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1Pharmapack Symposium – February 2015 - Mexico
Impacto de las Nuevas
TendenciasRegulatorias en la Producción
de Parenterales
Empaques Primarios y Tendencias Farmaceuticas para Inyectables
2Pharmapack Symposium – February 2015 - Mexico
International Support
Momentum Life Science™
Support in R&D
Engineering, Design & Construction Support
Qualification, Validation & Management
Technology Transfer
IT in Compliance
Business Development & Alliance
Regulatory Affairs
Quality in Outsourcing & Auditing
Training
Business Process Re-engineering
Feasibility Studies
3Pharmapack Symposium – February 2015 - Mexico
References
4Pharmapack Symposium – February 2015 - Mexico
What is changing
in Pharmaceutical
world
Emerging Regulations
Harmonisation Principle
Quality by Design
Impact of International Tendences in Business
5Pharmapack Symposium – February 2015 - Mexico
1. 50% of actual outsourcing activity will be
directed towards countries such as China,
India, Korea and other emerging countries
(where available good quality of work &
low production cost)
2. companies will invest in social media 10%
of the marketing budget.
3. Internet marketing investment will exceed
the investment in traditional media
4. American model of direct to consumer
advertising will not be imported into Europe.
... Some generic tendences of the
Global Market for 2010 to 2020...
Pharmaceutical World is Changing
6Pharmapack Symposium – February 2015 - Mexico
5. Traditional selling model will become obsolete
(informants visits = more = better relationships
with doctors = more sales)
6. Smartphones applications will become the next
big marketing opportunity (affecting business in
doctor-patient/ company-patient)
7. Patient will become more informed and aware
(patient active role )
8. The adverse effects of the drugs will be reduced
by more personalized therapies
9. Sales of drugs will remain stable in the USA and
Europe but will grow in emerging markets, which
in 2013 will be worth more than a third of the
global market
... Some generic tendences of the
Global Market for 2010 to 2020...
Pharmaceutical World is Changing
7Pharmapack Symposium – February 2015 - Mexico
Pharmaceutical World is Changing
… and more… Credit Management, Globalisation, Demographic and epidemiological pressures,
Advances in communication, Declining R&D productivity, Healthcare reforms, increments of
global population aged 65+, change of f ocus on key mature markets v/s growth markets….
8Pharmapack Symposium – February 2015 - Mexico
Pharmaceutical World is Changing
9Pharmapack Symposium – February 2015 - Mexico
… Some
impact
of
Changes
….
Pharmaceutical World is Changing
10Pharmapack Symposium – February 2015 - Mexico
Some Numbers for South America
… GlobalData stated that «in recent years» investments in
merger and acquisition strategies have soared in the continent
to the record peak of 12.7 billion dollars
… With its constant growth, in Price’s opinion, Brazil is poised
to climb up to the fourth place worldwide among the fastest-
developing healthcare markets, only outpaced by the United
States, China and Japan….
… Also favored by its belonging to Nafta area Mexico is
steadily growing too, with chances to generate a 20 billion
dollars revenue by the end of this year; and the
pharmaceutical business is also enlarging in Colombia and
Argentina…
"Brazil is the largest medical device market in Latin America, followed by
Mexico, Venezuela, Colombia and Argentina respectively."
Pharmaceutical World is Changing
11Pharmapack Symposium – February 2015 - Mexico
HARMONISATION PRINCIPLES
… and what is changing in
International Regulatory Requirements??
12Pharmapack Symposium – February 2015 - Mexico
Evaluation of Supply Chain’s Risk (US Source)
Why new rules & harmonisation?
13Pharmapack Symposium – February 2015 - Mexico
1. For a better and uniform control
2. To establish common and references
rules
3. To supply univoque parameters for both,
inspector, and producer
4. To enforce common understanding,
product knowledge, process knowledge
5. To harmonize validation activities
6. To harmonize registration ®ulatory
issues
7. To improve competition on quality
8. To demonstrate consistent ToT
9. ….
The need to Hamonize
Why new rules & harmonisation?
14Pharmapack Symposium – February 2015 - Mexico
"Coming together is a beginning.
Keeping together is progress.
Working together is success."
Henry Ford
“ …,Regulatory harmonization
offers many direct benefits to both
regulatory authorities and the
pharmaceutical industry with
beneficial impact for the protection
of public health.
… preventing duplication of
clinical trials in humans…
….streamlining the regulatory
assessment process for new drug
applications….
…. reducing the development
times and resources for drug
development…
ICH International Council of Harmonisation
15Pharmapack Symposium – February 2015 - Mexico
Q8 Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System
Q11 Development and manufacture of drug substances
Q12 Technical and Regulatory Consideration for PHARMACEUTICAL PRODUCT LIFECYCLE
Annex 11: “Good Manufacturing Practice Medicinal Products for Human and Veterinary Use” – Computerized System
Using Risk Based Approach within Integrated QMS and Quality By Design for a general better Process Understanding, enforce modern concept of Business Quality & Risk based driven pharmaceutical product development and Manufacturing
The need to Harmonize – Part of a long History
Why new rules & harmonisation?
16Pharmapack Symposium – February 2015 - Mexico
As of September 2013,
34,466 drug and device
establishments around the
world were registered with
the FDA, pursuant to section
510 of the FD&C Act. Of
these, 12,878 were based
overseas, and 3,493 of those
were drug establishments.
Real-time monitoring, rather than annual
inspections, would mean consistently higher
qualities of both medical devices and drugs.
To help ease the burden, the
FDA should join forces with
many other large-scale
organizations in monitoring
their registered locations
Pharmaceutical World is Changing
17Pharmapack Symposium – February 2015 - Mexico
1. For a better SAFETY
2. To Protect both, patient and LOCAL
INDUSTRY
3. For a FASTER Analysis / check
4. For mutual support
5. Speaking the same language
6. Requiring same controls
7. Comparing supplier, processes, final
product, report mode
8. For a SIMILAR submission
9. ..
The need to Cooperate, in a GLOBAL environment
… So, New Rules & Harmonisation..
18Pharmapack Symposium – February 2015 - Mexico
PQMS, PQLI, QUALITY BY DESIGN
… and what is changing in
International Regulatory Requirements??
….. FDA and EMA protect and promote public and animal health, through evaluation and supervision of medicines for human and
veterinary use. They want to expand the public’s knowledge of medicines, medical devices, and cosmetics, so they have been
closely collaborate in development of standards.
Process validation is not ANYMORE as a one-off event.
A lifecycle approach should be applied couple product and process development, validation of the commercial manufacturing
process and maintenance of the process in a state of control during routine commercial production …
19Pharmapack Symposium – February 2015 - Mexico
This Guide is the first in a series of ISPE Product Quality Lifecycle Implementation (PQLI®)
Good Practice Guides (GPGs) that will describe enhanced, quality by design approaches
to product realization, and is an introduction to and an overview of the Guides Series.
Product realization is the achievement of a product with the quality attributes appropriate to
meet the needs of patients, health care professionals, regulatory authorities… (including
compliance with marketing authorization), and internal customers’
This Overview Guide and the subsequent ISPE PQLI GPG Series address product and
process development, transfer to, and establishment of, commercial manufacture using
science- and risk-based approaches. Other Guides in the Series will cover:
Critical Quality Attributes and Critical Process Parameters
Design Space
Control Strategy
Illustrative Example using a Small Molecule Case Study
The Guide uses ICH Guidelines Q8 (R2), Pharmaceutical Development, Q9, Quality Risk
Management, and Q10, Pharmaceutical Quality System as a basis, together with other
relevant ICH Guidelines.
PQLI – Product Quality Lifecycle Implementation
20Pharmapack Symposium – February 2015 - Mexico
Quality cannot be
tested into products;
it should be built-in or
should be by design
(QBD)”
“Design” in Quality by Design..
21Pharmapack Symposium – February 2015 - Mexico21
Quality by Design: identifying
Process Issues, CQA, CPP
Design Space: identifying possible
ranges, using DoE
Risk Management: To better
identifying Process & Controls Risks
Continuous Improvement:
establish how to analyze data and to
improve efficiency of analysis
Integrated System Approach:
Using Process & Process
Knowledge to establish Continiuos
Monitoring
Real Time Release: identifying
Process Issues, CQA, CPP
Component Summary(an example of In & ON Process Control)
PQLI & PAT
22Pharmapack Symposium – February 2015 - Mexico
PQLI – Product Quality Lifecycle
23Pharmapack Symposium – February 2015 - Mexico
Future & Trend Direction – Vision 2025
24Pharmapack Symposium – February 2015 - Mexico
Impact on Regulatory Policies
25Pharmapack Symposium – February 2015 - Mexico
Impact on Regulatory Policies
26Pharmapack Symposium – February 2015 - Mexico
MEDICINE selection criteria
Regulatory Agency & Government are
introducing criteria to reduce public
expenses respecting criteria's barriers
1. Quality (efficacy, accuracy, document
control)
2. Availability of R&D, Process, Clinical,
Analytical Price
3. (Best available price)
4. Documented production Consistency
5. Availability
Parameters for Medicine Selection
27Pharmapack Symposium – February 2015 - Mexico
Re-enforce control capability through specific
evidence requirement on Process & Product
Knowledge & Validation
Improve AUDIT method & efficacy through
Cooperation & interchange of Information
Using Harmonized Standard
Improve & harmonize regulatory requirements for
submission & clinical evidence, even for generics
Introducing generic regulation access policy into
government program, re-enforcing principle of
equivalence, efficacy, quality, documentation
Speed up Regulatory Process using Harmonized
Policy
Impact on Regulatory Policies
28Pharmapack Symposium – February 2015 - Mexico
Annex 15(Highlights)
EMAGuide Line for Process
Validation
29Pharmapack Symposium – February 2015 - Mexico
EU Directive 2001/83
ANNEX 15 – European Commission Health
and Consumer Directorate-General (Eudra Lex, the rules governing medicinal products
in the European Union, Volume 4, EU Guidelines for
Good Manufacturing Practice for Medicinal Products
for Human and Veterinary Use)
Annex 15: Qualification and Validation
“...Principle of Qualification and Validation
applicable to Facilities, Equipment, Utilities
and Process used for manufacture of
Medicinal Product...”
Guideline on process Validation for Finished Products (information
and data to be provided in regulatory Submission) –
EMA – European Medicine Agency - New Requirements and Guideline for
Validation, introducing and re-enforcing Process Understanding, Process
Control, Product Quality through RB Approach
Annex 15 & EMA Validation Process Guideline
30Pharmapack Symposium – February 2015 - Mexico
Continuous Process Verification
Hybrid Approach
Design Space Verification
Scale-Up
Post Approval Change Control
Standard v/s NON standard
methods of Manufacture
EMA Guide Line on Process Validation
31Pharmapack Symposium – February 2015 - Mexico
Pharmaceutical Development (Q8)
Past: Data transfer / Variable output
Present: Knowledge transfer / Science
based / Consistent output
Quality Risk Management (Q9)
Past: Used, however poorly defined
Present: Structured Process Thinking
Pharmaceutical Quality Systems (Q10)
Past: GMP checklist
Present: Quality Systems across product
life cycle
Changed
Paradigm
Incremental Steps
32Pharmapack Symposium – February 2015 - Mexico
ICH Q10 ‘PQS Model’
33Pharmapack Symposium – February 2015 - Mexico
Control Operation through QUALIFICATION and
Validation over PRODUCT & PROCESS LIFECYCLE
.. Planned Changes.. For Facilities, Equipment, Utilities &
Processes which may effect Product Quality should be
documented- Impact Assessment REQUIRED
… COMPUTERIZED SYSTEM used for the manufacture
of medicinal products should be validated according with
EU Annex 11…
ICH Q8, Q9, Q10, Q11 OR Other system .. Guaranteeing
the same level of product quality & security should be
used to support validation & qualification..
Data supporting qualification &/or validation studies
obtained from external sources needs to be verified
(Provider own Validation &/or in place data controls
procedures)…
Impact Annex 15
Basic Principles
34Pharmapack Symposium – February 2015 - Mexico
Planned Qualification & Validation Activities,
taking into account
Equipment, Process & Product Life Cycle
(… Processes Impact Components)
Approved Validation Procedures & Trained
Personnel
Precise Responsibility within the “involved”
personnel
(… NOT only QA &/or Validation Manager)
VMP as a key element of the required
Policy/Approach
Impact Annex 15Organizing & Planning Validation Activities
35Pharmapack Symposium – February 2015 - Mexico
VMP has to contain:
Validation Policy
Organizational Structure of Validation Activity
On site Facilities, System, Equipment, Processes summary &
validation status
Template for verification documents
Planning
Change Control and Deviation Management policy references
Acceptance Criteria
References to existing documents
Assessment of required resources
Validation Strategy (incl. Re-Validation & Re-Qualification)
Statement on Materials, support, suppliers qualification level
(appropriate)
Complex Projects may require separate VMP
Quality Risk Management use and QRM improvement life-cycle
Policy
Design
Qualification
Factory /Site
Acceptance
Operational
Qualification
Performance
Qualification
Installation
Qualification
VA
LID
AT
ION
MA
ST
ER
PLA
N
Organizing & Planning Validation Activities
Impact Annex 15
36Pharmapack Symposium – February 2015 - Mexico
Knowledge Management – Good Document
Practice
PQMS will define Documents’ Life Cycle (including
Doc. Role & responsibility)
Inter-relationship document approach required (e.g.:
Traceability matrix. Doc hierarchy)
Validation protocols will includes CSA (Critical
System Attributes) and Acceptance Criteria
Harmonization and Alignment between Company
Policy & Provider Verification Docs
Protocol and Validation report Changes & Deviation
and Conclusion have to be formally recorded and
supported by scientific analysis and investigation
(within Change Control Procedure)
Validation Life Cycle: URS, DQ, FAT/SAT, IQ, OQ, PQ
Document Management
Impact Annex 15
37Pharmapack Symposium – February 2015 - Mexico
N.B.: Life Cycle Approach to link Product & Process Dev – Validation of
Commercial manufacturing Process & Maintenance of Process State of
control for routine production
Traditional Approach OR Continuous verification Approach (processes robustness for consistent product quality)
Proof of Process Robustness & Prospective Validation PRIOR to
product marketing
New Product Process Validation should cover all TARGET
market strength
Technology Transfer, Product Transfer, Product Updates
should be documented in Marketing Authorization document (and its
variation)
Product Validation – CQA and CPP – to ensure Validation Status and
Product Quality – trough scientific basis and risk assessment
Number of Validation Batches – and size of validation Batches can be
justified by Risk Assessment and Continuous Monitoring
Process Validation – All Pharmaceutical Dosage Form -EMA Guideline for Process Validation)
Impact Annex 15
38Pharmapack Symposium – February 2015 - Mexico
Facilities, Systems and Equipment used for Process Validation should be
validated and test methods should be validated
Process Knowledge from Development Studies should be accessible to
manufacturing site.. And should be the basis for Validation activities (tech.
transf.)
Process Validation Batches must be done by Trained production Personnel
Supplier should be qualified under Quality Risk management procedures
prior Validation Batches (including packaging materials)
Design Space Justification – Mathematical (Statistical) Models used to
confirm a state of control should be available
Concurrent Validation ( incomplete validation for exceptional cases) –
justified in approved VMP and supported by sufficient (& consistent) data
(uniformity, and comply defined acceptance criteria) – may be acceptable
(document should be available to the QP)
Organizing & Planning Validation Activities
Impact Annex 15
39Pharmapack Symposium – February 2015 - Mexico
Nr. Of Batches under routine conditions required and based on Risk
Management Principles
The minimum of three batches could be changed in case of similar product
or processes already used and validated into the same site/line
Process Validation Protocol – using defined CPP & CQA (Documented
Product/Process Knowledge)
Included into Validation Protocol:
Short Process description
CQA summary
CCP and limits
other justified NON critical attributes
list of equipment and calibration
status
analytical (validated) methods
In Process Control
Additional testing
Sampling plan
Evaluating/recording methods
Batch release certification process
Function & responsibilities
Timing
Traditional Approach to Validation
Impact Annex 15
40Pharmapack Symposium – February 2015 - Mexico
Quality by Design Approach – QbD development allows routine
process controls with high degree of Product Quality Assurance –
Continuous Process Verification used as an alternative to
Traditional Process Validation
Continuous Process Verification:
• Required Attributes for Incoming Materials
Science Based Control Strategy
• Product RealizationCQA,CPP
• In- Process Control
• On-Process Control
• At-Process Control
PAT&
Multivariate Statistic
Continuous Process Verification
Impact Annex 15
41Pharmapack Symposium – February 2015 - Mexico
Monitoring Product Quality showing life cycle
state of control, analyzing process trends
Verification change and improvement of
Frequency and extension of Process Verification
using increased Process Understanding
On Going Process Verification Protocols (&
Report) also supported by statistical tools
(Variation & State of Control)
PQR should be supported by On Going Process
Verification
On Going Process Verification monitoring
incremental changes in Product Life Cycle
On-Going Process Verification
Impact Annex 15
42Pharmapack Symposium – February 2015 - Mexico
“ … in line with ICH Q8, Q9, Q10 … and the possibility to use
Continuous Process Verification in addition to, or instead of,
traditional process validation described into previous guideline has
been added and is encouraged.”
“ … dos NOT introduce new requirements on Med. Products …..
But clarify how companies can take ADVANTAGE of the new
possibility given when applying enhanced PROCESS
UNDERSTANDING , COUPLED WITH Risk Management tools,
under an Efficient QUALITY System…”
Process validation as described into ICH Q7
Continuous Process Verification has been introduced to cover
an alternative approach to Process Validation based on a
CONTINUOUS MONITORING OF MANUFACTURING
PERFORMANCES”
Approach based on Product & Process Development studies
Knowledge &/or previous manufacturing experience.
… Applicable to both traditional & enhanced approach to
Pharmaceutical Development
Continuous Process Verification
Guide Line on Process Validation
43Pharmapack Symposium – February 2015 - Mexico
“ …Process validation should NOT be viewed as a ONE-OFF event; have to
incorporates a Life Cycle Approach, linking all phases of Product life cycle;
Guidance on Process Validation Information and data to be Provided in Regulatory
Submission (finished dosage form – chemical medicinal product – Human & Vet.),
joint with ICH Q11 recommendation;
Applicable also on Biological, with the appropriate approach due to the Bio
Substances;
Regulatory Submission information;
• Process DesignICH Q8R2
• Manufacturing ProcessValidation
EMA Guideline forProcess
Validation
• On-Going Process VerificationEU GMP Annex 15
Continuous Process Verification
Guide Line on Process Validation
44Pharmapack Symposium – February 2015 - Mexico
“ …Manufacturing Process Should be Validated prior Marketing..
Process Validation should confirm the adequate Control Strategy
and the adequate Product Quality
.. For all TARGET market strength, for all sites, for all product…
(to demonstrate the adequate site’s control strategy)
Continuous Process verification … a risk-based real-time
approach to verify and demonstrate that a process operate within
pre-defined specific parameters (CQAs) and control strategy
requirements (CPP);
… in-line, at-line, on-line , trends , PAT
… should be influenced by
Prior Development & manufactory Knowledge
Process understanding gained by manufacturin experience
Product / Process Complexity
Technology & Process Automation
(legacy) process robustness, manufacturing history ..
General Consideration
Guide Line on Process Validation
45Pharmapack Symposium – February 2015 - Mexico
“ …Hybrid Approach and Traditional approach have to be
described into dossier, and have to be clear where (step) it is
used one or the other;
.. Traditional approach may requires Design Space
verification
… Continuous Process Verification, allows validity of
design space throughout the Product Life Cycle
.. Design Space
“ …scaling Up from laboratory though Pilot up to Industrial
scale (Normal Operating Range).
.. Those part must be described into Dossier (3.2.P.2 –
3.2.P.3) ..
… Ranges of Batches Proposed – justify that scaling up
batches sizes NOT Alters Homogeneity of CQAs
.. Scale Up
Other Consideration
Guide Line on Process Validation
46Pharmapack Symposium – February 2015 - Mexico
Gilberto Rossi [email protected]
+39.348.7216946
+54.911.50608387
www.latconsultores.com.ar
Leandro [email protected]
+54 911 5934.0673
+54 11 4796.5510
www.latconsultores.com.ar
... Thanks for your attention!