A importância dos excipientes para a Qualidade dos produtos farmacêuticos

Introdução

A qualidade dos produtos farmacêuticos tem alcançado níveis elevados nos últimos anos. Contribuíram para isso, os últimos avanços nas técnicas de análise dos fármacos e produtos, os equipamentos e suas inovações tecnológicas, a implementação de controles no processo, a melhoria da qualidade dos fornecedores, os importantes avanços das normativas regulatórias, nos quais a ANVISA está inserida, entre outros elementos.

Apesar da melhoria na qualidade e do conhecimento técnico-científico exercidos sobre os Insumos Farmacêuticos Ativos (IFAs), nota-se que não existem normas específicas de Boas Práticas de Fabricação para os excipientes utilizados nos produtos farmacêuticos.

Com o avanço do conhecimento científico sobre os processos farmacêuticos, cada vez mais torna-se necessário ampliar o conhecimento sobre produtos e processos, desde o desenvolvimento farmacotécnico e, neste contexto, os excipientes estão sendo mais e mais inseridos e avaliados como tendo importância e impacto na qualidade semelhantes aos IFAs.

Excipientes: Passado

Embora sempre tenham sido consideradas substâncias inertes em uma formulação farmacêutica, os excipientes possuem um papel relevante no desempenho dos medicamentos.  Os motivos pelos quais aos excipientes tenha sido atribuída uma importância relativa, explica-se através de alguns destes elementos:

• Denotava-se importância relativa aos IFAs (APIs) e quase nenhuma aos excipientes.
• Poucos critérios de qualidade para os estudos de estabilidade.
• Pouca tecnologia aplicada às análises de Controle de Qualidade, entre outros.

Fase de transição

Paulatinamente o conhecimento científico passou a interferir na percepção da qualidade dos excipientes e sua relação com a qualidade do medicamento. Porém, não foi um fato isolado, mas o conjunto da evolução técnico-regulatória com a tecnologia e o conhecimento científico que propiciaram o início do entendimento sobre as necessidades de se aplicar conhecimentos científicos e controles sobre os excipientes.

Neste sentido, os processos, as normas, os equipamentos e técnicas continuaram a evoluir, possibilitando que também os excipientes pudessem se beneficiar das tecnologias disponíveis. Os seguintes elementos podem ser considerados dentro deste painel de transição entre passado e presente:

ü   Maior ênfase na qualidade do produto farmacêutico e de seus insumos.

ü   Investigação de desvios de qualidade de produto e avaliação da interferência dos excipientes como fato causador.

ü   Rigor regulatório.

ü   Melhoria tecnológica na identificação e análise, ou seja, mais equipamentos.

ü   Melhores e mais consistentes conhecimento sobre estabilidade.

ü   Maior conhecimento sobre insumos farmacêuticos ativos, entre os mais importantes.

Importância dos excipientes na atualidade.

Os excipientes podem atuar como elementos carreadores dos IFAs, facilitadores da absorção, modificadores do sabor, facilitadores da deglutição, permitir a aplicação da unidade posológica, entre os mais importantes.

Normalmente os excipientes de uma formulação são planejados para não interagir no organismo provocando efeitos farmacológicos ou apresentando efeitos adversos. Quando não bem estudados e avaliados no desenvolvimento do produto, podem interagir com o IFA (fármaco), com outros excipientes e com a embalagem provocando eventos não esperados durante o processamento e armazenagem.

Entre os principais problemas potenciais em produtos farmacêuticos, que podem ter atuação ou interferência dos excipientes, podemos citar:

Biodisponibilidade do fármaco;
Produtos de degradação;
Impurezas;
Falhas e desvios de qualidade do produto;
Perfil de dissolução do produto.

Neste sentido, a Qualidade dos Excipientes no âmbito da qualidade do processo e do produto e, ainda, conforme as normas atuais, se relaciona e impacta com:

ü   Os estudos de estabilidade.

ü   A Biodisponibilidade e Equivalência farmacêutica.

ü   Os Estudos de Pré-Formulação.

ü    Impurezas e produtos de degradação.

ü   A Caracterização dos Fármacos e Excipientes.

ü   A imprescindível  Qualificação dos Fornecedores.

ü   A Determinação/avaliação  corretas das Especificações. 

ü   A Determinação dos Atributos Críticos de Qualidade (ACQs).

ü   O Gerenciamento do Risco na Qualidade.

 Portanto, no desenvolvimento do produto farmacêutico, além do estabelecimento do insumo farmacêutico ativo e a definição das etapas criticas do processo, a determinação da qualidade dos excipientes é de fundamental importância para a definição da qualidade do produto final.

 Novos conhecimentos

Nesta nova era do conhecimento, as inovações técnicas acontecem muito rapidamente, estabelecendo parâmetros que antes, ou eram desconhecidos ou não  poderiam ser investigados e determinados devido à inexistência de tecnologia.

Assim, para o formulador, não basta apenas assegurar a qualidade do excipiente através de métodos analíticos e seus resultados. É preciso ter fornecimento de materiais através de fornecedores qualificados e certificados, onde as especificações tenham sido acordadas e profundamente estudadas e os ACQs tenham sido identificados.

Estas características dos excipientes afetam a qualidade, a segurança e a eficácia do produto e a segurança para o paciente, de acordo com figura 1. 

Fig. 1 – Fluxograma demonstrando que a segurança do paciente também se relaciona com especificações de excipientes. Fonte: Jair Calixto.

Importância da Qualificação  de Fornecedores

Apesar de não ser algo novo, a qualificação de fornecedores ganha importância multiplicada em virtude da complexidade das operações das empresas e dos novos fabricantes mundiais de insumos.

A qualificação de fornecedores possibilita às indústrias farmacêuticas conhecerem os insumos presentes em seus processos de fabricação, os fabricantes e os fornecedores, possibilitando a segurança necessária para a aquisição e uso de insumos em seus produtos.

Ressalte-se que o fabricante do produto farmacêutico responde pelo produto final e pelos excipientes e fármacos que coloca em seu produto.  

              Além de servir para confirmar as Especificações e os ACQs anteriormente determinadas, a qualificação de fornecedores de IFAs e excipientes é relevante, também, para prevenir a entrada de materiais incorretos no sistema, conforme a figura 2 abaixo demonstra.

               

Fig. 2 – Gráfico demonstrando a relevância da qualificação de fornecedores. Fonte: Jair Calixto

A importância dos Atributos críticos de Qualidade (ACQs)

Ao se determinar as especificações dos excipientes, deve-se estabelecer os ACQs.  ACQs são propriedades físicas, químicas, biológicas ou microbiológicas ou características que deveriam ter um limite de controle apropriado, faixas ou distribuição para assegurar a qualidade desejada do produto. ACQs são, geralmente, associados com substâncias ativas, excipientes, intermediários e produtos finais.

Exemplos de ACQs para substâncias ativas ou intermediários: distribuição e tamanho de partículas, pH, porosidade, tipo de cristal, entre outros. Quando não determinados e controlados, podem interferir e afetar a continuidade do processo ou influenciar  diretamente no desempenho e na qualidade do medicamento.

ACQs dos produtos incluem as propriedades que concedem a qualidade, segurança e eficácia desejadas. Para sólidos orais são aqueles aspectos que afetam a pureza do produto, a potência, a estabilidade e a liberação do fármaco. ACQs para outros sistemas de liberação podem, adicionalmente, incluir aspectos específicos do produto, tais como propriedades aerodinâmicas para produtos inalados, esterilidade para parenterais e força adesiva para os patches transdérmicos.

A importância da Pré-formulação
A pré-formulação é uma triagem, uma prévia do estudo de estabilidade, onde a aplicação de testes multivariados com o fármaco e os excipientes em condições ambientais de estresse pode identificar eventuais incompatibilidades.

Então, o estudo de Pré-formulação estabelece uma matriz de alguns testes prévios entre os excipientes prováveis e entre o fármaco e os excipientes prováveis, para verificar a estabilidade das misturas, a degradação, a compatibilidade dos excipientes. Os testes prévios são submetidos a condições de ambientais controladas e os resultados das interações verificados. As condições dos testes podem ser: temperatura, umidade, oxigênio, metais, luz, pH.

Assim, um rigoroso estudo de pré-formulação e o estabelecimento adequado e controle das especificações dos excipientes levam à prevenção de problemas futuros, eliminando-se possíveis interações e reações de excipientes com insumos ativos e embalagens e minimização de problemas de qualidade do produto farmacêutico.

 Caracterização dos Fármacos e Excipientes

A caracterização de fármacos e excipientes é uma abordagem nova, que utiliza alta tecnologia para a determinação de parâmetros científicos que até o momento não têm sido controlados na rotina dos laboratórios de controle de qualidade das indústrias farmacêuticas. Para muitos fármaco e excipientes, certos atributos podem causar forte impacto sobre a qualidade do processo farmacêutico e do produto.

Apesar de nem todas estas tecnologias  serem absolutamente novas, as mais novas ainda estão em desenvolvimento, mas face às complexidades e necessidades técnicas, tenderão a se tornar rotineiras na qualificação dos excipientes e fármacos. 

Conclusões

Com os novos conhecimentos e o avanço da tecnologia direcionada para os processos farmacêuticos, observa-se a necessidade de aquisição de excipientes bem conhecidos e com suas propriedades de qualidade definidas e controladas pelo fabricante. Por outro lado, o fabricante do medicamento também deve determinar suas próprias necessidades relativas a especificações físicas, químicas e microbiológicas para os fármacos e excipientes utilizados em seus produtos, de modo que possa controlar a qualidade do produto final.

Assim os elementos e conceitos mais relevantes no desenvolvimento de produtos, no âmbito dos excipientes farmacêuticos são:

Ø  Qualificação de Fornecedores.

Ø  Estudos de Pré-formulação.

Ø  Caracterização dos Fármacos e Excipientes.

Ø  ACQs e Especificações.

Estes elementos, quando bem gerenciados e monitorados pela empresa, conduzem-na a obter produtos farmacêuticos com alto grau de qualidade e com riscos potenciais diminuídos.

Bibliografia:

(1)  Botet, Jordi. Sistema de Calidad Farmacéutica Del Siglo XXI. S.Paulo:Editora RCN, 2008.

(2)  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use ICH Harmonised Tripartite Guideline. ICH Q8 (R2) – Pharmaceutical Development. ICH, Step 4 version, 2009.  .

(3)  U.S. Department of Health and Human Services - Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and

Research (CBER).  ICH Q9 – Guidance for Industry - Quality Risk Management. Rockville, MD: FDA, June 2006.

(4)  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH Harmonised Tripartite Guideline. ICH Q10 – Pharmaceutical Quality System. ICH. Step 4 version,june 2008.

D. Moretto

(5)  Moretto, LD; Calixto, J.  Estrutura do Novo Sistema da Qualidade para a Indústria Farmacêutica. São Paulo: Finazzi Propaganda, volume 5, 2009.

(6)  Moretto, LD; Calixto, J. Guias IPEC Excipientes - Boas Práticas de Fabricação - Boas Práticas de Distribuição. São Paulo: Finazzi Propaganda, volume 7, 2009.

Jair Calixto

Farmacêutico Bioquímico graduado em 1985 pela Faculdade de Ciências Farmacêuticas da USP, graduado em 1992 em Administração Industrial pela Fundação Vanzolini – Poli USP e em 2004 em Master Business Administration  pela FGV. Atualmente é Gerente de Boas Práticas e Auditorias Farmacêuticas no SINDUSFARMA - Sindicato da Indústria de Produtos Farmacêuticos no Estado de São Paulo, onde é responsável por coordenar grupos de trabalho sobre Consultas Públicas da área técnico-regulatória, workshops técnicos, a elaboração de livros técnicos e a coordenação do Prêmio Sindusfarma de Qualidade Analítica e do Prêmio Sindusfarma de Qualidade de Fornecedores da Indústria.

Adoption of the ICH Q8, Q9 and Q10 Guidances

Adoption of ICH Guidelines Q8, Q9 and Q10:
a real need today

 *Jair Calixto

**Lauro D. Moretto

1.    INTRODUCTION                                                               

     Throughout XX century, the notion of quality has undergone three major modifications. It started with the old concept of "analyzed quality" i.e., completing the manufacturing process; the excellence of a product was determined by analysis.

     However, as there were many drawbacks of this approach (both logistical and technical), in the middle of the century it was replaced by the idea of ​​"manufactured quality​​".The essential was to define a manufacture a procedure that would work, and then repeat it exactly the same way. The process validation was the resource used to verify that effectively had a process in place to get the product. The analysis was restricted to a secondary role.

     At the end of XX century, the notion that quality should be "manufactured" arises, but only after having been "conceived". The concept is that a poorly designed product is unlikely to have quality, even if it is manufactured and analyzed under the best quality concepts. The new philosophy establishes the concept that quality is initially designed (in product, in process and in control) and then is manufactured, controlled and evaluated, which is known as "global or integrated quality."

2.    NEW INITIATIVES

                                                                                                 

            In August 2002, the Food and Drug Administration (FDA) announced a new initiative known as "FDA  Pharmaceutical cGMPS for the 21 century– a risk-based approach”. The intention was not to propose new GMPs, but interpret them in a more "modern" and "scientific" manner.

        In the international scope of this initiative developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) are government agencies and industry associations from the United States, European Union and Japan.

        ICH has no regulatory autonomy. As a result, developed and approved guidelines have been internalized by FDA (United States), EMA (European Union) and PMDA (Japan). ICH Q11 document is still in draft phase.

3. IMPORTANCE OF THE ADOPTION OF THE NEW QUALITY SYSTEM

            ICH guidelines reflect the new thinking about the quality of medicines in the world and, as already demonstrated above, it was internalized in Japan, U.S. and Europe.
            As Brazil has not taken this initiative yet, it is important that these guidelines are incorporated into the regulatory framework, so that companies and professionals interested may learn and study them.

The future manufacturing procedures, control and medicine marketing will have to base on these new guidelines, which should bring great benefits to companies, beyond those intrinsic to Guides, mainly addressed to patients.

            The various reasons why the guidelines will bring greater agility and safety to procedures may be extracted in these Guides, when performing a deeper analysis. We may classify them into two areas: Quality and Global Harmonization. 

1^st aspect: Quality

Change from Product-Based Focus  to Patient-Based Focus

• The greatest interest is to achieve the desirable requirements for patients,                                  providing them security in medicine use. 

Continual Improvement

• Establish policy and philosophy. Ongoing effort to improve process,  product and services.

Risk Management

• Transient establishment of control points based on prior knowledge, history and perception to risk analysis associated with each process step. 

Knowledge Management

• Personal: managing personal competences acquired and enable continued development.
• Product: specific learning to each registered product throughout its Life Cycle, serving as a tool for Continual Improvement.

Regulatory flexibility

• Implement mechanisms that provide the independence of the process. 

Proven and Extended Work Ranges

• Ensuring product quality and drastically reduce quality deviations, expanding ranges of specifications and CCPs through the use of modern techniques such as Design of Experiments.

Decisions Based on Scientific Knowledge

• Rescue attitudes based on science, rather than empirical attitudes, with no   scientific basis.
• 
  
• Decisions on quality through the use of good science.

• Establishment of standards and specifications using risk analysis.

            The adoption of these concepts will bring, as an immediate consequence, several direct and indirect benefits to product, patient and company, the most important:

• strengthen product quality;
• increasing patient safety;
• improvement in company's image;
• increase in employee morale;
• process robustness;
• reduction of quality deviations and post-registration changes;
• reduction in the number of complaints and returns;
• recognition or increase in perceived product quality.
• Other indirect benefits may also be related when analyzing ICH guidelines.

2^nd aspect: Global Harmonization

Ø  Harmonization of  Good Manufacturing Practices technical requirements;

Ø  Harmonization of pharmacopoeial specifications;

Ø  Harmonization of inspection for the purpose of GMP certification;

Ø  Standardization of regulations that affect production and medicines control on a global level;

Ø  Improving medicines quality on a global level;

Ø  Facilitating medicine marketing;

Ø  Integration of various international regulatory agencies;

Ø  Uniformity in combating fraud in medicines;

Ø  Improving access to medicines in different countries;

Ø  Establishment of unique requirements for traceability and authenticity of medicines;

Ø  Implementation of procedures for mutual recognition of GMP certification  between different regulatory agencies.

4.    MAIN GUIDE CONCEPTS

ICH Q8 (R2) – Pharmaceutical Development

            One of the concepts on the Guide ICH Q8 (R2) is the establishment of quality in medicine development, attributing high importance of correctly setting the specifications and Critical Quality Attributes (CQAs) of active pharmaceutical ingredient and finished product, with implicit qualification and suppliers’ evaluation of critical components.

            In the universe of raw materials, it becomes necessary suppliers qualification, where are evaluated their quality system, adherence to the specifications and to the customer quality system, the treatment that is given to the need of Continual Improvement of their processes, how they resolve customer complaints, through a formal investigation of deviations and gaps, and how they apply corrective, preventive and contingency actions (CAPA System = "Corrective Action, Preventive Action") required. 

Quality by Conception (Quality by Design) e Conception Space (Design Space)        

            Quality must be planned since the design of the product. Thus, Guide ICH Q8 (R2) introduces a new model for achieving quality, which is through a process called Quality by Design (QbD). Quality by Design is part of a larger and more complex universe, the Design Space (DS).

            Therefore, the quality should be established during the product design using the Design Space and its tools as a field of work.

            To better understand this topic, it is necessary to explain the importance of variables. The critical variables of inputs and Critical Process Points (CPCs) must be known to avoid they adversely affect CQAs of final product and, consequently, product quality.

            Two approaches are acceptable for this:

            - The first, more simple and traditional, is to establish the acceptable allowable range for each critical variable. Product quality is maintained to the extent that the variables remain within the range.

            - The second is the DS. The aim is to integrate all the information (input variables, process parameters and finished product specifications) in a space in which all the essential CQAs are satisfied and where, consequently, product quality is assured.

            EC determination requires to develop a major research work, because it supposes to submit to test variations behavior in face of the variations of each one. Therefore, statistical techniques are used for Design of Experiments (DoE), which promise to limit the number of required experiments.

 

Knowledge Space - KS

Design Space – DS

Normal Operation Space - NOS

Figure 1 – Demonstration of Design Space in Knowledge Space (adapted by Emil Ciurczak and Maria Teresa Cruañes)

           
            It can be observed that Design Space is a space larger than Normal Operation Space. Normal Operation Space has the security of Design Space. Any change within Design Space is not considered changes in post-registration procedures. Moving out of Design Space assumes a post-registration regulatory process.

Knowledge Space (KS): extensive knowledge of the impact and interaction of input variables (material, process, environment) of CQAs products.

            Design Space (DS): range of conditions within KS which ensures that the product find CQAs.

            Normal Operating Space (NOS: operating range within DS that is applied during manufacture routine.

            Although DS may be graphically represented, the ideal would be to establish a predictive mathematical model.

            It’s important to remember that authorities do not require registration of Design Space. It's just one possibility for registration applicant.

            DS main advantages are:

• A more robust process;

• Better knowledge of the product;

• Greater flexibility in production;

• Decrease in post-registration alterations;

• Increased confidence in product quality by regulatory authorities.

            EC is applicable to both new products as the old ones and all dosage forms, even the more complex, such as solid, are preferred.

Continual Improvement

            Another important point is the implementation of Continual Improvement in manufacturing processes, systems, materials and products, maintaining a criticism routine aimed to evolution and  increasingly higher comprehension of quality parameters.

            The process of Continual Improvement is more than a work tool. It is a philosophy of quality, where the company, as a whole, is focused on improving its procedures, processes and products. This philosophy intends that people be prepared to evaluate, at any moment, the parameters that measure the quality, performance, productivity, costs, defects, failures, and especially customer complaints.

            On table in Figure 2, there is a list of potential sources that contribute to Continual Improvement of products:

Source of Improvement

External Audits

Internal Audits

Quality Deviations (related to GMP)

Non-conformities

Customer Complaints

Gatherings

Failures

Out of specification results

Periodic Product Review

Figure 2 – Table: Sources of Continual Improvement

            Precisely analyze customer complaints or carefully investigate the faults and quality deviations leads the company to climb steps toward improvement of product quality. All the points listed above can lead product improvement and its process.

Figure 3 – Graphical interpretation of Continual Improvement and its relationship with the management of Product Life Cycle given by Jair Calixto

Management of Product Life Cycle

            The Management of Product Life Cycle is related to periodic review of both product and process to ensure its operation as established in the project, complying with the attributes of product quality. The different stages of product Life Cycle are summarized in four steps:

                        - The Pharmaceutical Development

                        - The Technology Transfer

                        - The Commercial Manufacturing

                        - The Product Discontinuation

            DS may provide flexibility that can optimize and adjust the process in accordance with the management of your quality system, as an DS is not necessarily static in nature.

            Guidelines ICH Q8 (R2) provide encouragement to the use of risk analysis tools, which help companies to establish the mentioned CQAs, pointing and determining, through a formal, critical and systematic process, the Critical Control Points (CCPs ). CCPs reports points where control interventions are needed, and more precisely establish parameters that will be controlled and that will keep the process operating as intended and desired, that is, as its DS.

             

Figure 4 – Interpretation of concept integrating of Guide ICH Q8 (R2) given by Jair Calixto

            Figure 4 explanation: Life Cycle management is a period of time where DS coexists, consisting of QbD, where the product and its process are established using DoE tools in identifying CQAs. QRM application assists in identifying CCPs and CPPs. QbD has inter-relationship with PPP, which is monitored and improved through CI and MK.

            Legend: CQA: Critical Quality Attribute. DoE: Design of Experiments. PPP: Performance of Process and Product. DS: Space Design. KM: Knowledge Management. QRM: Quality Risk Management. CI: Continual Improvement. QPTP: Quality Profile of Target Product. CCP: Critical Control Point. CPP: Critical Process Parameter. QbD: Quality by Design.

ICH Q9 –Quality Risk Management

            Guide ICH Q9 – Quality Risk Management - deals with the risk and its proper management through tools that guide the user to adopt techniques of determination, assessment and risk control. The risk analysis links the design of the manufacturing process to product quality.

            The use of risk analysis as a quality tool offers an effective assessment of the central points and of manufacturing processes and CCPs limits.

            It also assesses safety of existing products through the integration of products and processes design tools, using analysis of potential risks and an integrated quality management.

            In product development, during the establishment of specifications and CQAs, it is recommend the use of risk analysis tools for an evaluation of points and parameters subject to process control that will assist in security, efficiency and product quality.

            Among the most important tools for risk analyses are:

          - FMEA: Failure Mode Effect Analysis

          - FMECA: Failure Mode, Effects and Criticality Analysis

          - HACCP: Hazard Analysis and Critical Control Points

            The purpose of using these tools is to find CCPs, where the dangers are and where we should exercise effective control to eliminate them.

            These tools are included in the main mechanism of risk analysis, of  Quality Risk Management (QRM), used to establish a product and its manufacturing process with quality, so as to provide the performance of planned production.

            The fundamental principles of risk analysis management are:

               i. The assessment of quality risk should be based on scientific information and finally connect it to the patient protection; and

            ii. The level of effort, formality and process documentation of quality risk management                   should be commensurate with risk level.

            Possible steps used to initiate and plan a quality management process may include:

            • Defining the problem and/or risk factor, including appropriate assumptions that identify potential risk;

            • Gather prior information and/or data of relevant potential risks, danger or personal impact for risk analysis;

            • Identify a leader and necessary resources;

            • Specification of term, results and appropriate level of decision-making for process of risk management.

ICH Q10 – Pharmaceutial Quality System

                Guide ICH Q10 - Pharmaceutical Quality System - describes a model for an effective system of quality management in the pharmaceutical industry, valid for all stages of Life Cycle and applicable both in the manufacture of Active Pharmaceutical Ingredients (APIs) and excipients, as in pharmaceutical products.

               
            The following components belong to ICH Q10:

                 

                a. Quality Manual;

               
            b. Responsibilities of management towards quality;

                 

                c. Establishing a quality policy (intentions regarding quality);

                 

                d. Quality Planning (alignment with the company's strategic plans);

                 

                e. Quality management (resources, communication, review, management);

                 

                f. Continual Improvement Process.

                 

                The Quality Manual is a tool for formatting of pharmaceutical product quality process, which describes the activities performed within the organization, with summarized presentation of all procedures, scripts, procedures, manuals, instructions and other documents approved in the productive area, that will form the basis of quality process and product organization. It includes:

               
            (a) Quality policy;

                (b) The purpose of Pharmaceutical Quality System;

                (c) Identification of Pharmaceutical Quality System and its processes, as its sequences,                relationships and interdependencies;

           (d) Management responsibilities within Pharmaceutical Quality System.

Facilitators

            Pharmaceutical Quality System provides two important tools.

            Knowledge Management (with product and process knowledge being managed from the development, during marketing product´s life, including its withdrawal from the market) is a systematic procedure for acquisition, analysis, storage and dissemination of information regarding the products, manufacturing processes and components.

            Quality Risk Management, an integral part of an effective pharmaceutical quality system, can provide a propositional procedure for identification, scientific evaluation and control of potential risks to quality. It facilitates Continual Improvement of process performance and product quality throughout its life cycle, whose principles are provided by Guide ICH Q9.

            The elements described below may be required in part, under regional GMP regulations. However, Guide ICH Q10 aims to be the highlight of these elements in order to promote Life Cycle approach to product quality:

o   Process performance and product quality monitoring system;

o   Corrective action and preventive action (CAPA) system;

o   Change management system;

o   Management review of process performance and product quality.

             

Figure 5 – Interpretation of concept integrating of Guide ICH Q10 given by Jair Calixto

            Figure 5 explanation: the main blocks of Guide ICH Q10 are: Pharmaceutical Quality System, Continual Improvement, Continual Improvement of Pharmaceutical Quality System and Liability Management.

            Legend: PLC: Product Life Cycle. MLC: Management of Life Cycle. KM: Knowledge Management. QRM:  Quality Risk Management. QM: Quality Manual. CI: Continual Improvement. PQS: Pharmaceutical Quality System.

(5) TOTAL QUALITY CONCEPT

            The set of stages throughout a product life from its conception to its withdrawal from market, ending its period of production and marketing, is known as Life Cycle.

            As a step influences the other, talking about the quality of a product only makes sense if it is applied to your entire Life Cycle.

            The foundation of Life Cycle is to design a product able to satisfy patients' needs and requirements that were specified, both physicochemical and pharmacological, and manufactured following a process in which the steps and operations have a scientific basis.

            In summary, you should:

ü  Define product profile in relation to quality, safety and efficacy;

ü  Identify product CQAs;

ü  Identify parameters and quality specifications of Active Pharmaceutical Ingredient and excipients;

ü  Set a robust and appropriate manufacturing process;

ü  Identify the attributes of materials and critical process parameters;

ü  Identify a monitoring and control strategy of critical parameters;

ü  Determine functional relationships between attributes of materials and process parameters for Critical Quality Attributes.

Figure 6 – Graphic Representation of Q8, Q9, Q10 System Integration, as interpretation given by Jair Calixto

(6) CONCLUSIONS

            The adoption of ICH guidelines mentioned in the text will contribute in an especial way the improvement in the control of medicine manufacturing, introducing new principles, new approaches and new concepts, as well as rescue concepts already known.

            New concepts like focus on patient safety, the rescue of vision and action focused on Continual Improvement, Quality Risk Management, Knowledge Management and decisions based on scientific knowledge will change the way companies and professionals will control and manage the processes and pharmaceutical products.

            This new form of management begins in development and continues throughout product life  throught:

            (1)  identification of the patients needs;

           

            (2) identification and mitigation of risks related to process and product;

           

            (3) scientific decisions during Life Cycle, in order to keep the process under control to eliminate the health risk to the patient.

            As these new approaches will reach more and more countries, it makes sense to recommend that efforts be directed toward the global harmonization of regulations implicit in these guidelines as a mechanism for standardization of GMP, GMP certifications and inspections related to them. Other harmonization related to specifications and on quality control methodologies are also, equally necessary.   

(7) REFERENCES

BOTET, Jordi. Sistema de Calidad Farmacéutica Del Siglo XXI. RCN, 2008.

CIURCZAK, Emil W. Workshop Manufacturing Initiative for the 21st Century. QbD Overview. São Paulo: SINDUSFARMA, jun.  2010.

_______________. Workshop GMP for the 21st Century - FDA initiative. São Paulo: SINDUSFARMA, jun.  2010.

CRUAÑES, Maria Teresa. Workshop Manufacturing Initiative for the 21st Century.  QbD Overview. São Paulo: SINDUSFARMA, jun. 2010.

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. ICH Q8 (R1) – Desenvolvimento de Produtos. Versão vigente da Etapa 4, datada de 10 de novembro de 2005.

____________________. ICH Q9 – Quality Risk Management - U.S. Department of Health and Human Services - Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), June 2006,  ICH.

____________________. Pharmaceutical Quality System Q10. Current step 4 version, 4 June 2008.

____________________. Pharmaceutical Development Q8 (R2). Current step 4 version, August 2009.

MORETTO, L. D.; CALIXTO, J. Diretrizes para o Gerenciamento de Riscos nos Processos da Indústria Farmacêutica. São Paulo: SINDUSFARMA, 2011. volume 13.          

______________________. Estrutura do Novo Sistema da Qualidade. São Paulo: SINDUSFARMA, 2011. volume 5.1.         

U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry. PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), Office of Regulatory Affairs (ORA), Pharmaceutical CGMPs, September 2004.

ZARDO, Humberto. Workshop Sistema de qualidade farmacêutica aplicando desenho, análise de riscos e monitoramento - Uso de ICH Q8, Q9, Q10 & CGMP XXI Century. São Paulo: SINDUSFARMA, 2008. 

_______________. Texto Gerenciamento de riscos: do desenvolvimento de produtos à cadeia de distribuição. Rev. 2, maio 2010. 

* Minicurriculum - Jair Calixto

Manager of Good Practices and Pharmaceutical Audit

Pharmacist-Biochemistry majored in 1985 by Faculty of Pharmaceutical Sciences at University of São Paulo (FCF-USP), in Industrial Business in 1992 by Vanzolini Foundation at Poli USP Master in Business Administration from FGV in 2004.

In 1972, he began his career in marketing Pharmacy. After graduating from FCF-USP, worked in the pharmaceutical industry, where he worked in Quality Assurance, Quality Control, Production and Product Development areas.

He is currently Manager of Good Practices and Pharmaceutical Audit at SINDUSFARMA - Union of Pharmaceutical Industry in State of São Paulo, where he is responsible, among other, for coordinating the working groups on Public Consultation at ANVISA of technical-regulatory area, international technical workshops, develop technical books and coordinate Sindusfarma Analytical Quality Award and Sindusfarma Quality Award of Industry Supplier.

** Minicurriculum - Dr. Lauro D. Moretto

Executive Vice-President

Vice President of Sindusfarma, President of National Academy of Pharmacy. Pharmacist-Biochemistry, with a Masters in Chemical-Pharmaceutical Technology and a doctorate degree in food science by Faculty of Pharmaceutical Sciences at University of Sao Paulo. He worked in various Pharmaceutical Companies, having held technical and managerial positions in the following companies: Johnson & Johnson, Institute Angeli of Brazil and Boehringer Angeli Chemicals and Pharmaceuticals. Responsible for Sindusfarma Education Program - PES-SINDUSFARMA. Book writer, coordinator of various technical, scientific and regulatory manual preparation, for pharmaceutical professionals working in pharmaceutical industry. Several papers published in national and international journals. Lecturer on scientific, technological and regulatory area of pharmaceutical industry.