Stephen T. Colgan

Assay and purity evaluation of 5-chlorooxindole by liquid chromatography.

5-Chlorooxindole (5-CO) is a starting material for tenidap sodium, a pharmaceutical drug candidate produced by Pfizer. To insure potency and purity of the drug substance, it is necessary to demonstrate that commercial supplies of 5-CO are free from elevated levels of chemical analogs that could be carried through the synthetic scheme. This is accomplished using a single highly specific normal-phase chromatographic system that allows the quantitation of 5-CO concomitantly with all of its potential positional isomers. This paper describes the chromatographic system and its supportive validation data.

The Application of Science- and Risk-Based Concepts to Drug Substance Stability Strategies

The International Conference on Harmonization (ICH) has provided practical guidance on the amount and type of drug substance stability data needed to support marketing applications (International Conference on Harmonization 2001, 2002, 2003a, b). Additional guidance has been issued by the World Health Organization (WHO 2009). Recent scientific advances and practices have resulted in improved scientific understanding of the chemical and physical attributes that contribute directly or indirectly to drug substance stability. Combining this improved understanding with the science- and risk-based approaches detailed in ICH Q8, Q9, and Q10 allows for alternative and more scientifically driven approaches to meet the scientific and regulatory objectives for drug substance stability (International Conference on Harmonization 2005, 2008, 2009). In this paper, proposals are presented to more fully leverage enhanced product knowledge to design improved stability strategies. The chemical and physical attributes that potentially impact drug substance stability are discussed, and strategies that leverage accelerated stability studies are presented.

Opportunities for Lean Stability Strategies

The International Conference on Harmonization (ICH) has provided practical guidance on the amount and type of stability data needed to support marketing applications (International Conference on Harmonization Guideline Q1A(R2), 2003; International Conference on Harmonization Guideline Q1C, 1996; International Conference on Harmonization Guideline Q7A, 2001). Additional guidance has been issued by the World Health Organization (WHO, 2009). Recent scientific advances and practices have resulted in improved scientific understanding of the chemical and physical attributes that contribute directly or indirectly to drug substance and drug product stability. Combining this improved understanding with the science- and risk-based approaches detailed in ICH Q8–Q11 allow for alternative and more scientifically driven approaches to meet the scientific and regulatory objectives for drug substance and drug product stability (International Conference on Harmonization Guideline Q8(R2), 2009; International Conference on Harmonization Guideline Q9, 2005; International Conference on Harmonization Guideline Q10, 2008; International Conference on Harmonization Guideline Q11, 2012). This paper follows and expands on the concept and application of the lean stability strategies that were introduced for drug substance (Colgan et al., J Pharm Innov 7:205–213, 2012). Herein, proposals are presented to more fully leverage enhanced product knowledge to design and prosecute improved stability strategies throughout the developmental lifecycle. The chemical and physical attributes that could impact stability and the tools that can be leveraged in pursuit of optimized stability strategies are discussed. Dove-tailing these stability strategies into regulatory filings for products with extensive product knowledge and the reception of these strategies by regulatory authorities in both major and emerging markets are summarized.

Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid–Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms

Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug products shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.

Assay and purity evaluation of sunepitron hydrochloride by reversed-phase liquid chromatography using a reference standard composite.

A reference standard composite was prepared that contained the active pharmaceutical ingredient sunepitron and three potential impurities. This standard was characterized and used for concomitant quantitation of sunepitron and its potential impurities in samples of drug substance and drug product. This approach minimizes the number and quantity of reference standards which often are expensive to synthesize, characterize, and maintain. In addition, running assays becomes simpler because the number of reference standard solutions required for each assay is reduced. Reference standard composites can also be used for qualitative applications such as demonstrating system suitability or for retention times markers for process related impurities or degradants.

Assay and purity evaluation of CP-93,393-1 by reversed-phase liquid chromatography. A snapshot of current practices for liquid chromatography methods development and validation

CP-93,393-1 is a new chemical entity under development for the treatment of anxiety and depression. This paper describes the selection and validation of a chromatographic system which was engineered to: (1) ensure acceptability by world-wide regulatory agencies, (2) maximize sample throughput, (3) simplify the analysis, (4) minimize ambiguity in peak assignments, and (5) facilitate the technology-transfer process. These objectives were achieved using a single, compound-specific and purity-indicating, isocratic, reversed-phase chromatographic system that allows quantitation of CP-93,393 concomitantly with all potential impurities from the same injection. A novel experimental matrix was employed to validate the chromatographic system.

A Design Space Verification Protocol for a Small Molecule Drug Substance

Regulatory expectations regarding design space verification in the designated manufacturing facility at commercial scale are not consistent across global markets. The extent and level of verification of design space boundaries are (a) predicated on the degree of risk and impact of that risk for movement within the design space and (b) are continually evaluated over the life cycle of a product and not necessarily defined as a moment in time (such as a submission date). Additionally, accommodations for differences in scientific disciplines are also important when determining design space verification strategies, for example design space verification approaches may vary between large molecule vs. small molecule drug substance, drug product, batch processes, continuous flow processes, or to assess device performance in combination products, etc. Several strategies and guiding principles to illustrate multiple opportunities and possibilities for the different disciplines to achieve design space verification using sound science and riskbased processes and procedures have recently been published [1, 2]. This publication will present a specific case study for assuring consistent quality within a design space for a recent small molecule drug substance example (of which elements are applicable across the other disciplines). It is not practical to execute and/or repeat experiments at commercial scale in a manufacturing facility to verify design space boundaries when the benefits are nebulous and the cost is prohibitive. Based on suggestions from regulatory authorities, a protocol was prepared to describe the life cycle approach and process for demonstrating design space verification. Publishing this protocol is intended to share the results of a successful interaction with regulators while continuing to facilitate open communication and opportunities for addressing the concept of design space verification. The protocol is presented within Appendix 1.

Validation of an HPLC method for the determination of CP-93,393 in CP-93,393-1 tablets

A reversed-phase high performance liquid chromatographic (HPLC) assay developed for the CP-93,393-1 drug substance was adapted for use with CP-93,393-1 tablets. Using a novel experimental matrix, validation was performed to obtain linearity, reproducibility and recovery and to meet current regulatory requirements. Deviations in the sample preparation procedure were performed to demonstrate the ruggedness of the assay.

Regulatory Expectations and Industry Practice on Stability Testing

Abstract The purpose of this chapter is to summarize global regulatory stability guidance and to propose how and when accelerated predictive stability (APS) approaches, such as accelerated stability assessment program (ASAP), can be leveraged in support of regulatory filings. While APS is primarily used as a tool for product development and packaging selection, it also can be used as supportive stability data in regulatory filings and in some cases can be the only stability data provided in the filing. The chapter also introduces the concept of lean stability and how APS can be leveraged as a tool for lean stability strategies.