Forced degradation studies comparison between ich, ema, fda. Forced degradation or stress testing is undertaken to demonstrate specificity when developing stabilityindicating methods, particularly when little information is available about potential degradation. Also the mass balance results were calculated for all stressed samples and found to be 99101%, thus showing the suitability of the analytical method to examine for the degradation products. Impact from the recent issuance of anvisa resolution rdc532015 on. Advanced strategies to evaluate mass balance in forced. Degradation products are not eluted from the hplc column 2. The stress samples are assayed against a qualified reference standard and the mass balance is found close to 99. They ensure developed methods are optimized to be suitable for finished product application. Stabilityindicating hplc method for the determination of. Since the molecular mass of the expected synthesisrelated impurities is known, the hyphenation of mass detection with lc enables putative identification of peaks without the need for standards. Concept paper forced degradation studies for therapeutic proteins 6 3 definitions a forced degradation study is the intentional degradation of the api andor dp to an appropriate extent by means of various stress conditions such as ph, temperature, light, oxidising agents, mechanical stress.
Forced degradation, ich, fda guidance, validation, method. Forced degradation is the process or state in which new drug substance and drug. Forceddegradation evaluation of erythromycin by hplc and. An lctandem mass spectrometry msms system agilent 1200 series liquid chromatograph coupled with applied biosystems 4000 q trap triple quadruple mass spectrometer with analyst 1. Significant degradation is observed in acid and base stress conditions. Mar 31, 2016 forced degradation studies fds are essential in the development of stability indicating methods to gain understanding of the intrinsic stability characteristics of a drug substance ds. Stability indicating hplc method for celecoxib related. Study of relative response factors and mass balance in forced. The forced degradation studies are not performed earlier it is very vital to conduct them during the phase iii fda guidance states to demonstrate the stability of a drug substance, potential degradation pathways and capability and suitability of proposed analytical procedures. If 100%level is not achieved, efforts to account for the missing mass should be made e. This article explores the various methods by which mass balance can and should be measured, expressed, and evaluated in conjunction with degradation chemistry.
Summary of forced degradation study of nicardipine stress condition time assay % mass balance remarks acid hydrolysis base hydrolysis oxidation thermal uv 254 nm 48 h 48 h 48 h 7 days 48 h 99. Forced degradation studies and stress testing element. Mass balance is to be achieved at least up to 95% level. Purity factor celecoxib by forced degradation studies was mentioned in table 2. Questions and answers on current good manufacturing practices. Pdf forced degradation study an essential approach to.
Mobile phasea consists a mixture of wateracetonitrileformic acid. Forced degradation of recombinant monoclonal antibodies. The mass detector showed an excellent purity for sofosbuvir and every degradation product, which proves the specificity of the method. Forced degradation is synonymous with stress testing and purposeful degradation. Mass balance for forced degrdation studies laboratory. In mass balance calculations, the amount of drug remaining in stresses sample is determined from an assay by hplc method, and the increase in degradation products is determined by related substances by hplc method. Pdf assessing mass balance in pharmaceutical drug products. A draft guidance document suggests that results of one time forced degradation studies should be included in phase 3 inds investigational new drugs. It helps to know about the impurities developed during the storage of drug products in various environmental. Mass spectrometric ms detection can address the limitations of uvbased lc purity analysis in forced degradation studies. Development of forced degradation and stability indicating. Current trends in performance of forced degradation.
Forced degradation studies comparison between ich, ema. Stress testing of the drug substance can aid to identify the likely degradation products, which can in turn help establish the degradation pathways. Stabilityindicating method and lcmsms characterization. Study of relative response factors and mass balance in. Regulatory agencies use mass balance to assess the. Mass balance calculations were performed using the peak area.
Mass balance correlates the measured loss of a drug api to the measured increase in the amount of degradation products. Forced degradation studies fds are essential in the development of stability indicating methods to gain understanding of the intrinsic stability characteristics of a drug substance ds. These studies illustrate the chemical stability of the molecule which further facilitates the development of stable formulation with suitable storage conditions. If the mass balance is less than the required criteria investigation to be done and justified. Forced degradation studies or stress testing studies is the process of subjecting drug compounds i.
The forced degradation study is a vital analytical aspect of the drug. Oct 17, 2016 the mass detector showed an excellent purity for sofosbuvir and every degradation product, which proves the specificity of the method. A reaction scheme was derived for the thermal degradation of thyroxine in the solid state, using data obtained from ultrahighperformance liquid chromatography and highresolution mass spectrometry uhplchrms. It is imperative to know the impurity profile and behavior of a drug substance under various stress conditions. During the forced degradation study, any batch that will not be the part of regulatory submission can be used. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of new formulation and its packaging strategy. To study the reaction mechanism and kinetics of the thermal degradation of the pharmaceutical in the solid state, a workflow was developed by generating. Degradation conditions, regulatory requirements, stability indicating hplc method development, method validation received 09 sept 2014 received in revised form 24 sept 2014 accepted 30 sept 2014. An introduction to forced degradation studies for drug. Impact from the recent issuance of anvisa resolution rdc53.
Degradation pathway for pitavastatin calcium by validated. For solutionstate studies the drug substance is exposed to a range of ph values. Use of rrf resulted in a decrease in mass balance with values closer to 100% than the apparent mass balance. The photo diode array detector was used for peak homogeneity testing during stress study experiments and the overall mass balance was found to be 99. Stabilityindicating method and lcmsms characterization of. Forced degradation or stress testing typically involves exposure of. Pharmtech reconciling mass balance in forced degradation st. Paul wrezel, regis director of analytical method development, overviews forced degradation studies and stress treatment strategies in the first part of six which compile his forced.
Current trends in performance of forced degradation studies and. Mass balance values were within the acceptance limit. Different forced degradation conditions utilized for drug substances and finished dosage form is shown in the fig. Stabilityindicating methods chromatography online home page. Investigation of reaction mechanisms of drug degradation. A forced degradation study is a crucial step in the design of a regulatory compliant stability program for both drug substances and products, and formalized as a regulatory requirement in. Mass balance establishes adequacy of a stability indicating method though it is not achievable in all circumstances. Forced degradation is also known as stress testing and a drug is degraded forcefully by applying artificial methods. Main peak was separated from known impurity and unknown impurities in forced degradation.
Note that achieving this is dependent on two things. Characterizations and mass balance of the forced degradation study. In the following study, we will conduct a forced degradation study which will also include mass balance studies using triple detection. We start with stress degradation studies and hplc method development. This article will look at this topic from other perspectives.
From early stage candidate selection to postapproval, forced degradation studies are frequently performed to support manufacturability assessments, formulation development, establishment of stabilityindicating methods and comparability. Jan 01, 2012 forced degradation or stress testing typically involves exposure of drug substances to heat, heat and humidity and light for solidstate studies. A sensitive, stability indicating uplc method for the. Mass balance in forced degradation chromatography forum. Forced degradation of gliquidone and development of validated stabilityindicating hplc and lc methods braz. By looking the importance of hplc technique, a simple, linear and accurate related substance method was developed for the. Reconciling mass balance in forced degradation studies.
As per fda guidance, stability indicating test procedure is a. Purposeful degradation can be a useful tool to predict the stability of a drug substance or a drug product with effects on purity, potency, and safety. Peak areas for noxide and epoxide impurities were adjusted using the rrf values. Current trends in performance of forced degradation studies and stability indicating studies of. The experimental samples produced are then used to demonstrate that a proposed analytical method is stability indicating, i. Forced degradation studies for therapeutic proteins. Forced degradation studies include the degradation of new drug substance and drug product at conditions more severe than accelerated conditions. Investigation of mass balance in stress samples show the suitability of analytical method to examine for degradation products. For more information about our forced degradation studies or to request a quote, contact us today. Usually 100% should be reached by adding assay value and levels of degradation products.
Sachin zade, padma there sunanda aswale, and shashikant. Validated gradient stability indicating uplc method for the. Performance of stress studies under various conditions allows prediction of the possible degradants that may be obtained during registrational long term stability studies ltss. Ich guidelines demonstrate certain degradation conditions like. In recent years fda strictly asking mass balance in forced degradation of related compound method to prove specificity and capability to quantify degradation impurities. An introduction to forced degradation studies for drug substance. The fda and international conference on harmonization. Mar 26, 2012 mass balance is to be achieved at least up to 95% level. The chromatographic separation was achieved with waters symmetryshield.
Photostability should be an integral part of forced degradation study design. Nda new drug application registration requires data of forced degradation studies as forced degradation products, degradation reaction kinetics, structure, mass balance, drug peak purity, etc. Four impurities are studied among which impurity4 is found prominent degradant. Forced degradation study in pharmaceutical stability. Forced degradation studies comparison between ich, ema, fda and. The result of forced degradation studies are given in the following table 1. Degradation products that do not form in accelerated or long term stability may not have to be isolated or have their structure determined. Mass balance calculation from typical forced degradation conditions or expired sample. Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. Forced degradation studies are typically performed to understand the degradation pathway of pharmaceuticals. All the degradantsimpurities must be calculated during mass balance evaluations. While doing forced degradation, the assay of the api dropped to 80% label claim, but there was no degradant peak. The mass balance concept is based on the law of conversion of mass which states mass can neither created nor destroyed mass balance means i will give a simple example with a small story.
Even within the ich guidelines more than one term for the description of forced degradation is used e. Ich q1a 1 uses the term stress testing, while ich q1b 7 uses the term. A case study was performed using photodiode array detection pda in combination with evaporative light scattering els detection and mass spectrometry ms to assess both mass balance and the relative response factors rrfs in the forced degradation studies of the drug substance, glimepiride. Current trends in performance of forced degradation studies. It is a useful tool to predict the stability of any active pharmaceutical ingredient api or formulation product. Our chromatographic specialists develop methods that ensure all degradation products are fully resolved, and a proper mass balance is achieved. Assessing mass balance in pharmaceutical drug products. Sachin zade, padma there sunanda aswale, and shashikant aswale. When we add together the assay value for the drug and the adjusted responses of all the degradants, they should equal the initial value mass balance of 100%. Forced degradation study an essential approach to develop. Stability indicating hplc method development and validation. Mds sciex, foster city, ca was used for the unknown compounds formed during forced degradation studies.
Mass balance should be demonstrated during the degradation study and it should be around 100 percent, taking into consideration margins of analytical errors. There is no proper guidance from any regulatory authorities for mass balance calculation during forced degradation study. Pdf forced degradation study an essential approach to develop. Generally, in determining whether it is necessary to conduct forced degradation studies of the drug product, the specificity of the test method should be evaluated for its ability to assay drug.
A forced degradation study is a crucial step in the design of a regulatory compliant stability. Chemical degradation and mass balance study of entacapone api by hplc. Forced degradation is an integral part of recombinant monoclonal antibody mab therapeutics research and development. Mass balance correlates the measured loss of a parent drug to the measured increase in the amount of degradation products. Jan 09, 2020 mass balance should be demonstrated during the degradation study and it should be around 100 percent, taking into consideration margins of analytical errors. Outcomes of forced degradation studies forced degradation studies offer the following information 2,3,10. Not all degradants will appear under the same chromatographic conditions used to test the product. No mass balance is 100% since we dont count the water produced as an example. Thus, 85% is acceptable if it can be justified scientifically.
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