Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
pubs.acs.org/OPRD
Development of Universal, Automated Sample Acquisition, Preparation, and Delivery Devices and Methods for Pharmaceutical Applications Gordon R. Lambertus,*,† Luke P. Webster,† Timothy M. Braden,† Bradley M. Campbell,† Jennifer McClary Groh,† Todd D. Maloney,† Paul Milenbaugh,§ Richard D. Spencer,‡ Wei-ming Sun,† and Martin D. Johnson† Downloaded via IOWA STATE UNIV on January 23, 2019 at 05:59:13 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland § D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States ‡
S Supporting Information *
ABSTRACT: Continued emphasis in the pharmaceutical industry toward development of hybrid and continuous processes has led to a resurgence in process analytical technologies. The need to consistently and rapidly monitor the quality of material being made from these processes is a significant challenge that requires integrated, online analytics. Often the most challenging aspect of implementing real-time monitoring is ensuring that the analytical instrumentation is receiving a representative sample from the process. The Small Molecule Design and Development organization at Eli Lilly and Company has developed a highly adaptable process-to-analytics interface that has been broadly implemented across the development portfolio. The automated sample carts use only gravity and low-pressure nitrogen to obtain representative process samples, typically on the order of 0.3−6 mL. Subsequent sample preparation operations including quenching, derivatization, and most commonly dilution (10−250× is customary, but not restrictive) in a high-performance liquid chromatography-compatible diluent. Samples are then delivered to the receiving online chromatographic instrument in a manner conducive to injection and analysis for that specific platform. These carts have demonstrated robust performance, and qualification data routinely meets less than 2.0% relative standard deviation on sample-to-sample reproducibility and less than 5% carryover between samples when optimized. Implementation within and across pharmaceutical processes have spanned 5 orders of magnitude in volumetric scale, while completing tens of thousands of on-process cycles. Automated sampling has proven invaluable to our organization, significantly increasing the speed of development/optimization for continuous unit operations by providing real-time process understanding and rapid diagnosis and troubleshooting of events. Operational criteria and performance assessment of the carts are provided. Several applications will be highlighted with integration to a variety of continuous manufacturing platforms in both pharmaceutical development laboratories and good manufacturing processes manufacturing. Cart function is thoroughly described in Supporting Information. KEYWORDS: continuous manufacturing, sample preparation, PAT, online HPLC and processes for small molecule drug substances.1−11 Continuous processes allow access to enabling chemistries that can be run under more extreme conditions (pressures and temperatures) than are common (limited by equipment or safety limitations) in traditional batch equipment. Many of these same advantages realized via continuous processing consequently lead to significant complications in online analytical instrumentation and, more specifically, sample acquisition. As continuous processes become more prevalent and processing equipment continues to evolve, the analytical technologies required to support these processes have to gain operational efficiency. The compartmentalized analytical functions of sample acquisition, sample analysis, data processing, and data reporting must be highly integrated and
1. INTRODUCTION Pharmaceutical companies, for a variety of reasons, are constantly evolving and becoming more efficient in delivering molecules to the market. As a result, all facets of molecule/ process development are streamlined, and fewer resources are expected to deliver more complex, comprehensive data packages in a shorter amount of time. The rapid pace and cost of development have led pharmaceutical companies to develop, codevelop, and/or identify technologies that lead to efficiency gains within their organizations. Tangible evidence includes increases in the prevalence of technology and innovation centric groups within pharmaceutical companies, collaborative technology initiatives across the industry, participation in academic and industrial consortia, and efforts to integrate these technologies into the regulatory framework. Eli Lilly and Company’s Small Molecule Design and Development (SMDD) organization has made a significant investment in developing continuous manufacturing platforms © XXXX American Chemical Society
Received: August 28, 2018 Published: December 12, 2018 A
DOI: 10.1021/acs.oprd.8b00280 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Figure 1. Complete fluidic diagram of an automated sample cart including integration to an analytical instrument with a valve-based injection (VBI) using a vapor/liquid separator (VLS).
automated to fully enable the rapid turnaround required to support control strategies for continuous processes. For the traditional pharmaceutical development chemist, high-performance liquid chromatography (HPLC) analysis is the primary data source for reaction understanding. While holding true for continuous processing, the analytical burden is exponentially increased over an extended state of control requiring frequent analysis rather than a single end of reaction sample as in a batch scenario. To reduce analytical burden, atline and online analytical instrumentation is brought to the process, providing more robust information packages while minimizing data generation timelines. Delivery of a representative sample to the online analytical instrument is often the most complicated aspect of the workflow. Most chromatographic equipment is not amenable to injection of neat process samples, as primary limitations include reactive process species, process concentrations, and compatibility of materials of construction. To make samples chromatographically viable, they may require quenching, derivatization, and/or dilution in compatible solvents. A thorough investigation of many of the commercially available automated sampling/analysis systems identified significant gaps in both the application and operation of this equipment relative to established needs.1,7−10,12−15 Many of the offerings, primarily designed for aseptic processes, were limited to aqueous-based sample matrices and exhibited limited robustness from a material of construction perspective when exposed to organic process materials. Also significantly, there is no commercially available option for sampling at the full range of pressures and temperatures necessary. With intensified processes, the risk of fouling is increased, particularly in small diameter tubing on auxiliary devices, where it is difficult to maintain elevated temperatures. Devices that rely on 1/16 in. o.d. tubing to acquire process samples without an immediate dilution step have led to numerous,
albeit process-dependent, sampling line fouling issues. Additional consideration should be given to the desire for easy integration with other online sampling and analysis tools for real-time data generation. This work focuses on the developmental elements and process implementation approaches for an automated, online sample preparation system designed to interface directly with the targeted unit operation and the downstream analytical instrumentation. A primary objective for these automated sample carts is mitigation of many of the failure modes experienced with commercial devices, while obtaining representative process samples from a closed system (maximum containment, compatible at temperature and pressure). The sample preparation phase uses low-pressure nitrogen to move solutions for further execution of any required operations (i.e., quenching, dilution, derivatization, etc.) and finally deliver the sample to the analytical instrument, whereby reliable analysis provides the user with real-time process information. The operation, performance characteristics, and broad application of this system are described.
2. EXPERIMENTAL SECTION 2.1. Functional Description. Functionally, automated sample carts can be separated into five independent operations: diluent measure out, process sampling, mixing, sample delivery to the analytical instrument (including the instrument interface), and the overarching automation control. The diluent measure out, process sampling, and mixing operations are all designed to be the same between applications. Sample delivery to the analytical instrument is, of course, dependent on the analytical needs of that process unit operation and will vary between a few selections as the analytical measurement changes. The carts, however, are designed to readily accommodate any potential changes in B
DOI: 10.1021/acs.oprd.8b00280 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Figure 2. Digital image of both sides of a sampling cart showing (A) the sample drop zone and diluent wash zone and (B) the diluent measure out zone, diluent overflow zone, and mixing zone. Most of the fluidic lines are 1/8 in. PFA, while the pneumatic lines are 1/4 in. The diluent can, waste can, and VLS (located at this analytical instrument) are not shown.
mixtures in CSTRs. Adaptable platforms maximize opportunities for fit-for-purpose equipment and implementation of unit operations with widely ranging process conditions but increase the flexibility required for integration of a universal sampling cart across platforms. To accommodate fluidic integration across such a wide variety of reactors the design of the sampling interface needs to operate independently of the aforementioned criteria. Continuous processes operate under conditions where starting materials are consistently input, while products are consistently discharged. Consequently, these processes are comprised of either continuously or intermittently flowing liquids, gases, and/or solids. The sampling cart design takes advantage of a processes characteristic ability to deliver a sample via this continuous flow. The design further overcomes the significant challenge around process-to-process variabilities in scale, equipment configuration, and operational conditions with a fixed volume cell, located below an overflow Tee, between two block valves (A and B valves in Figure 3). Design criteria for the overflow Tee include consideration of the diameter of the process line into the overflow Tee and the diameter of the Tee itself. For example, PFRs can range from 1/16 in. coiled Teflon or metal tubes to 3 in. diameter stainless steel pipes-in-series, and the volumetric flow rate delivered by these processes can differ by several orders of magnitude. The same type of sampling and dilution carts have been used with reactor throughputs from 0.02 mL/min at research scale6 to 500 mL/min at production scale.8 The overflow Tee can be as little as 3/8 in. compression fittings with 1/16 in. inlet and outlet tubing for research scale or 3/4 in. compression fittings with 3/8 in. inlet and outlet tubing for production scale. It is important to note that at low reactor throughputs (e.g., 0.02 mL/min), automated sampling carts using this configuration will consume a significant fraction of the process material. The Tee relies on being fed by the natural flow of the process. It is
the downstream analysis. For example, all required valves for the most complicated function are included in the base design and may not be used for simpler operations. The automation control has been developed to include any of the required functionality and is adjusted by simple user input during automation start-up. A fluidic diagram of the cart (Figure 1) and digital images (Figure 2) provide an overview of the layout. Analytics-to-process integration is the most challenging part of obtaining representative process samples, and development of a robust interface is often the most critical component in the sampling system. Design criteria and function of the process interface will be described in detail in the following section. For detailed descriptions and valve sequencing tables of subsequent sampling cart operations refer to the Supporting Information, “Functional Description of Automated Sampling Carts Operations”. 2.2. Process Sampling Interface. A limiting factor to broad implementation of most automated sampling platforms is the design of a robust, scale, and process-independent sampling interface. While there are two fundamental types of continuous reactors, namely, plug flow reactors (PFR) and continuously stirred tank reactors (CSTR), there are, however, a wide variety of factors that can be changed within a platform allowing for a maximum of process flexibility. For PFRs these factors include: tubing length, diameter, length/diameter ratio, flow rate, pressure, material of construction, heat transfer surface area per unit volume, microchannel versus cylindrical tubing, alternative energy input, static mixers, and multiple injection points, while for CSTRs the factors include: volume, flow rate, number of vessels in series, pressure, material of construction, temperature, continuous versus intermittent flow out, fill level, and agitation speed. The reactors may also process heterogeneous mixtures, for example, gas/liquid or liquid/liquid mixtures in PFRs and solid/liquid or liquid/liquid C
DOI: 10.1021/acs.oprd.8b00280 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
2.3. Summary of Cart Operation. The design of the automated sampling carts provides maximum flexibility in dilution factor by using modular, interchangeable sample and dilution zones. The lower end of the dilution range is more operationally challenging with this cart, as the volume in the downstream sample delivery fluidics makes it more difficult to move smaller diluted sample volumes. The cart is simple in design, easy to integrate, and operates at room temperature utilizing only house nitrogen (15−45 psi) and automated valving (based on either timing or pressure control) to move material from one zone to another. The sampling and mixing components of the sequence typically take 1−3 min to execute, while the sample delivery process can take an additional 2−15 min to complete. Sample delivery time is governed by the physical location of the analytical instrument relative to the dilution cart (distance between the sample cart and the analytical instrument), the length and internal diameter of the tubing, viscosity and volume of the diluted sample, and the nitrogen pressure available. Designed to be small and mobile, the sampling cart is ideal for colocation with the reactor. Having the sampling device proximal to the reactor helps to maintain sample integrity via collection and preparion within a minimal amount of time. Additionally, the sampling carts have been built using all electrically classified components and can reside on a manufacturing plant floor. With the ability to push samples long distances using nitrogen, analytical equipment does not need to be collocated with the process. As a result, analytical equipment can reside in nearby nonclassified laboratories, saving both capital investment and operational complications.
Figure 3. Schematic showing the process sampling interface of the automated sampling cart. A (generally open) and B (generally closed) valves together form the sampling zone on the automated sample cart, and the volume of the gap between the balls of the valves define the sample volume. Bold arrows indicate direction of process flow.
common for coupled continuous processes to have intermittent liquid/gas flow throughout them. For this reason the overflow Tee must have a large enough diameter (>3/8 in. o.d. for organic streams or >1/2 in. o.d. for aqueous streams) that, for heterogeneous liquid/gas matrices (intermittent flow or reactive gases, e.g. hydrogenations), allow the vapor to bubble up through the Tee and out the overflow arm. The overflow (of both liquid and gas) is subsequently directed toward a product tank or a downstream unit operation. The “from process” line in Figure 3 is the input to the overflow Tee and comes from upstream unit operations (PFR, CSTR, etc.). The outlet of this tube is located such that process material exits the tube just above A valve, shown in Figure 3. The proximity to the A valve allows for complete flushing of the overflow Tee and the sample volume, as the process material enters the overflow Tee. As the Tee operates normally liquid filled, all excess material exits via the side leg labeled “to product collection”. At low flow rates the interior of the ball of A valve can act as a low dead leg. This can be overcome by taking waste cuts on the sampling cart. A valve, normally open, isolates the sample to be prepared by the cart from the rest of the process, and ensures that material in the sample zone is representative of the process. The inlet dip tube extends as close to the ball of valve A as possible. B valve, normally closed, isolates the sample volume from the rest of the fluidics on the automated sample cart. When both valves are closed, one of the steps in sample acquisition, the fixed volume between the two valves is isolated. This is the neat process sample to be prepared by the cart. The simple, highly flexible, and adaptive design of the process interface for the automated sampling carts has made them the most widely deployed piece of equipment in our development laboratories. While maintaining containment within the processing equipment, this interface offers minimal risk to the process, as there are no automated valves or sample loops in the main process flow path, and the only direct process contact with the sampling cart are the overflow Tee and A and B valves. Valve interlocks are programmed into the automation, preventing a situation where both A valve and B valve can open at the same time. By doing this, dilution solvent cannot get into the process stream. Any failure (mechanical, automation) on the sampling cart that causes it to shut down will not impact the process in any way, as both valves are failclosed.
3. DISCUSSION The universality and simplicity of the process interface for the automated sampling carts has made them applicable across a wide range of applications that relate to pharmaceutical development and manufacturing. This discussion will first address general performance characteristics of dilution carts and assessment on a case-to-case basis. The utility of the carts across diverse applications will be illustrated through three sections, (1) a cradle-to-grave application on a continuous reductive amination reaction, where carts were implemented from small-scale development runs through large-scale manufacturing, (2) highlight a variety of unique sampling challenges experienced across applications in development laboratories, and (3) illustrate qualification strategy, operational performance, and application in good manufacturing practice (GMP) manufacturing. Modifications to the functionality and operation of the cart will be highlighted in each section. 3.1. Performance Assessment. Performance assessment of automated sample carts typically relies on the downstream analytical measurements. Critical metrics include precision, carryover, dilution factor, and an assessment of fouling risk. Most routinely, online HPLC is used to assess performance characteristics of the dilution carts. Precision is determined by calculating the relative standard deviation of a set of samples at a steady-state condition. During performance qualification this is often done by recirculating a representative process sample through the process sampling interface and preparing and analyzing a series of diluted samples of the same material in a mock steady-state scenario. A relative standard deviation (RSD) of the peak area via HPLC (or GC) can then be calculated and used to understand analytical variability within D
DOI: 10.1021/acs.oprd.8b00280 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
time-consuming part of a sequence and is not included in a waste cut). An alternative method of washing the system utilizes a waste cut, or double cycle, sent through the M1 valve to the VLS and the rest of the downstream sample fluidics. In this case, no injection is done on the analytical system during this wash cycle, but the amount of time required to execute the full dilution cart cycle doubles. Double cycles are most beneficial if the dilution factor is low (
