Case Studies in the Development of Drug Substance Control

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Case Studies in the Development of Drug Substance Control Strategies Nicholas Murray Thomson, Robert Alan Singer, Kevin Seibert, Carla Luciani, Sushil Srivastava, William F Kiesman, Erwin Irdam, John Lepore, and Luke Schenck Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 02 Jun 2015 Downloaded from http://pubs.acs.org on June 3, 2015

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Organic Process Research & Development

Case Studies in the Development of Drug Substance Control Strategies Nicholas M. Thomson*#, Robert Singer#, Kevin D. Seibertŧ, Carla V. Lucianiŧ, Sushil Srivastava¥, William F. Kiesman‡, Erwin A. Irdam‡, John V. Lepore€ and Luke Schenck€ #

ŧ

Chemical Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA. Small Molecule Design and Development, Eli Lilly and Co., Lilly Technology Center, Indianapolis, IN

46285, USA. ¥

Chemical Development, Bristol-Myers Squibb Company, One Squibb Dr, New Brunswick, NJ, 08903,

USA. ‡

Chemical Process Research and Development, Biogen, 14 Cambridge Center, Cambridge, MA 02142,

USA. €

Chemical Process Development and Commercialization, Merck, 126 E. Lincoln Ave, Rahway, NJ,

07065, USA.

Corresponding Author *[email protected]

ACS Paragon Plus Environment


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GRAPHIC FOR TABLE OF CONTENTS

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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, required to assure 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. KEYWORDS Control Strategy, Quality by Design, Process, Methods, Models

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INTRODUCTION The material in this manuscript 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 assure 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. BACKGROUND The term control strategy emerged in ICH Q8 and subsequent revisions, defined as: “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

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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 control strategy as it applies to drug substance processing. 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 •

Controls on material attributes (including raw materials, starting materials, reagents, and primary packaging for 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 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 purge 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 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, illustrated in a series of case studies. Concepts such as understanding impurity 5



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formation (what side reactions form them), fate (what they may convert to 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.

Case studies elaborated upon in this publication will demonstrate a number of

approaches appropriate to control impurities in drug substances, with the application of sound quality risk management, effective science founded on first principles and/or empirical process understanding. Each approach to impurity control can be placed somewhere in the graphic shown in Figure 1.

Figure 1. Different Approaches to Drug Substance Control The nature of the case studies 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 process development. As the reader will see, strategies can be implemented for a small, but important subset of critical quality 6


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attributes (CQAs), such as heavy metals, organic solvents and the like, or 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 API manufacture can facilitate continual improvement that should be accompanied by reduced post approval 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 a design space to 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 (PAR’s) 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. 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 pro-drug for treatment of tumors at various stages, developed at Bristol-Myers Squibb. A telescope process was developed for the synthesis of drug substance which includes the 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 particle size (Scheme 1). The critical quality attributes were identified based on the Quality Target Product Profile (QTPP) of the drug product. 7



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Scheme 1. Manufacturing Process of a Bristol Myers Squibb Drug Substance A number of key challenges were faced during the development of the process. The prodrug ester is inherently sensitive to moisture, thus impacting long term stability. For example, the parent drug can be formed by the action of carbon dioxide and water in the final step work-up. In the reductive amine deprotection, the catalyst can be irreversibly poisoned by the carbon dioxide by-product in the absence of hydrogen and the reaction must go to 99.4% completion for quality, but is susceptible to overreduction.

During the process, a number of impurities (stereochemical and genotoxic) must be

controlled and the particle size requires in-line milling for adjustment. 8


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Based on a risk assessment, material attributes and process parameters were identified to control the established drug substance CQAs.

Both steps of the synthesis were evaluated using design of

experiment (DOE) methodology to identify interdependencies of the parameters and their PAR’s. A control strategy was developed and implemented during development and commercial manufacturing to consistently afford high quality and stable drug substance. Table 1 outlines elements of the final drug substance control strategy, and is representative of a typical justification. Key elements of the control strategy include; control of material attributes to set specifications by testing, control of critical parameters within defined PAR’s (defined based on DOE studies) verification of PAR’s at pilot scale to assure consistent quality within the range, in-process controls including PAT with validated analytical methods, and control of drug substance by release test with validated analytical methods according to verified specifications.

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Control Strategy for Drug Substance Critical Quality Attributes Attribute/Control Specifications

Linked to: (DP CQA)

Control

Justification

Identity

Identity

Design of the Process

The identity of the drug substance is confirmed by IR or Raman and HPLC (retention time) using a well characterized reference standard.

Assay “as is” 97.0%-102.0%

Potency

Controls described below ensures that drug substance will meet the acceptance criteria Input specifications Parametric & IPCs controls Design of the manufacturing process

Controls are in place to ensure minimal impurity content in the drug substance, which is confirmed by the drug substance meeting the acceptance criteria for assay.

Impurities

Impurity content

Input final intermediate attribute specification:

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 final intermediate during work-up. 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.

Input-related: Imp-283; ≤0.15% Imp-621; ≤0.13% Imp-832; ≤0.20% Imp-405 ≤0.35%

Process-related: 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%

Imp-514 ≤0.48% Imp-621 ≤0.25% Imp-519 ≤0.34% Imp-407 ≤1.9% Crystallization Parameters: Concentration, & Temperature PARs

impurity content

Input final intermediate specifications/ IPC Input192:: Water content ≤0.20% Water content ≤0.5% THF: Water content ≤0.05% Acylation reaction process parameters: Input-192-01 Molar equivalents (1.15-1.30) Reaction temperature (-7° to +5°C) IPC for acylation reaction completion-residual input Work-up 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)

Adventitious water facilitates the hydrolysis of EDAC to urea by and impacts acylation reaction completion. 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 by-products and Imp-192 from the Residual Int-656. The IPC for residual water controls the hydrolysis of DS to final intermediate during and after the hydrogenolysis reaction. Interdependent hydrogenolysis process parameters [catalyst loading, temperature, pressure, concentration, and water content] ensure the reaction will proceed at a rate sufficient to complete reaction and control residual Imp-656 within a defined time. These conditions provide control of process-related impurities final intemediate, Imp-494, and over reduction impurity Imp-176.

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Linked to: (DP CQA)

Control

Justification

Pressure (1.93-3.1 barg) Concentration (≥6.99 L/kg) Mass transfer coefficient (low - moderate)

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Linked to: (DP CQA)

Control IPC for hydrogenolysis reaction completion: % w/w Imp-656 (FTIR) (≥99.9%) 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) Ratio of heptanes to ethyl acetate (1.8:1-2.2:1) Temperature (40°-60°C)

Stereoisomers:

impurity content

Dia-393 + Dia-516 ≤0.50%

Final intermediate specifications:: Enantiomer Enan-216 ≤0.35% Imp-192-01 ≤0.30%:Enantiomer Enan-194 Acylation reaction process parameter: Temperature (-7° to +5°C) Addition order of reagents Crystallization procedure

Justification The IPC during hydrogenation ensures reaction kinetics will be sufficient to complete reaction within the desired time to control impurities and allows addition of a kicker charge of catalyst, if required, to achieve the 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 purgability of impurities In addition, control of the ratio of anti-solvent (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. The limit for Imp-216 in final intermediate controls the Iso-516 in the reaction stream. The limit for Enan-194 controls Iso-393 in the reaction stream. The acylation reaction temperature and addition order of the reagents minimize epimerization. Once DS has formed, epimerization at the Lalanine chiral center does not occur under the reaction conditions. The limit for Dia-216 in final intermediate and the crystallization control the level of Dia-516 at

Case Studies in the Development of Drug Substance Control

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