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Brazilian Biologics Regulatory Management

Brazilian Biologics Regulatory Management : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자 관리자 카테고리 전문가 인사이트
작성일 2016-04-26 조회수 1,699
원문
출처

Brazilian Biologics Regulatory Management: The Regulatory Agency (ANVISA) Strategy; a point of view of the regulated sector

전문가
글 Vera Lucia M. Noguchi
GPKOL위원
학력사항
  • 2012 ICTQ / Quality Management / Post-graduate
  • 1988 UFRJ / Industrial Pharma
경력사항
  • 2007-2016 Instituto Vital Brazil SA QA/RA Manager
  • 1998-2007 CENTRALERG Ltda QA/RA Manager
세부 전문분야 및 컨설팅 내용
  • GMP: Quality System management and Good Drug Manufacturing Practices.
  • RA: Preparation and submission of generic and biological drug registration dossiers with ANVISA.

Introdution

The chain of biological products, from manufacturing to the final consumer, is made up of several stages, which are supported by laws and regulatory acts, that cover not only registration, post-registration and renewals, but also the consumption in the pharmaceutical market in the Country.

As the professionals involved in these activities start registration actions and their changes, they make use of specific health legislation in pursuit of knowledge of the procedures and legal requirements in the context of biological products, available in several legal sources, which lead to difficulties and delays in search and interpretation of all the conditions required for the regulatory act.

 

In this context, the regulatory Agency has been engaged to facilitate the registration process for biological products in Brazil, with the publication of compiled, guides and resolutions, as well as the wide dissemination through speeches and discussions with the regulated sector, with the aim to make registration processes more agile, reduce analysis time of ANVISA and thus make the product available in a timely manner to the population.

This presentation addresses topics regarding the structure of ANVISA; the main sanitary laws; the registration and post-registration processes of biological products; the critical points that generate requirements in the register process of biological; other related laws and ANVISA strategies to facilitate the registration and post-registration process.

Organizational structure of ANVISA

The management responsible for the registration of biological products at ANVISA is the Biological Product Management, subject to Board of Authorization and Sanitary Registration, as can be seen in the organizational structure of ANVISA (Figure 1).

이미지4

Figure 2 Imports of vaccines to Ecuador in 2014. Value Free On Board
(FOB) per country and per animal population. Source: AGROCALIDAD, 2015.

Main sanitary laws related to biological products

• Law 6.360/1976 – First Sanitary Legislation for products under sanitary vigilance

We present the main sanitaries legislation, among which we highlight the first sanitary law in the country, considered the legal basis for the registration of medicines, the Law 6.360 / 1976. This law deals with all the products that are under sanitary surveillance in Brazil, not only medicines, but also cosmetics, cleaning products, foods etc. and points out that "any product, including imported, can be industrialized, exposed for sale or delivered consumption before being registered in the country".

• Law 9.782/1999 – Establishment of the Agency – ANVISA

In 1999 it was published the Law 9.782 that established the National Agency for Sanitary Vigilance, whose main structure is the Authorization Management and Sanitaries Registrations and Biological Product Management, responsible for drugs and biological products registration.

  • Resolution RDC 80/2002 – First specific legislation for Biological Products
  • Resolution RDC 315/2005 – Review of RDC 80/2002
  • Resolution RDC 55/2010 – Registration of Biological Products
  • Resolution RDC 50/2011 – Stability of biological products
  • Resolution RDC 49/2011 – Post-registration changes of Biological Products
  • Resolution RDC 17/2010 – Good Manufacturing Practices of Medicines
  • * Decree 8.077/2013 - It regulates the operation of Companies, for products under the Law 6.360/76, related to the Licenses and Authorizations

The first legislation dealing specifically with biological products was the resolution RDC 80/2002, which was repealed by Resolution RDC 315/2005 and only in 2010 we had the publication of the resolution RDC 55/2011, specific to the current registration of biological products. The following year were published the resolutions RDC 50/2011, which addresses the stability studies required in the composition of registration dossier and the RDC 49/2011, which deals with post-registration changes.

 

Despite the legal framework for products under sanitary surveillance, the Law 6.360 / 1976, have been published for 37 years, only recently was published the Decree 8.077 / 2013, which regulates the conditions of operations of the companies that manufacture the products under surveillance and treats of Licenses and Authorizations companies.

 

The decree mentioned above is closely related to the resolution published, by ANVISA, the RDC 17/2010, of Good Manufacturing Practice of Pharmaceutical, which all drug manufacturers must be in compliance in order to obtain the Good Manufacturing Practices Certificate (GMPC), necessary for the registration of drugs.

Registration of Biological Products

Currently in Brazil, biological medicines register are made based on RESOLUTION ANVISA RDC 55/2010, that provides on the registration of new biological products and biological products, giving other provisions.  According to this resolution, article 4, the biological products that are subject to registration in Brazil are:

  • Vaccines;
  • Hyperimmune serums;
  • Hemoderivatives;
  • Biodrugs classified into: a) Biological fluids or tissues of animal origin and b) Biotechnological procedures;
  • Monoclonal antibodies;
  • Drugs containing live, attenuated or dead microorganisms;

In addition to the RDC 55/2010 resolution, for the registration of biological products, other legislation related to various activities must be consulted, such as:

  • Resolution RDC 47/2009 e RDC 60/2012 - for adequacy of  insert package;
  • Resolution RDC 71/2009 e RDC 61/2012 – for adequacy of labels;
  • Resolution RDC 81/2008 – for import of medicines;
  • Resolution RDC 234/2005 – for Quality Control analysis
  • Ordinance 174/1996 – specific for production and quality control of hyperimmune sera
  • Resolution RDC 46/2000 – specific for hemoderivatives products

According to resolution RDC 55/2010, for the purpose of register, biological products are defined as follows:

  • New Biological product  - new molecule in the country, not yet registered;
  • Biological Product - not new molecule, already registered in the country;
  • Biological Product Comparator (BPC) - registered product with complete dossier containing proof of quality, safety and efficacy.

Products named as biological, can be registered in two different ways, which may be by the route of individual development or the route of comparability development. For biologicals registered through individual development path, we highlight the resolution cited the articles dealing with clinical studies.

  • Article 39. The extent of the nonclinical studies may be reduced, considering factors like molecule complexity, level of structure characterization, extent of characterization of the product’s level of impurity, product’s action mechanism, toxicity potential and therapeutic index.
  • Article 40. The phase I and II clinical studies, when necessary, will not mandatorily be comparative.
  • Article 41. The phase III clinical studies will always be necessary.
  • Sole paragraph. The phase III clinical studies must be comparative (non-inferiority, clinical equivalence or superiority) in relation to the new biological product, except for hemoderivatives, vaccines and biological products with oncological indication.
  • Article 42. When available, phase IV clinical studies results must be submitted.

For biological products registered by the route of comparability development, which are obtained by comparison of the molecules of the biological product and comparer biological product (reference product), we highlight the following articles regarding clinical studies.

  • Article 43 ,  I to XIII – paragraphs 1, 2
    1. . Paragraph 3 All studies of the biological product’s development program must be of comparative nature.
  • Article 44 …the applicant company must submit the complete reports of the nonclinical studies.
  • Article 46 … the applicant company must submit the protocols and reports of the following clinical studies:  pharmacokinetic, pharmacodynamic studies; and pivotal clinical safety and efficacy studies.

Clinical Studies

Also with respect to clinical studies, was published by ANVISA in 2015, the Resolution RDC No. 9, which deals with the subject in which it advocated the need for multicenter, phase I, II and III studies and also the register of them on the databases: International Clinical Trials Registration Platform; World Health Organization (ICTRP / WHO) or Other Recognized by the International Committee of Medical Journals Editors (ICMJE).

Definition

"Any research in humans, aiming to discover or verify the pharmacodynamic, pharmacological, clinical and / or other product effect (s) and / or identify any adverse reactions to the product (s) under investigation in order to ascertain their safety and / or efficacy."(EMEA, 1997)

Phases of clinical study

Pre-clinical:  application of new molecule in animals after trials identified in vitro as having therapeutic potential in order to obtain preliminary information on pharmacological activity and toxicity. Over 90% of the substances studied on this stage are eliminated because they do not demonstrate adequate pharmacological activity or are too toxic for human. The molecules that present specific pharmacological activity and toxicity profile acceptable go to the next stage.

 

Phase l: initial evaluation in humans (20-100), of a new active ingredient or new formulation,  to check the tolerance in healthy volunteers in order to establish: more tolerable dose; less effective dose; relation dose-effect; duration of effect  and side effects.

 

Phase II: first controlled studies in patients (100-200), to demonstrate the potential effectiveness of the medication that is an indication of the efficacy, safety confirmation and Bioavailability and Bioequivalence of different formulation.

 

Phase III: international studies, large-scale, multi-center, with different patient populations to demonstrate efficacy and safety (minimum population approx. 800) to Establishment of therapeutic profile (indications; dose and route of administration; contraindications; side effects; precautionary measures; therapeutic advantage demonstration when compared to competitors).

 

Phase IV: after approval for marketing the product to detect adverse events infrequent or unexpected (post-marketing surveillance); marketing support studies; comparative additional studies with competing products or new formulations, with the aim of establish the therapeutic value, the emergence of new adverse reactions and / or confirm the emergence of frequency of known, and treatment strategies. In this phase research should be following the same ethical and scientific standards applied to research in the previous phases.

Assembling of the dossier for registration:

The dossier for product registration is basically composed of four groups of documents: Registration application forms - FP1 and FP2; Legal documentation; Technical documentation e Therapeutic experimentation report. The forms for application register, FP1 and FP2, must be completed by the Company at the time of registration, in which are embedded information such as summary of the characteristics of the registration and responsibilities of the parties involved. There is also a place reserved for the decision of ANVISA and the publication of the regulatory Act. The legal documentation is related to the regulation of the Company and involves the following documentation:
  •  License Company operation;
  • Company operating authorizations - AFE / AE;
  • Certificate of Good Manufacturing Practices - CBPF;
  •  Regularity Technical Certificate, technical responsible pharmacist - CRT;
  • Auto Inspection of Fire Department - AVCB;
  • Environmental License of the State Environmental Institute - INEA

The technical documentation is related to the product, from the earliest stages of development to the finished product and must prove their quality. The technical report contains general product information, historical development, manufacturing steps, quality control information, validation of analytical methods, the transport chain validation, and stability studies.

 

When dealing with Blood Products, Vaccines and Biotechnological Products, the documentation of production and quality control should meet the specific checklist of the RDC 55/2010 resolution for these product categories.

The therapeutic experimentation report attests the safety and efficacy of the product and must contain the full report of the non-clinical studies, complete protocols and reports of clinical studies phases I, II and III and immunogenicity report. In addition to these documents to complete the registration dossier it is also necessary to add the postmarketing Pharmacovigilance Report and Risk Minimization Plan.


After the submission of the dossier for product registration, there will be the analysis of ANVISA and during this period may occur questions of the Agency's technical. In such cases this may require the company to submit more supporting technical documents of quality, safety and efficacy of the product candidate.

 

Considering the complexity of the regulatory environment, which involves several laws to be consulted and understood, which often are misunderstood, the need for professionals in regulatory affairs with adequate training and knowing that not always these conditions are met, ANVISA has encountered numerous technical requirements during the analysis of the registration dossier, promoting delays in the analysis of the documentation and release of results

 

We quote below some of the key items that require technical requirements:

  1. Stability Study
  2. Validation of Analytical Methodology
  3. Transport chain qualification
  4. Therapeutic  Experimentation Report
  5. Good Manufacturing Practices Certificate
  6. Registration in the Country of origin
  7. Comparability Exercise

Currently the time of ANVISA analysis for verification of documentation, that is, the submission of the Company's registration dossier to the approval of the Agency is approximately 18 months and post approval 15 months.

 

In case of PDPs (partnerships for productive development), the Anvisa analysis time is less, since the Anvisa addresses these partnerships through the Regulatory Technical Committee, formed by members of the Ministry of Health, Anvisa and the public partner, specifically to deal with partnerships. Furthermore, the public partner has the right to request prioritization analysis after each petitioning in the agency. This time is estimated at 90 days, according to the legal framework that deals with PDPs, Ordinance 2.531/2014 of the Health Ministry.

 

After examination of the Agency, it will release the results on its website, with the technical bases for registration approval, according to RDC 55/2010, article 47, and is available for consultation at the address http://www.ANVISA.gov.br/Fila_de_analise/index.asp.

Post-approval Changes

The Resolution RDC 49/2011 that provides on post-registration changes and inclusions, suspension and reactivation of manufacturing and cancellations of biological product registration, giving other provisions, should be follow for post approval changes.

Classification of Post-approval Changes

The post-approval changes are classified on bases of risk analysis and may be of 3 levels as below:

Source: Sinfar Meeting / 2015 Management of Biological Products / GPBIO / ANVISA

Level 1 change (minor change): post-registration changes of low complexity, that waive prior authorization from ANVISA for implementation.

Examples: batch size change up to 10 times; location change of secondary packaging; adequacy of specifications and compendial analytical methods.

Level 2 change (moderate change): post-registration changes of average complexity that require prior authorization from ANVISA for implementation.

Examples: establishment of new WCB of biotechnology products and vaccines;  changing trade name of the drug; adequacy of specifications and not compendious analytical methods;  location change of manufacturing the product in its primary packaging; location change of manufacturing  the product in bulk.

Level 3 change (major change): post-registration changes of high complexity, that require prior authorization from ANVISA for implementation.

Examples: location change of manufacturing of the active ingredient; Inclusion of a new concentration, route of administration change.

ANVISA strategies to facilitate the registration and post-registration process

Knowing that the product may only be marketed in Brazil, after obtaining the ANVISA registration, ANVISA analysis time is a factor that can have an impact on the economy and development of the pharmaceutical industry in the country, since it can promote delays the launch of new products on the market. Another point that may cause delays in completion of the registration process is the submission of documentation fragile, weak, because of misinterpretation of the law by the regulated sector.

 

In order to facilitate understanding of the laws, reduce their time analysis of process registration and post approval of medicines, the Agency has promoted actions to facilitate the ongoing dialogue with the regulated sector.

Among these actions the Agency has published compiled of specific legislation and also orientation guidelines for the Regulated Sector. Also has often promoted or participated in workshops, seminars, lectures and meetings, which have been quite positive for the sector.

 

In these events, RA professionals have the opportunity to take their doubts and questions, being beneficial for both the regulated sector, which will provide a more robust documentation and to ANVISA that require less technical requirements and will take less time completion of the analysis of the registration process. This way, streamlining the biological product registration process in Brazil it means that the Pharmaceutical Companies can make the products available in less timely to the public.

Contact: Vera Lucia M. Noguchi

Vital Brazil Institute

  • Rua Maestro Jose Botelho nº 64, Vital Brazil, Niteroi, RJ, CEP: 24230.410.
    Telefone: + 55  21 2711-9223
    www.vitalbrazil.rj.gov.br

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