Communication pubs.acs.org/OPRD
Case Studies in the Development of Drug Substance Control Strategies Nicholas M. Thomson,*,† Robert Singer,† Kevin D. Seibert,‡ Carla V. Luciani,‡ Sushil Srivastava,§ William F. Kiesman,∥ Erwin A. Irdam,∥ John V. Lepore,⊥ and Luke Schenck⊥ †
Chemical Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States Small Molecule Design and Development, Eli Lilly and Co., Lilly Technology Center, Indianapolis, Indiana 46285, United States § Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States ∥ Chemical Process Research and Development, Biogen, 14 Cambridge Center, Cambridge, Massachusetts 02142, United States ⊥ Chemical Process Development and Commercialization, Merck, 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
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“A planned set of controls, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.”1 Until ICH Q11 emerged, drug substance development practitioners interpreted this guidance as it was applicable to the control of physical attributes, such as particle size, crystal phase, etc., and chemical properties, such as impurities. ICH Q11 more fully clarified the concept of a control strategy as it applies to drug substance processing. The development of a control strategy is a mandatory element of developing a process and has been the domain of process chemists and engineers for many years. Many different approaches to putting a control strategy into place have been successfully developed and implemented. The typical elements are specified in Q11, but the listing is not all inclusive:2
ABSTRACT: A series of case histories from IQ consortium member companies are presented in order to exemplify many of the different elements of drug substance control strategies that are required in order to ensure process performance and product quality. Control through process, method, and/or model design can combine to form a holistic control strategy that effectively manages risk and assures quality for the patient. A typical drug substance control strategy overview is presented, along with a number of detailed case histories that aim to demonstrate the use of process design and the development of methods and modeling to ensure control of critical quality attributes where appropriate, whether in the final drug substance or through upstream controls.
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INTRODUCTION
The material in this article was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically driven standards and regulations for pharmaceutical and biotechnology products worldwide. Today, IQ represents 37 pharmaceutical and biotechnology companies. Please visit www. iqconsortium.org for more information. Within the IQ framework, a Quality by Design (QbD) Working Group has been chartered with the aim of sharing strategies and practices for QbD drug substance development among member companies. An important and evolving element of QbD drug substance development is the setting of appropriate control strategies to ensure process performance and product quality. This paper aims to set out a number of case histories to exemplify many of the different approaches and considerations in the setting of drug substance control strategies.
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• controls on material attributes (including raw materials, starting materials, reagents, and primary packaging for the drug substance); • controls implicit in the design of the manufacturing process [e.g., sequence of purification steps (biotechnological/biological drug substances) or order of addition of reagents (chemical entities)]; • in-process controls (including in-process tests and process parameters); • controls on the drug substance (e.g., release testing). Impurities are of particular interest in the development of drug substances since they must be controlled during drug substance manufacture (there is no opportunity for purging in downstream drug product manufacture). During drug product manufacture, the impurities that can form are generally a function of physicochemical lability of the drug substance in its Special Issue: Application of ICH Q11 Principles to Process Development
BACKGROUND
The term “control strategy” emerged in ICH Q8 and subsequent revisions and is defined as follows: © 2015 American Chemical Society
Received: May 8, 2015 Published: June 2, 2015 935
DOI: 10.1021/acs.oprd.5b00146 Org. Process Res. Dev. 2015, 19, 935−948
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Communication
formulation matrix, either during processing or over its shelf life. This paper will focus on the development of control strategies for the impurities from the syntheses of drug substances, as illustrated in a series of case studies. Concepts such as understanding impurity formation (what side reactions form them), fate (substances to which they may be converted in downstream chemical steps), and purge (where initial impurities or the impurities they become in later steps are rejected from the process) are well-known and widely employed in the establishment of appropriate controls over these impurities. The case studies described in this publication demonstrate a number of approaches appropriate for control of impurities in drug substances, with the application of sound quality risk management and effective science founded on firstprinciples and/or empirical process understanding. Each approach to impurity control can be placed somewhere in the graphic shown in Figure 1.
process development. As the reader will see, strategies can be implemented for a small but important subset of critical quality attributes (CQAs), such as heavy metals, organic solvents, and the like, or can be part of a comprehensive designation of process controls covering multiple steps and CQAs. Effective demonstration of control and a well-integrated control strategy for active pharmaceutical ingredient manufacture can facilitate continual improvement that should be accompanied by reduced postapproval regulatory oversight. Many of the case histories refer to a design space, which is an optional component of a control strategy. A design space is defined as the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.2 As such, a design space is built upon multivariate experimentation and process understanding. A design space might be chosen as a component of a control strategy when there are identified functional relationships between parameters and/or material attributes that might warrant additional control and/or flexibility in process variation. A highly robust process might not necessarily warrant that a design space be proposed as an element of the control strategy for particular CQAs. For such cases, the data sets from multivariate and univariate experimentation can be represented by proven acceptable ranges (PARs) that have been demonstrated to provide assurance of quality. The authors note that the definition of a PAR has many different connotations to companies and regions as they relate to ICH definitions.
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CASE HISTORIES Case History 1: An Example of How To Summarize a Control Strategy in a Regulatory Dossier. The drug substance described in our first example is an oncology prodrug for treatment of tumors at various stages, developed at BristolMyers Squibb. A telescope process was developed for the synthesis of the drug substance that includes acylation of the final intermediate with CBz-L-alanine, reductive deprotection of the amine protecting group, and subsequent crystallization to afford the free-base prodrug with wet milling to control the
Figure 1. Different approaches to drug substance control.
The natures of the case studies presented here span a wide range of technical approaches, all intended to arrive at an effective risk management strategy (assessment, experimentation, criticality designation, control) for a wide variety of common issues encountered in the course of drug substance
Scheme 1. Manufacturing process for a Bristol-Myers Squibb drug substance
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DOI: 10.1021/acs.oprd.5b00146 Org. Process Res. Dev. 2015, 19, 935−948
identity potency
impurity content
impurity content
assay “as is” 97.0%−102.0%
input-related impurities: Imp-283: ≤0.15% Imp-621: ≤0.13% Imp-832: ≤0.20% Imp-405: ≤0.35%
process-related impurities: Imp-176: ≤0.25% Imp-494: ≤0.25% residual Int-215: ≤1.0% Imp-249: ≤0.20% Imp-445: ≤0.25% residual Int.-656: ≤0.13% individual unspecified impurities: ≤0.10% total impurities: ≤2.0%
linked to (DP CQA)
identity
attribute/control specifications
control
input final intermediate specifications/IPC Input-192: water content: ≤0.20% water content: ≤0.5% THF: water content ≤0.05% acylation reaction process parameters: Input-192-01 molar equiv: 1.15−1.30 reaction temperature: −7 to +5 °C IPC for acylation reaction completion−residual input workup of acylation reaction IPC for drying distillation: water content: ≤0.05% input THF specification: water content hydrogenolysis reaction process parameters: catalyst loading, dry basis: 7.75−9.30% w/w temperature: 23−35 °C pressure: 1.93−3.1 barg concentration: ≥6.99 L/kg mass transfer coefficient: low to moderate IPC for hydrogenolysis reaction completion: Imp-656 (FTIR): ≥99.9% w/w residual Imp-656: ≤0.3 area % IPC (Raman) for solvent exchange: THF: ≤7.5% v/v crystallization process parameters: concentration by IPC of DS: 16.0−22.0% w/w heptanes:ethyl acetate ratio: 1.8:1 to 2.2:1 temperature: 40−60 °C
input final intermediate attribute specification: Imp-514: ≤0.48% Imp-621: ≤0.25% Imp-519: ≤0.34% Imp-407: ≤1.9% crystallization parameters: concentration temperature PARs
the controls described below ensure that drug substance will meet the acceptance criteria: input specifications parametric and IPC controls design of the manufacturing process
design of the process
justification
• Adventitious water facilitates the hydrolysis of EDAC to urea and impacts completion of the acylation reaction. • Controls for water, acylation process parameters, and the reaction completion IPC ensure the control of residual final intermediate. • Workup: appropriately saturated aqueous acidic, basic, and neutral washes remove residual reagent byproducts and Imp-192 from the residual Int-656. • The IPC for residual water controls the hydrolysis of DS to the final intermediate during and after the hydrogenolysis reaction. • The interdependent hydrogenolysis process parameters (catalyst loading, temperature, pressure, concentration, and water content) ensure that the reaction will proceed at a rate sufficient to reach completion and control residual Imp-656 within a defined time. These conditions provide control of process-related impurities final intermediate, Imp-494, and over-reduction impurity Imp-176. • The IPC during hydrogenation ensures that the reaction kinetics will be sufficient to complete the reaction within the desired time to control impurities and allows addition of a kicker charge of catalyst, if required, to achieve reaction completion. • Contingency: If FTIR is not operational, HPLC may be used to determine reaction completion. • A controlled crystallization rejects impurities efficiently. Concentration and temperature impact the purgability of impurities. In addition, control of the ratio of antisolvent (heptanes) to solvent (ethyl acetate) provides optimum purgability of impurities during crystallization. • The controls described above ensure that process-related impurities are within the specified limits.
• Imp-514, Imp-519, and Imp-407 react under the reaction conditions to produce Imp-283, Imp-832, and Imp-405, respectively. Imp-621 reacts to form a transient intermediate during acylation, which quantitatively hydrolyzes back to the final intermediate during workup. • Imp-283, Imp-621, Imp-832, and Imp-405 are reduced in the crystallization of the drug substance. • Appropriate limits for the parent impurities in input final intermediate coupled with purge data ensure that the corresponding drug substance impurities are within the specified limits.
Controls are in place to ensure minimal impurity content in the drug substance, which is confirmed when the drug substance meets the acceptance criteria for the assay.
The identity of the drug substance is confirmed by IR or Raman spectroscopy and HPLC (retention time) using a well-characterized reference standard.
Control Strategy for Drug Substance Critical Quality Attributes
Table 1. Control strategy for a Bristol-Myers Squibb oncology candidate
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DOI: 10.1021/acs.oprd.5b00146 Org. Process Res. Dev. 2015, 19, 935−948
drug product dissolution
impurity content
palladium ≤20 ppm
particle size distribution D[50]: ≥10.0 μm D[90]: ≤120 μm
impurity content
water content: ≤0.1%
impurity content
impurity content
genotoxic impurities: propylene oxide: ≤0.03% EDAC:
