Corso di Laurea Magistrale in Chimica e Tecnologia...

Prof. Andrea Gazzaniga

The Quality System in a pharmaceutical company

Corso di Laurea Magistrale in Chimica e Tecnologia Farmaceutiche – E25

Fabbricazione Industriale dei Medicinali – 4 CFU

Sezione di Tecnologia e Legislazione Farmaceutiche Maria Edvige Sangalli

Dott. Alessandro Regola

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The Quality System

in a pharmaceutical company

Alessandro Regola – Qualified Person

Intendis Manufacturing SpA, Bayer Group

Segrate (Milano)

October 2013

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Introduction

Commercial Manufacturing (ICH Q10)

The goals of manufacturing activities include :

- achieving product realization

- establishing and maintaining a state of control

- facilitating continual improvement

The pharmaceutical quality system should assure that :

- the desired product quality is routinely met

- suitable process performance is achieved

- the set of controls are appropriate

- improvement opportunities are identified and evaluated

- the body of knowledge is continually expanded

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Introduction

Quality

• Every pharmaceutical product has established identity,

strenght, purity, and other quality characteristics designed to ensure the required levels of safety and effectiveness (FDA guideline on Quality Systems)

• Degree to which a set of inherent characteristics (of a product, process or system) fulfils requirements (ISO 9000:2005; ICH Q9-Q10)

• A measure of a product’s or service’s ability to satisfy the customer’s stated or implied needs (FDA guideline on Quality Systems)

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Introduction

Quality of a pharmaceutical product

• Pharmaceutical (chemical and microbiological purity, assay,

physical properties, technological performance)

• Regulatorial (compliance with the Marketing Authorization and

to applicable laws)

• Medical (safety and efficacy)

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Introduction

Evolution of the approach to Quality

Final Quality Control

+ In Process Control

+ Quality Assurance

+ Risk evaluation and management

+ Quality by Design

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Introduction

Why is Quality important ?

• Safety and efficacy of the product

• Patient compliance

• Achievement and maintenance of Manufacturing and Marketing Authorizations

• Achievement and maintenance of market share (customer satisfaction)

• Stipulation and maintenance of contracts with third parties

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Introduction

Quality (Management) System

• Management system to direct and control an organization

with regard to quality (ISO 9000:2005; ICH Q10)

• The organizational, procedural and structural measures

implemented to assure :

– the quality of products and services,

– the customer satisfaction,

– the continual improvement

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Introduction

Why is a Quality “System” necessary ?

• To assure compliance of products to cGMPs (EU, USA,

Japan, Other Countries)

• To assure compliance of products to Marketing Authorizations

• To establish a continual improvement process

• To establish a system to promptly and effectively reacting to

non conformance situations

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References

• Mandatory regulations

– EU GMP

– USA GMP

– Other GMPs (China, Brasil, Canada, WHO)

– GDP (Good Distribution Practices)

– Laws governing pharmaceutical products

– Pharmacopoeias

– Regulatory and GMP guidelines

• Voluntary regulations

– ISO 9000 series (9000, 9001 and 9004)

– Industry / Academy guidelines (PDA, ISPE, BS, IPEC, etc)

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References

Regulations specifically referred

to the Quality System

• EU GMP, Part I, Chapter I (Finished Products)

• EU GMP, Part II, Chapter I (Active Ingredients)

• FDA Guidance for Industry : Quality Systems Approach to

Pharmaceutical cGMP Regulations (09.2006)

• ICH Q10 (EU GMP Part III)

• ISO 9000 series (9000, 9001, 9004)

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Objectives

• Quality of products and services : – products (medicinal products)

– services (distribution, farmacovigilance, complaints handling, scientific information)

• Customer satisfaction : – Patients

– Medical doctors

– Pharmacies

– Hospitals

– Wholesalers and Distributors

– Other pharmaceutical companies (contract manufacturing)

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Objectives

Continual improvement :

– Efficacy (capacity to supply the product and / or the service

required)

– Efficiency (costs)

– Quality (quality level of products and services)

A system to measure and monitor the continual

improvement must be implemented

performance indicators

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Objectives

Continual improvement (ICH Q10)

of process performance and product quality

of the pharmaceutical quality system

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Monitoring of quality

Performance indicators

• Efficacy (related to degree of targets achievement)

• Efficiency (related to resources used to achieve targets)

• Quality (related to quality level of products or services)

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Performance indicators (Processes and Products)

Example : production and release process of

product «A»

• Efficacy : number of returns / recalls

• Efficiency : time to release

• Quality : % released batches / manufactured batches

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Performance indicators (Quality System)

Example : market complaints handling

process

• Efficacy : % complaints investigated timely (e.g. in 30

days)

• Efficiency : hours used for investigation / complaint

• Quality : % investigations successfully completed

(e.g. with identification of root cause of quality defect)

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Product Quality Review (EU GMP, chapter 1.5)

Critical revision of :

o Starting materials and packaging materials

o In process controls and finished product testing

results

o Rejected, reworked, reprocessed, repackaged

batches

o Significant deviations and related investigations

o Changes (composition, process, analysis)

o Variations to Marketing Authorizations

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Critical revision of : (continues)

o Stability studies

o Returns, complaints and recalls (with related

investigations)

o Corrective actions (on the process or equipment)

o Post-marketing commitments with Health Authorities

o Qualification of equipment and systems

o Contracts / quality agreements with third parties

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o Trend analysis (trends, shifts)

o Process capability analysis

o Identification of recurrences

o Evaluation of efficacy of corrective and preventive

actions

o Definition of additional corrective and preventive

actions

o Initiation of changes / improvement plans

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Elements

1. Management responsibility / involvement

2. Resources management

3. Productive activities (Products and Services)

4. Control and Monitoring

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Elements

Management responsibility / involvement

• The Quality System must be sponsorized and supported by the Upper Management (alignment of quality system and strategical plans and economical objectives of the company)

• The Upper Management must be involved in the definition and of the handling of the Quality System :

– Roles and organization charts

– Improvement targets

– Periodic review of the system efficacy and efficiency

– Periodic review of quality indicators, significant non conformities and quality problems, results of internal audits and inspections by third parties

• The Upper Management must assure the resources necessary for the Quality System management

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Elements

Management responsibility / involvement

• A periodic Management Review of the quality system must

be performed by the management :

– to review the quality of products and processes

– to review the efficacy and efficiency of the Quality System

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Organisation - Personnel

Fundamental functions

• Qualified Person

• Quality Assurance

• Quality Control

• Production / Operations

• Procurement / Purchasing

• Logistics / Distribution

• Project Engineering

• Maintenance

• Validation (calibration, qualification, computer validation, process and cleaning validation)

• Development (analytical, pharmaceutical, process)

• Regulatory Affairs

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Qualified Person

Assurance of production and distribution according to GMP and Marketing Authorization

Information to Health Authorities of any significant quality problem on products on the market

Tasks : – Approval of production (Master Batch Records) and analytical

(Analytical Methods and Quality Specifications) documentation

– Approval of changes

– Release of finished products for the market (or for investigational use)

– Evaluation of product defects and process deviations

– Evaluation and review of market complaints

– Recall of batches / products from the market (of from investigational use)

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Quality Assurance

– Management of Quality System

– Documentation management

– Internal and external auditing

– Market complaints handling

– Management of non-conformities (deviations & investigations)

– CAPA (corrective / preventive actions) system management

– General training on GMP

– Batch records review (for batch release)

– Product Quality Reviews

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Quality Control

– Sampling (plan, execution)

– Analytical testing

– Approval of starting materials, packaging materials,

intermediates, bulk products, finished products

– In process controls

– Monitoring of utilities

– Environmental monitoring

– Analytical results trending

– Stability studies (follow-up)

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Elements

Resources management

Resources

• Personnel (training, qualification, motivation)

• Equipment and premises (design, calibration, qualification,

maintenance, cleaning)

• Products (formulations, processes)

• Materials (suppliers, specifications)

• Documentation, methods e specifications

• Technological-scientific know-how

• Economical resources

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Elements

Resources management

Outsourcing

• Resources can be identified outside the company (service

providers, contract manufacturing and analysis, rent workers, etc. )

• The company keeps the responsibility of the outsourced acitivies (performed outside or internally by third party personnel)

• The outsourced activities must be regulated by contracts and / or quality agreements

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Elements

Productive activities

• Design and development of products and processes

• Definition of Design Space and Control Strategy

• Control of starting materials (active ingredients, excipients,

utilities, packaging materials, shipping materials)

• Performing and monitoring productive processes

(validation, in process control, critical parameters control,

recording and revision of process data, PAT)

• Management of non-conformities / deviations

• Change management

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Elements

Control and Monitoring

• Data analysis (trend analysis, product quality review,

revision of design space and control strategy)

• Internal auditing

• Risk analysis

• Corrective actions

• Preventive actions

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Non conformities

Prevention of non-conformities

• The modern interpretation of GMP requires prevention of

non conformities of products and processes

• Prevention is preferred over handling of non conformities as it is more ethical (safer for patients) and more economical

• The modern quality systems are now designed to prevent non-conformities but have to assure the management of unavoidable deviations and quality problems

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Non conformities

Prevention tools / systems

• Quality of product / process development

• Documentation system

• Personnel selection and training

• Design, test and validation of equipment and processes

• Maintenance of systems, premises and equipment

• Selection and control of suppliers and service givers

• Internal and external auditing

• Preventive actions

• Change management

• Risk management

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Non conformities

Handling of non-conformities

• The occurrence of non conformities is practically

unavoidable

• Every company must be ready to timely and effectively handle the non conformities

• A suitable and effective system for identifying and recording of non conformities and for their communication to competent and responsible functions (escalation process) must be in place and should be periodically tested.

• The training and involvement, at different levels and with different modes, of all personnel performing GMP activities on non- conformities handling and the possible consequences on patients must be assured

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Non conformities

Handling of n.c. : tools / systems

• Deviations (product and non-product related)

• Repair (of equipment)

• Complaints (quality and medical)

• Rejections

• Reworking, reprocessing, repackaging, rechecks

• Returns (quality related)

• Distribution stop / Batch or product recall (quality related)

• Corrective actions

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Non conformities

Handling of n.c. : procedure

Every non-conformity must be :

– Immediately treated and corrected (if possible)

– Timely communicated to the competent company functions and, if applicable, to Health Authorities

– Investigated to identify the root cause and to remove it (with a suitable corrective action)

– Evaluated for its impact on the quality of the batch(es) / product(s) involved

– Recorded including all consequent activities to assure traceability (corrections, investigations, decisions, corrective actions, product disposition)

– Periodically evaluated together with all other deviations (to identify trends and recurrences)

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