Global integrated development of new medicines;

Quality management

Márta Vajdai PharmD

Quality Manager, Internal Audit EMEA

PPD, Global Quality & Compliance 1

Medicinal Product

• As defined by EU laws:

Any substance or combination of substances presented as having properties for treating or preventing disease in human beings

• Must be approved/registered before allowing to be marketed

• Safety, efficacy and quality must be ensured

The role of the Regulatory Agencies to protect the health and safety of the population

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Major groups of regulations

• Good Laboratory Practices (GLP)

• safety (preclinical studies)

• animal, tissue, and cell studies

• Good Manufacturing Practices (GMP)

• manufacturing and packaging

• Good Clinical Practices (GCP)

• safety and efficacy in human

• conduct of clinical trials 3

GLP Good Laboratory Practice (GLP) is a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported

• Should apply to all non-clinical health and environmental safety studies required by regulations for the purpose of registering or licensing • pharmaceutical products

• pesticides

• food and feed additives

• cosmetic products

• veterinary drug products

• industrial chemicals

Non-clinical health and environmental safety studies covered by the Principles of Good Laboratory Practice include work conducted in the laboratory, in greenhouses, and in the field

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GMP Good Manufacturing Practice is that part of Quality Management which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorization, Clinical Trial Authorization or product specification. Good Manufacturing Practice is concerned with both production and quality control

• Applicable to the manufacture of

• manufacture of medicinal products for human use

• including medicinal gases, herbal medicinal products, radiopharmaceuticals, products derived from human blood or human plasma

• veterinary medicinal products

EU GMP Annex 13. Manufacture of Investigational Medicinal Products

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GCP

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible

• GCP guideline should be followed when

• generating clinical trial data that are intended to be submitted to regulatory authorities

• other clinical investigations that may have an impact on the safety and well-being of human subjects

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EU Legislation - Eudralex

• Basic Legislation • Volume 1 - EU pharmaceutical legislation for medicinal products for human use

• Volume 5 - EU pharmaceutical legislation for medicinal products for veterinary use

• Series of guidelines • Volume 2 - Notice to applicants and regulatory guidelines for medicinal

products for human use

• Volume 3 - Scientific guidelines for medicinal products for human use

• Volume 4 - Guidelines for good manufacturing practices for medicinal

products for human and veterinary use

• Volume 6 - Notice to applicants and regulatory guidelines for medicinal products for

veterinary use

• Volume 7 - Scientific guidelines for medicinal products for veterinary use

• Volume 8 - Maximum residue limits

• Volume 9 - Guidelines for pharmacovigilance for medicinal products for human and

veterinary use

• Volume 10 - Guidelines for clinical trial 7

GLP, GMP and GCP in the drug development

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Common Focus across GXPs

• Organization and Personnel

• Facilities

• Equipment

• Materials

• Records and reports

• Ethical consideration

• Quality management

Data integrity, patient safety, quality oversight

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Quality Management is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product

The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one

Main elements of the quality system

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Quality System – Quality Policy

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Quality Policy

• Short document

• Demonstrates the management’s commitment

• Signed by the CEO and the Quality Director

Quality System - Organization

• Organization Chart

• Clearly defined reporting line

• Job descriptions

• Responsibilities

• Direct report

• Adequate authority to carry out responsibilities

• No gaps or overlaps in the responsibilities

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Quality system - Resources

• Adequate number of personnel

• Necessary qualifications

• Practical experience

• Training

• professional training

• quality training

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Quality System - Documentation

• Type of documents • Instruction (procedures, specifications etc.)

• Report /record

• Document life-cycle • Preparation

• Approval

• Distribution

• Withdrawal

• Archive 15

Quality Documents

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Quality system - Processes

• All processes should be clearly defined, systematically reviewed

• Processes that affect quality • Risk analysis and risk management

• Management of non-compliances

• Corrective and preventive actions

• Management of deviations

• Management of change controls

• Management of quality complaints

• Release (GMP)

• Recall (GMP)

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Quality system – Quality Goals

• Continuous improvement • Periodic review of the Quality System

• Results of audit and inspections

• Quality indicators

• Trend analysis

• Quality Program

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Quality Organization

• Direct report to the management

• Must be independent

• Responsibilities • Implementing and maintaining quality

management system

• Management of quality documents

• Reviewing documents

• Performing audits

• Release (GMP)

• Quality training

• Advisory activities

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Quality by Design ICH Q8 Pharmaceutical Development

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Quality by Design ICH Q8 Pharmaceutical Development

• Aim of the Pharmaceutical Development

• design a quality product

• develop manufacturing process of the product

• consistently deliver the intended performance of the product

Quality must be built and cannot be tested into the products

Quality should be built in by design

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Quality by Design

• Pharmaceutical Development • Defining the quality target product profile (QTPP)

• quality, safety and efficacy

• Identifying potential critical quality attributes (CQAs) • product characteristics must be kept within appropriate limits

to ensure the desired product quality

• Determining the critical quality attributes of drug substance and excipients

• Selecting an appropriate manufacturing process

• Defining a control strategy

• Systematic evaluation, understanding and refining of the formulation and manufacturing process

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Design Space The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

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Design Space

Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process

Design space is proposed by the applicant and is subject to regulatory assessment and approval

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QbD - Risk Management approach

Differing Approaches to Pharmaceutical Development

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EMPIRICAL APPROACH SYSTEMATIC APPROACH (QBD)

Quality assured by testing and inspection

Quality built into product & process by design based on scientific understanding

Data intensive submission Knowledge rich submission – showing product knowledge and process understanding

Specifications based on batch history

Specifications based on product performance

Fixed manufacturing process Flexible process within design space

Focus on reproducibility Focus on robustness –understanding and controlling

Quality by Design

•More flexible regulatory approaches • Risk-based regulatory decisions (reviews and

inspections)

• Manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review

• Reduction of post-approval submissions

• Real-time quality control, leading to a reduction of end-product release testing

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Quality by Design in clinical development?

Quality System approach from the design to the end of the study

E.g.

• Study protocol should focus on proactive risk management

• scientific risk assessments

• operational risk assessments

• Selecting qualified investigators

• Ensure adequate monitoring (traditional, risk-based)

• Quality of the documentation

• Data quality

• Human factors concerns

• Risk mitigation

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„Quality is never an accident.

It is always the result of intelligent

effort.” (John Ruskin)

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THANK YOU FOR YOUR ATTENTION!

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