The procedures for approval of ANVISA GMP certificate in Brazil

The procedures for approval of ANVISA GMP certificate in Brazil : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자	임이슬	카테고리	전문가 인사이트
작성일	2017-10-20	조회수	5,860
원문
출처

글 Priscilla, Lima Viana Palhano: GPKOL위원

세부 전문분야 및 컨설팅 내용

Regulatory affairs: Register of products in ANVISA, including the obtaining of necessary license and certificates
GMP: Prepare the company for Sanitary Inspection to obtain the Brazilian GMP (CBPF), and other required certificates

Abstract

1. Introduction

The implementation and compliance with the Good Manufacturing Practices (GMP) standards is a legal requirement of the Brazilian Ministry of Health for all establishments manufacturing medicines, health products and cosmetics in Brazil, and CBPF (Certificate of Good Manufacturing Practice ) is the document certifying that the company complies with good practice. It presents the company data and certified production lines and the validity of the certification. The concession of the CBPF occurs by verifying compliance with the technical requirements contained in the current legislation of GMP and correlated, through inspections and monitoring of data by Anvisa.

According to ANVISA, GMP encompasses all operations involved in the manufacture of drugs, including drugs under development for clinical trials. They contemplate the care that must be taken from the acquisition of raw material to the production process, which includes the operations of receiving the materials, preparation of medicines, processing, finished product and conditioning. Quality control is also part of the GMP role; qualification of the workforce; adequacy of facilities, with appropriate and identified spaces; computerized equipment and systems; materials, containers and labels; procedures and instructions approved and in force; adequate storage of inputs, products and packaging; and compatible shipment, transportation and logistics; beyond the control of the process as a whole.

In the case of companies that have never owned ANVISA's GMP certificate, but wish to obtain the certificate, it is sufficient to make a formal request to Anvisa, following the procedures for registration, documentation and payment of the determined fees. The technical area of the agency will review the documentation and inspection report of the local health surveillance that shows compliance with good practice. If everything is within the requirements, the GMP certificated is issued. The time for sanitary inspection related to the GMP’s first request of the company, can vary between 12 and 20 months for international companies.

According to Anvisa, the GMP certification is valid for two years, without extension. Close to expiration, the company must request a new certificate. Its expiration does not constitute prohibition or stoppage of productive activities, but for publication of the new certification without interruption of continuity with the one in force, the petition must be filed in a period between 270 and 180 days before the expiration of the current certificate .

Once the technical and protocol requirements have been assessed, Anvisa will be responsible for declaring or rejecting the request until the expiration date of the certificate. The absence of manifestation by the responsible technical area of the agency until the expiry date of the certificate will cause the publication in the Official Gazette of the Union of its automatic renewal. On the other hand, the refusal, failure to pronounce or cancel the sanitary inspection by the company concerned will prevent automatic renewal or will automatically cancel the renewed certificate. Automatic renewals will also be canceled in cases where the establishment is classified as demanding or unsatisfactory. According to Anvisa, the automatic renewal does not exclude the possibility of the analysis and its eventual cancellation if it is proven that the establishment does not comply with good practices.

The biggest challenge of GMP is not in its implementation, since its requirements are widely known by companies and consolidated in national and international legislation, but in the maintenance and control of their requirements due to the numerous processes involved in the manufacture of medicines and in all the variables involved in these procedures. One of the great tests for maintenance of GMP is the control of activities that have human intervention. The more interventions, the greater the risks of cross-contamination or particles, exchanges and mixtures, where we consider process monitoring and data analysis through GMP tools, such as Periodic Review of Products, important allies of control and to be actions to mitigate the risks of quality deviations.

As challenging as ensure the quality of products in accordance with GMP is to face the bureaucracy for its implementation and maintenance. Under the GMP rules, periodic product review (RPP) should be performed annually, checking the quality behavior in various analyzes. Imagine a company that has 300 products registered. It is an extensive report and demands knowledge and use of statistical and personnel tools in a lean structure.

Even if you adopt quality control procedures, even preventively, problems can occur at any stage of production and, if they are not detected and corrected, the company may even lose the Good Manufacturing Practices Certificate, since inspection is severe. The GMP certificate may be canceled at any time if the competent health authority proves the non-compliance with the GMP. The prohibition or prohibition of production activities, according to Anvisa, can be determined as a consequence of critical nonconformities detected during the inspections, through a risk assessment of the inspection team. Failure to comply with Good Manufacturing Practices also constitutes a sanitary infraction, as provided for in Law 6,437 / 1977. Companies that do not comply with the determination may suffer penalties for warning, seizure, destruction, prohibition, cancellation of authorization for operation or registration of the product and all without prejudice to civil or criminal sanctions. The loss of the GMP certificate implies problems for the laboratory, such as the impossibility of renewing drug registration or disqualification for participation in bids. Without GMP certification, the company also can not export medicines or import pharmaceutical supplies and, therefore, the company will be prohibited from marketing its product in the Brazilian Market.

It is important to emphasize that the company must be attentive to the entire production chain in order to guarantee the quality standard of the final product, and thus arise the questions: How are the conditions of storage of the distributor? Is the product handled properly during distribution logistics? The vehicle carrying the product is the ideal? What GMP training is submitted who handles the medicine at the factory? And in the drugstore? And in the hospital? All these premises should be present in the entire chain. It follows that the health risk still has a lot of space to be minimized along the production chain.

2. Main Subject

a. Preparation of the company to obtain ANVISA GMP certificate for medicines:

Good Manufacturing Practices is the part of Quality Assurance that ensures that products are consistently produced and controlled, with quality standards appropriate to the intended use and required by the registration.

Compliance with GMP is primarily aimed at reducing the risks inherent in any pharmaceutical production, which can not be detected by conducting tests on finished products.

The risks are essentially cross-contamination, particle contamination, exchange or product mix.

GMP determines that:

I - all manufacturing processes must be clearly defined and systematically reviewed in the light of experience. In addition, they must be able to manufacture medicines within the required quality standards, according to their specifications;
II - the necessary qualifications and validations are carried out;
III - all necessary resources are provided, including:
- a) qualified and properly trained personnel;
- b) adequate and identified facilities and space;
- c) equipment, computer systems and adequate services;
- d) appropriate materials, containers and labels;
- e) approved and current procedures and instructions;
- f) adequate storage and transport; and
- g) facilities, equipment and qualified personnel for process control.
IV - instructions and procedures must be written in clear, unambiguous language and be specifically applicable to the facilities used;
V - employees must be trained to perform procedures correctly;
VI - records (manually and / or by recording instruments) must be made during production to demonstrate that all steps in the procedures and instructions have been followed and that the quantity and quality of the product obtained are in line with the expected . Any significant deviations should be recorded and investigated;
VII - records relating to manufacture and distribution, which enable the complete tracking of a lot, are filed in an organized and easily accessible manner;
VIII - storage is adequate and product distribution minimizes any risk to its quality;
IX - a system capable of collecting any batch after its commercialization or distribution is in place; and
X - complaints about marketed products should be examined, recorded and the causes of quality deviations investigated and documented. Measures should be taken with regard to products with quality deviations and measures should be taken to prevent recurrences.

The manufacture of medicines requires a high level of sanitation and hygiene that must be observed at all stages. Sanitation and hygiene activities shall include personnel, facilities, equipment and utensils, production materials and containers, cleaning and disinfection products and any other aspects that may constitute a source of contamination for the product. Potential sources of contamination should be eliminated through a comprehensive sanitation and hygiene program.

In line with GMP, the company must identify which qualification and validation work is required to prove that all critical aspects of operation are under control. The key elements of a company's qualification and validation program should be clearly defined and documented in a validation master plan.

In this way, qualification and validation should establish and provide documented evidence that:

I - facilities, utilities, computer systems, equipment and processes have been designed in line with the requirements of GMP (project qualification or QP);
II - facilities, utilities, computer systems and equipment were built and installed according to their design specifications (installation qualification or IQ);
III - facilities, utilities, computer systems and equipment operate according to their planned specifications (operation qualification or QO); and
IV - A specific process will consistently produce a product that meets its specifications and quality attributes (process validation or VP, also called in some cases performance qualification or QD).

Any aspect of the operation, including significant changes in facilities, location, computer systems, equipment or processes, that may affect the quality of the product, directly or indirectly, must be qualified and / or validated. Thus, the qualification and validation should not be considered unique exercises. Following the approval of the qualification and / or validation report there should be a continuous monitoring program, which should be based on a periodic review. The commitment to maintaining the qualification / validation situation should be described in relevant company documents, such as the quality manual or master validation plan, and the responsibility for performing the validation should be clearly defined.

Validation studies are an essential part of GMP and should be conducted according to pre-defined and approved protocols, and qualification and validation reports containing results and conclusions should be prepared and archived. The processes and procedures shall be established on the basis of the results of the validation performed and the cleaning procedures, analytical methods and computerized systems shall also be validated.

Self-Inspection Procedure:

Self-inspection should assess the manufacturer's compliance with GMP in all respects. The program should be designed to detect any deviation in the implementation of GMP and to recommend the necessary corrective actions. In this way self-inspections should be carried out routinely and can also be carried out on special occasions, such as in the case of collections, repeated rejections of products or before an inspection to be carried out by a health authority .
The personnel responsible for self-inspection should be able to assess the implementation of GMP in an objective manner.

In this process, all corrective action recommendations should be implemented and the self-inspection procedure documented, where an effective monitoring program is required.

A written procedure for self-inspection should be established and it may include questionnaires on GMP requirements covering at least the following aspects:

I - personnel;
II - facilities, including locker rooms;
III - maintenance of buildings and equipment;
IV - storage of raw materials, packaging materials, intermediate products and finished products;
V - equipment;
VI - production and process controls;
VII - quality control;
VIII - documentation;
IX - sanitation and hygiene;
X - validation and revalidation programs;
XI - calibration of instruments or measuring systems;
XII - collection procedures;
XIII - claims management;
XIV - control of labels;
XV - results of previous self-inspections and any corrective measures taken;
XVI - computer systems relevant to Good Manufacturing Practices;
XVII - transportation of medicines and intermediates; and
XVIII - waste management.

Quality Assurance should appoint a team to conduct self-inspection, consisting of qualified professionals, experts in their own areas of expertise and familiar with GMP, and team members can be in-house professionals or outside experts.

The frequency with which the self-inspections are conducted must be established in procedure, and this may depend on the characteristics of the company, and should be preferably annual.

After completion of the self-inspection, a report should be prepared, which should include:

a) results of self-inspection;
b) evaluation and conclusions; and
c) recommended corrective actions.

There should be an effective monitoring program for self-inspection activities by Quality Assurance, and the company management should evaluate both self-inspection reports and recommended corrective actions if necessary.

In some cases, completing self-inspection with quality audits may be necessary, and this consists of examining and evaluating all or part of a particular quality system, with the specific aim of improving it. In general, this audit is performed by external, independent experts, or by a team designated by management for that purpose.

It is important to emphasize that audits can be extended to suppliers and contractors. The person designated by the Quality Assurance must have joint responsibility with other relevant departments to approve reliable suppliers of raw materials and packaging materials that meet the specifications. In this case, before suppliers are included in the list of qualified suppliers, they must be evaluated according to the procedure or program previously defined, and this evaluation should include compliance with legal requirements, as well as the supplier's history and the nature of the materials to be considered. provided. Where audits are required, they should demonstrate the supplier's ability to meet GMP standards.

b. Procedure for obtaining ANVISA's international BPF certificate:

Six steps are necessary to obtain CBPF from ANVISA by an international company:
Step 1) A national company applies on behalf of the international company, CBPF through electronic petition
Step 2) ANVISA analyzes and petition submitted by the company
Step 3) AVNISA executes the planning, scheduling and inspection at the international company premises.
Step 4) After the inspection, ANVISA prepares the sanitary inspection report.
Step 5) ANVISA elaborates the technical opinion and the draft of the official media publication of Brazil.
Step 6) ANVISA publishes in the brazilian official media the certificate of good manufacturing practices of the company.

c. About the Electronic Petition Process:

It is important to remember that the entire process of requesting the BPF certificate of an international company must be done at ANVISA by a Brazilian company registered in Brazil, which will be responsible for importing the product. This company could be a subsidiary of the international company to be inspected, or it could simply be a partner company in which a commercial import / export agreement was established.

To begin the process of applying for GMP certification, the company must carry out the electronic request of the request on the ANVISA website, and for this, the first step is the payment of the sanitary inspection fee to be paid to ANVISA. After payment has been made to the company requesting the BPF certificate, it must return to ANVISA's electronic filing system and proceed with the electronic sending of the following documents:

a) Duly completed petition form
b) Proof of original payment of the sanitary inspection fee (GRU)
c) Certificate of Good Manufacturing Practices, valid, issued by the sanitary authority of the country where the producing establishment is located. Certificates issued in the English, Spanish or Portuguese languages will be accepted without need of sworn translation.
d) Site Master File (SMF) of the company to be certified in an exclusively electronic environment. They will be accepted without need of sworn translation, SMF issued in English, Spanish or Portuguese. If this document, for reasons of confidentiality, has to be filed separately from the application for certification, this protocol must refer to the name of the requesting company, the number of the certification process and should be referred to the COIME / GIMEP / GGIMP care.
e) Periodic Reviews of Products (RPP) in accordance with the following guidelines:Deve ser apresentada em meio exclusivamente eletrônico em português, inglês ou espanhol.
- It should not be in the Summary Report, because it will generate a requirement that will delay the completion of the analysis.
- For renewal, all batches produced of the medicines requested since the last certification period should be included, regardless of the market for which they are intended.
- For the initial concession of a manufacturer already certified to another applicant, the RPP should be sent to all batches produced of the medicines requested for the last two years of production from the date of the request, regardless of the market for which they are intended.
- For the initial grant in which the production of the drug (s) has not yet started, this must be informed in the application for certification and the process validation of the drug (s) and the analysis of risk for the insertion of this product (s) into the production line (s), including the impacts on the validation of the previously established cleaning procedures.
- If this document, for reasons of confidentiality, has to be filed separately from the application for certification, this protocol must refer to the name of the requesting company and the number of the certification process. The document should be sent to COIME / GGINP

d. About the Sanitary Inspection process:

Scheduling phase:

At this stage Anvisa sends to the company the suggestion of date and the request for basic documentation to be sent prior to the day of the inspection.

Regarding the date will be required a lock of the company's schedule for 5 days and this period from Monday to Friday. After ANVISA send the date proposed for the company, this should answer a confirmation within 96 hours after receipt of the proposal. Inspectors may request the company to adjust the inspection period, but the company will not be able to request a readjustment.

The basic documentation that ANVISA will request from the company will include the following documents:

Quality Manual
Product List Update
Layout or floor plan of the factory
General Production Flow, containing the identification of the steps performed in the plant to be inspected.O envio desta documentação previamente à inspeção é muito importante para que os inspetores da ANVISA possam se organizar para a inspeção de forma otimizada.

After sending the documentation and confirming the date, the company must wait for the contact of the ANVISA inspectors.

e. Preparation of the sanitary inspection by ANVISA:

Before ANVISA carries out the sanitary inspection in the facilities of the international company, there is a stage of preparation so that all the previous documentation is evaluated and the schedule of the inspection is organized and thus the following activities are carried out by ANVISA:

Analysis of legal documentation:

In this stage, the legal documents of the Brazilian company requesting CBPF and the international company to be inspected are evaluated, comprising:

Operation Permit and Sanitary License.
Acts of sanitary infraction (prohibitions, seizures and gatherings);
Production Plant
Stage 1 Documentation - Receipt and AnalysisRevisão do Histórico de Inspeções:

At this stage, ANVISA identifies the inspection history of the international company in order to previously draw up a profile for the company and to evaluate the health risk in which it is in the current situation. The analyzed parameters are:

Inspection reports and tax terms issued in the last two inspections.
Open corrective actions.
Identification of risk points.f

And finally ANVISA sets up an inspection agenda, an important stage for the organization of the activities to be followed by the International Company and the Inspection Team. This step is carried out the planning of the inspection schedule optimization.

f. The Inspection:

Conduct of Inspection:

This stage begins with an initial meeting, where the presence of the highest administrative and technical positions of the company is of paramount importance. At this meeting, the objective of the inspection is presented, adjustments made to the inspection schedule, if necessary, and the presentation of the inspection team and others involved.

During the inspection, visits are made to the premises of the international company, and later documentation of the most varied types (quality assurance, production, quality control, commercial, etc.) is requested, in order to evaluate their respective conformity.

There will always be a member of the ANVISA team responsible for monitoring the activities according to the inspection schedule established to ensure compliance with the deadlines established for the inspection period.

In the process of finalizing the sanitary inspection, the nonconformities found are reviewed, and deadlines are established for the delivery of the report, and compliance with nonconformities.

The sanitary inspection procedure follows the guidelines of the legislation of ANVISA RDC nº 16 of 2013, which reports the following points:

CHAPTER 1 - General Provisions
CHAPTER 2 - General Requirements of the Quality System
CHAPTER 3 - Documents and Quality Records
CHAPTER 4 - Project Control and Product Master Registration (RMP)
CHAPTER 5 - Process and Production Controls
CHAPTER 6 - Handling, Storage, Distribution and Traceability
CHAPTER 7 - Corrective and Preventive Actions
CHAPTER 8 - Installation and Technical Assistance
CHAPTER 9 - Statistics Techniques

At the end of the inspection the possible results to be achieved by the international company are:

Satisfactory;
Requirement;
Unsatisfactory without Field Action;
Unsatisfactory with Field Action;

g. About ANVISA's Inspection Report:

The inspection report to be elaborated will contemplate the following points, being:

General information of the company,
Areas inspected,
Unconformities,
Legal classification and foundation,
Risk analysis and
Classification of the company inspected.

Inspection result referrals:

If the result of the inspection is considered SATISFACTORY, the certificate will be published directly in the official media;

If the result of the inspection is considered REQUIREMENT, the international company will have the term of up to 120 consecutive days for compliance and protocolization of the requirements listed by ANVISA in the Inspection report. After this stage Anvisa will announce the result of the deferment or rejection in official media.

If the result of the Inspection is considered to be UNSATISFACTORY, the rejection will be published directly in the official media, and Anvisa will notify about additional actions to be taken by the company. In this case a new CBPF request process should be started.

h. Completion of the process:

After completing the inspection report of the international company, it is forwarded and analyzed internally in ANVISA and in a positive case the draft publication of the CBPF deferment is prepared and later published in official media.

i. Some technical reasons for requirement or refusal:

I. No Separation of areas for production of hormones
- a. HVAC System was not independent from production of other material
- b. Personnel flow was not separated for operators involved in manufacturing of cytotoxic substances
- c. High potent drugs were produced using the same area as non-toxic drugs
- d. No clear separation of material flow for toxic-drugs and non-toxic drugs
II. No Confirmation that the plant does not produce animal products in the same line that human products are produced
III. Non-pharmaceutical products are produced in areas or used equipment in use for pharmaceutical drugs production.

j. Some administrative reasons for requirement or refusal status:

I. No suitability for clone medication was requested
II. Failure to comply with legal requirements
III. It was not requested the extension of the term for the fulfillment of requirement within the legal term
IV. It was not requested to reopen the process within the legal deadline
V. No documentation has been sent regarding quality control carried out by the importer
VI. No production process validation summary report was sent
VII. No documentation was submitted on the development of the formulation
VIII. No quality control documentation was submitted by the manufacturer of the drug
IX. No photo-stability study of the medicinal product
X. No IFA quality control reports have been issued by the IFA manufacturer *
XI. No certificate of registration of the medicinal product in the country of origin
XII. No information on finished product was sent in accordance with the model set out in Annex I of RDC No. 60/2014
XIII. The validation of analytical methods for the IFA performed by the manufacturer of the drug was not sent
XIV. Absence of electronic media
XV. Sanitary permit of the Brazilian company requesting the CBPF expired at the time of registration protocol.

3. Conclusion

This article tried to address the main points to be considered by international companies for CBPF's request at ANVISA for any area of the pharmaceutical industry (synthetic drugs, biological medicines, health products and cosmetics). However, although different issues have been addressed, many specific points must be analyzed and implemented by companies so that they are able to receive a sanitary inspection.

The technical parameters of compliance with the Good Manufacturing Practices can be found in ANVISA's RDC legislation no. 17/2010 and the administrative procedures for petitioning CBPF in ANVISA can be found in more detail in the law RDC 39/2013.

If the international company does not feel confident in carrying out all the preparation to receive ANVISA inspection, it is advisable to hire a consulting team specialized in Brazilian sanitary surveillance in order to ensure that the parameters of good practices demanded by ANVISA will be met with excellence avoiding the rejection of CBPF.

And lastly, it is worth recapitulating that having a partner, a branch or a subsidiary in Brazil is a basic condition for starting the whole process, since ANVISA requires that the requesting company be registered in Brazil.

References :

Agência Nacional de Vigilância Sanitária – Anvisa. Resolução RDC Nº 39, de 14 de agosto de 2013. Dispõe sobre os procedimentos administrativos para concessão da Certificação de Boas Práticas de Fabricação e da Certificação de Boas Práticas de Distribuição e/ou Armazenagem. Diário Oficial União. 15 de agosto de 2013
Agência Nacional de Vigilância Sanitária – Anvisa. Resolução RDC Nº 17, de 16 de abril de 2010. Dispõe sobre as Boas Práticas de Fabricação de Medicamentos. Diário Oficial União. 17 de abril de 2010.

Profile :

Priscilla Viana Palhano Lima was Manager of Regulatory Affairs and Special Projects of the Brazilian public laboratory. He was directly in charge of the legal compliance of technology transfers with foreign companies from France, Poland, the United States and South Korea. He has experience in dossier analysis and elaboration of Partnership for Productive Development projects for the Ministry of Health. She is currently a consultant Regulatory Affairs and organizations of Partnership Projects for Productive Development for the Ministry of Health. Priscilla is the founder of the Argo Consulting company that promotes consulting in the areas of regulatory affairs, business development, international partnerships and technology transfers in partnership with MM Assessoria Industrial company.

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The procedures for approval of ANVISA GMP certificate in Brazil

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