Impacto de las Nuevas Tendencias - Latino America · PDF fileImpacto de las Nuevas Tendencias...

1Pharmapack Symposium – February 2015 - Mexico

Impacto de las Nuevas

TendenciasRegulatorias en la Producción

de Parenterales

Empaques Primarios y Tendencias Farmaceuticas para Inyectables


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


References


What is changing

in Pharmaceutical

world

Emerging Regulations

Harmonisation Principle

Quality by Design

Impact of International Tendences in Business

http://www.latinlink.com/wp-content/uploads/2014/05/Pharmaceutical-globalisation.jpg



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




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...






… 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….


… Some

impact

of

Changes

….



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."



HARMONISATION PRINCIPLES

… and what is changing in

International Regulatory Requirements??


Evaluation of Supply Chain’s Risk (US Source)

Why new rules & harmonisation?


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 &regulatory

issues

7. To improve competition on quality

8. To demonstrate consistent ToT

9. ….

The need to Hamonize



"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


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



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



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..


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 …


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


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


PQLI – Product Quality Lifecycle


Future & Trend Direction – Vision 2025


Impact on Regulatory Policies


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


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



Annex 15(Highlights)

EMAGuide Line for Process

Validation




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


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


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


ICH Q10 ‘PQS Model’


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


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


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


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


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


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


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


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


Impact Annex 15


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


“ … 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


Guide Line on Process Validation


“ …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




“ …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



“ …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



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!

mailto:gilberto.rossi@

mailto:[email protected]

http://www.latconsultores.com.ar/

mailto:[email protected]

http://www.latconsultores.com.ar/

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