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 for

Introduction

ld-consulting.webnode.cz

https://ld-consulting.webnode.cz/



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





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)





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)





Work-life balance





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

www.ld-consulting.webnode.cz

http://www.ld-consulting.webnode.cz/




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: <231>

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.


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 <232> <233>

Ph.Eur 5.20

2.4.20 Current

Heavy metals

USP <231>, EP 2.4.8

Wet Chemistry ICP-MS (sensitive, fast, multi-elemental)

KLIK rešerže\Elemental Impurities in marketed products.pdf

rešerže/Elemental Impurities in marketed products.pdf



KLIK rešerže\implementation strategy of ICH Q3D guideline.pdf

rešerže/implementation strategy of ICH Q3D guideline.pdf





Jablko 10 Banán 1 Kokos 2 Celkem 14

Elemental Impurities – a risk based approach

25.4. 2018

Lukáš Dvořák







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

Drug substance / Excipient

• Synthetic pathway – intentionally added catalysts and/or its residues and/or metal (elemental) impurities

• Source materials

• Environment

• → DMF, COA, ICH Q3D statement, questionaire

Container closure system

• Liquid and semi-solid products are in a higher risk • Manufacturing process is secret (washing, sterilization,

irradiation) • Source materials

• → COA, ICH Q3D statement, questionaire

Container closure system

Packaging type Dosage form Score (FMEA)

Ampoule liquid 96

Glass bottle (1) liquid 72

Plastic bottle (1) liquid 48

Aluminium tube semi-solid 36

Plastic tube semi-solid 24

Glass bottle (2) liquid 18

Plastic bag liquid 8

Alumium foil solid 6

Plastic bottle (2) solid 4

→ ICP/MS testing, EI as a parameter in the specification

→ ICP/MS testing, just monitoring

→ no action is taken

Manufacturing equipments

Low Risk Middle Risk High Risk

Solid product Semi-solids Liquids, suspensions

Auxiliary equipment Secondary equipment Primary equipment

Stainless Steel 316, 316L Stainless Steel 304, 304L Different stainless steel quality

PDE x ppm

ICH Q3D provides PDE limits in µg/day for elemental impurities.

However, concentration limits in µg/g are more useful for evaluating sample impurity content.

Chapter 7 of ICH Q3D offers Options for translating:

-Option 1 assumes daily intake of the drug product is 10 g or less

-Option 2A uses an actual maximum daily intake (versus assuming 10 g)

-Option 2B sums known component impurity levels

-Option 3 measures the concentration of elements in the final drug product

Ulrich Reichert, Elemental Impurities: Implications for Manufacturers of Drug Products, APIs & Excipients

Take home message

Step 1 • Identify risks

Step 2 • Evaluate risks

Step 3 • Design experiment

Step 4 • Evaluation & Control

D O C U M E N T E A C H S T E P

Data Integrity - introduction

25.4. 2018

Lukáš Dvořák






How it starts…

• FDA classification – 483, Warning Letter • EMA area – minor, major, critical

• Producer has to declare safety, quality and efficacy of

manufactured pharmaceutical products

• FDA observations in details: Approximately 80 percent of all warning letters in 2015 and

2016 include a data integrity component, and approximately 70 percent of the published Eudra reports of GMP non-compliance cite similar shortcomings.


http://eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do







2016
















WHERE to find detailed informations






Attributable – mít vlastnost, znak, cestu, symbol Legible – čitelný Contemporaneous – současný, souběžný Original – původní Accurate – správný, přesný, pravdivý











Field of interest






• • § 211.68 (requiring that “backup data are exact and complete,”

and “secure from alteration, inadvertent erasures, or loss”); • • § 212.110(b) (requiring that data be “stored to prevent

deterioration or loss”); • • §§ 211.100 and 211.160 (requiring that certain activities be

“documented at the time of performance” and that laboratory controls be “scientifically sound”);

• • § 211.180 (requiring that records be retained as “original records,” “true copies,” or other “accurate reproductions of the original records”); and

• • §§ 211.188, 211.194, and 212.60(g) (requiring “complete information,” “complete data derived from all tests,” “complete record of all data,” and “complete records of all tests performed”).

• Electronic signature and record-keeping requirements are laid out in 21 CFR part 11 and apply to certain records subject to records requirements set forth in Agency regulations, including parts 210, 211, and 212. For more information, see guidance for industry Part 11, Electronic Records; Electronic Signatures — Scope and Application.

• What is “metadata”? • Metadata is the contextual information required to

understand data. A data value is by itself meaningless without additional information about the data. Metadata is often described as data about data. Metadata is structured information that describes, explains, or otherwise makes it easier to retrieve, use, or manage data. For example, the number “23” is meaningless without metadata, such as an indication of the unit “mg.” Among other things, metadata for a particular piece of data could include a date/time stamp for when the data were acquired, a user ID of the person who conducted the test or analysis that generated the data, the instrument ID used to acquire the data, audit trails, etc.

• What is an “audit trail”? • means a secure, computer-generated, time-stamped electronic record

that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. An audit trail is a chronology of the “who, what, when, and why” of a record. For example, the audit trail for a high performance liquid chromatography (HPLC) run could include the user name, date/time of the run, the integration parameters used, and details of a reprocessing, if any, including change justification for the reprocessing.

• Electronic audit trails include those that track creation, modification, or deletion of data (such as processing parameters and results) and those that track actions at the record or system level (such as attempts to access the system or rename or delete a file).

• CGMP-compliant record-keeping practices prevent data from being lost or obscured (see §§ 211.160(a), 211.194, and 212.110(b)). Electronic record-keeping systems, which include audit trails, can fulfill these CGMP requirements.

“static” and “dynamic”

• static is used to indicate a fixed-data document such as a paper record or an electronic image

• dynamic means that the record format allows interaction between the user and the record content

dynamic chromatographic record may allow the user to change the baseline and reprocess chromatographic data so that the resulting peaks may appear smaller or larger. It also may allow the user to modify formulas or entries in a spreadsheet used to compute test results or other information such as calculated yield.

audit trail review

• FDA recommends that audit trails that capture changes to critical data be reviewed with each record and before final approval of the record. Audit trails subject to regular review should include, but are not limited to, the following: the change history of finished product test results, changes to sample run sequences, changes to sample identification, and changes to critical process parameters.

• FDA recommends routine scheduled audit trail review based on the complexity of the system and its intended use.

• Personnel responsible for record review under CGMP should review the audit trails that capture changes to critical data associated with the record as they review the rest of the record

• all production and control records, which includes audit trails, must be reviewed and approved by the quality unit

personnel should be trained in detecting data integrity issues as part of a routine CGMP training program

Documents

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 for