52° SIMPOSIO AFI 30-31 MAGGIO
1GIUGNO 2012 - RIMINI
La qualità del farmaco
sperimentale come partner
indispensabile per la ricerca
clinica
Luciano Gambini
1
L’obiettivo di qualità del farmaco sperimentale è definito
dall’Annex 13:
obiettivo etico, principale
to ensure that trial subjects are
not placed at risk,
obiettivo scientifico
the results of clinical trials are unaffected by
inadequate safety, quality or efficacy arising from
unsatisfactory manufacture
L’obiettivo di qualità del farmaco sperimentale è definito
dall’Annex 13:
Caratteristiche riproducibili
Equally, it is intended to ensure that there is
consistency between batches of the same
investigational medicinal product used in the
same or different clinical trials
Miglioramenti qualitativi durante lo sviluppo
and that changes during the development of an
investigational medicinal product are adequately
documented and justified
Quali strumenti per ottenere gli obiettivi desiderati
Attuale ed obbligatorio
L’applicazione delle Good
Manufacturing Practice durante la
produzione ed il controllo
Attuale, desiderabile, il
futuro
Applicare le linee guida ICH :
• Q8 Pharmaceutical development
• Q9 Quality Risk management
• Q10 Pharmaceutical Quality System
• Q11 Development and Manufacture of Drug Substances
(chemical entities and biotechnological/biological
entities)
Quali strumenti per ottenere gli obiettivi desiderati
Oltre le Good Manufacturing Practice ?
Esempi : Q10 Pharmaceutical Quality System
Quali strumenti per ottenere gli obiettivi desiderati
3.1.1 Pharmaceutical Development - Q10
The goal of pharmaceutical development activities is to
design a product and its manufacturing process to
consistently deliver the intended performance and meet the
needs of patients and healthcare professionals, and
regulatory authorities and internal customers’ requirements.
Con quale sistema di qualità
Non obbligatoriamente in GMP, ma con un sistema di
qualità strutturato
Quali strumenti per ottenere gli obiettivi desiderati
3.1.1 Pharmaceutical Development - Q10
Approaches to pharmaceutical development are
described in ICH Q8. The results of exploratory
and clinical development studies, while outside the
scope of this guidance, are inputs to
pharmaceutical development
Con quale sistema di qualità
…e organizzato trasversalmente fra le varie discipline
aziendali interessate
(Medicinal Chemistry, Tox, Clinical Development,
Pharmaceutical Development)
…e che conoscono i processi e le normative applicabili
Quali strumenti per ottenere gli obiettivi desiderati
Incominciando dalla sintesi del principio
attivo – Q11
Q11 provides guidance on what information
should be provided on product and process
development and where this information
could be presented. Enhanced approach
In an enhanced approach, risk assessment and scientific
knowledge are used to select process parameters and unit operations
that impact critical quality attributes (CQAs) for evaluation in
multivariant DOE studies to establish any design space(s) and control
strategies applicable over the lifecycle of the drug substance.
Quali strumenti per ottenere gli obiettivi desiderati
Incominciando dalla sintesi del principio
attivo – Q11
Q11 provides guidance on what information
should be provided on product and process
The guideline does
development and where this information
not apply to
could be presented.
contents of
submissions for drug products during the
clinical research stages of drug
development. However, the principles in
this guideline are important to consider
during those stages as well.
Quali strumenti per ottenere gli obiettivi desiderati
Drug Substance Quality Link to Drug Product
The intended quality of the drug substance is
determined through consideration of its intended use
in the drug product as well as from knowledge and
understanding of its physical, chemical, biological,
and microbiological properties or characteristics.
The characteristics of the drug substance can influence the development
of the drug product (e.g., the solubility of the drug substance can affect
the choice of dosage form).
The Quality Target Product Profile (QTPP) and potential Critical
QualityAttributes (CQAs) of the drug product can help identify potential
CQAs of the drug substance. Knowledge and understanding of the QTPP
and critical quality attributes evolve during the course of development.
Quali strumenti per ottenere gli obiettivi desiderati
Per arrivare al Pharmaceutical Development
Information from pharmaceutical development
studies can be a basis for quality risk
management. It is important to recognize that
quality cannot be tested into products; i.e.,
quality should be built in by design.
Changes in formulation and manufacturing processes during
development and lifecycle management should be looked
upon as opportunities to gain additional knowledge and
further support establishment of the design space.
.
Quali strumenti per ottenere gli obiettivi desiderati
Per arrivare al Pharmaceutical Development
A greater understanding of the product and its
manufacturing process can create a basis for more flexible
regulatory approaches. The degree of regulatory flexibility
is predicated on the level of relevant scientific knowledge
provided in the registration application. It is the knowledge gained
and submitted to the authorities, and not the volume of data collected, that
forms the basis for science- and risk-based submissions and regulatory
evaluations.
Nevertheless, appropriate data demonstrating that this
knowledge is based on sound scientific principles should be
presented with each application.
Quali strumenti per ottenere gli obiettivi desiderati
Pharmaceutical development
should include, at a minimum, the following elements:
• Defining the quality target product profile1 (QTPP) as it relates to
quality, safety and efficacy, considering e.g., the route of
administration, dosage form, bioavailability, strength, and stability
• Identifying potential critical quality attributes1 (CQAs) of the drug
product, so that those product characteristics having an impact on
product quality can be studied and controlled
• Determining the critical quality attributes of the drug substance,
excipients etc., and selecting the type and amount of excipients to
deliver drug product of the desired quality
• Selecting an appropriate manufacturing process
• Defining a control strategy
Quali strumenti per ottenere gli obiettivi desiderati
Using the enhanced product and process
understanding in combination with quality risk
management to establish an appropriate control
strategy which can, for example, include a proposal
for a design space(s) and/or real-time release
testing
Oltre le Good Manufacturing Practice
Come mettere in pratica questi strumenti
• Superando blocchi culturali
• Compartecipazione delle diverse competenze
aziendali
• Coinvolgimento del senior management
• Collaborazione con le Autorità regolatorie