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

Compilation of API drug master file with reference to ICH M4 Q (R1) guideline

Compilation of API drug master file with reference to ICH M4 Q (R1) guideline

This article is a summary of contents that should be part of API drug master file. Contents are referenced from ICH M4 Q (R1) guideline. Since this article is based on ICH guidelines, no changes have been made to content of guidelines and most of the data is included in as is form from the guideline. The information which is included in as is form is represented by “#” symbol at the end of respective title.

Module 2: Quality overall summary (QOS).

As the name suggests, this module should contain section wise summary of information which is presented in module 3.

Information that should be part of QOS:

• ü Sufficient information from each section to provide the quality reviewer with an overview of module 3.
• ü Should emphasize on critical key parameters of the product.
• ü  In case, any guideline is not followed in module 3, justification of the same should be included.

 Information that should NOT be part of QOS:

• Ø  Information, data or justification that was not already included in Module 3 or in other parts of the CTD.
• Ø  QOS normally should not exceed 40 pages of text, excluding tables and figures.

Below is a brief description summary of contents that should be included in quality over all summary (QOS).

Section number	Section name
2.3.S.1	General information
2.3.S.2	Manufacturer
2.3.S.3	Characterisation
2.3.S.4	Control of drug substance
2.3.S.5	Reference standards or materials
2.3.S.6	Container closure system
2.3.S.7	Stability

Section 2.3.S.1           General information

• Summarized (but not complete) Information included in section 3.2.S.1 should be presented.

Section 2.3.S.2           Manufacturer #

•  Information on the manufacturer;
•  A brief description of the manufacturing process (including, for example, reference to starting materials, critical steps, and reprocessing) and the controls that are intended to result in the routine and consistent production of material(s) of appropriate quality;
• A flow diagram, as provided in 3.2.S.2.2;
• A description of the source and Starting Material and raw materials of biological origin used in the manufacture of the drug substance, as described in 3.2.S.2.3;
• A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Highlight critical process intermediates, as described in 3.2.S.2.4;
• A description of process validation and/or evaluation, as described in 3.2.S.2.5.
• A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency, as described in 3.2.S.2.6. The QOS should also cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes, as provided in the CTD-S and CTD-E modules of the dossier.

Section 2.3.S.3           Characterisation 

• A summary of the interpretation of evidence of structure and isomerism, as described in 3.2.S.3.1 and 3.2.S.3.2 should be included.

Section 2.3.S.4           Control of Drug Substance

• Brief summary of information included in section 3.2.S.4.1 specification should be included. This can be in tabular format.
• Similarly, summarized information on section 3.2.S.4.2 and 3.2.S.4.3 should be included.
• For batch analysis, tabulated summary of section 3.2.S.4.4 should be presented. E.g.:

Parameters	Specification	Batch 001	Batch 002	Batch 003
Description	Abc
Solubility	Xyz

Section 2.3.S.5           Reference Standards or Materials #

• Information from 3.2.S.5 (tabulated presentation, where appropriate) should be included.

Section 2.3.S.6           Container closure system #

• A brief description and discussion of the information, from 3.2.S.6 should be included.

Section 2.3.S.7           Stability #

This section should include a summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions, the proposed storage conditions, retest date or shelf-life, where relevant, as described in 3.2.S.7.1.

The post-approval stability protocol, as described in 3.2.S.7.2, should be included.

A tabulated summary of the stability results from 3.2.S.7.3, with graphical representation

where appropriate, should be provided.

Module 3.2.S Drug Substance

Section number	Section name	Reference ICH Guidelines
3.2.S.1	General information
3.2.S.1.1	Nomenclature
3.2.S.1.2	Structure
3.2.S.1.3	General properties	Q6A and Q6B
3.2.S.2	Manufacturer
3.2.S.2.1	Manufacturer(s)
3.2.S.2.2	Description of manufacturing process and process controls
3.2.S.2.3	Control of materials	Q6A and Q6B
3.2.S.2.4	Control of critical steps and intermediates	Q6A and Q6B
3.2.S.2.5	Process validation and evaluation
3.2.S.2.6	Manufacturing process development	Q3A
3.2.S.3	Characterisation
3.2.S.3.1	Elucidation of structure and other characteristics	Q6A
3.2.S.3.2	Impurities	Q3A, Q3C, Q5C, Q6A, and Q6B
3.2.S.4	Control of drug substance
3.2.S.4.1	Specification	Q6A and Q6B
3.2.S.4.2	Analytical procedures	Q2A and Q6B
3.2.S.4.3	Validation of analytical procedures	Q2A, Q2B, and Q6B
3.2.S.4.4	Batch analysis	Q3A, Q3C, Q6A, and Q6B
3.2.S.4.5	Justification of specification	Q3A, Q3C, Q6A, and Q6B
3.2.S.5	Reference standards or materials	Q6A and Q6B
3.2.S.6	Container closure system
3.2.S.7	Stability
3.2.S.7.1	Stability summary and  conclusions	Q1A, Q1B, and Q5C
3.2.S.7.2	Post approval stability protocol and stability commitment	Q1A and Q5C
3.2.S.7.3	Stability data	Q1A, Q1B, Q2A, Q2B, and Q5C

3.1. TABLE OF CONTENTS OF MODULE 3

A Table of Contents for the filed application should be provided.

3.2. BODY OF DATA

3.2.S DRUG SUBSTANCE

3.2.S.1 General Information (name, manufacturer) #

3.2.S.1.1 Nomenclature

Information on the nomenclature of the drug substance should be provided.  For example:

• Recommended International Non-proprietary Name (INN);
• Compendial name if relevant;
• Chemical name(s);
• Company or laboratory code;
• Other non-proprietary name(s), e.g., national name, United States Adopted Name (USAN), Japanese Accepted Name (JAN); British Approved Name (BAN), and
• Chemical Abstracts Service (CAS) registry number.

3.2.S.1.3 General Properties

A list should be provided of physicochemical and other relevant properties of the drug substance, including biological activity for Biotech.

Reference ICH Guidelines:  Q6A and Q6B

Examples that should be included are description, solubility profile, pH values, melting point, boiling point, polymorphism, isomerism etc.

3.2.S.2 Manufacture #

3.2.S.2.1 Manufacturer(s)

The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

3.2.S.2.2 Description of Manufacturing Process and Process Controls

The description of the drug substance manufacturing process represents the applicant’s commitment for the manufacture of the drug substance.  Information should be provided to adequately describe the manufacturing process and process controls.

A flow diagram of the synthetic process(es) should be provided that includes molecular formulae, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and drug substance reflecting stereochemistry, and identifies operating conditions and solvents.

A sequential procedural narrative of the manufacturing process should be submitted.  The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g., temperature, pressure, pH, time).

Alternate processes should be explained and described with the same level of detail as the primary process.  Reprocessing steps should be identified and justified.  Any data to support this justification should be either referenced or filed in 3.2.S.2.5.

3.2.S.2.3 Control of Materials #

Materials used in the manufacture of the drug substance (e.g., raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process.  Information on the quality and control of these materials should be provided.

3.2.S.2.4 Controls of Critical Steps and Intermediates #

Critical Steps:  Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.

Intermediates:  Information on the quality and control of intermediates isolated during the process should be provided. All in-process specifications, intermediate specifications and its certificate of analysis should be included in this section.

Reference ICH Guidelines:  Q6A and Q6B 

3.2.S.2.5 Process Validation and/or Evaluation #

Process validation and/or evaluation studies for aseptic processing and sterilisation should be included. A process validation report should be attached in this section of drug master file.

3.2.S.2.6 Manufacturing Process Development #

A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the drug substance used in producing nonclinical, clinical, scale-up, pilot, and, if available, production scale batches. Reference should be made to the drug substance data provided in section 3.2.S.4.4.

Reference ICH Guideline: Q3A

3.2.S.3 Characterisation #

3.2.S.3.1 Elucidation of Structure and other Characteristics

Confirmation of structure based on e.g., synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.

3.2.S.3.2 Impurities

This section is most important part of drug master file. This part can also be termed as “heart of drug master file” and can prove to be the toughest part for compilation of drug master file. All possible impurities should be identified, listed and described. A discussion should be included for control of impurities. Below is example for listing of impurities in tabular form:

Sr. No.	impurity name & structure	Type of impurity/ source of impurity
01.	Abc	Process related impurity
02.	Xyz	Degradation impurity

Reference ICH Guidelines:  Q3A, Q3C, Q5C, Q6A, and Q6B

3.2.S.4 Control of Drug Substance #

3.2.S.4.1 Specification

The specification for the drug substance should be provided.

Reference ICH Guidelines: Q6A and Q6B

3.2.S.4.2 Analytical Procedures #

The analytical procedures used for testing the drug substance should be provided.

Reference ICH Guidelines: Q2A and Q6B

3.2.S.4.3 Validation of Analytical Procedures #

Analytical validation information, including experimental data for the analytical procedures used for testing the drug substance, should be provided.

Reference ICH Guidelines: Q2A, Q2B, and Q6B

3.2.S.4.4 Batch Analyses #

Description of batches and results of batch analyses should be provided.

Reference ICH Guidelines: Q3A, Q3C, Q6A, and Q6B

3.2.S.4.5 Justification of Specification #

Justification for the drug substance specification should be provided.

Reference ICH Guidelines: Q3A, Q3C, Q6A and Q6B

3.2.S.5 Reference Standards or Materials #

Information on the reference standards or reference materials used for testing of the drug substance should be provided.

Reference ICH Guidelines: Q6A and Q6B

3.2.S.6 Container Closure System #

A description of the container closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). Non-compendial methods (with validation) should be included, where appropriate.

The suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the drug substance, including sorption to container and leaching, and/or safety of materials of construction.

3.2.S.7 Stability #

3.2.S.7.1 Stability Summary and Conclusions

The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.

Reference ICH Guidelines:  Q1A, Q1B, and Q5C

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment

The post-approval stability protocol and stability commitment should be provided.

Reference ICH Guidelines:  Q1A and Q5C

3.2.S.7.3 Stability Data

Results of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.

Reference ICH Guidelines:  Q1A, Q1B, Q2A, Q2B, and Q5C