ABSTRACT
An area of particular interest during the development of human pharmaceutics is the control of potential genotoxic impurities (PGIs) and genotoxic impurities (GTIs) This chapter provides an overview of pharmaceutical industry practices relating to the control of PGIs and GTIs during pharmaceutical development as gleaned from responses by pharmaceutical company representatives to benchmarking questions conducted annually over the period 2008-2012, as shared by the API Development GMP Forum (API Forum) participants We gratefully acknowledge the Chair of the 2012 API Development GMP Forum Mr Dennis O’Connor for bringing our request to use the benchmarking responses to the company representatives and the representatives for agreeing to allow the use of the information in an anonymous manner
The API Development GMP Forum is an informal, interactive conference organized by individuals in the pharmaceutical industry who focus on the application of current good manufacturing practices (GMPs) during active pharmaceutical ingredient (API) development The API Forum seeks to provide an opportunity for individuals involved in clinical development to benchmark systems, procedures, facilities, and philosophies that may be impacted by GMP regulations Participation in the
171 Genotoxic Impurity Assessment, Control, and Regulatory Perspective 468 172 Impurities 482 173 Starting Materials and Intermediates, Regulatory Aspects 483 174 Specifications 485 175 In-Process Controls and Validation, Quality Oversight 488 176 Quality Oversight 490 177 Batch Records and Good Manufacturing Practice Documentation 493 178 External Sourcing 494 179 Equipment Cleaning during Active Pharmaceutical Ingredient Pilot
Plant Manufacturing 497 1710 Quality by Design: Design Space and Control Strategy 500
forum is targeted on API development, including associated quality assurance and analytical sciences personnel who are closely involved with the philosophies, procedures, and systems in API development
The API Forum is held once a year over a 2-day time frame typically in early fall Each year, an individual volunteers to chair a steering committee of interested individuals from bio/pharmaceutical companies who then represent their company and plan the conference The goal of the API Forum is to share information through a series of roundtable breakout discussions, presentations by subject matter experts (SMEs), and benchmarking exercises To accomplish this, the steering committee identifies volunteers to moderate each of the breakout sessions and SMEs to present “hot topics” By design, the API Forum is informal to encourage networking interactions between participants and thus is generally limited to about 80 participants so that the roundtable discussions are typically small with no more than 20 participants in each group The representatives of companies who participated in the API Development GMP Forum over the survey period of 2008 through 2012 are presented in Table 171
The survey topics and responses should be of interest to anyone interested in the control of PGIs and GTIs encountered during the development of pharmaceuticals Responses to all survey questions are reported in aggregate so as to maintain the confidentiality of each company’s responses, that is, no single company is associated with a particular response Note, due to the nature of the survey and reporting of responses, that it is difficult to quantify the responses To give relative weight to responses, in cases where the same response was shared by a majority of participants it is noted as a “majority” and where the same response was shared by more than one company it is noted as “multiple” A list of acronyms used throughout this chapter is provided in Table 172
In Section 171, responses from the 2008 through 2012 surveys are presented, which illustrate the evolving dynamic as the industry struggled to find efficient approaches to address this evolving regulatory topic
1 When determining route selection, do your companies take into account PGIs as part of the decision process? Would your companies abandon a more cost-effective route solely on the basis of PGIs?
