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
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.