Legislation
Resolution

Resolution - RE nº 560, of April 2, 2002
(Official Journal of 03/04/2002)

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;
Resolution GMC No 53/96 on Stability of Drug Products harmonized within Mercosur;
that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the Guide for the Undertaking of Stability Studies, attached.

Article 2 - Resolution RE 485, published in the Official Journal of the Union on March 20, 2002, and version 01/2002 of the Guide for the Undertaking of Stability Studies, are hereby revoked.

Article 3 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR UNDERTAKING STABILITY STUDIES - 2/2002

The purpose of the stability test is to evaluate the behavior of drugs or drug products that undergo alterations over time due to a variety of environmental factors, such as temperature, humidity and light.

1. TYPES OF STUDY

1.1. Accelerated stability studies
studies destined to raise the speed of chemical degradation and physical modification of a substance and/or alterations of characteristics of the dosage form, using forced storage conditions, with a view to monitoring the degradation reactions and predicting the expiry date in normal storage conditions;

1.2. Long term stability studies
are experiment validations in relation to physical, chemical, biological characteristics of the drug product, during and after the expected expiry date.

2. PROCEDURE

2.1. Sampling
2.1.1. for authorization purposes: three batches
2.1.1.1. the sampling batches must contain a minimum of 100.000 pharmaceutical units for solid dosage forms of oral use;
2.1.1.2. for drug products with high added value, the sampling batches must contain a minimum of 30.000 pharmaceutical units. Smaller batches must be technically justified;
2.1.1.3. for the remaining dosage forms, batches of at least ten percent of the industrial batch are required;
2.1.1.4. the batches must be manufactured with different batches of the drug;
2.1.2. The study must contain all details about the batch:
a) batch number;
b) batch size;
c) storage conditions;
d) assay results;
e) date of manufacture;
f) type of packing material;
g) number of samples tested per batch;
h) number of samples analyzed per period;

2.1.3. The study must be undertaken with the drug product in its original packing for commercialization.

2.2. Assay conditions

2.2.1. the accelerated stability study must be undertaken at 40 ± 2 °C / 75 ± 5% of relative humidity (RH), during six months, with analysis in 0, 30, 60, 90, and 180 days, or at 50 ± 2ºC / 9± 5% of RH during three months, with analysis in 0, 30, 60 and 90 days;

2.2.2. the long term stability study must be undertaken at 30 ± 2 °C / 70 ± 5% of RH, for the period in which the product stability is intended to be proved. In this case, in the first year, the samples must be analyzed at 0, 3, 6, 9 and 12 months, and once a year after this period;

2.2.3. for drug products whose drug is sensitive to heat and that require storage in alternative lower temperature conditions, the accelerated stability studies must be undertaken at a minimum of 15 ºC above the recommended storage temperature. This study must be conducted for six months, under appropriate relative humidity. Other conditions may be accepted under justification;

2.2.4. special considerations may be necessary for drug products likely to suffer physical and/or chemical alterations due to low temperatures; for example, suspensions or emulsions that can produce sediment, creams, oils or semi-solid preparations that can present alterations in viscosity; and liquid preparations that can cause precipitation problems, for instance, concentrated solutions;

2.2.5. when drug products are packed in containers which pose a barrier for water vapor (ampoule, ampoule bottle, full syringes), there is no need for storage in high relative humidity conditions. Low relative humidity may adversely affect liquid drug products packed in semi-permeable packages (solutions in plastic bags, nasal drops in plastic bottles, and similar). In these cases the accelerated stability study must also be undertaken in the same conditions;

2.2.6. the study protocol must consider physical, chemical, physical-chemical and biological assessments, whenever necessary. The qualitative or quantitative presence or building up of sub-products and/or degradation products must also be appraised using the appropriate methodology.

3. GENERAL PROVISIONS

3.1. the accelerated stability assays allow the establishment of a temporary shelf life. These assays must be complemented with long term studies undertaken in appropriate storage conditions for the drug product. They are part of a stability program;

3.2. The results of the long term stability studies are employed to:
a) establish the shelf life of the drug product;
b) confirm the projected shelf life;
c) define storage conditions based on the results of the studies undertaken;

3.3. the accelerated stability studies for the determination of the shelf life and storage conditions may be temporarily accepted for a period of 6 months, or three months, in drastic situations, as a requirement for a drug product registration;

3.4. once the period defined as temporary is expired, the shelf life must be confirmed through presentation of a long term stability study;

3.5. The shelf life is always determined according to storage conditions;

3.6. if the batches of a certain drug present different stability profiles, the proposed shelf life must be the one based on the less stable batch;

3.7. a tentative shelf life of 24 months may be established when:
a) the active principle is considered stable;
b) the studies undertaken according to the protocol are positive;
d) the long term studies are continued until the end of the shelf life.
3.8. after the stability is assessed, the following storage conditions must appear on the secondary and primary packaging of the drug product:
a) keep at room temperature (15ºC - 30ºC);
b) keep between 2ºC e 8ºC, under refrigeration;
c) keep below 8ºC, under refrigeration;
d) keep frozen (-5ºC - -20ºC);
e) keep below - 18ºC;

3.9. Additional information such as: keep out of sun light and keep in dry place and other necessary information based on the results of the stability studies must always be included provided that they do not conceal stability problems;

3.10. In the case of products that require reconstitution or dilution, the period during which the product maintains its stability after reconstitution, in determined storage conditions, must be reported;

3.11. the studies must be conducted using the diluent specified for reconstitution of the drug product or, if there is more than one, using the one with which the less stable reconstituted drug product is to be obtained, in the most disadvantageous temperature conditions.