REVIEW ON STABILITY INDICATING ASSAY METHODS (SIAMS)

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ABOUT AUTHORS:
Salma S. Quadri*, Lalit V. Sonwane, Bhagwat N. Poul, Sharada N. Kamshette
Department of Quality Assurance,
MSS’s Maharashtra College of Pharmacy, Nilanga,
Latur, Maharashtra, India.
Salmaq13@gmail.com

ABSTRACT
The main contemporary goal of stability indicating methods is to provide information about condition for stress testing so as to establish the stability of drug substances and product. This paper reviews the regulatory aspects for development of stability indicating methods. SIMs are used to differentiate the API from its potential decomposition product. Regulatory guidance in ICH Q1A (R2) ICH Q3B (R2) Q6A and FDA 21 CFR section 211 requires validated stability indicating methods. Force degradation is required to demonstrate the specificity when developing SIMs and for this reason, it should be perform prior to implementing the stability studies. Force degradation of drug standard and excipients is carried out under different conditions to determine whether the analytical method is stability indicating. The approaches for the development of stability indicating method is discussed.

REFERENCE ID: PHARMATUTOR-ART-2225

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 8

Received On: 06/06/2014; Accepted On: 15/06/2014; Published On: 01/08/2014

How to cite this article: SS Quadri, LV Sonwane, B Poul, S Kamshette; Review on Stability Indicating Assay Methods (SIAMs); PharmaTutor; 2014; 2(8); 16-31

INTRODUCTION
Chemical stability of pharmaceutical molecules is a matter of great concern as it affects the safety and efficacy of the drug product. The FDA and ICH guidance states the requirement of stability testing data to understand how the quality of a drug substance and drug product changes with time under the influence of various environmental factors. Knowledge of the stability of molecule helps in selecting proper formulation and package as well as providing proper storage conditions and shelf life, which is essential for regulatory documentation. Forced degradation is a process that involves degradation of drug products and drug substances at conditions more severe than accelerated conditions and thus generates degradation products that can be studied to determine the stability of the molecule. The ICH guideline states that stress testing is intended to identify the likely degradation products which further helps in determination of the intrinsic stability of the molecule, establishing degradation pathways and to validate the stability indicating procedures used [1]. But these guidelines are very general in conduct of forced degradation and do not provide details about the practical approach towards stress testing. Although forced degradation studies are a regulatory requirement and scientific necessity during drug development, it is not considered as a requirement for formal stability program. It has become mandatory to perform stability studies of new drug moiety before filing in registration dossier. The stability studies include long term studies (12 months) and accelerated stability studies (6 months). But intermediate studies (6 months) can be performed at conditions milder than that used in accelerated studies. So the study of degradation products like separation, identification and quantitation would take even more time. As compared to stability studies, forced degradation studies help in generating degradants in much shorter span of time, mostly a few weeks. The samples generated from forced degradation can be used to develop stability indicating method which can be applied latter for the analysis of samples generated from accelerated and long term stability studies. This review provides a proposal on the practical performance of forced degradation and its application for the development of stability indicating method. The stability-indicating assay is a method that is employed for the analysis of stability samples in pharmaceutical industry. With the advent of International Conference on Harmonisation (ICH) guidelines, the requirement of establishment of stability-indicating assay method (SIAM) has become more clearly mandated. The guidelines explicitly require conduct of forced decomposition studies under a variety of conditions, like pH, light, oxidation, dry heat, etc. and separation of drug from degradation products. The method is expected to allow analysis of individual degradation products. A review of literature reveals a large number of methods reported over the period of last 3–4 decades under the nomenclature ‘stability-indicating’. However, most of the reported methods fall short in meeting the current regulatory requirements. Accordingly, the purpose of this write-up is to suggest a systematic approach for the development of validated SIAMs that should meet the current ICH and regulatory requirements. The discussion also touches upon various critical issues, such as the extent of separation of degradation products, establishment of mass balance, etc., which are important with respect to the development of stability-indicating assays, but are not yet fully resolved. Some other aspects like suitability of pharmacopoeial methods for the purpose and the role of SIAMs in stability evaluation of biological/ biotechnological substances and products are also delved upon.

According to FDA guideline (Guidance for Industry, Analytical Procedures and Methods Validation, FDA, 2000), a Stability Indicating Method (SIM) is defined as a validated analytical procedure that accurate and precisely measure active ingredients (drug substance or drug product) free from process impurities, excipients and degradation products. The FDA recommends that all assay procedures for stability should be stability indicating. The main objective of a stability indicating method is to monitor results during stability studies in order to guarantee safety, efficacy and quality. It represents also a powerful tool when investigating out-of-trend (OOT)[2] or out-of-specification (OOS) [3] results in quality control processes.

REGULATORY STATUS OF STABILITY-INDICATING ASSAYS
The ICH guidelines have been incorporated as law in the EU, Japan and in the US, but in reality, besides these other countries are also using them. As these guidelines reflect the current inspectional tendencies, they carry the de facto force of regulation. The ICH guideline Q1A on Stability Testing of New Drug Substances and Products [4] emphasizes that the testing of those features which are susceptible to change during storage and are likely to influence quality, safety and/or efficacy must be done by validated stability-indicating testing methods. It is also mentioned that forced decomposition studies (stress testing) at temperatures in 10 °C increments above the accelerated temperatures, extremes of pH and under oxidative and photolytic conditions should be carried out on the drug substance so as to establish the inherent stability characteristics and degradation pathways to support the suitability of the proposed analytical procedures. The ICH guideline Q3B entitled ‘Impurities in New Drug Products’ emphasizes on providing documented evidence that analytical procedures are validated and suitable for the detection and Quantitation of degradation products [5]. It is also required that analytical methods should be validated to demonstrate that impurities unique to the new drug substance do not interfere with or are separated from specified and unspecified degradation products in the drug product. The ICH guideline Q6A, which provides note for guidance on specification [6] also, mentions the requirement of stability-indicating assays under Universal Tests/Criteria for both drug substances and drug products. The same is also a requirement in the guideline Q5C on Stability Testing of Biotechnological/Biological Products [7]. Since there is no single assay or parameter that profiles the stability characteristics of such products, the onus has been put on the manufacturer to propose a stability-indicating profile that provides assurance on detection of changes in identity, purity and potency of the product. Unfortunately, none of the ICH guidelines provides an exact definition of a stability-indicating method. Elaborate definitions of stability-indicating methodology are, however, provided in the United States-Food and Drug Administration (US-FDA) stability guideline of 1987 [8] and the draft guideline of 1998 [9]. Stability-indicating methods according to 1987 guideline were defined as the ‘quantitative analytical methods that are based on the characteristic structural, chemical or biological properties of each active ingredient of a drug product and that will distinguish each active ingredient from its degradation products so that the active ingredient content can be accurately measured.’This definition in the draft guideline of 1998 reads as: ‘validated quantitative analytical methods that can detect the changes with time in the chemical, physical, or microbiological properties of the drug substance and drug product, and that are specific so that the contents of active ingredient, degradation products, and other components of interest can be accurately measured without interference.’ The major changes brought in the new guideline are with respect to (i) introduction of the requirement of validation, and (ii) the requirement of analysis of degradation products and other components, apart from the active ingredients(s). The requirement is also listed in World Health Organization (WHO), European Committee for Proprietary Medicinal Products and Canadian Therapeutic Products Directorate’s guidelines on stability testing of well established or existing drug substances and products [10,11,12]. Even the United States Pharmacopoeia (USP) has a requirement listed under ‘Stability Studies in Manufacturing’, which says that samples of the products should be assayed for potency by the use of a stability-indicating assay [13]. The requirement in such explicit manner is, however, absent in other pharmacopoeias.

Current ICH guideline on Good Manufacturing Practices for Active Pharmaceutical Ingredients (Q7A), which is under adoption by WHO, also clearly mentions that the test procedures used in stability testing should be validated and be stability- indicating [14].

OBJECTIVE OF STABILITY STUDIES
Stability studies are performed to establish the shelf life and storage condition of API and product. In recently adopted stability guidelines, the committee for proprietary medicinal product (CPMP) indicates the objective of stability testing is to provide evidence on how much quality of an API varies with time under influence of the variety of environmental factor such as temperature, humidity and light. The stability of API does not mean “fix” or “not likely change” but it means “controlled and acceptable change”. Force degradation condition, stress agent concentration and time of stress are to be establishing in such a way that, they effect degradation preferably 10-20% of parent constituent. Stability testing is performed for welfare of the patient and to protect   reputation of producer, as a requirement of regulatory agencies to provide data that may be of value in formulation of other product [15].

STEPS INVOLVED DURING THE DEVELOPMENT OF STABILITY–INDICATING ANALYTICAL METHODS (SIAMs)
A SIAMs is an estimative analytical method used to detect a trace level amount or residual levels of the API present due to degradation or designing of its synthesis route. As per the FDA regulations, a SIAMs is defined as a completely validated method that accurately and precisely measures API free from potential interferences like degradants, biproducts, intermediates, and exicipients and the FDA recommend that all assay content methodologies for stability studies be stability indicating [16]. There are three components necessary for implementing a SIAMs.
1. Generation of degraded samples for testing selectivity of the method,
2. Method development,
3. Method validation

Step 1: Generation of degraded samples for testing selectivity of the method
Here lies one of the main concerns related to a development of a SIM, since the available guidance documents do not state the extent to which stress tests should be carried out – that is, how much stress should be applied or how much degradation should be aimed for. In fact, there is not a “gold rule” that attends this issue and therefore, it is important to keep in mind that experimental conditions of stress tests, should be realistic and lead to “purposeful degradation” [17].

Stress tests should generate representative samples to assess drug substance and drug product stability, provide information about possible degradation pathway and demonstrate the stability indicating power of the analytical procedures applied.

1) Determination of Limit of Quantification (LOQ)
In close relation to the determination of the amount of degradation is the evaluation of Limit of Detection (LOD) and Limit of Quantification (LOQ) of the method. These limits should be closely related to the Reporting, Identification and Qualification of degradation products, as stated in ICH Q3B (R2) [5].These thresholds aredetermined either as percentage of drug substance or total daily intake (TDI) of degradation product. The analytical methods are usually expected to be validated for the ability to quantify potential degradation products and drug impurities with a LOD and LOQ at least as sensitive as the ICH threshold (see Figure 1).

Figure 1: ICH thresholds for degradation products in New Drug Application (ICH Q3B)

Reporting threshold
Maximum daily dose 1                          Threshold 2,3
       ≤ 1 g                                              0.1%
         > 1 g                                              0.05%

Identification threshold
Maximum daily dose1                                               Threshold 2,3
<1mg                              1.0% or 5μg TDI, whichever is lower
1mg-10mg                        0.5% or 20μg TDI, whichever is lower
>10mg-2g                         0.2% or 2mg TDI, whichever is lower 0.10%

Qualification threshold
Maximum daily dose1                                                 Threshold 2,3
<10 mg                            1.0% or 50μg TDI, whichever is lower
  10mg – 100 mg                  0.5% or 200μg TDI, whichever is lower
>100mg-2g                      0.2% or 3mg TDI, whichever is lower
>2g                                                    0.15%

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