provide maximum dose flexibility; modified release formulations are possible; and taste masking is generally effective.

Mini-tablets are small tablets averaging 1.5-3mm in diameter that can be filled into capsules, compressed into bigger tablets or loaded into sachets or stick packs. They not only provide flexible dosing (by simply increasing the number of mini-tabs) and sustained/timed release options with coating, but are easy to swallow, can be effectively taste-masked and allow different incompatible APIs to be formulated into a single dosage form. If APIs are unstable in liquid forms, mini-tablets can also be reconstituted and dosed as a suspension.

Modified feeding bottles allow delivery of medication while the baby drinks its formula. Dose-sipping technology, which consists of a specially designed straw, enables the delivery of a single dose of small-sized pellets.

Specialised expertise is often required

The choice of formulation type for pediatric patients is often dictated by the physiochemical properties and the taste of the active drug substance, along with the intended dose for different age groups. Each formulation must be appropriate for the child in terms of dose, convenience and acceptability to ensure compliance.

Expertise in the wide range of possible oral dosage forms is essential for ensuring the most age-appropriate, efficacious and cost-effective option is selected for any given API. Collaboration with contract development and manufacturing organisations with long-term experience and demonstrated success developing and producing right-sized dosage forms tailored for children from infants to teens at clinical to commercial scale can provide competitive advantage, reduce time to launch and ensure market success.


About the authors

Dr Yanjun Zhao,

Market Intelligence Manager,

Cambrex

First published: European Pharmaceutical Manufacturer

(EPM)

Title: The complexities of developing pediatric oral doses

Date: June 27, 2019

Dr Anthony Qu,


Cambrex


Fixed-dose combination drugs formulated with two or more APIs in a single product to improve compliance through simplification of medication needs have been a popular and beneficial lifecycle management strategy. Controlled-release formulations are also a subject of continued interest in the pharmaceutical industry.

“There is a particular focus on creating smarter dosage forms that primarily meet the therapeutic index by maintaining the desired plasma concentrations for extended time periods,” states Deep Patel, a Senior Formulation Scientist with Cambrex. “Reducing the frequency of administration to prolong the duration of effective blood levels increases patient compliance, particularly when API combinations are involved,” he adds. Combining multiple APIs in a single product can create a complex situation, if the actives have varying and/or conflicting properties. Selection of the right excipients can be crucial to the successful development of controlled-release products containing multiple APIs.

Achieving the desired drug-release profile

There are many different types of controlled-release formulations, and one of the first steps must be to establish whether the drug should be formulated as delayed-release, sustained-release, controlled-release, etc., according to Ronak Savla, Global Scientific Affairs Manager at Catalent.

The next step is to determine the optimal release kinetics (zero order, first order, or pseudo-zero order), after which point the formulator must design a formulation that meets the dissolution (release) profile. Catalent uses physiologically-based pharmacokinetic modeling (PBPK) to determine the optimal desired dissolution rate via construction of a plasma concentration profile.

Establishing in-vitro–in-vivo correlation is still one of the biggest challenges, according to Patel, along with risk management of dose dumping under different gastrointestinal (GI) tract conditions. Designing controlled-release delivery systems for biologic APIs that deliver abuse resistance and meet specific requirements for pediatric dosage forms are also key areas of focus.

Each modified-release dosage form faces both common and unique challenges and requires prototyping to fine-tune the drug release rate and achieve the target pharmacokinetics. “Because modified-release dosage forms contain higher drug loads than immediate-release dosage forms, the potential for dose dumping is a greater concern and must be addressed. API compatibility and stability with excipients must also be assured,” Savla notes. Manufacturing challenges unique to each dosage form include the coating level and drying requirements for coated tablets and multi-layered drug-containing beads and ensuring a homogeneous viscosity and uniform filling of semi-sold fill material incorporated into soft capsules.

Different target patient populations also present different

A design strategy can ensure conflicting properties are managed appropriately for multi-API, controlled-release formulations.




challenges. “Controlled-release formulations are typically solid dosage forms that can be rather large. Patient populations prone to swallowability issues, such as geriatric and pediatric patients, may not be able to swallow the intact dosage forms,” says Savla. For these patient populations, coated beads (or ‘sprinkles’) filled in two-piece capsules are a popular option. The capsule can be opened, and the contents can be mixed with food or certain liquids. Mini-tablets are another attractive option for toddlers and older children. Another consideration for pediatric patients is whether the excipients are acceptable for use in the population.

In addition, because controlled-release formulations typically aim to provide once-daily dosing, the drug must have some colonic absorption, which can be an issue for poorly-soluble APIs. With the increasing prevalence of poorly-soluble drug candidates, the use of solubility-enhancing technologies such as amorphous solid dispersions and lipid-based drug delivery systems are necessary. “Coupling solubility enhancement and modified-release requires the use of a significant quantity of excipients and presents great difficulty to achieve target drug load while retaining a patient-friendly dosage form size,” Savla observes.

Added challenges with multi-API formulations

The critical properties of controlled-release drugs containing two or more APIs include the potential dose differential and varying release profiles for the different drug substances, the stability and compatibility of the APIs with one another and other ingredients in the formulation, and content uniformity, according to Anil Kane, Executive Director and Global Head of Technology and Scientific Affairs at Thermo Fisher Scientific. “If the APIs reside within a monolithic tablet or capsule, additional steps may be required to ensure dose uniformity and compatibility and to maintain the target release rate,” agrees Savla.

One of the critical considerations during design of controlled-release formulations containing multiple APIs is the half-lives of each API, which may be different and generally require careful selection of excipients to control each drug release, according to Kane. The dose differential is also important. “Combining a very low dose API (e.g., 1–5mg) with an API with a high dose (450–550mg) could be another challenge to controlling the release of each in a specific target site in the GI tract,” he states. The site of absorption of each API may also be different, making it difficult to design a controlled-release strategy for the best clinical efficacy.

The size of fixed-dose combinations (FDCs) formulated as controlled-release products must be considered where swallowability may be an issue, because these dosage forms cannot be split or crushed due to the modified-release functionality. It is prudent, according to Savla, to not create FDCs of two or more APIs with doses in the hundreds of milligrams.

“A promising approach to creating modified-release FDCs in tablet form would be to borrow and learn from formulations containing both immediate-release and modified-release functionalities,” Savla says. He points to multi-layered drugs containing beads, which allow the creation of multiple-release profiles within a single dosage form.

Development strategy is essential

Designing a strategy for development of a controlled-release target product profile is important for many reasons. To achieve this goal, according to Kane, a thorough understanding of the pharmacokinetic and pharmacodynamic profile of the small molecule related to its clinical efficacy is needed.

A proper design strategy can have many benefits, including reduction of the frequency of dosing (once-a-day or twice-a-day preparation) and increased safety through avoidance of the possibility of dose dumping. The target patient population may better comply to the medication regimen when consideration is given to the size of the pill to swallow and the time of administration. Another potential benefit is the ability to formulate small molecule APIs into controlled-release oral solid dosage formats (e.g., tablets, capsules, etc.) or as long-acting sterile injectables.

Crucial role for excipients

The primary role of functional excipients in controlled-release formulations is to modify the release of the drug from the dosage form. There are numerous mechanisms by which these excipients function to release drug, according to Savla: time; pH responsiveness; erosion; osmotic concentration, etc. Controlled-release characteristics can be achieved by the use of polymeric coatings over solid dosage forms such as tablets, capsules, granules, sugar spheres, or ion exchange resins, or alternatively by incorporating polymer matrix systems within solid dosage forms or systems that respond to changes in physical conditions within the formulation, adds Patel.

Excipients used in controlled-release formulations can, according to Patel, also help to overcome the bitter taste of active ingredients or to protect the gastric mucosa. In some cases, these excipients can be used to deter abuse or to help avoid alcohol-induced dumping. In addition, excipients can be used wisely to target the release of the active drug at a specific site of the gastrointestinal tract, behavior that is triggered by pH of the specific region of the GI tract.

“The choice of the right excipient in terms of its properties as well as the right quantity and quality, directly impact the release of the drug in the gut for an oral solid dose controlled-release preparation or in the plasma concentration in the systemic circulation for an injectable form,” says Kane. The level of excipients is critical from a safety aspect as well. Patel adds that proper selection of excipients can help drug product manufacturing through improved flowability, enhanced compressibility, improved bioavailability, and particle size distribution specifically when using different combinations of APIs.

The following categories of excipients and the grade selection are critical in developing an optimal controlled-release formulation, he notes:

• Solubility/permeability enhancers/modifiers

• pH modifiers (to improve stability or release at a targeted region of the gastrointestinal tract)

• Polymers that retard the release of the drug based on diffusion, erosion, swelling, etc.

• Excipients/materials that can act as physical barriers.

Savla provides two examples. pH-responsive polymers are a




Title: Combo drugs require a complex design approach


About the author

Deep Patel,

Senior Formulation Scientist,

Cambrex

good choice to protect acid-labile APIs from gastric acid or for those APIs that need to reach the colon. Matrix tablets and semi-solid lipids within soft capsules work via erosion and are options for sustained-release delivery.

Pulsatile release polymeric excipients, meanwhile, control the selective delivery (when and where) the API is desired, according to Patel. “These excipients provide a unique advantage due to the timely release that is controlled by coating the drug with selective polymers having sustained or enteric modified-release characteristics,” he observes.

“Overall, the quality and consistency of performance of the excipients, in-vitro as well as in-vivo, are critical to the success of controlled-release dosage forms,” Kane concludes.

Consider excipient variability

While the selection of the excipients with the proper functionality at appropriate levels in the drug product formulation are crucial to drug product performance, a deeper understanding of how variability in the excipients can affect drug product performance is also essential. “Maintaining variability of critical material attributes within an acceptable range is important for a given drug product as excipient concentration and characteristics greatly influence drug product performance with respect to stability, bioavailability, and manufacturability,” Patel notes. In addition, says Kane, development of a control strategy is an important component of improved drug product development.

“A number of drug product recalls identified excipient variability, and therefore a lack of an adequate control strategy, as a contributor to failure of the drug product, further underscoring the need for improved excipient variability understanding,” he observes. To date, however, Kane notes that evaluating the impact of excipient variability on drug product performance has presented a greater challenge than evaluating API and process impacts.

The overall variability in a particular critical quality attribute is a combination of the variability of the API, the excipients, the manufacturing process, and interactions of any of these individual factors, he notes.

“At Thermo Fisher Scientific, we have found that identification of the most impactful material properties is critical to evaluating the effects of excipient variability on drug product performance. This excipient variability understanding can then be combined with the knowledge of each of the API properties and the process parameters used to manufacture the drug product to develop an appropriate control strategy that ensures consistent supply of safe and efficacious drug product,” Kane says.

Experience and expertise are key

In the end, says Kane, the experience of the formulation scientists is the key to developing robust optimized controlled-release formulations that perform consistently in a predictable manner. For controlled-release formulations with multiple APIs, a systematic and well-characterized data set for each of the APIs, along with a scientifically designed strategy for the dosage form and the selection of the right quantity and quality of excipients, are key to successful formulation development. The experience and expertise of the formulator

will help to avoid any ‘trial and error’ experimentation and can bring speed to these projects, he concludes.

For Patel, new excipient development is also essential. “The development of excipients that are capable of fulfilling multifunctional roles such as enhancing drug bioavailability and drug stability, as well as controlling the release of the drug according to the therapeutic need, is one of the most important prerequisites for further progress in the design of novel drug delivery systems,” he asserts.


Pharmaceutical Outsourcing (PO): What are some of the current critical issues facing the industry in regard to delivering dosages to various populations — and why is it so important?

Anthony Qu (AQ): In drug product manufacturing, it is critically important to adequately treat each patient based on their individual needs. Pediatric populations require special considerations when formulating drug delivery methods.

The pediatric population covers a vast age range from infants to teenagers, and in some cases, pediatric dosage forms are also administered to those who have difficulty consuming traditional solids, such as stroke patients or those with degenerative diseases, for example Parkinson’s and Alzheimer’s. Each age subgroup has different pharmacokinetic responses, dosage requirements, swallowing abilities and taste preferences, which are all important factors in the ultimate success of a formulation.

PO: Regarding pediatric dosage forms, what are some unique problems or challenges that manufacturers might face when developing a product from scratch? Is the pediatric market a growing one?

AQ: Specifically knowing which APIs are stable and in what form (liquid versus solid) is a start. For example, there are many benefits to a liquid delivery, however a shortened shelf-life and refrigeration requirements should be taken into

consideration when compared with solid forms. If you decide to formulate solid doses, knowing your patient population’s ability to take solid medications is key. Other considerations include taste, solubility, and the required measurable dose form based on mg/kg of body weight.

The important questions to ask during the dosage form process should include:

• Can the patient swallow a tablet? If not, a liquid formulation should be considered.

• Is the API stable in the liquid formulation? If not, a solid formulation should be considered.

• Can the taste be masked?

• Is a flexible dosage formulation required to cover all age populations?

All these factors can pose their own unique challenges when developing a new drug product.

The global pediatric dosage form market is expected to reach $110 billion in 2019. This represents around a 5% year on year growth from three years ago, when the market was valued at $95 billion. The US occupies approximately 44% of this $110 billion, EMEA 33%, and APAC 22%. Some areas of the market grow slightly more than 5%, while some areas grow just under 5%, with the average being approximately 5%. This market presents exceptional opportunities with growth expected to remain at this rate until 2021.

Pharmaceutical Outsourcing spoke with Anthony Qu, PhD about pediatric dosage form manufacturing.




In the last 20 years pediatric drug approvals increased five-fold, with an average of 10-20 approvals per year to 50-60 approvals annually today. Oncology, central nervous system (CNS), and infectious disease applications are three areas which lead the pediatric dosage trends in clinical trials, and of more than 1,000 pediatric trials currently ongoing, half of them are small molecules.

PO: What are some concerns a pharmaceutical company might have when reformulating an adult product into a pediatric dosage form? Is this approach viable?

AQ: From the pediatric patient perspective, this group is unique. People often assume that pediatric dosing is straightforward and that the adult formulation is suitable, however this is not the case. For example, with an adult dosage tablet, it is not as simple as cutting the dose into a smaller size for a pediatric patient. In addition to the different age/dosage correlation, consideration must be given to the difference in preferences, abilities and body weights, making their pharmacokinetic profiles different.

PO: When pharmaceutical companies are choosing a company to help them develop a new pediatric dosage form, what questions should they ask? What qualities and expertise should pediatric dosage form developer/manufacturer/service provider have to ensure that their client gets the best quality product?

AQ: The questions to ask for any drug formulation include the “five right” drug development paradigms:

1. Right Drug 2. Right Dose 3. Right Population 4. Right Trial Design 5. Right Endpoints

When seeking a supplier to work with, asking if the company has a designated subject matter expert (SME) is a start, as is ensuring that the company has the right facilities and equipment to accommodate production. Due to the delicate nature of pediatric formulation, having someone who is dedicated in this area and well-versed with adequate experience in coordinating age, dosage forms, and taste preferences is important.

Also knowing whether the company has complied with any regulatory approvals is another important consideration. In the US, pediatric drug development laws are covered by the following:

(a) The Pediatric Research Equity Act (PREA) (b) Best Pharmaceutical for Children Act (BPCA) (c) Title V of FDA Safety and Innovation Act (FDASIA)

The Pediatric Research Equity Act (PREA) is triggered by an application of at least one of the following criteria:

i. New indication ii. New dosage form iii. New dosing regimen iv. New route administration v. New active ingredient.

The act requires companies to conduct studies for drugs and other biological products that will be used in younger populations to determine if they are compliant with regulations or guidance on formulation by age. This goes alongside adequate labelling for each product to ensure they are given properly, both in form and regimen.

PO: Are there different and perhaps conflicting requirements for pediatric dosage forms worldwide? How can a pharmaceutical company plan for these differences to ensure a quality product and a smooth product launch?

AQ: Different regulations come from different regions, including the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada (HC) and the Australian Therapeutic Goods Administration (TGA), to name a few.

There can be regulatory challenges stemming from the different pediatric drug development regulatory programs. For example, in the EU, pediatric regulations have been enforced from 2007 (EC No1901/2006) while the US follows the BPCA and PREA acts, and Canada has no specific requirement to conduct pediatric studies under their current food and drug regulations.

Harmonization among different regions has been discussed for many years, and some regions such as Canada, support international harmonization efforts. If a company developed a pediatric drug product and received approval from a US regulatory agency and then wants to expand to Europe, it will be required to make a separate submission for EMA regulatory agencies for approval. Even if most of development and validation data to support US requirement may be used for other regional submissions, it is highly recommended to discuss the details with local regulatory agencies.

PO: Looking ahead do you see the pediatric market as a growing one? Should pharma companies devote the time and resources to develop pediatrics forms of all future products?

AQ: As mentioned previously, the pediatric market was discounted for a long time, but in the past decade, we see it is growing quickly.

There are close to 1,300 clinical trials under way investigating over 600 drug substances, so it is safe to say that it is beneficial for pharma companies to at least consider exploring. With the additional opportunity to adapt these methods to patients with degenerative and long-term diseases, such as Parkinson’s and Alzheimer’s disease, there is even further opportunity for pharma companies that are looking to generate reliable sources of income, while addressing critical needs in the industry.


First published: Pharmaceutical Outsourcing

Title: An interview with Anthony Qu, PhD

Date: October 1, 2019

About the author

Dr Anthony Qu,


Cambrex


In the manufacture of small molecule APIs, developers must be wary of the phenomenon of polymorphism, where an organic molecule can adopt a number of crystalline forms. Controlling the solid form of an API is a critical step in ensuring manufacturing control, as the uncontrolled occurrence of polymorphs can affect the filtration and drying characteristics during the synthesis, as well as the drug’s formulation, long-term stability, and solubility properties.

The drug ritonavir had to be temporarily withdrawn from the market following launch, after a less-soluble polymorph that caused the drug to have much reduced therapeutic effect was discovered1. Production of the drug was halted until a new formulation of the drug was developed, causing disruption to patients, as well as having financial consequences for manufacturers.

A number of strategies can be employed to control the polymorphic form during manufacturing. These strategies include seeding — where a small amount of the desired polymorphic form is introduced to promote crystallization of that form via nucleation — and screening for and choosing an appropriate solvent to perform the crystallization step. In another method, crystallization control, the crystallization is designed with the use of a quality-by-design (QbD) procedure and monitored using process analytical tools (PAT) to ensure it is robust and predictable during changes to temperature, solvent composition/anti-solvent addition, or agitation rates.

In all cases, the key step in delivering the desired solid form of an API is understanding and characterizing the polymorphic landscape to identify and predict phase transitions.

Hydrate formation and associated risks

Due to the ubiquitous nature of water vapour, hydrates are often very stable under ambient conditions. It is estimated that up to 75% of all pharmaceuticals are affected by hydrate formation2, which has a direct effect on the physical properties of the API, and subsequently how a drug will eventually perform in vivo, in terms of stability, solubility, and bioavailability.

Hydrate formation can become apparent at any stage of development or manufacturing operations; specific steps can be taken to avoid this, but only once the hydrate has been understood. The risk of hydrate formation is increased upon formation of ionic species (salts) or a molecule having polar functional groups such as carbonyl, hydroxyl, or amino functionalities.

Studies to predict polymorphism and hydrate formation are possible using computational methods and correlate well with experimental data3–5. Standard techniques for characterization are shown in Table I.

An understanding — during early development — of the solid form landscape of an API can enhance product quality and manufacturing processes.





Once the studies are complete, the results offer crucial structural data on the solid forms, allowing crystallization development to be undertaken to enhance particle morphologies and give better control over the solid forms as the product progresses through scale-up and development. Avoiding hydrate formation allows efficient large-scale manufacturing, yielding an API with good handling and processing properties, as well as being optimized for the formulation of patient-ready dose forms.

Case study: Locating and understanding hydrated forms of an API

As discussed, facile hydrate formation can drastically alter the processability, stability, and aqueous solubility of a given API, and this example shows how an API was fully characterized to allow the development of a reliable method for synthesis, avoiding an undesirable hemi-hydrated form that was uncovered during a polymorph screening project.

Upon arrival, the single-crystal structure of the preferred polymorphic form, Form 1, was determined wherein the structure was found to be close-packed with normal density (1.3 g/cm3) and no solvent/water accessible voids. Similarly, thermal gravimetric analysis (TGA) confirmed the anhydrous, non-solvated nature of the form, while analysis by dynamic vapour sorption (DVS) at 25°C, showed minor hysteresis with a maximum mass uptake of 0.95 wt.% at 90% relative humidity (RH), confirming its status as a developable form (Figure 1).

During further screening, it became apparent that the changes in water activity could promote morphological changes in the API. As shown in Figure 2, when slurried in alcohol:water systems of varying water activity (Aw), the morphology changed from an irregular morphology at 0.1 Aw to a plate-like morphology at 0.3 Aw and finally, to a rod-like morphology at 0.9 Aw. It was noted that at 0.5 Aw, a mixed morphology was apparent, comprised of both plates and rods, which indicated that competing growth kinetics could be exploited to maximize processability and filterability of the API at a later stage of the development programme.

Investigation into the solid form recovered at high water activity (0.9 Aw) by X-ray powder diffraction (XRPD) showed that this was a novel form, herein denoted as Form 2, and found to be hemi-hydrated when characterized by TGA and Karl Fisher titration.

To properly de-risk the novel, hemi-hydrated Form 2, a suitable sample was characterized by DVS, which showed that the input Form 2 was stable between 10–90% RH, but dehydrated rapidly below 10% RH, forming a novel anhydrous species, Form 3 (Figure 3). When the relative humidity at 25°C was cycled back to 40% RH, Form 3 prevailed, but rapidly rehydrated when cycled to 50% RH. These observations highlighted significant risk with development of the hemi-hydrated species for two reasons: the structure of the hemi-hydrated form collapsed on dehydration, forming a novel, anhydrous form; and upon rehydration, Form 3 collapsed and became amorphous prior to re-crystallizing to Form 2.

Variable humidity X-ray diffraction confirmed this observation. It was seen that within the window 30–70% RH, re-hydration of Form 3 to Form 2 was facile, and predictable, but proceeded via an increase in amorphous content (Figure 4), significantly heightening the risk associated with the development of either Forms 2 or 3. Based on the evidence, it was clear that the anhydrous Form 1 was the most desirable form for further development. However, to understand the conditions under which Form 1 would prevail, competitive slurry experiments were performed on Form 1 (anhydrous),

Table 1: Analytical techniques for physical and structural analysis of polymorphs.

Techniques

Thermal analysis

Hygroscopicity measurements

Critical water activity studies/maps

Kinetic and thermodynamic solubility Van’t Ho� Plots

Intrinsic dissolution rates (IDR)

Morphology

X-ray di�raction

In-situ characterization techniques

High-performance liquid chromatography (HPLC)

Infrared spectroscopy (IR)Near-infrared spectroscopy (NIR)Raman spectroscopy

Polarized light microscopy (PLM)Scanning electron microscopy (SEM)

Single crystal X-ray di�raction (SC-XRD)X-ray powder di�raction (XRPD)

Method(s)

Thermal gravimetric analysis (TGA)Di�erential scanning calorimetry (DSC)Variable temperature X-ray powder di�raction (VT-XRPD)

Dynamic vapour sorption (DVS)Variable humidity X-ray powder di�raction (VH-XRPD)

Table 1: Analytical techniques for physical and structural analysis of polymorphs. All figures courtesy of the author

Cycle 1 sorp Cycle 1 desorp

Cycle 2 desorpCycle 2 sorp

Cycle 3 sorp

0 10 20 30 40 50 60 70 80 90 100

DVS Isotherm Plot of form 1

Ch

an

ge in

mass

(%

) -

Ref

Target RH (%)

1.2

1.1

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Figure 1: Dynamic vapor sorption (DVS) isotherm plot of Form 1. RH is relative humidity

0.1 A W W W W W

Increasing water activity

0.3 A 0.5 A 0.7 A 0.9 A

Figure 2: Light micrographs showing morphological control

0

DVS Isotherm Plot of form 2

Ch

an

ge in

mass

(%

) -

Ref

Target RH (%)

10 20 30 40 50 60 70 80 90 100

4

3.5

3

2.5

2

1.5

1

0.5

0

Cycle 1 sorp

Cycle 2 desorpCycle 1 desorp

Cycle 3 sorpCycle 2 sorp

Figure 3: Dynamic vapor sorption DVS Isotherm Plot of Form 2. RH is relative humidity



Title: Uncovering hidden risks in solid-state API properties


About the author

Jonathan Loughrey,

Head of Screening Services,

CambrexForm 2 (hemi-hydrate) and Form 3 (anhydrous) in process-relevant media. These experiments clearly showed Form 1 to be the preferred, thermodynamic form under anhydrous conditions for further development.

Despite being the thermo-dynamically preferred form, a key disadvantage for the development of Form 1 was found to be its poor particle morphology. During the screening studies, however, morphological differences were noticed due to competing crystal growth kinetics in systems containing varying water activity. Using the non-random two-liquid (NRTL) equation and measured water activity, a detailed hydration map was investigated across multiple organic solvents; it was found that the morphology of Form 1 was greatly improved using small volume aliquots of water in ICH class 3 solvents (e.g., 0.5 Aw = 95 % isopropanol: 5 % water, % v/v) to minimize the risk of hemi-hydrate formation. This vast improvement in particle morphology was exemplified by scanning electron microscopy (SEM) as shown in Figure 5.

The significant increase in particle size coincided with an increase in crystallinity and improvement in material handling properties, specifically with respect to flowability and bulk density. Once the preferred Form 1 was isolated with improved particle morphology, crystallization development was able to be undertaken to carry the compound forward by thoroughly investigating the metastable zone and understanding the critical process parameters of the isolation step directly from solution using a design of experiments approach.

De-risking the solid form landscape of an API early in development is of utmost importance to ensure success as a viable drug candidate. By controlling the solid-state properties of an API, downstream processing and manufacture will benefit from predictable stability, solubility, and bioavailability, minimizing development timelines and cost. This case study exemplified the risk that hidden hydrates may pose to process development, but when the solid form landscape is thoroughly investigated and stringently controlled, significant advantages in particle control may be realized.

References/Sources

1J. Bauer, et. al., Pharmaceutical Research, 18 (6) 859–866.

Date: 2001

2L. Infantes, et. al., CrystEngComm, 5 (85) 480-486.

Date: 2003

3D. E. Braun, et. al., Cryst. Growth Des., 14 (4), 2056-2072.

Date: 2014

4D. E. Braun, et. al., Mol. Pharmaceut., 12 (8), 3069-3088.

Date: 2015

5S.L. Price, et. al., Chem. Commun., 44, 7076-7077.

Date: 2016

30% RH

35% RH

40% RH

45% RH

55% RH

60% RH

65% RH

70% RH

Figure 4: Variable humidity X-ray powder diffraction 2O diffractograms (Black: Form 3; Blue: Form 2). RH is relative humidity

Figure 5: SEM images of Form 1 before (top 6 images) and after (bottom 3 images) morphology development


With the improvements in the capabilities of automation, many aspects of the analysis can now be performed without a great deal of input from the analyst, however, this does not make human input redundant from the process, as there are many skills that cannot be replicated by computer.

When deciding to use LC/MS, it may not be as straightforward as preparing the sample for analysis and then choosing the most responsive mass-to-charge ratio on the instrument. The mass of interest can often only be identified by extracting each mass-to-charge ratio in order to distinguish the mass from the baseline, larger peaks in the spectra, or co-eluting impurities. Changes in energy, heat, flow, polarity, and even the source can be made to the mass spectrometer (MS) to ensure that an accurate analysis is achieved. Automation is a valuable tool in LC/MS analysis, but at present, cannot apply the level of scrutiny required to produce reliable results. This article will examine the role that automation does play and highlight examples where an analyst is still essential. For the purposes of this article, it is assumed that the HPLC conditions are MS compatible and can remain unaltered for analysis.

Automation has been beneficial in sample preparation, and instruments have been proven to be capable of accurately changing the sample concentration, and even weighing and diluting samples. Sample preparation is critical in the LC/MS analysis to ensure that the impurity of interest can be detected properly. If the impurity of interest has good separation in the analytical method from other impurities and the main peak, the sample concentration or injection volume can be increased

to produce a better response. However, if the on-column concentration is increased, the sample should also be analysed at the nominal concentration, as the use of two concentrations helps to positively identify the peak by eliminating masses seen in both injections with the same response, and focus on masses that alter based on concentration.

When setting up the analysis on the LC/MS, automation can assist with all of these steps as it is recommended to:

• Always use the ultra violet (UV) detector in line with the MS: in most cases, the analyst will use an existing HPLC-UV method in which the location of the impurity of interest is known. Keeping the UV in line with the MS allows the analyst to see the profile as it was viewed by HPLC-UV and allow easier identification of the peak of interest. Even if the impurity of interest does not have a chromophore and will not be visible using a UV detector, it is important to use this detector to eliminate false peaks in the baseline.

• Run a blank of the diluent: the blank will help to establish the background of the MS analysis, showing the difference between a mass of interest and background noise. Most software systems can subtract this background for easier analysis.

• Do at least two injections of each sample preparation: mass-to-charge ratios that can be attributed to a peak of interest will appear consistently. If the mass-to-charge only appears in one injection of one sample, this is not appropriate evidence of identification. It is possible to

High Pressure Liquid Chromatography Mass Spectrometry (LC/MS) is an important technique to accurately and correctly identify impurities within pharmaceutical products and intermediates.




have a mass-to-charge ratio that is appropriate for the peak of interest that is not present in every sample, but this should only occur for peaks with low MS response and the mass should appear in most of the samples to ensure proper identification.

• Begin analysis in electrospray ionisation (ESI) mode: most compounds are detectable by ESI; and while some systems require a manual change of the detector type, other instruments have a multimode source which can be switched by the software.

• Analyse the sample in positive and negative mode: for impurity detection it is not recommended to use dual mode as this will divide the energy further and lower the detection abilities of the MS. Ideally, the analyst should programme the entire sequence in one mode, then switch to the other mode and re-analyse the sequence.

• Set the scanning range from about one quarter to two times the estimated mass of the peak of interest: for example, for a theoretical compound with the mass of 400, the range would be set from 100 to 1000m/z. If a main peak was 400, then the range may be set higher to allow for full examination of degradants and dimers that may form during the MS analysis. If a library is to be used, the mass may need to be set as low as 30 - 50 for better identification by the software.

• Set some “typical” MS parameters for the laboratory for identification: it is a good idea to always use the same starting point to ensure that identification was not missed due to a change in the procedure. The parameters can be changed after the first analysis if a mass cannot be found for the peak of interest. Table 1 lists some typical ESI source parameters for performing scanning analysis.

After careful examination of the data, if the peak of interest cannot be extracted, the MS conditions should be altered to determine if a change in energy, temperature, or lastly, the detection type will allow for the detection of the peak. On occasion, it may be necessary to use a detector equipped with Atmospheric-Pressure Chemical Ionisation (APCI), which produces less fragmentation than ESI, but requires more fine-tuning of the source parameters to achieve acceptable results.

Software systems are capable of generating a mass-to-charge ratio and comparing that with a programmed library, but if the compound is unknown or the scanning range was not sufficient, the identification will not be correct or possible. To overcome this problem, software is available that will estimate related compounds from a proposed structure, but this relies heavily on the input from the analyst of one or multiple structures, and is not capable of knowing the process to produce the material and derive all the process-related compounds. For most peak identifications, the analyst is still needed to make informed decisions about the elution order, response, and mass of the peak of interest.

Once the HPLC analysis is complete, the chromatograms must be scrutinised to ensure a positive identification is made. An ideal peak identification would show a well-separated peak in the UV and MS chromatograms, and one large peak for the mass-to-charge ratio, as in Figure 1 where the identification of Peak 1 is determined to be 635.5m/z in ESI negative mode.

This type of identification can be completed by automation to recognise the best responding peak as the peak of interest. However, most peak identification is not so straightforward. Figures 2, 3, and 4 show three different example fragmentations in which peaks were identified, and each of the example fragmentations highlights a different challenge that can be encountered during mass identification.

Parameter

Ion Source: ESI

300Gas temprature (°C)

5Gas flow (L/minute):

45Nebuliser (psi)

250Sheath gas (°C)

500Nozzle (V):

2500Capillary (V):

135Fragmentation (V):

Value

11Sheath gas flow (L/min)

Table 1: ESI source parameters for performing scanning analysis


1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

7.8

7.7

7.6

7.5

7.4

7.3

X107

X101

- ESI TIC Scan Frag=135.0V

DAD1 - A:Sig=210.0.4.0 Ref=off

Peak 2

Peak 2

Peak 1

Peak 3

Peak 3

Peak 1

Response vs. Acquisition time (min)

130

120

110

100

90

80

70

4

3

2

1

0

X105

-ESI Scan

Counts vs. Mass-to-charge (m/z)

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

20

5.1

45

7.4

63

5.5

671.

5

720

.6

1271.

9

F7

Figure 1: Chromatograms of Peak 1 showing LC/MS-ESI scan (top), HPLC-UV (middle), and fragmentation of Peak 1 (bottom)

2

1.5

1

0.5

0

X105 +ESI Scan


100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

114

.1

20

5.1

25

2.3

30

1.2

39

1.3

44

2.5

46

5.4

626

.5

95

1.8

+ESI Scan

F3

Figure 2: Fragmentation of a peak, Example A


Figure 2 shows a large response for 465.4m/z and 467.4m/z, both of which are related to a neighbouring peak and not the impurity of interest. The third largest peak, 391.3m/z, would then be a likely candidate for the identification of Example A. An extraction of 391.3m/z confirms that this mass-to-charge ratio is appropriate for identification of Example A as no other significant peaks are seen in the chromatogram with this mass, as shown in Figure 5.

It may be possible to programme software to ignore the peaks associated with the neighbouring peak, but it would become more difficult if the neighbouring peak is not a main, or previously identified component, and if both peaks give good extracted chromatograms.

The peak of interest may also give a very poor response on the MS, and in Figure 3, a number of peaks are visible from 100 – 980m/z, but an examination of the extractions by the analyst of these fragments revealed that all of the masses were related to neighbouring peaks or the baseline. The baseline of Figure 3 was examined to reveal a very small peak at 317.1m/z which was reproducible in other injections and samples and unique to the peak of interest.

However, the peak of 317.1m/z does present a challenge as the response is low for an extraction - as shown in Figure 6 — which led to the peak not being detected in one of six injections. For a complete identification, the structure of the impurity must

be theorised, the impurity obtained, and injected. This is a case where it would not have been possible for software to identify this low responding peak in this fragmentation.

Figure 4 shows a good example of complete identification. The peak was identified through extraction at 343.4m/z, which was an expected impurity in the process. The impurity was prepared per the method at the nominal concentration of the sample and it was spiked into three samples at 1% of the nominal concentration. The spiked samples, impurity sample, and an un-spiked sample were then analysed using the same MS conditions used to obtain the extraction at 343.4m/z. This combination of samples allowed for analysis of mass and retention time by UV and MS to positively confirm the identification of the impurity.

Although the MS can produce a theoretical mass, it is only possible to confirm the identity of the impurity with a comparison study of the peak obtained during mass identification and the impurity gathered from an outside source.

There are other challenges that may be encountered during mass identification, including no peak being visible in the MS chromatogram at the retention time of interest. In this instance, a fragmentation should still be produced, and extraction performed as the MS can possibly reveal the desired mass without a visible peak.

Interference from neighbouring peaks is one of the most common problems, and is especially prevalent when a large main peak is close to the impurity of interest. When this is the case, the analyst must closely examine all the masses obtained during the MS scan, and keep in mind that as close eluting peaks, the masses are probably not very different and could even be chiral with the same mass. It may be necessary to obtain fractions to completely separate the impurity from the interference, and if appropriate, a Time-of-Flight (TOF) Mass Spectrometer could be used which can give a more exact mass and more precise separation of closely eluting peaks.

Mass identification by LC/MS can present many challenges which can be overcome by careful adjustment of the mass spectrometer parameters and examination of the data generated. The amount of data produced from a single sample in duplicate analysed in both positive and negative mode is significant and should be carefully inspected to ensure positive identification. Although automation can assist with changes to the instrument, sample preparation, and producing a mass-to-charge ratio, it requires an experienced analyst to determine the mass based on knowledge of the chemical process, related compounds, and chromatographic conditions, and to confirm that identification with a spiking study.


4

3

2

1

0


2.5

2

1.5

1

0.5

0

X105 -ESI Scan

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

100

.9

311

.3

46

3.3

48

9.4

525

.4

60

3.4

979

.8

F4

Figure 3: Fragmentation of a peak, Example B

2

1.5

1

0.5

0

8

6

4

2

0

X104 +APCI Scan


100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

121.

0

164

.1

28

3.1

34

3.4

419

.34

65

.34

91.

45

19.1

F8

Figure 4: Fragmentation of a peak, Example C

7.8

7.7

7.6

7.5

7.4

7.3

+ESI EIC (391.3)

2

1.5

1

0.5

0

X101

5

Counts vs. Acquisition time (min)

Example A1

F5

Figure 5: Extraction of Example A at 391.3 m/z in ESI positive mode

+ESI EIC (317.1)

6

5

4

3

2

1

0

X104

Counts vs. Acquisition time (min)

Example B1 1

F6

Figure 6: Extraction of Example B at 317.1 m/z



About the author

Karen Spillman,

Associate Director, Analytical Research

and Development,

Cambrex


Title: Peak identification by LC/MS: Automation

versus analyst



Expert Insight & Awards

Chelsea FritzAdvanced Scientist II

Matt KehrliChemist


What are your company’s major accomplishments over the past year?

In 2018, Cambrex diversified its business with two acquisitions, Halo Pharma and Avista Pharma Solutions. Prior to these acquisitions, Cambrex had been wholly focused on providing customers with development and manufacturing of APIs and advanced intermediates for branded and generic pharmaceuticals.

Both acquisitions have expanded Cambrex into new markets, while maintaining our focus on small molecule therapeutics.

Both the new drug product and early-stage development and analytical testing services offerings complement our existing capabilities and expertise. The businesses were a natural fit and bring a wider customer base and increase the opportunities for us to offer a wide range of services to new and existing customers. Avista provides services for preclinical and early clinical stage small molecule therapeutics, and Halo adds formulation and drug product development and manufacturing capabilities. The combination of both, alongside the existing Cambrex capabilities, under one brand, allows an integrated offering and the potential to feed and expand the clinical and commercial manufacturing pipelines.

In addition to the acquisitions, Cambrex has also continued its investment at our manufacturing sites to ensure the company meets the demands of the industry. 2018 saw numerous investments at our US facilities in High Point, NC, and Charles City, IA, including the purchase of a new 45,000 sq. ft. building adjacent to the current one in High Point, allowing the site to expand its clinical supply and process development capacity.

What do you want your company to be known for?

Both acquisitions have been undertaken to continue Cambrex’s commitment to providing best-in-class services to meet the needs of our global pharmaceutical, biotech and generic customers. The company’s goal is to be the leading global small molecule CDMO offering clients end-to-end solutions.

Our network of 12 facilities across North America and Europe now offers customers the opportunity to access services from early-stage discovery through to clinical and commercial manufacturing of drug substance and drug products, either as an integrated solution or in standalone activities.

What are the most pressing challenges the industry faces and what are some possible solutions?

The pharma industry continues to evolve, and we see a healthy clinical pipeline as well as a high number of FDA approvals for small molecules. However, the nature of the molecules has changed. Commercial products are no longer the blockbusters that require hundreds of metric tons of API annually; and the drug substance’s requirement may be under a ton to meet an orphan drug demand, or could be highly potent so requires contained manufacture. As a CDMO, we must recognize these changing needs and adapt accordingly to be able to offer the most suitable solutions in terms of capacity, expertise and technologies to customers.


Five minutes withShawn CavanaghPresident and Chief Operating Officer


Customers change too: Alongside the multinational pharmaceutical companies, are the small and virtual companies that are investing more, and progressing products further down the clinical pipeline. The needs of each are different, but have some commonality in that they are looking to reduce the burden of managing complex supply chains and work with a smaller number of strategic outsourcing partners and suppliers. This has led to the consolidation in the service sector, and has been pivotal in the strategic decisions Cambrex has made to invest in technologies, specific manufacturing capabilities and capacity, and acquisitions to broaden our service offering.

What areas of innovation or technology development within the company or in the industry generally are you most excited about?

As a company we have made a number of investments over the last two years in continuous flow capabilities at both development and commercial scale, to match industry demand. The advantages that continuous flow has for chemical synthesis include both safety and efficiency, and there are a number of examples of pharmaceutical companies looking to leverage the technology for process improvements in clinical-phase development.

Cambrex identified a need for continuous process development capabilities within the CDMO industry and took the decision to develop a continuous flow Center of Excellence at its High Point, NC facility. A number of continuous flow reactor platforms have been installed at the site and process development work carried out can now be seamlessly transferred to any site within the Cambrex global network for commercial manufacture.

Another recent investment in this area has been made at our Milan, Italy, site which develops and manufactures intermediates and generic APIs under GMP conditions. A new flow chemistry platform has been installed in a recently completed R&D laboratory to assist in the efficient development of new products.


About the author

Shawn Cavanagh,


Cambrex



What are your company’s major accomplishments over the past year?

With the completion of the acquisition of Avista Pharma Solutions for early- phase API support and Halo Pharma for drug product supply, Cambrex can now service the entire continuum of the pharmaceutical market. Avista provided services for preclinical and early clinical stage small molecule therapeutics, while Halo added formulation development and drug product manufacturing capabilities. The combination of both, alongside the existing Cambrex small molecule drug substance capabilities, allows the company to offer an integrated solution, with the potential to feed the clinical and commercial manufacturing pipelines.

With our new and diverse set of services, customers have the choice of selecting the appropriate offerings. For companies who may not have the time or resource to manage multiple service providers, they also have the option of benefitting from an integrated approach to maintain a project and product with Cambrex throughout its entire lifecycle. That is a service offer that few other companies in our space can provide.

What are some of your company’s goals for the next 12 months?

Cambrex now employs over 2,000 people, operating in 13 locations across Europe and North America, with the company offering three distinct capabilities: Drug Substance, Drug Product and Analytical Services. The acquisitions mentioned above have allowed us to expand our services

and evolve the business with a broader customer base. As we continue to integrate these services into a single company, and align functions together over the next 12 months, we will aim to make it simpler for customers to work with us and leverage the expertise we have across all aspects of small molecule drug development.

What areas of innovation or technology development within the company or in the industry are you most excited about?

Although continuous flow has been utilised in a variety of industries for over a century, the pharmaceutical industry has been slow to adopt this technology for historical and regulatory reasons.

The strategic initiative taken by Cambrex to develop a continuous flow Centre of Excellence in High Point, NC, aims to strategically fill the shortfall of continuous flow process development capabilities within the CDMO industry supporting pharmaceutical companies. As a result, we now have several continuous flow projects under way with pharma customers of varying sizes. We have the benefit of a dedicated engineering group at our High Point facility, focused on continuous flow projects with the aim of developing those for scale-up to our commercial drug substance facilities in the US and Europe. That, coupled with our existing commercial continuous flow nitration capabilities in Europe, creates an interesting and attractive offering to the market.


Five minutes withJoe NettletonPresident, Drug Substance, Cambrex


How would you describe your company’s culture?

In a word, transparent. Cambrex employees understand the importance of transparency and being able to advise our customers up front what we can deliver and what is outside of our realm. We are also always striving for process improvement and operational excellence. Project teams are empowered to continually be looking for ways to enhance the offering to our customers, whether that be strengthening process robustness, reducing manufacturing costs, or increasing throughput. Our teams throughout the organisation are focused on delivering meaningful gains to our customers.

What do you find most rewarding about working in the industry?

The ability to change the quality of life for someone I may never meet. As a young chemical engineer, I never imagined I would have the opportunity to impact global health in the ways that I now am able to. It has been incredibly rewarding to be a part of the supply chain for several drugs that since launch have changed the global landscape of medicine and quality of life for so many people. I truly look forward to the next one.

What advice would you give to younger professionals?

Stick with your passion. Being a part of the pharmaceutical industry can be incredibly rewarding. Your passion and dedication may lead to the launch of a drug that can save millions of lives including those of family and friends. In the end, that global change in quality of life is what it is all about.


About the author

Joe Nettleton,

President, Drug Substance,

Cambrex



Award winning

Awardwinning

Cambrex was recognized across five categories in the annual CMO (Contract Manufacturing Organization) Leadership Awards, which were announced at a ceremony in New York, in March 2019.

Cambrex received CMO awards for five consecutive years, and this year, has been recognized in the following categories: Compatibility, Service, Expertise, Quality and Reliability; and were noted for four individual attribute awards for Accessible Senior Management, Reputation, Right First Time, and Strength of Science.

“Cambrex is once again honored to be recognized as a leading supplier to the pharmaceutical industry,” commented Steven Klosk, President and Chief Executive Officer at Cambrex.

He added, “With our recent acquisitions of Halo Pharma and Avista Pharma Solutions, we have created a leading, fully

Breakthroughs at the bench, novel technologies and groundbreaking policies and regulation have helped the pharma industry grow from strength to strength.

The Medicine Maker 2019 Power List features 100 of the industry’s pioneers across four categories: Industry Influencers, Business Captains, Masters of the Bench, and Champions of Change.

Cambrex President and Chief Executive Officer, Steven Klosk, was recognized in the Business Captains category of The Medicine Maker Power List in 2019.

integrated small molecule CDMO across the entire drug lifecycle offering more products and services to our customers. Being the recipient of a 2019 Leadership Award is a testament to the hard work of all our employees across the entire company.”

Established in 2011, the CMO Leadership Awards recognize top outsourcing partners, determined by feedback from sponsor companies who outsource manufacturing. The awards are presented by Life Science Leader magazine and Industry Standard Research.

When asked by The Medicine Maker, "What’s the luckiest break of your career?", Steven commented: “Joining Cambrex early in my career, because the experiences I have had and the people I have shared my time with have given me 28 years of steady personal and professional growth. In addition, building a strong team of experts within Cambrex has ensured our success.”

Cambrex recognized at 2019 CMO Leadership Awards

Steven Klosk recognized in industry Power List 2019


Awardwinning

Award winning

Cambrex won the ‘Excellence in Pharma: API Development’ category at the annual CPhI Pharma Awards, which took place at a Gala Dinner at CPhI Worldwide in Frankfurt on November 5th. This marks the third time that Cambrex has won the category in the past four years, having previously won in 2016 and 2017. The company was also judged ‘highly commended’ in the same category in 2018.

The winning entry, for the company’s crystallization screening and process development service, highlighted a peptide crystallization project bridging the gap between the laboratory and manufacturing plant, providing a controlled, robust and scalable crystallization process.

Cambrex’s advanced expertise and innovative approach to peptide crystallization allowed for the delivery of a robust, scalable and transferable process affording effective isolation and batch-to-batch consistency and reducing the cost of the purification and manufacturing process. The development also resulted in a crystalline solid form of the peptide, which showed enhanced physical properties and allowed for improvements to be made in downstream processing.

“We thank the judges and our industry peers for this unprecedented third API Development award,” commented Hayley Reece, Executive Director, Technical Services at Cambrex Edinburgh. She added, “This project was undertaken at our

Edinburgh site, which is a world leader in providing solid-form development services for drug substance and drug product and where we recently announced a strategic expansion, to enable us to serve more customers in the solid-state screening and crystallization process development market.”

Established in 2004, the CPhI Pharma Awards are among the most prestigious recognitions within the pharmaceutical industry. The awards celebrate thinkers and creators breaking new ground and strongly advocate companies committed to driving the industry forward.

Cambrex Wins CPhI Pharma Award for API Development


Salah-Eddine RiahiMaterial Handler

Kayla ThomasAssociate Scientist

Cambrex WebinarsAlongside our contributions to these thought leadership articles for industry publications, you can watch our experts’ informative, educational webinars online.

Cambrex Webinars

The global pediatric dosage form market is expected to reach $110 billion in 2019 — a 5% year on year growth from 2016. With a five-fold increase in drug approvals over the last 20 years, pediatric drug developments offer advantages to younger patients — and to the sponsor pharma companies through extended exclusivity for their marketed product.

Pediatric dosage form development:Challenges and opportunities

Webinar: Pediatric dosage form development

This market, which requires different oral dosage forms from adults due to differences in swallowing abilities, taste preferences and dosage requirements, presents great growth opportunities and is expected to remain at this rate until 2021.

Watch now

Contributor

Dr Anthony Qu


Cambrex

This Cambrex webinar:• Provides an overview of the pediatric market

and presents potential growth areas

• Considers the challenges and opportunities of pediatric formulations

• Reviews several pediatric formulation dosage forms including liquid dosage forms and solid dosage forms (mini-tablets, orodispersible tablets (ODT) and chewable formulation)

• Concludes with an overview of the regulatory considerations for new pediatric formulations.

Date: May 8, 2019

https://www.cambrex.com/cambrex_resources/pediatric-dosage-form-development-challenges-and-opportunities/

Cambrex Webinars

The market for solid-state services (including salt, polymorph and crystallization screening) is worth around $150 million and there is a growing trend from pharmaceutical companies to outsource much of this activity to CDMOs such as Cambrex.

De-risking the solid form landscape of an API early in development is of utmost importance to ensure its success as a viable drug candidate. Entrusting your project to an outsourced supplier requires careful consideration. Our Edinburgh site is a world leader in providing solid-form development services for drug substance and drug product.

Contributors

Dr David Pearson

Chief Scientific Officer,

Cambrex Edinburgh

This Cambrex webinar:• Discusses how predictable stability and solubility

can minimize development timelines and cost

• Provides an introduction and overview of the solid-state market

• Discusses the importance of de-risking the solid state landscape of an API

• Considers two examples of typical issues faced during development of an API

• Provides a brief overview of hydrates, and why understanding their formation is so critical.

De-risking the solid form landscape of an API: How predictable stability and solubility can minimize development timelines and cost

Webinar: De-risking the solid form landscape of an API

Watch now


https://www.cambrex.com/cambrex_resources/de-risking-the-solid-form-landscape-of-an-api/

As we enter a new decade, the next 12 months represent another opportunity for investment and growth. Having expanded operations beyond small molecule API development and manufacturing into the drug product segment, we are investing in our sites, capabilities and people to maintain our leading position as the small molecule company.

We have doubled the cGMP liquid filling capacity at our Mirabel Québec facility. Edinburgh’s strategic expansion, increase in headcount and investment in new equipment in Europe will enable us to serve more customers in the solid-state screening market. The new 6,500 sq. ft. facility at our site in Karlskoga, incorporating labs for process and analytical development, is also now complete.

This will help us with our strategy of providing best-in-class services to meet the needs of our global pharmaceutical, biotech and generic customers.

These are exciting times. As always, we will do our best at Cambrex to serve you, our customers, by being the experts you enjoy working with.

Shawn Cavanagh

President and Chief Operating Officer

Future focus: Our 2020 vision

Shawn CavanaghPresident and Chief Operating Officer

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