Why is it so important that assay and related substance methods for drug substance (DS) and drug products (DP) should be a stability-indicating method? The answer is two words, safety, and efficacy.
Different organizations, based on their own understanding and knowledge, approach stability-indicating methods differently. They will typically write a forced degradation study protocol, set acceptance criteria for each task and execute the study. Then if each task meets the acceptance criteria, they proceed with validating the method. Further, upon completion of the study, if the acceptance criteria were met, a final report is written, and the study is completed. I have noticed that forced degradation studies are often conducted based on an area percent (area %) approach and/or with inadequate mass balance, and/or with inadequate acceptance criteria, yet, the organizations claim that the method is a “stability–indicating” method. But is it really?
The whole concept behind a stability indicating method is that the method, or methods can detect and quantify accurately the assay or potency of a substance and evaluate its total impurities profile. It also aims to prove that, based on the maximum daily dose (MDD) of the drug and establishment of the Limit of Quantitation (LOQ) for the impurities, the DS or DP is safe, efficacious, meets the specs, and the total mass balance is acceptable. A typical specification for the assay of an API is 98.0 to 102.0%, and the same spec applies to the stability studies of the API product. However, for a drug product, the typical release specification for potency is 96 to 104%, and for its stability study the specification is 90 to 110%. Therefore, it is very crucial to have a solid understanding of the molecule and its reactivity, along with its physical characteristics.
Usually when one conducts a forced degradation study for a DS or DP, it is desirable to degrade the molecule beyond its specification limits (yet it’s desirable to do so without overstressing, or under stressing it). If the study is performed based on an area percent concept (which often lack purity mass balance), one may very well have a method which is not “stability-indicating.” Let’s assume an acid hydrolysis study of a DS showed an assay of 95% (W/W %), and its related substance method showed a purity of 96% by area %. At first glance, the acid hydrolysis study for the DS was successful, and the study met the acceptance criteria, but was it?
When an area percent approach for calculating the degree of degradation of the sample by the related substance method is used, the scientist assumes the method is linear for the entire sample concentration range (which is a wrong assumption), each impurity has a response factor of 1 with respect to the main analyte, and all the impurities were detected by the method. If the study uses a non UV-VIS type detector, such as CAD or ELSD or other type of detector, which have a different linearity range, and different response factors versus UV-VIS detectors, then the magnitude of result inaccuracy will increase considerably. Therefore, an attempt has to be made to avoid conducting a forced degradation study by area percent. An effective approach to forced degradation studies is when they are conducted based on weight/weight percent for both assay and related substance methods, and data is fully evaluated to ensure the integrity of the results.
Looking at Stability-Indicating Methods From a New Angle
Now let’s look at the concept of a “Stability-Indicating” method from a different angle. The whole objective of having a stability-indicating method or methods is to have a better understanding of the overall API or DP stability, its stability under different environmental and chemical conditions, its overall impurity profile based on the raw materials/reagents used, and the process-related impurities that might exist in the product. As a result, the method or methods must be developed so that all of the impurities are identified (if possible), the method is specific (no peak co-elution), and that the method is sensitive enough that the impurities are able to be quantified. Further, if some of the impurities can be purged out by the manufacturing process, or if the process can be designed to prevent their formation in the first place, it will certainly improve the product quality. I can’t emphasize enough that these type of activities require reliable, robust and accurate methods, developed and designed by a strong analytical team, in collaboration with a strong organic/process team.
It’s important that extensive and thorough effort goes into understanding the key raw materials’ impurities, their degradation pathway and the fate of each impurity in the raw materials process and final product. Understanding the fate of each impurity, performing comprehensive process mapping, spiking studies and purge studies are very crucial and important in having a robust process. These types of studies not only deliver a purer product, but also, the methods are designed in a way to effectively monitor those impurities and quantify them. Although typically a stability-indicating method does not include these types of studies, in reality it should always be part of the stability-indicating method, since the main objective of a stability-indicating method is to detect and monitor impurities (including genotoxic compounds), and establish product stability (safety, and efficacy).
When developing a method, or conducting a forced degradation study, it pays to look at the molecule very comprehensively and study the entire process with a group of knowledgeable and experienced organic chemists, process chemists, and analytical chemists. Performing process mapping, identifying unknown impurities from the entire process by LC/MS and GC/MS, synthesizing impurity reference standards, and conducting purging studies, allow one to assess the degradation pathway of the molecule under each set of conditions in depth. And of course, in order to conduct these tasks, adequate design of an experimental study is crucial. These are critical requirements which should be conducted under cGMP and be protocol driven.
Stability-indicating methods can be complex and they are approached differently by each organization; yet, there are some requirements that should be standard practice. Claiming a method is a stability-indicating one should not solely rely on forced degradation studies, but requires a strong team of analytical and organic chemists, with a full understanding of the molecule ‘s reactivity, the process, and effect of reagents and environmental conditions on the molecule.
Author Biography
Dr. Yazdi received his Ph.D. in Analytical Chemistry in 1989 in the areas of chromatography and spectroscopy. He started his career at Ciba-Geigy a large specialty/pharmaceutical company. Dr. Yazdi has over 30 years of experience in pharmaceutical industries with bulk pharmaceutical manufacturers, Contract Manufacturing Organizations, Contract Research Organizations, Specialty Pharmaceutical Companies, API manufacturers, and finished dose pharmaceutical manufacturers. He has a solid understanding and knowledge of all aspects of the pharmaceutical business in the areas of analytical chemistry, product development, product formulation, process chemistry, CMC and FDA filing. He also has over 10 years of experience working with specialty chemical companies. Dr. Yazdi has established and managed for over 30 years several highly successful, very efficient, compliance driven, and result oriented Method Development, Method Validation, Quality Control, Stability Study program departments, and Formulation departments. He is also experienced with outsourcing projects to various organizations which operate under cGMP, FDA, DEA, ISO-9000, and EPA guidelines and regulations. Due to his vast experience, and background, he has established strong troubleshooting, and know-how skills in all aspects of pharmaceutical industries, and manufacturing facility. He joined Seqens NA / PCI Synthesis in May 2011.