Does your new or existing drug product filing come under ANVISA Resolution RDC-53 and require forced degradation?
ANVISA Regulatory Authority Forced Degradation Studies RDC-53
RDC 53 sets out parameters for verifying degradation products in medications, and for preparing the corresponding degradation profile for the reporting of degradation products. The ANVISA forced degradation study requirements have an expansion of forced degradation beyond the work already performed during the various stages of drug and formulation development. This differs from the approaches adopted by ICH, EMA & FDA guidelines.
Additionally, application of the findings will generate value by mitigating risks through systematically building on the molecule and formulated product knowledge throughout development.
The ANVISA recommended stressed conditions for all drug products are shown in the table below:
Stresses Conditions for all Drug Products and Drug Strengths
|Type of Study||Conditions||Time||Extreme Conditions|
|Acid Hydrolysis||0.1 – 1N HCl at 70oC||Few hours – 7 days||1N HCl at 70oC for 7 Days|
|Base Hydrolysis||0.1 – 1N NaOH at 70oC||Few hours – 7 days||1N NaOH at 70oC for 7 Days|
|Oxidative Solutions||0.3 – 3% H2O2 at ambient in the dark||Few hours – 7 days||3% H2O2 for 7 days|
|5mM Fe III or Cu II at room temperature||Few hours – 7 days||7 days|
|Thermal (Dry heat)||Exposure at 70oC||Up to 3 weeks||3 weeks|
|Thermal & Humidity (Wet Heat)||70oC/75%RH||Up to 3 weeks||3 weeks at 70oC/75%RH|
|Photo-Degradation||Fluorescent & UV light||*Greater than 2 times the ICH Q1B option 2 conditions||*Greater than 4 times the ICH Q1B option 2 conditions|
*ICH Q1B option 2 – at 5000 ± 200 lux white light and 2 ± 0.2 watts/square meter. This means a complete test takes: ~10 days white light (when set to 5kLux) & ~4 days UV light (when set to 2 watts/square meter). To achieve 1.2 million lux hours and 200 watt hrs/square meter. A control sample is to be placed in the cabinet but is to be protected from light.
Drug substances have an additional oxidative forced degradation using Fe (III) and CU (II).
It is normal practice that stability is a critical quality attribute of the drug substance and the drug product and that stability profiles need to be established for drug product to assure safety, efficacy and quality. Well thought out forced degradation studies can support the establishment of products stability profiles.
The forced degradation should be applied to placebo, formulation and drug substance for all conditions, and a control (reference standard) should be included in any analysis. Fixed-dose combinations should be tested as a combination of the drug substance and formulations for all conditions. Typically 10-15% degradation is desired as a forced degradation endpoint for each of the different conditions, so sampling must take place over the duration of the trial, which can finish when the appropriate level of degradation is achieved. None of the ICH guidelines specifies the exact value of degradation during the study. Mass balance analysis should be performed using stability indicating methods to demonstrate that there is no co-elution of impurities with the drug substance. This is not identified in ICH guidelines. Thus developing stability indicating methods with an MS detector would be advantageous.
However not all compounds or formulations will degrade by 10% under even extreme conditions, but a sufficient attempt must be taken to promote degradation. Any stability observed from the studies must be scientifically explained and justified in case of low degradation levels (i.e. < 10%).
None of the ICH guidelines have included recommendations or requirements to perform a test with metal ions. However, with ANVISA metals, such as Fe (III) and CU (II) should be used to assess drug substance susceptibility to metal catalysed oxidation and if any degradation is observed, the study should be repeated for the drug product. If alternate scientific data demonstrating stability, e.g., results from drug-excipient compatibility studies are already available, it could be used to justify why the studies are not performed on the drug product.
Thermal stress testing also includes heat and humidity stress for up to 3 weeks at 70C/75%RH on solids. This can be achieved by using ASAPprime®, which will also provide a statistical analysis for future shelf life.
The ASAPprime (Accelerated Stability Assessment Programme) system is the perfect tool to provide a rapid and cost effective method for screening APIs or formulations under controlled temperature and humidity conditions. ASAPprime is an approach based on the Arrhenius equation whereby degradation increases with temperature (every 10oC increase doubles the rate of a chemical reaction) and therefore using appropriate testing vessels and statistical analysis, it is possible to project the degradation rate at low temperature from the data generated under accelerated or stressed conditions. This enables the prediction of which excipients will give the most stable formulation, without entering into multiple stability programs, in weeks rather than months. The set up allows for accelerated testing to be performed at multiple temperatures and humidity’s ranging from 10-80⁰C /0-95%RH, using multiple humidity chambers in the one oven.
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- Helen Janzen, Prof. Dr. Usfeya Muazzam & Dr. Christin Selent-Stier – Forced degradation studies –comparison between ICH, EMA, FDA and WHO guidelines and ANVISA’s resolution RDC 53/201