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Steven W. Baertschi, PhD is a senior research scientist at Eli Lilly and Company.
Saji Thomas, is with Par Pharmaceuticals;
Dilip R. Choudhury, PhD,* is with Allergan and can be reached at firstname.lastname@example.org
Bekki Komas, is with Glaxo Smith Kline
Robert H. Seevers, PhD, is with Eli Lilly and Company.
John Bobiak, PhD, is with Bristol-Myers Squibb
Ramesh K. Sood, PhD, is with FDA
M. J. Skibic, PhD, is with Elli Lilly and Company
Kim Huynh-Ba is the Technical Director of PHARMALYTIK.
A two-day workshop on the "science behind pharmaceutical stability" was held in conjunction with the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS) on Oct. 21-22, 2011 in Washington, DC.
A two-day workshop on the "science behind pharmaceutical stability" was held in conjunction with the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS) on Oct. 21–22, 2011, in Washington, DC. This article summarizes some of the topics presented on various scientific aspects affecting pharmaceutical stability, including a regulatory roundtable discussion with a panel of regulatory experts from industry. The workshop presenters are noted herein.
The full summary of the workshop is available at www.PharmTech.com/AAPSstability.
Current FDA thinking on stability practices for new drug products (small molecules)
Ramesh K. Sood
The presentation addressed stability considerations at both the investigational new drug (IND) and new drug application (NDA) stages. It was emphasized that stability data which commensurate with the duration of the clinical study are required in all phases of the IND stage to demonstrate that the drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical studies. Additionally, each pharmaceutical product that is to be marketed in the United States needs to have an expiration dating period assigned. The speaker elaborated on considerations for designing and executing a proper stability study that would generate appropriate stability data to support a proposed expiration period and presented two case studies on this subject.
Design of stability indicating methods utilizing QbD concepts—a phase-appropriate approach
Dilip R. Choudhury
The speaker presented a unique approach on the design of stability-indicating methods utilizing quality-by-design (QbD) concepts in a phase-appropriate manner from the beginning of clinical development. The analytical target profile (ATP) is defined early on to describe the method performance requirements to measure a specific critical quality attribute (CQA) of the drug product. The principle of continuous learning and improvement is applied as the method evolves in parallel with the drug development process; the final method will, therefore, incorporate the impact of the critical method parameters and formulation and process variables on the method performance. In conclusion, applying QbD concept to the design of analytical methods in a phase appropriate manner provides a scientifically sound method at all stages of drug development with good understanding of method risks and critical method parameters, hence offering better assurance of the robustness and long-term performance of the method.
Drug-product fingerprints: stability-indicating spectroscopic tests
Control strategies for ensuring the quality of drug products rely on stability data to identify acceptable ranges for ingredients, processing conditions, and storage/shipping conditions. The speaker provided an example in which degradation product and impurity testing of drug products were waived by proving that process-related impurities contained in the drug substance were the only source of impurity content of the drug product and that no new impurities or degradants were formed during the manufacture of drug product or at the long-term storage, accelerated, and stress conditions used in long-term stability studies. The use of molecular spectroscopy to monitor form conversion during a drug product stability program was also described. Near infra-red (NIR) and powder x-ray diffraction (PXRD) were able to detect changes in crystallinity for stressed drug products subjected to moderate and extreme conditions. Dissolution testing, however, did not identify crystallinity changes of the API (BCS I). Impurities were detected in samples of lowest crystallinity. The use of NIR provided detailed understanding of the impact of storage conditions, temperature excursions, and packaging types on crystallinity. In summary, both traditional and emerging techniques offer insight to stability profiles.
Method validation at pre- and postapproval stages utilizing QbD approaches
The use of design of experiments (DOE)/QbD method validation approaches to support stability programs was discussed. The speaker presented a unique approach using DOE to validate a range of formulations, so that formulation changes within this range do not require revalidation. This is coupled with accelerated stability modeling tools to ensure formulation and process changes do not generate new degradation products which require revalidation. Case studies were presented using DOE/QbD to define a formulation operating range, including one where DOE was used to assess intermediate precision to ensure that there is no increase in method variability. The speaker also provided an example of the accuracy to precision model, a key DOE/QbD output, starting in early development with a generic gradient high-performance liquid chromatography (HPLC) method, followed by a product specific gradient method, an isocratic HPLC method and finally, an ultra-performance liquid chromatography (UPLC) or process analytical technology (PAT) method for product commercialization. This use of DOE/QbD and accelerated stability models provides powerful tools for developing a lean stability program based on sound science and statistical rigor.
ICH Q1B photostability guideline —time for a revision?
Steven W. Baertschi
The presentation, based on a recent publication (1), highlighted the deficiencies with the International Conference on Harmonization (ICH) Q1B photostability guideline implemented in the US, EU, and Japan. The presenters noted that since publication in November 1996, the guideline has provided a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution; however, the guideline does not cover the photostability of drugs under conditions of patient use. Areas that would benefit from revision include specifications of the option 2 UVA and visible lamp choices as well as the current recommendation of quinine as an actinometer, which should be specified only for a specific option 2 UVA lamp. These assertions were supported with examples and literature references.
Designing stability studies for global development programs
A global approach to stability beyond ICH requirements was discussed. Case studies on post-approval changes and emerging market draft guidelines were shared. A decision tree with consideration of product stability and the countries where the drug is marketed provided a clear recommendation for long-term and accelerated stability conditions. Current emerging market draft guidelines including the draft ASEAN stability and variations guidelines and challenges associated were outlined for group discussion. Key messages from the presentation were that regional stability guidance exists for emerging markets and may be different from the WHO stability guideline. Science- and risk-based approaches are not always accepted. Some new guidelines indicate an acceptance of stability commitments instead of upfront data for process changes. The ICH Global Cooperation Group, which includes six regional harmonization initiatives APEC, ASEAN, Global Cooperation Council, PANDRH, SADC East Africa Community, are making improvements towards harmonization.
Artifactual formylation of the secondary amine of duloxetine hydrochloride by acetonitrile in the presence of titanium dioxide: implications for HPLC method development
M. J. Skibic
This presentation was based on a recent publication (2) that showed that duloxetine hydrochloride, a secondary amine containing pharmaceutical, undergoes N-formylation as an artifact of sample preparation prior to HPLC analysis for impurities. The reaction is catalyzed by sonication and/or light in the presence of titanium dioxide and is proposed to occur via a hydroxyl radical-initiated mechanism. This reaction can be eliminated or minimized by replacing acetonitrile with methanol, or by simply adding at least 10% methanol to the sample diluents. The authors provided a rationale for the use of methanol considering that 1) sonication is commonly used to aid dissolution of pharmaceuticals in acetonitrile for HPLC analysis, 2) titanium dioxide is a commonly used excipient, 3) the amount of light found in modern analytical laboratories is sufficient to trigger this reaction, and 4) secondary amines are present in the structures of many pharmaceuticals.
Strategies for controlling genotoxic degradants in drug products: mitigation strategy and a case study
Brian W. Pack, Evan M. Hetrick, Linda Dow, Steve Baertschi, and Marvin Hansen
This presentation outlined a novel strategy implemented at Eli Lilly that hinged upon stress studies which have been well designed to understand the most probable degradation pathways a compound may undergo, thus limiting the number of potential degradation products to assess for genotoxic potential. The development of an analytical method with a limit of quantification (LOQ) at 10% of the threshold of toxicological concern (TTC) was recommended if the potential degradant had an alerting structure and was Ames positive. It was proposed that an inactive degradation pathway of <10% TTC in the drug product long-term stability profile indicated that appropriate due diligence had been demonstrated, and hence would pose no risk to patient safety. The speaker used a case study to demonstrate that genotoxic impurities (GTI) levels at the end of the recommended shelf life can be predicted with the information based on Arrhenius predictions from accelerated stability studies used to quickly screen multiple formulations. This approach enables informed decisions to be made around formulation, package, and storage conditions relating to GTI formation.
Dissolution failure and failure mode analysis of a hot-melt extrusion product—a case study
The step-by-step investigation of a dissolution failure of a melt extrusion product, which failed at six months under accelerated stability conditions, was discussed as case study. Because the initial investigation did not result in identifying the root cause, a five-factorial/eight-experiment design was used to evaluate the robustness of the method based on a normal probability plot of the data generated from the DOE. Products cured at 50°C were analyzed using solid-state nuclear magnetic resonance (SSNMR), environmental electron scanning microscope, and time of flight-secondary ion mass spectroscopy (TOF–SIMS). The dissolution failure was found to be caused by the stearyl alcohol migrating to the surface of the product when exposed to heat.
Stability testing to support distribution of temperature-sensitive pharmaceuticals
Robert H. Seevers
This presentation discussed the other types of testing which may be conducted in addition to the standard ICH conditions that permit a stability budget to be created for a pharmaceutical. Besides using data from long-term and accelerated testing such as that provided for in the ICH guidances, the speaker proposed adding freeze-thaw and temperature cycling studies to create a fuller picture of a drug's susceptibility to temperature changes during the entire distribution process from manufacture to transport, storage, and end use. It was shown that the concept of time out of refrigeration, which allows for room temperature operations such as packaging and labeling of refrigerated products, can be expanded to the entire distribution process.
Effective approaches for conducting method transfer
Method transfer is a process of which an analytical laboratory is qualified to perform a testing procedure as part of method validation. The speaker discussed the options of transfering analytical procedures from one laboratory to another and effective approaches to be considered when conducting method transfer. Transfer activities are conducted according to a protocol with predetermined acceptance criteria agreed upon by all sites involved. This includes certain SOPs such as data review, data reporting, and out-of -specification (OOS) / out-of-trend (OOT) investigation from both sites. Conclusion of the transfer must be documented with all data reported. It is important that validation data are available to the receiving lab as part of the transferring background package and the receiving lab must conduct a thorough gap analysis before any testing can be done.
Interesting and challenging stability-related regulatory questions: a roundtable discussion
Panelists: Stephen Colgan, Robert J. Timpano, Ganapathy Mohan, and David Lin
The roundtable discussion was focused on regulatory queries, with science and risk-based approaches to stability/shelf-life and stability protocols being of particular interest. Firstly, it was noted that FDA does not provide guidance on biorelevance in stability protocols; the audience was, however, encouraged to use science to support stability testing protocols. Secondly, whilst scientific engagement with the regulators in the ICH regions would be welcomed, this is not the case for most of the emerging market regions. There was also a discussion that science-based stability protocols should only focus on the relevant product attributes because this approach would be leaner, and would protect the patient as well as non-lean protocols. The panel noted that the quality target product profile (QTPP) could be leveraged to advocated lean stability protocols.
The most enthusiastic discussion was on a liquid product in a semi-permeable or non-permeable container and the suitability of a matrixed stability protocol for containers stored upright, upside down, and lying down. Developing a matrixed protocol can be difficult and the panel recommended reviewing the protocol with the regulatory authorities before execution. From a scientific point of view, the panel noted that a stability risk assessment would help define attributes that should be monitored for stability, including effects of container orientation, and determine whether a matrixed approach was required. It was agreed that science and knowledge of the regulations should be key drivers when developing stability protocols.
Lead author: Dilip R. Choudhury, PhD,* is with Allergan and can be reached at email@example.com, tel: 714.246.2288. Additional contributors: Ramesh K. Sood, PhD, is with FDA; John Bobiak, PhD, is with Bristol-Myers Squibb; Mark Alasandro, PhD, is with Allergan, Inc., Steven W. Baertschi, PhD, is with Elli Lilly and Company; Bekki Komas, is with Glaxo Smith Kline; M. J. Skibic, PhD, is with Elli Lilly and Company; Brian W. Pack, PhD, is with Elli Lilly and Company; Saji Thomas, is with Par Pharmaceuticals; Robert H. Seevers, PhD, is with Eli Lilly and Company; Kim Huynh-Ba, is with Pharmalytik; and Stephen Colgan, PhD, is with Pfizer.
*To whom all correspondence should be addressed.
1. S.W. Baertschi, K.M. Alsante and H.H. Tonesen, J. Pharm. Sci. 99 (7) 2934–2940 (2010).
2. M.J. Skibic et al. J. Pharm. Biomed. Analysis. 53 (3) 432–439 (2010).