Brazil guidelines for compilation of API drug master file.

Brazil guidelines for compilation of API drug master file.

Section number	Section name	Reference RDC Guidelines
3.2.S.1	General information	RDC nº 57/2009
3.2.S.1.1	Nomenclature
3.2.S.1.2	Structure
3.2.S.1.3	General properties
3.2.S.2	Manufacturer	RDC nº 57/2009
3.2.S.2.1	Manufacturer(s)
3.2.S.2.2	Description of manufacturing process and process controls	RDC n° 57/2009 RDC nº 69/2014
3.2.S.2.3	Control of materials
3.2.S.2.4	Control of critical steps and intermediates
3.2.S.2.5	Process validation and evaluation
3.2.S.2.6	Manufacturing process development	RDC nº 57/2009
3.2.S.3	Characterization	RDC nº 57/2009
3.2.S.3.1	Elucidation of structure and other characteristics
3.2.S.3.2	Impurities	RDC nº 57/2009 NT (Technical Note) 01/2016
3.2.S.4	Control of drug substance	RDC nº 57/2009 RDC n° 37/2009
3.2.S.4.1	Specification
3.2.S.4.2	Analytical procedures	RDC nº 57/2009
3.2.S.4.3	Validation of analytical procedures	RDC nº 57/2009 RE nº 899/2003 RDC nº 166/2017
3.2.S.4.4	Batch analysis	RDC nº 57/2009
3.2.S.4.5	Justification of specification	RDC nº 57/2009 RDC n° 37/2009
3.2.S.5	Reference standards or materials	RDC nº 57/2009
3.2.S.6	Container closure system
3.2.S.7	Stability	RDC nº 57/2009 RDC nº 45/2012 Procedure Orientation (OS) nº 2/2013
3.2.S.7.1	Stability summary and  conclusions
3.2.S.7.2	Post approval stability protocol and stability commitment
3.2.S.7.3	Stability data

Following is the cumulative list of guidelines required to be referred for compilation of API drug master file for Brazil market.

1. RDC nº 57/2009
2. RDC nº 69/2014
3. NT (Technical Note) 01/2016
4. RDC n° 37/2009
5. RE nº 899/2003
6. RDC nº 166/2017
7. RDC nº 45/2012
8. Procedure Orientation (OS) nº 2/2013

 RDC nº 57/2009

RDC nº 57/2009 provides for the registration of active pharmaceutical ingredients (API) and takes other measures. All CTD sections i.e. section 3.2.S.1 to 3.2.S.7 mention reference of this guideline. This guideline is basically summary of technical requirements for registration of drug in Brazil market. This guideline includes following:

• Definitions of basic terminologies are provided, some of which include Brazilian Non-Proprietary Name (BNN), International Non-Proprietary Name (INN), Impurity, Label, Solvent etc.
• Documents required for registration. They include Duly completed application forms, proof of payment, company’s valid cGMP certificate etc.
• Technical information on API: generalized requirements of every sections is summarized under this section.
• Documents required for registration renewal: this section mentions about documents required for renewal of registration. Some of which include- duly completed application forms, original copy of proof of payment, post registration amendments, long term stability results, etc.

RDC nº 45/2012

RDC nº 45/2012 provides on the conduction of stability testing on active pharmaceutical ingredients. This is one of the most important guideline for API stability testing guideline in Brazil market. Only major requirements as per sections are mentioned below, however if any sections/ points are important then such sections/ points are included in as is form from the guideline. This guideline includes following:

• Chapter 1, initial provisions mentions certain definitions like retest date, package, Accelerated stability testing, Long term stability testing etc.
• Chapter 2 mentions about technical regulations on stability requirements. It forms main body of this guideline.
• Chapter 3 mentions about final provisions stating date of publication of the guideline. Non observance of the guidelines is liable to the penalties provided for by that law, without prejudice to the applicable civil, administrative, and criminal responsibilities.

Following are the highlights of this guideline:

Section-I General Considerations:

• The re-test date or shelf life should be included on the label
• The batches to be sampled should be representative of the manufacturing process, in both pilot and industrial scales.

Section-II Batch selection:

• The re-test date or the expiration date of the active pharmaceutical ingredient may be based on the stability testing of the pilot-scale batches.
• The accelerated and the long term stability testing should be carried out with at least three batches of active pharmaceutical ingredients.

Section-III Packaging and labeling:

• Terms such as “environment condition” or “environment temperature” should be avoided.

Section-IV Specifications:

• The protocol of the stability testing should consider physical, chemical, physical-chemical, biological, and microbiological assessments, when applicable.

Section-V Testing Frequency:

• The tests related to the accelerated stability testing should be carried out in 0 (zero), 3 (three), and 6 (six) months and should include assay of the active pharmaceutical ingredient, quantification of the degradation products and, when applicable, identification of the degradation products.
• The tests related to the long term studies should be carried out in 0 (zero), 3 (three), and 6 (six), 9 (nine), 12 (twelve), 18 (eighteen), and 24 (twenty-four) months and should include assay of the active pharmaceutical ingredient, quantification of the degradation products and, when applicable, identification of the degradation products.

Section-VI Storage Conditions:

ANVISA has defined storage conditions at which accelerated and long term stability studies of APIs should be conducted.

Accelerated stability conditions:

API storage condition	Temperature of accelerated stability conditions
Up to 30°C	40ºC ± 2ºC / 75% RH ± 5% RH
2ºC to 8ºC.	25ºC ± 2ºC / 60% RH ± 5% RH

• As per article 24 of RDC nº 45/2012, If significant changes occur in the results obtained in the accelerated testing conditions, the re-test period or expiration date should be based on the long term tests.
• If the API with storage condition of 2ºC to 8ºC yield results out of specification (OOS) results in the first 3 (three) months of the accelerated testing, then its effect of variations should be assessed in short periods, out of the recommended storage condition, for example, during expedition or handling.
• ‘assessment’ in above paragraph means additional tests carried out in a single batch of the active pharmaceutical ingredient for a period shorter than 3 (three) months, performing tests more frequently than the usual.
• It is not necessary to continue the testing up to 6 (six) months.

Long term stability conditions:

API storage condition	Temperature of long term stability conditions
Upto 30° C	40 ºC ± 2 ºC / 75% RH ± 5% RH
2ºC to 8ºC.	25 ºC ± 2 ºC / 60% RH ± 5% RH
-15 ºC to -25 ºC	-20 ºC ± 5 ºC.
below -20 ºC	On individual basis*

* Meaning of ‘On individual basis’ is not elaborated in guideline.

• The expiration date or re-test date shall be based only on the long term tests for active pharmaceutical ingredients with storage condition of -15ºC to -25ºC.
• Tests should be carried out at least on a batch at a higher temperature (e.g. 5ºC ± 3ºC or 25ºC ± 2ºC), for an adequate period of time, in order to determine the effect of short intervals of the material’s permanence out of the storage conditions described on the label, as occurs, for example, during handling or transportation.

 Section-VII Follow up tests:

•  The follow up test may only be carried out if the active pharmaceutical ingredient does not suffer any significant alterations after the conclusion of the long term stability test.
• If there is a significant alteration in the active pharmaceutical ingredient, a new stability test should be carried out, as provided for in this Resolution.
• The first three commercial production batches should be included in the stability monitoring program in order to confirm the re-test date or the validity period.
• When the data from previous tests show that the active pharmaceutical ingredient is stable for at least 2 (two) years, less than 3 (three) batches may be used.
• At least one batch per year of active pharmaceutical ingredient produced should be added to the stability follow up test and tested in order to confirm stability, except if no batch has been produced that year

 Section-VIII Tests for forced degradation:

• The tests may be carried out on only one batch of the active pharmaceutical ingredient, and should include the effects of temperature, humidity, oxidation, light, and susceptibility to hydrolysis on a wide range of pH values.
• If any of the tests mentioned is not carried out, such absence should be technically justified.

 Section-IX Photostability testing:

• Photostability testing may be performed with one batch of the active pharmaceutical ingredient. If photostability is not conducted, then reason for not conducting the tests should be technically justified with scientific evidence that the active pharmaceutical ingredient does not suffer degradation in the presence of light.
• The photostability testing must comprise two parts: forced degradation and confirmation test.
• For development and validation purposes, it is appropriate to limit the exposure of the active pharmaceutical ingredient and finish the tests before excessive decomposition.
• The exposure levels used by the company must be justified.
• Under forced conditions, decomposition products may be observed, which are unlikely to be formed under the conditions used in the confirmation tests.
• There is no need to assess the degradation products, if verified they are not formed in the confirmation tests.
• If the active pharmaceutical ingredient is tested during the development phase, the photostability characteristics should be confirmed in a batch representing the production.
• If the results from the confirmation test are not conclusive, testing must be repeated with up to 2 (two) additional batches representing the production.

Section-IX; Subsection-I Light sources:

• A light source similar to D65/ ID65 emission standard may be used as an artificial fluorescent lamp, combining visible and UV emission. 
• The internationally acknowledged standard for daylight, according to definition in ISO 10977(1993), is D65 and the equivalent to indoor indirect light standard is ID65. 
• Filter(s) must be used to eliminate radiations, for light sources that emit significant radiation under 320 nm.
• The sample may also be exposed to the combination of cold fluorescent white lamp, similar to ISO 10977(1993) and the UV fluorescent lamp with spectrum distributed between 320 nm and 400nm, and maximum energy emission between 350 nm and 370 nm.
• A significant proportion of ultraviolet light should be between 320 nm and 360 nm and between 360 nm and 400 nm.
• Other conditions may be used when carrying out testing, as long as they are justified.

Section-IX; Subsection-II Procedure:

• The samples should be exposed to at least 1.2 million lux hours, integrated to an ultraviolet energy near at least 200 watt hours/m²  for confirmation tests.

Section-IX; Subsection-III Presentation:

• Care should be taken to ensure the physical characteristics of the samples being tested are preserved, such as cooling and/or placing the samples into sealed recipients, allowing to minimize alterations of physical state, such as sublimation, evaporation, or fusion.
• The solid samples provided for in the caption of this article should be spread, so they are not thicker than 3 mm.

Section X Report:

• The stability testing report should present at least the following information or the technical justification of its absence:

1. Identification of the active pharmaceutical ingredient through DCB (Denominação Comum Brasileira – Brazilian Common Denomination), INN (International Non-proprietary Name) or CAS (Chemical Abstract Service);
2. Batch number(s);
3. Batch size(s);
4. Specification of packaging material;
5. Batch manufacturing date(s);
6. Initial date of the test (day/month/year);
7. Number of samples tested per batch;
8. Number of samples analysed per period;
9. Storage conditions;
10. Frequency of tests and specifications;
11. Results from the following tests:

• Aspect;
• Content and the corresponding analytical method;
• Quantification of degradation products and the corresponding analytical method;
• Microbial limits, when applicable;
• Physical characterization; 
• Physical stability; and
• Other tests carried out. 

12. Conclusion

Section XI Assessment of results:

• The objective of the stability testing is to determine a re-test period or shelf life applicable to all active pharmaceutical ingredient batches that will be produced under the same circumstances.
• The absence of a statistical method to assess the results should be justified.

References:

1. https://www20.anvisa.gov.br/coifaeng/pdf/rdc57.pdf
2. https://www20.anvisa.gov.br/coifaeng/pdf/rdc45.pdf