Article pubs.acs.org/OPRD
Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium Margaret M. Faul,†,* Carl A. Busacca,‡ Magnus C. Eriksson,‡ Fred Hicks,§ William F. Kiesman,∥ Maciej Smulkowski,⊥ John D. Orr,# and Steven Pfeiffer¶ †
Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320, United States Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877, United States § Takeda Pharmaceuticals International Company, Cambridge, Massachusetts 02139, United States ∥ Chemical Process Research and Development, Biogen Idec, Cambridge, Massachusetts 02142, United States ⊥ Chicago Pharmaceutical Science Group, Takeda Development Center Americas, Inc., Deerfield, Illinois 60015, United States # US API Process Research and Development, Pharm. Sci. & Tech., Eisai Inc., Andover, Massachusetts 01810, United States ¶ Process Development and Manufacturing, Kythera Biopharmaceuticals, Calabasas, California 91301, United States ‡
S Supporting Information *
ABSTRACT: Designation and justification of active pharmaceutical ingredient starting material (API SM) is a standard part of the drug development and commercialization process. However, knowledge of current practices used within the industry varies, depending on the individual company interpretation of regulatory guidelines. In 2011, the API and Analytical Leadership Groups within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ), established a Working Group on API SMs to determine current practices within the pharmaceutical industry on this topic. A survey composed of four key areas, representing (1) drug substance (DS) attributes, (2) API SM attributes, (3) control strategy, and (4) regulatory practices and strategy, was developed and distributed to IQ member companies. Data representing a total of 50 API SMs (used to prepare 24 late stage clinical or marketed DSs) were obtained. This data was used to gain a better understanding of approaches utilized by pharmaceutical companies to define API SMs. The data gathered was anonymous, and the key information obtained is summarized in this manuscript. While no single approach to justifying API SMs emerged from the survey data, key trends were evident that will provide valuable insight for the reader on this important topic.
1. INTRODUCTION The material in this manuscript was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ). The IQ Consortium is a not-for-profit organization composed 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. A major deliverable during drug development is the selection, designation and justification of the active pharmaceutical ingredient starting material (API SM), the point in the synthesis of the drug substance (DS) where GMP processing begins. However, selection of the API SMs for DS manufacture continues to be a much debated topic and industry practices for their selection vary based upon company experience and interpretation of regulatory guidances. In 2011, the API and Analytical Leadership Groups, within the IQ Consortium, established an API SM Working Group (WG), to assess how IQ member companies make important decisions around how to designate and justify API SMs and their associated regulatory practices. The API SM WG chose to define this area by posing three fundamental questions: © 2014 American Chemical Society
(1) How has the regulatory perspective on API SM designation developed? (2) How are peer companies approaching API SM designation and justification? (3) What should the industry do, if anything, to improve the current process? Part 1 of this series answers question 1 and has been published as an introduction to the current manuscript.1 This manuscript, Part 2, examines question 2 and will outline the current practices used by the IQ member companies to support their API SM designation with the regulatory agencies. These practices are summarized on the basis of the results of a survey that comprised case studies of 50 API SMs [that were used to prepare 24 late stage clinical or marketed DSs].2 Part 3 of this series is expected to be published in the future and will outline opportunities to improve the process in alignment with ICH Q11.
2. RESULTS AND DISCUSSION 2.1. Survey Composition. The survey focused on four main areas: (i) DS attributes; (ii) API SM attributes; (iii) Received: February 17, 2014 Published: April 10, 2014 594
dx.doi.org/10.1021/op5000607 | Org. Process Res. Dev. 2014, 18, 594−600
Organic Process Research & Development
Article
Table 1. Overview of API SM survey focus areasa
a
DS attributes
API SM attributes
•synthesis •complexity •lot history •chiral impurities •impurities
•complexity •manufacturing and validation •sourcing •propinquity •impurities
control strategy
regulatory strategy
•process control •manufacturing •propinquity
•regulatory status •filing structure •information shared for justifications •timing of final API SM strategy communication •regulatory communications with US, Canada, and EU
Analytical Control Impurities Controlb •acceptance criteria •analytical methods •characterization •fate and purge •GTIs and pGTIs
All the raw data for the API SM survey is included in the Supporting Information. bExpanded list of the impurity control.
Table 2. Comparison of DS complexity to attributes survey sumsa for DS MW
DS complexity
survey averages
self rated complexity
no. survey cases
650
steps from RMs to DSb
DS rings
DS stereocenters
DS synthesis typesc
High Medium Low
8 9 6
3 2 3
2 7 3
3 0 0
12.6 9.3 4.7
5.0 3.6 2.2
4.5 1.1 0.8
4C, 4L 5C, 4L 2C, 4L
a Number of DSs of self-rated complexity and MW (molecular weight, in amu) value shown. bAverage number of steps from raw materials (RMs) to DS. The number of steps for each case study is the sum of the steps to make each API SM and the steps from the (first) API SM to the DS. cC = convergent, L = linear.
While there was no route type trend for medium and high complexity DSs, linear routes were used twice as much as convergent routes to prepare low complexity DSs. The number of rings correlated well to the self-rated complexity, with average ring counts of 5.0 for the high category, and 3.6 and 2.2 for the medium and low categories, respectively. The number of stereogenic centers provided a weaker correlation to complexity. Two DSs with zero or one stereogenic center were rated as highly complex, showing the importance of multiple factors in assessing DS complexity. Increased stereochemical richness did, however, track with complexity in a more general way. The average stereocenter counts were 4.5 for the high category and 1.1 and 0.8 respectively for the medium and low complexity DSs. The survey showed that DS complexity correlated with the number of DS stereocenters, rings, functional groups, and the degree of justification required to demonstrate adequate control of the DS Critical Quality Attributes. 2.3. API SM Attributes.4 In analyzing the data collected for API SM attributes, three major categories emerged where significant correlations could be drawn to a number of attributes: complexity, sourcing, and propinquity. Each of these concepts have been recurrent themes in the evolving regulatory guidances with respect to appropriate definition of API SMs. In terms of complexity, finding the balance between having an API SM represent a significant structural fragment of the DS per ICH guidance and having an API SM which is deemed too similar in complexity to the DS is a component of API SM designation. Propinquity was communicated in ICH Q115 as the relationship between potential impact of material attributes or operating conditions to their proximity to the DS. This survey sought to understand if companies were making decisions or arguments for their API SMs based upon the idea of propinquity or independent of it. The difference between the justification burden for commercial or commodity vs custom
control strategy and (iv) regulatory practices and strategy. The primary focus in each of these areas is summarized in Table 1. For the first time, data for each of these key areas was collected and is shared through this manuscript to give an unprecedented look at current industry practices in API SM designation. Additionally, we sought to analyze the data not only for simple trends between case studies but also to probe for connections between seemingly unrelated focus areas of the survey. The key objectives of the survey were to learn how companies developed their control strategies to justify the designation of their API SMs, how the information is filed with regulatory agencies, and the resulting outcome of their proposals. 2.2. DS Attributes.3 In terms of understanding API SM designation practices, it was first important to understand the nature of DSs. We collected information on a number of DS attributes, and one was (survey respondent) self-rated complexity. No standard definition was provided to the survey respondents; rather, they were asked to provide an assessment, based upon their companies’ perspectives, to facilitate the development of a complexity definition. Correlation of DS complexity to its key attributes, indicated that MW provided some correlation to complexity. Each DS in the highest MW category (>650 amu) was rated as highly complex; however, three DSs self-rated to be highly complex, had MWs in the lowest category (400, while low complexity API SMs typically have a MW
