Adoption of ICH
Guidelines Q8, Q9 and Q10:
a real need today
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
ICH has no regulatory autonomy. As a result, developed and approved guidelines have been internalized by FDA (
- 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 .
AsBrazil
As
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.
1st 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.
2nd 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:
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
- 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
_______________. Workshop GMP
for the 21st Century - FDA initiative. São Paulo
CRUAÑES, Maria Teresa. Workshop Manufacturing Initiative for the 21st Century. QbD Overview. São Paulo
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
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
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 University of Sao Paulo
