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Introduction - Úvod | Konference & Semináře ... PDE x ppm ICH Q3D provides PDE limits in µg/day for elemental impurities. However, concentration limits in µg/g are more useful

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  • Introduction

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  • Lukáš Dvořák - Working experiences

    • 2006 - 2007 UP Olomouc, Faculty of Science, Department of Inorganic Chemistry – Scientific Researcher

    • 10/2009 – 12/2010 Teva Czech Industries s.r.o. – Quality Control Specialist

    • 01/2011 – 09/2011 Teva Czech Industries s.r.o. – Incoming Control Laboratory Supervisor

    • 10/2011 - 05/2015 - Teva Czech Industries s.r.o. – Head of TSA QC dept. (Technical and Scientific Affairs)

    • 06/2015 – 04/2017 - Teva Czech Industries s.r.o. – TSA Manager (Production Technologies)

    • 05/2017 - 03/2018 – Favea a.s. - Qualified Person – control and certification of human or veterinal products; investigation, batch documentation control

    • 04/2018 till now – Favea a.s. – QC Senior Specialist & Qualified Person

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  • Extrawork • 01/2016 till now – external expert supporting

    GMP area in Czech Accreditation Institute

    • 09/2017 till now QDP supervisor in two shipper companies

    • 01/2018 till now – Parliament of the Czech republic – consultant (healthy committee of the Chamber of Deputies)

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  • Additional education & courses

    • 2015 Teva Early Talent Programme

    • 2014 Course for Qualified Person of Manufacturers of medicinbal Products to be in accordance with Czech National Law 378/2007

    • 2011 Validation manager courses (presented by IIR)

    • 2011 Competent leadership (presented by AHRA – 8 days module: Key Manager Competencies, Leadership, Change Control, Creativity)

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  • Work-life balance

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  • ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human

    Use - Quality

    • Q1 Stability Issue • Q2 Validation issue • Q3 Impurities • Q4 Pharmacopoeias • Q5 Quality of Biotechnological Products • Q6 Specifications • Q7 GMP for API • Q8 Pharmaceutical Development • Q9 Pharmaceutical Risk Management • Q10 Pharmaceutical Quality Systém • Q11 Development and Manufacture of DS • Q12 Lifecycle Management

  • ICH Q7 general chapters

  • • There should be an adequate number of personnel qualified by appropriate education, training and/or experience to perform and supervise the manufacture of intermediates and APIs

    • The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing

    • Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed.

  • • Personnel should avoid direct contact with intermediates or APIs.

    • Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn when necessary, to protect intermediates and APIs from contamination.

  • • Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof

    • Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants

  • • Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size.

    • Suitably located for its intended use, cleaning, sanitization (where appropriate), and maintenance.

    • Production equipment should only be used within its qualified operating range.

    • Closed or contained equipment should be used whenever appropriate.

    • Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs.

  • • Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material.

    • Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants.

    • Non-dedicated equipment should be cleaned between production of different materials to prevent cross- contamination.

  • • The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented.

    • The critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should be defined.

  • Process Design Process Qualification Continued Process

    Verification

    Define

    •Critical Process parameters set up

    •Critical Quality Atributes set up

    Design Space

    •Ranges

    •Limits

    Support

    •ICH Q11

    •EudraLex, Volume 4, Annex 15

    •FDA Guid. For Industry: Process Validation

    Define

    •CQA & CPP evaluation under actual conditions of use

    •Scale up, commercial scale

    •Specification

    Methodology

    •Validated analytical methods

    •Impurity profile

    •Cleaning validation

    •Hold time studies

    Support

    •ICH Q2(R1)

    •EudraLex, Volume 4, Annex 15

    •FDA Guid. For Industry: Analytical Procedures and Methods Validation for Drugs

    Control

    • Continued monitoring

    • On-going stability programme

    Correlation & Action

    • Cp, cpk indexes

    • Trend analysis

    • CAPA system

    Support

    • ICH Q9

    • FDA Guid. For Industry: Process Validation

    DOCUMENTATION ON EACH STEP OF VALIDATION

  • Validation - Qualification

  • Take home message

  • Elemental Impurities - history

    25.4. 2018

    Lukáš Dvořák

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  • Simon Sinek – Golden Circle

    PROČ?

    JAK – ICH Q3D

    CO – změna legislativy

  • Colour of Sulfites

  • • Over 100 years old (circa 1905) • Semi-quantitative method based on color reaction • Very low sensitivity • Non-specific for individual metals • Some metals cannot be tested (Pd, Pt, Ni, V) • Not accurate for volatile elements (Hg, Sb, Se, Pb)

    “Although still widely accepted and used in the pharmaceutical industry, these methods based on the intensity of the color of sulfide precipitation are non-specific, insensitive, time-consuming, labor intensive, and more often than hoped, yield low recoveries or no recoveries at all.” Ref.: Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)

  • Schott hot plate and beaker explosion - photodocumentation

    Calcium Stearate NF:

  • Zákon o léčivech 378/2007 §33 (1)

    Držitel rozhodnutí o registraci musí provádět veškeré změny potřebné k tomu, aby bylo možné léčivý přípravek vyrábět a kontrolovat obecně uznávanými vědeckými metodami.

  • ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human

    Use - Quality

    • Q1 Stability Issue • Q2 Validation issue • Q3 Impurities: • A) Q3A • B) Q3B • C) Q3C • D) Q3D • Q4 Pharmacopoeias • Q5 Quality of Biotechnological Products • Q6 Specifications • Q6A Specifications for New DS and FP:Chemical Substances • Q7 GMP for API • Q8 Pharmaceutical Development • Q10 Pharmaceutical Risk Management • Q11 Development and Manufacture of DS • Q12 Lifecycle Management

  • Elemental Impurities - Guidelines change

    Step 4 Effective

    Dec 2015 (?) 2018

    ICH Q3D

    USP

    Ph.Eur 5.20

    2.4.20 Current

    Heavy metals

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