In Brazil, the health authority (ANVISA) will require that all Active Pharmaceutical Ingredients (APIs) manufactured in Brazil, imported for manufacturing of drug products, or included in imported finished products, are registered with the agency.
This regulation has been put in place in 2009, and the implementation has been gradual: ANVISA created a scheme that includes the different API categories in different “waves” of implementation.
In the first implementation wave (deadlines to register in 2010) the following drug substances were included: Cyclosporine, Clozapine, Clindamycin Chlorhydrate, Ciclophosphamide, Ciprofloxacin, Methotrexate, Carbamazepine, Lithium Carbonate, Phenytoin, Sodium Phenytoin, Lamivudine, Penicillamine, Thiabendazole, Efavirenz, Nevirapine, Rifampicin, Ritonavir, Zidovudine, Acyclovir and Ampicillin.
In June 2013, the second implementation wave was announced, including the following substances: Azithromycin, Benzylpenicillin, Cabergoline, Carboplatin, Cephalexin, Cephalothin, Ceftazidime, Cisplatin, Clarithromycin, Ceftriaxone and their respective salts, esters, ethers and hydrates, and the salts, esters, ethers and hydrates of the APIs included in the first tier. Companies can register the APIs starting on the 1st of January of 2014. From the 1st of January of 2015, only companies that have already applied for API registration can import or commercialize those APIs or drug products containing those APIs. From the 1st of January of 2016, only companies that hold the (approved) registration of the APIs can import or commercialize those APIs or drug products containing those APIs.
Here is an extract of the technical regulation on the matter. You can consult the full regulation (in English) in the following link.
Technical Regulation for the registration of Active Pharmaceutical Ingredients (APIs) in Brazil
APIs, including imported ones, shall not be industrialized, exposed for sale, or commercialized in Brazil before being registered by ANVISA, except the API that will be used for scientific or technological research, as well as for research and development of formulations.
The registration of APIs destined for export only will be optional.
The registration will be valid for five years and may be revalidated for equal and successive periods of time, the initial record number being maintained. Registration revalidation shall be requested in the first semester of the last valid year, from the date of publication of the registration, being considered automatically revalidated, regardless of decision, if the latter is not announced until the date its validation is terminated. The preclusion of product registration will be declared, if its revalidation is not requested within the period of time above mentioned.
The registration of the APIs will not be granted when the conditions, requirements, and procedures provided for in the regulation are not met. In case of emergency, or in a temporary situation, ANVISA may excuse from registration the APIs for exclusive use in the production of drugs to be used in public health programs by the Ministry of Health and their related organisms. This excuse from registration of the APIs will be authorized exclusively by Anvisa Collegiate Board of Directors, in a formal and public document signed by the Director-President.
The companies settled in Brazil that manufacture or import APIs must adjust their activities to the provisions hereof, in accordance with the schedule approved by the Collegiate Board of Directors. The publication of the schedule referred to herein will be issued in the form of a normative document by Anvisa Collegiate Board of Directors, where the deadline for adequacy will be established.
The APIs present in the formulation of imported medical drugs, either in the form of semi-finished or finished drug product, must be registered according to the provisions hereof.
The non-compliance of the provisions in this Resolution and in the Regulation approved by it is considered as sanitary infraction, and is subject to the appropriate civil, administrative, and penal liabilities.
This Resolution is applied to synthetic APIs used in the production of drug products. The registration of the APIs used in herbal drug products, dynamized medicines, and biological products, including sera and vaccines, are not included in this regulation.
DOCUMENTS FOR THE REGISTRATION
When protocolizing the petition of registration of API, the company shall protocolize a single process, containing the following documents:
- Petition forms properly filled out.
- Original copy of the receipt of payment of the health surveillance inspection fee, or exemption probative document, when applicable.
- Copy of the updated Operation License (Sanitary Permit) of the company.
- Copy of the Operation Authorization of the company, and Special Operation Authorization, when applicable, published in the Federal Official Gazette.
- Copy of the updated Certificate of Good Manufacturing Practices and Control of Pharmaceutical Ingredients, issued by Anvisa, or probative document of the Operational Technical Conditions issued by the local health authority, or a protocol requesting inspection by the local health authority, as long as a satisfactory situation according to the last inspection is presented.
- For imported APIs, copy of the Certificate of Good Manufacturing Practices and Control of Pharmaceutical Ingredients, issued by Anvisa, or a protocol requesting inspection by Anvisa, as long as a satisfactory situation according to the last inspection is presented.
- Copy of the Certificate of Technical Responsibility in force, related to the company requesting the registration, issued by the Regional Council of Chemistry or Pharmacy.
- Probative document of the API record at Anvisa.
- Documentation required in the legislation in force on the control of the Transmissible Spongiform Encephalopathy (TSE).
- Technical report containing the information described below.
All of the following documentation shall be presented on letterhead paper of the API manufacturing company in Portuguese language. The drug manufacturers have the option of sending directly to ANVISA the documentation described herein, duly identified with the related process number.
TECHNICAL INFORMATION ON THE API
The registration documentation must also contain the following information:
a) Nomenclature: Common Brazilian Denomination, or International Common Denomination, in case the former is not available;
b) CAS number;
c) Chemical name;
d) Synonyms with complete reference;
e) Molecule and structure formula;
f) Molecular weight;
g) Physical form;
h) Fusion or ebullition point;
i) Solubility;
j) Loss by drying;
k) Physical characteristics (crystalline, amorphous, particle size, solvatation, etc.);
l) pka and pH;
m) Conservation cautions;
n) Organoleptic properties.
- API manufacturing process:
a) Manufacturer(s): name, complete address, company responsible for each phase of the manufacturing process and quality control (including contracts and subcontracts);
b) Description of productive process, including materials, equipment, and operation conditions (for example, temperature, pressure, pH, time, speed, agitation ranges, etc.); and the process controls;
c) Identification of critical phases, including the respective tests and acceptance criteria;
d) Flow chart of the productive process, indicating the formation of intermediary products and possible impurities, including explanation of the respective chemical structures;
e) Indication of raw materials, solvents, catalyzers, etc;
f) Indicate production and yield scale;
g) Specifications of raw materials and packing materials.
- Characterization: Physical-chemical essays that allow for the duly characterization of API structure:
a) Analyses of an industrial batch, producing evidence of functional groups, chemical structure, and molecule formula expected for the API;
b) Possible isomers;
c) Polymorphism, describing the characteristics of the polymorph used, and of other ones related to the API.
a) Description of potential impurities, resulting from the synthesis, with brief description and indication of origin;
b) Organic impurities (of the process and related substances): (starting) raw materials, related products, intermediary products, degradation products, reagents and catalyzers;
c) Inorganic impurities: reagents and catalyzers, heavy metals, inorganic salts;
d) Residual solvents.
Specifications
a) (?)
b) Aspect;
c) Identification;
d) Dosage/ proportion;
e) Impurities (organic, inorganic, and individual solvents);
f) Physical-chemical properties (pH, fusion point etc.);
g) Granulometric distribution;
h) Polymorphism, including adopted analytical methodology and test results to determine the probable polymorphic agents of the ingredient;
i) For ingredients presenting chirality, data on the proportions of stereoisomers;
j) Humidity;
k) Microbiological limits: sterility, endotoxins (if applicable);
l) Specific optic rotation (if applicable).
Copy of report on quality control of three batches produced, with API identification, batch number, reference values and results of tests carried out.
Description of analytical methodology: Validation of analytical methodology according to specific technical regulation in force for the
validation of analytical and bioanalytical methods, when pharmacopoeia methodology is not used. In the case of pharmacopoeia methodology, the company shall present co-validation of the method.
- Packaging Material: description and specification of primary packaging material.
- Stability and Photostability Report: Stability and photostability studies must be carried out following the specific technical regulation in force in Brazil.
DOCUMENTATION FOR REGISTRATION RENEWAL:
For the renewal of registration of APIs, the company shall present the following documents:
- Petition forms duly filled out;
- Original copy of the receipt of payment of the health surveillance inspection fee, or exemption probative document, when applicable.
- Copy of the Certificate of Good Manufacturing Practices and Control issued by Anvisa for the API registered, or a copy of the protocol requesting inspection for the purposes of issuing the certificate aforementioned, as long as a satisfactory situation according to the last inspection is presented.
- In the case of ingredients registered exclusively for export purposes, according to this regulation, a probative document of export must be presented.
- List of all post-registration alterations and/ or inclusions occurred during the last valid period of the product registration.
- Conclusive results from long duration stability studies, according to a specific guide defined by Anvisa.
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