RDC 318/2019

API-related sections:

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Stability Studies

General Provisions

Art. 3º The stability studies of drug products and APIs to be marketed in Brazil should be conducted when required by specific resolutions regarding marketing authorization or variation applications, according to the parameters defined in this Resolution.

Single clause. Follow-up stability studies should be conducted according to this Resolution and provided when required by ANVISA.

Art. 4º For products imported and stored in bulk, additional studies that ensure the quality of the product until the primary packaging step should be conducted.

Art. 5º For initial CADIFA applications and marketing authorization applications concerning a new chemical entity, concluded accelerated stability studies and long-term stability studies with, at least, 12 months, should be provided at the time of submission.

Art. 6º For marketing authorization applications concerning APIs already approved in Brazil, as well as new concentration and new dosage form already approved in Brazil, and for CADIFA changes, concluded accelerated stability studies and long-term stability studies with, at least, 6 months, should be provided at the time of submission.

Single clause. Art 6º does not apply to variations/changes for which only accelerated and long-term stability protocols are required at the time of submission.

Art. 7º The concluded accelerated stability study should be provided even if the long-term stability study has been concluded.

Single clause. Art 7º does not apply to variations/changes for which only accelerated and long-term stability protocols are required at the time of submission.

Art. 8º Stability studies and protocols should be provided when required by ANVISA.

Art. 9° In the case of an out of specification result, the marketing authorization holder should conducted the necessary investigations to identify its root cause.

§1° If the investigation concludes that the out of specification results was not due an analytical error, the company should notify ANVISA and inform the actions taken to mitigate the risk to public health.

§2° The notification is not required when the marketing authorization or variation application has not yet been submitted.

Art. 10. Reduced designs (i.e., bracketing or matrixing) can be accepted.

Single clause. Reduced designs will only be accepted if representative of tested and non-tested time points.

Art. 11. The data from reduced design stability studies should be evaluated according to the same models and criteria of complete stability studies.

Single clause. An out of specification result of a test in a given time point means that all samples represented by the reduced design are out of specification.

Art. 12. When a requirement of this Resolution is not applicable, its non-compliance should be justified or data to support its absence should be provided.

Accelerated and Long-Term Stability Studies for APIs and Drug products

Art. 13. API stability studies should be conducted according to the Storage Conditions and Stability Conditions for Accelerated and Long-Term API Stability Studies.

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Art. 16. APIs and drug products that require different storage conditions than those described in this Resolution will be treated on a case-by-case basis, considering that the stability studies should ensure a retest period/shelf life and storage conditions which are feasible.

Art. 17. If an API or drug product with a storage condition of 2ºC to 8ºC shows out of specification results in the initial 3 (three) months of the accelerated stability study, the effect of short term excursions outside the label storage conditions should be evaluated, considering the recommended conditions for shipping and handling.

§1º In the case described in art. 17, the shelf life of drug products and APIs and retest period for APIs will be based only on long-term stability studies.

§2º The evaluation described in art. 17 should be based in additional studies conducted with (1) batch of the API or drug product, for a period shorter than 3 (three) months, with increased test frequency.

§3º In the case described in art. 17, it is not necessary to continue the stability study until the 6-month time point.

Art. 18. It is not necessary to conduct accelerated stability studies for APIs or drug products with a storage condition of -25ºC to -15ºC.

§1º In the case described in art. 18, the shelf life of drug products and APIs and retest period for APIs will be based only on long-term stability studies.

§2º In the case described in art. 18, additional studies to determine the effect of short term excursions outside the label storage conditions should be conducted, considering the recommended conditions for handling, shipping and transportation.

Art. 19. Follow-up stability studies should be conducted according to the Resolution that addresses Good Manufacturing Practices.

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Forced Degradation Studies of APIs

Art. 36. Forced degradation studies of APIs should be conducted with 1 (one) batch.

Art. 37. The susceptibility to temperature, humidity, oxidation, photolysis and hydrolysis in a across a wide range of pH values should be evaluated.

Single clause. If one of the conditions listed in art. 37 is not included, a technical justification should be provided.

Art. 38. For the purpose of analytical validation, the stress conditions should be sufficient to generate degradation products but not so intense as to lead to an excessive and complete degradation of the API.

§ 1° The studies can be finalized after an evident level of degradation which exceeds the variations of the analytical procedure.

§ 2° The stress conditions and the absence of degradation should be justified.

Art. 39. When demonstrated that a given impurity is not formed during accelerated and long-term conditions, it does not need to be investigated in accelerated, long-term and follow-up stability studies.

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Procedures for Stability and Photostability Studies

Procedure for the Stability Study

Art. 43. For stability studies, the sampling procedures should ensure the representativeness and homogeneity of the batches subject to the study.

Art. 44. The impact of the container closure system on the stability of the product should be evaluated across the stability study.

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Art. 46. For API stability studies, the samples should be stored in a container closure system with the same chemical and physical characteristics of the commercial container closure system.

Single clause. Containers of reduced size are acceptable, provided that they have the same chemical and physical characteristics of the commercial container closure system.

Art. 47. Analytical procedures used in stability studies should be stability indicating.

Art. 48. The replacement or change of analytical procedures during the stability study is only allowed when:

1. The procedures are equivalent or the proposed procedure is superior to the current; and
2. There is no impact on the trend of results, when a trend is present.

§ 1° The replacement or change of analytical procedures during the stability study should be technically justified.

§ 2° If an analytical procedure does not meet the criteria of art. 48, the proposed procedure should be added and the approved procedure maintained.

Art. 49. The analytical procedures should be validated according to RDC 166/2016.

**FOR APIs, VALIDATION ACCORDING TO ICH Q2 IS ALSO ACCEPTABLE], according to RDC 359/2020**

Art. 50. The stability results should be evaluated to verify which attributes can change across time and impact the quality of the API and drug product and performance of the drug product.

Art. 51. The statistical evaluation of long-term stability studies should be conducted when necessary, to support the proposed retest period/shelf life and ensure that the proposed retest period/shelf life is applicable to all batches manufactured in similar conditions.

Single clause. A formal statistical evaluation is not necessary when there are no significant variations in the results.

Art. 52. The statistical evaluation of long-term stability results should include the inter-batch variability and trend evaluation when applicable.

Single clause. The statistical evaluation should comprise separately the quantitative results for assay, degradation products and other appropriate parameters.

Art. 53. The influence of the inter-batch variation should be considered in the trend evaluation.

Art. 54. Out of trend results should be investigated and justified.

Art. 55. The evaluation of inter-batch variability and trend with a non-statistical tool should be justified.

Art. 56. The release and stability specifications of APIs and drug products should be established during their development, so as to ensure that they will meet the requirements across the retest period/shelf life.

Procedure for the Photostability Study

Art. 57. The photostability studies should demonstrate the effects of light exposure to the quality of the API or drug product.

Art. 58. The temperature of the photostability chamber should be adequately controlled.

Art. 59. The photostability chamber should be optically isolated.

Art. 60. The light source should contain the spectral distribution specification of the manufacturer, which should be compatible with the protocol defined by the company.

Art. 61. A light source with known spectral distribution and wavelengths in the ultraviolet and visible regions should be used.

Art. 62. Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/m2, in a appropriately qualified system.

Art. 63. To ensure the specified light exposure is obtained, a validated chemical actinometric system or a qualified lux meter or radiometer should be used.

Art. 64. The data on the qualification of the light source or actinometric system should be provided when requested by ANVISA.

Art. 65. Samples should be placed to ensure that all units or its content are directly exposed to the light source.

Art. 66. Samples that are directly exposed should be placed in chemically inert containers.

Art. 67. Control samples used to compensate for thermal variations should be placed along with the test samples.

Specific requirements for API stability studies.

Tests

Art. 68. All quality attributes of the API that may impact the quality, efficacy and safety and that may be affected by variations in time, temperature, moisture or any other factor should be tested.

Stability Protocol and Report

The API stability protocol should contain the following information:

1. DCB, INN or CAS registry number;
2. List of tests and acceptance criteria;
3. Schedule;
4. Name and address of API manufacturer;
5. Stability conditions;
6. Stability indicating methods used in all tests; and
7. Container closure system.

Art. 70 The API stability report should contain the stability results in table format, according the evaluation and stability protocol.

Art. 71. In addition to the information contained in the protocol, the API stability report should contain the following information:

1. Batch number;
2. Batch size;
3. Container closure system;
4. Date of manufacture;
5. Date of incubation (DD/MM/YYYY)
6. Storage conditions;
7. Test frequency;
8. Stability specifications;
9. Stability results;
10. Statistical evaluation of the results, if applicable; and
11. Conclusion.

Single clause. When the information described in art. 71 is not applicable, a technical justification should be provided.

Art. 72. The conclusion of the stability study should:

1. Address how the quality of the API changes over time;
2. Establish the retest period/shelf life; and
3. Establish the storage conditions.

Single clause. The choice for a retest period or shelf life should be explicitly mentioned in the conclusion.

Art. 73. The stability protocol and report are required for accelerated, long-term, photostability and forced degradation studies.

§1º If the forced degradation study, according to this Resolution, is included in the analytical validation report (3.2.S.4.3), there is no need for the study to be provided in Section 3.2.S.7.1.

§2º The stability protocol is optional when the stability report contains all information required for the protocol.

Batch selection

Art. 74. The accelerated and long-term stability studies should be conducted with, at least, 3 (three) batches of the API.

§1° The batches should be of, at least, pilot scale and manufactured by the same synthetic route and a manufacturing process that simulates the final process applied to industrial batches.

§2° The overall quality of the API batches should be representative of the of industrial scale batches.

§3° The required amount of batches can be fewer than 3 (three) if in accordance with RDC 359/2020.

Art. 75. Follow-up stability studies should be conducted with, at least, 1 (one) batch of the API every year, except if no batches were manufactured.

Retest Period and Shelf Life

Art. 76. The retest period or shelf life of the API should be determined by long-term stability studies, according the parameters defined in this Resolution.

Art. 77. The batches to be sampled should be representative of the manufacturing process.

Art. 78. The provisional retest period/shelf life should be defined according to the statistical evaluation of the stability results, limited to the addition of 12 months, considering the concluded accelerated study and ongoing long-term study.

Single clause. If the statistical evaluation is not applicable, a technical justification/rationale for the proposed retest period/shelf life should be provided.

Test Frequency in API Stability Studies

Art. 79. For accelerated stability studies, the following tests should be conducted in the initial, 3-month and 6-month timepoints:

1. Appearance;
2. Assay;
3. Individual and total degradation products; and
4. Identification of degradation products, when applicable.

Art. 80. For long-term stability studies, the following tests should be conducted in the initial timepoint, every 3 months, during the first year, every 6 months, during the second year, and annually thereafter, until the proposed retest period/shelf life.

Single clause. Other tests should be conducted in the final timepoint, considering as reference the initial timepoint.

Art. 81. In the case of submission of ongoing studies, all tests listed in the protocol should be included in at least one timepoint prior to submission.

Photostability Study

Art. 82. The study should be conducted with 1 (one) batch representative of industrial scale.

Single clause. If the result is inconclusive, the study should be conducted with 2 (two) additional batches representative of industrial scale.

Art. 83. The API photostability study should be conducted with a completely exposed sample of API.

§1° The use of inert transparent containers is acceptable when justified.

§2° In the case of out of specification results or presumed photosensitivity based on scientific literature, the study can be conducted in the container closure system.

Art. 84. After the exposure to light, according to art. 83 of this Resolution, all tests required to ensure the quality of the API should be conducted.

Art. 85. Based on the results, the company should:

1. Inform the precautions that should be taken during transportation of the API and manufacture of the drug product; and
2. Inform the need for the use of a photoprotective container closure system.

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Storage Conditions and Stability Conditions for Accelerated and Long-Term API Stability Studies

Storage Conditions	Long-Term or Follow-up Stability Studies*	Accelerated Stability Study*
-25°C a -15°C	-20°C±5°C	Not applicable
Refrigerator (2-8°C)	5±3°C	25°C±2°C/60%RH±5%RH or 30°C±2°C/75%RH±5%RH or 30°C±2°C/65%RH±5%RH
Controlled room temperature (between 15°C e 25°C)	25°C±2°C/60%RH±5%RH	40°C±2°C/75%RH±5%RH
Room temperature (between 15°C e 30°C) – protect from moisture	30°C±2°C/70%RH±5%RH	40°C±2°C/75%RH±5%RH
	30°C±2°C/65%RH±5%RH
Room temperature (between 15°C e 30°C)	30°C±2°C/75%RH±5%RH	40°C±2°C/75%RH±5%RH
*The temperature and relative humidity used in stability studies are exactly those described in the table. The variations are expected and tolerated due to the opening of the stability chambers.