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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Develop an understanding of FDA and global regulatory agency requirements for Laboratory Control System (LCS) operations In Laboratory Control System Operations in a GMP Environment, readers are given the guidance they need to implement a CGMP compliant Laboratory Control System (LCS) that fits within Global Regulatory guidelines. Using the Quality Systems Approach, regulatory agencies like the FDA and the European Medicine Agency have developed a scheme of systems for auditing pharmaceutical manufacturing facilities which includes evaluating the LCS. In this guide, readers learn the fundamental rules for operating a CGMP compliant Laboratory Control System. Designed to help leaders meet regulatory standards and operate more efficiently, the text includes chapters that cover Laboratory Equipment Qualification and Calibration, Laboratory Facilities, Method Validation and Method Transfer, Laboratory Computer Systems, Laboratory Investigations as well as Data Governance and Data Integrity. The text also includes chapters related to Laboratory Managerial and Administrative Systems, Laboratory Documentation Practices and Standard Operating Procedures and General Laboratory Compliance Practices. Additionally, a chapter outlining Stability Program operations is included in the text. In addition to these topics, it includes LCS information and tools such as: * End of chapter templates, checklists, and LCS guidance to help you follow the required standards * Electronic versions of each tool so users can use them outside of the text * An In-depth understanding of what is required by the FDA and other globally significant regulatory authorities for GMP compliant systems For quality assurance professionals working within the pharmaceutical or biopharma industries, this text provides the insight and tools necessary to implement government-defined regulations.
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Table of Contents
Cover
Preface
Note
About the Companion Website
1 Introduction to the Quality Systems Based Approach to CGMP Compliance
Overview of Quality Systems and the Laboratory Control System
Regulations and Regulatory Bodies
Regulatory Guidance
Application of This Text
Overlap and Redundancy
Tools and Templates
References
Note
2 Components of the Laboratory Managerial and Administrative Systems Sub Element (MS)
Description of the Laboratory Managerial and Administrative Systems Sub Element
Contents of the Sub Element
Tools and Templates
Reference
3 Components of the Laboratory Documentation Practices and Standard Operating Procedures Sub Element (OP)
Description of the Laboratory Documentation Practices and Standard Operating Procedures Sub Element
Contents of the Sub Element
Tools and Templates
4 Components of the Laboratory Equipment Sub Element (LE)
Description of the Laboratory Equipment Sub Element
Contents of the Sub Element
Tools and Templates
References
5 Components of the Laboratory Facilities Sub Element (LF)
Description of the Laboratory Facilities Sub Element
Contents of the Sub Element
Tools and Templates
References
6 Components of the Method Validation and Method Transfer Sub Element (MV)
Description of the Method Validation and Method Transfer Sub Element
Contents of the Sub Element
Tools and Templates
Glossary
References
7 Components of the Laboratory Computer Systems Sub Element (LC)
Description of the Laboratory Computer Systems Sub Element
Contents of the Sub Element
Tools and Templates
Glossary
References
8 Components of the Laboratory Investigations Sub Element (LI)
Background and Regulatory History of Out-of-Specification Investigations
Description of the Laboratory Investigations Sub Element
Contents of the Sub Element
Common Problems Related to Laboratory OOS Investigations
Tools and Templates
Glossary
References
9 Components of the Laboratory Data Governance and Data Integrity Sub Element (DI)
Background
Precepts Regarding Data Governance and Data Integrity
Description of the Laboratory Data Governance and Data Integrity Sub Element
Contents of the Sub Element
Tools and Templates
Glossary
References
Further Reading
10 Components of the Stability Program Sub Element (SB)
Description of the Stability Program Sub Element
Contents of the Sub Element
Model Standard Operating Procedures for Establishing and Maintaining a Stability Program
Tools and Templates
Glossary
References
Note
11 Components of the General Laboratory Compliance Practices Sub Element (CP)
Description of the General Laboratory Compliance Practices Sub Element
Contents of the Sub Element
Tools and Templates
12 Summary for Establishing and Maintaining a Laboratory Control System
A Brief Review of the Laboratory Control System and Its Sub Elements
How Things Can Go Wrong: Examples of Some Regulatory Citations Organized by Sub Element
Some Final Thoughts on Establishing and Maintaining a Compliance Laboratory Control System
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Components of the laboratory managerial and administrative systems ...
Chapter 3
Table 3.1 Model master laboratory SOP index.
Table 3.2 Model master laboratory SOP index with details.
Chapter 4
Table 4.1 Components of the laboratory equipment program.
Table 4.2 Suggestions for laboratory equipment-specific Standard Operating Pr...
Chapter 5
Table 5.1 Components of the laboratory facilities sub element.
Chapter 6
Table 6.1 Components of the method validation and Method Transfer sub element...
Chapter 7
Table 7.1 Components of the laboratory computers system sub element.
Chapter 8
Table 8.1 Description of the phases of a laboratory investigation.
Chapter 9
Table 9.1 ALCOA+ acronym for data integrity.
Table 9.2 Example gap analysis for manufacturing steps.
Table 9.3 Example gap analysis for a laboratory instrument data map.
Table 9.4a Example risk ranking and filtering tool: Risk definitions.
Table 9.4b Example risk ranking and filtering tool: Risk score calculations
Table 9.4b Some Example Lines from the Risk Ranking and Filtering Tool
Table 9.5 Example notebook and data review checklist.
Chapter 10
Table 10.1 Components of the stability program.
Table 10.2 Selection, qualification, calibration, and maintenance of stabilit...
Chapter 11
Table 11.1 Components of the general laboratory compliance practices sub elem...
Chapter 12
Table 12.1 The laboratory control system sub elements and some example regula...
List of Illustrations
Chapter 1
Figure 1.1 FDA guidance for Industry Quality Systems approach to pharmaceuti...
Chapter 8
Figure 8.1 The regulatory history of out-of-specification investigations.
Figure 8.2 The structure of laboratory investigations.
Figure 8.3 A model laboratory investigations work flow diagram.
Chapter 9
Figure 9.1 The lifecycle of laboratory data.
Figure 9.2 Data governance and data integrity hierarchy.
Figure 9.4 Example Data Map for the manufacture of a drug product.
Figure 9.5 A generic laboratory instrument data map.
Figure 9.6 Example laboratory data flow for notebook and data review.
Figure 9.7 Quality assurance data and operations audit program work flow.
Guide
Cover
Table of Contents
Begin Reading
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Laboratory Control System Operations in a GMP Environment
David M. Bliesner, Ph.D.
Delphi Analytical Services, Inc.Indian Rocks Beach, Florida
This edition first published 2020
© 2020 John Wiley & Sons Inc.,
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In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
Library of Congress Cataloging-in-Publication Data
Names: Bliesner, David M., author.
Title: Laboratory control system operations in a GMP environment / David M. Bliesner.
Description: Hoboken, NJ : Wiley, [2020] | Includes bibliographical references and index.
Identifiers: LCCN 2019052264 (print) | LCCN 2019052265 (ebook) | ISBN 9781119529231 (cloth) | ISBN 9781119529279 (adobe pdf) | ISBN 9781119529293 (epub)
Subjects: LCSH: Medical laboratories--Quality control. | Laboratories--Management. | Pharmacy--Research. | Manufacturing processes--Quality control.
Classification: LCC RB36.3.Q34 B55 2020 (print) | LCC RB36.3.Q34 (ebook) | DDC 610.28/4--dc23
LC record available at https://lccn.loc.gov/2019052264
LC ebook record available at https://lccn.loc.gov/2019052265
Cover Design: Wiley
Cover Image: © Image Journal-Photography/Getty Images
To my wife and best friend, Kathy.
Preface
Regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) mandate that companies who manufacture drugs for human and animal use be operated in a state of control by employing conditions and controls commonly referred to as good manufacturing practices (GMPs). In the United States the GMPs or CGMPs (where C = current) are codified in 21 Code of Federal Regulations Parts 210 and 211. In the European Union the GMPs are described in EudraLex – Volume 4, the Good Manufacturing Practice (GMP) guidelines. Other Regulatory bodies, such as the World Health Organization (WHO) and the International Council for Harmonization (ICH) also provide requirements and guidelines with respect to GMPs.
At the turn of the twenty-first century the FDA was actively engaged in regulatory actions against pharmaceutical companies whom they determined to be in significant violation of the CGMPs. As part of FDA's actions, several large companies entered into voluntary legal agreements referred to as Consent Decrees. These agreements existed for the expressed purpose of correcting the deficiencies related to CGMPs. Consent Decrees routinely require the contracting of independent third-party expert consultants. These consultants' duties include performing a baseline audit of the offending facilities, documenting their findings and helping the companies develop and implement corrective action plans.
To help collect evidence to support regulatory actions, FDA began using a Quality Systems approach to evaluate a firm's level of GMP compliance.
The Quality Systems approach is a scheme of systems for the manufacture of drugs and/or drug products. The general scheme of systems FDA used for auditing manufacture facilities consists of the following:
Quality System
Facilities and Equipment System
Materials System
Production System
Packaging and Labeling System
Laboratory Control System
According to FDA “The Quality System provides the foundation for the manufacturing systems that are linked and function within it.”1
This approach is commonly referred to as the six-system model and is still used today by the FDA to conduct inspections of GMP facilities.
During this time, Delphi Analytical Services, Inc. (Delphi) served as one of the third-party expert consulting firms on several Consent Decrees at major pharmaceutical companies. Delphi's core competency is the practical understanding of workings of the laboratory control system (LCS), the sixth quality system mentioned in the FDA model. Delphi was extensively involved in performing third-party audits of quality control (QC) and research and development (R&D) laboratories for companies under Consent Decree.
While executing these consulting assignments it became apparent that the CGMPs regulations, FDA Guidance Documents and FDA Internal Compliance Program Guides offered little direction or specifics of what was expected of a CGMP compliant LCS. Because of this, Delphi developed and documented a systematic means for performing the baseline audits, capturing deficiencies, reporting the results, and developing subsequent corrective action plans, for QC laboratories. In addition, Delphi also created instructional materials and began teaching courses on auditing QC laboratories at various client sites and scientific conferences.
Due to the inherent complexity of the LCS, Delphi divided it into seven sub systems or sub elements. These included the following:
Laboratory Managerial and Administrative Systems
Laboratory Documentation Practices and Standard Operating Procedures
Laboratory Equipment Qualification and Calibration
Laboratory Facilities
Methods Validation and Technology Transfer
Laboratory Computer Systems
Laboratory Investigations
Based on real-world experiences, Delphi then, in turn, developed detailed audit checklists for each LCS sub element. These became the basis for most of Delphi's consulting contracts and instruction material.
In March 2004 at the Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy (PittCon©), Delphi Analytical Services, Inc.'s president, Dr. David M. Bliesner, Ph.D., taught a one-day course titled “How to Establish a GMP Laboratory Audit System.” The course was well attended which led to a meeting with a representative of Wiley-Interscience, John Wiley & Sons, Inc. At the conclusion of that meeting, it was agreed that he would write a proposal for publication of a book. The proposal was accepted and became the book titled Establishing a CGMP Laboratory Audit System: A Practical Guide in 2006.
Over the course of the next 12 years (2006–2018), the pharmaceutical industry experienced a massive paradigm shift in its business and operational models. This in turn resulted in changes to the manner in which regulatory agencies enforced the GMPs. Some key elements of these changes included:
Substantial outsourcing of drug development, manufacturing, testing, and other functions
Offshoring of manufacturing and testing of
active pharmaceutical ingredient
s (
API
s) and drug products
Profit versus quality driven decision making
Reductions in experienced, permanent workforces
Increased regulatory activity by US FDA at overseas plants
Increased Global Regulatory Agency oversight, guidance, and cooperation
Because of these changes, and other factors, it became obvious that Establishing a CGMP Laboratory Audit System: A Practical Guide had much broader utility than just serving as an audit guide. In particular, the real value of the book over the years has not been as an auditing guide but:
A means to introduce
auality assurance
(
QA
) and QC personnel to the concept of quality systems and the LCS in particular
As a basis for instructing QA and QC personnel on Laboratory GMPs
To assist in interpreting and clarifying regulatory expectations for the LCS
As the basis for assisting laboratory management in implementing and maintaining CGMP compliant practices in their own QC laboratories
Therefore, the purpose of this new book titled Laboratory Control System Operations in a GMP Environment is to focus on LCS operations versus auditing.
The goal in writing this book is to publish a text, which when implemented in QC and R&D laboratories, provides the basis for operating a CGMP compliant LCS. This will improve an organization's chances for withstanding regulatory scrutiny and enhance operational efficiency. This new book is designed to be used in several ways, including:
Designing and implementing a new, from scratch, CGMP compliant LCS
Upgrading or tweaking an existing LCS
Laying a basis for initial and periodic LCS GMP training
Laying a basis for improving operational efficiency
Serving as an operational reference guide: Third party “sanity” check to help solve compliance challenges as they arise
Laboratory Control System Operations in a GMP Environment builds on the original auditing text described earlier. However, instead of emphasizing auditing, this new text not only focuses and upgrades the operational aspects of the original seven LCS sub elements but also expands the LCS to encompass three additional sub elements, which are marked with an asterisk(*) in the following list. This results in the following 10 chapters in the book:
Laboratory Managerial and Administrative Systems
Laboratory Documentation Practices and Standard Operating Procedures
Laboratory Equipment
Laboratory Facilities
Method Validation and Method Transfer
Laboratory Computer Systems
Laboratory Investigations
Data Governance and Data Integrity*
Stability Program*
General Laboratory Compliance Practices*
Each chapter in this text describes the critical functions of the LCS sub element so the reader understands what is expected from the FDA and other Global Regulatory Agencies. In addition, each chapter links to tools, templates, checklists, and Global Regulatory Agencies' guidances. All of these tools and templates are accessible for download online through a Wiley Interscience web portal for easy modification and application by the end-user in their own laboratories.
Readers, in using this book, may accomplish the following:
Fully implement a functional LCS which can withstand Global Regulatory scrutiny
Increase operational efficiency
Stay current with GMPs and industry trends
Save time by using the real-world tools and templates found in the book, which can be modified and used by the reader
Use the text as a benchmark reference to which they can assess the status of compliance of their own laboratories
Laboratory Control System Operations in a GMP Environment is written for a broad audience. It is applicable to both QC and QA professionals in small, medium, and large companies within the pharmaceutical and biopharmaceutical industries. R&D personnel working in non-GMP environments will also benefit by applying the organizational schemes and principals presented in this text.
This book is particularly helpful for personnel who work in smaller companies because they often do not have the financial, personnel resources, and existing “corporate knowledge” that large US- and European-based companies may possess. This means that smaller organizations are often left to “figure it out” on their own. For these smaller operations, this text is particularly valuable because of the example-templates and checklists it includes.
To our knowledge no such detailed operational text or guide exists in the marketplace. We hope you find Laboratory Control System Operations in a GMP Environment useful and wish you the best in your continuing quest to establish a quality-minded culture, improve operational efficiency, and thrive under Global Regulatory scrutiny.
January 2020
David M. Bliesner, Ph.D.
Indian Rocks Beach, Florida
Note
1
FDA Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations, September, 2006.
About the Companion Website
This book is accompanied by a companion website:
www.wiley.com/go/Bliesner/LabControl_GMPEnvironment
Scan this QR code to visit the companion website
The website includes Appendices and Weblinks.
1Introduction to the Quality Systems Based Approach to CGMP Compliance
Overview of Quality Systems and the Laboratory Control System
The US Food and Drug Administration (US FDA) mandates that a drug firm, and therefore the laboratory, be operated in a state of control by employing conditions and practices that assure compliance with the intent of the Federal Food, Drug, and Cosmetic Act and portions of the Current Good Manufacturing Practice (CGMP) regulations (e.g. 21 CFR Parts 210 and 211) that pertain to it. Activities found in drug firms, including operation of the laboratory, can be organized into systems that are sets of operations and related activities. Control of all systems helps to ensure the firm will produce drugs that are safe, have the proper identity and strength, and meet the quality and purity characteristics as intended [1, 2].
For drug firms, FDA has outlined the following general scheme of systems that impact the manufacture of drugs and drug products:
Quality System
. This system assures overall compliance with CGMPs and internal procedures and specifications. The system includes the quality control (QC) unit and all of its review and approval duties (e.g. change control, reprocessing, batch release, annual record review, validation protocols, reports, etc.). It also includes all product defect evaluations and evaluation of returned and salvaged drug products. (See the CGMP regulation, 21 CFR 211 subparts B, E, F, G, I, J, and K.)
Facilities and Equipment System
. This system includes the measures and activities that provide an appropriate physical environment and resources used in the production of the drugs or drug products. It includes:
Buildings and facilities along with maintenance.
Equipment qualifications (installation and operation); equipment calibration and preventative maintenance; and cleaning and validation of cleaning processes as appropriate. Process performance qualifications are included as part of process validation, which is done within the system where the process is employed.
Utilities that are not intended to be incorporated into the product such as
heating, ventilation, and air-conditioning
(
HVAC
), compressed gases, steam, and water systems. (See the CGMP regulation, 21 CFR 211 subparts B, C, D, and J.)
Materials System
. This system includes measures and activities to control finished products and components including water or gases that are incorporated into the product, containers, and closures. It includes validation of computerized inventory control processes, drug storage, distribution controls, and records. (See the CGMP regulation, 21 CFR 211 subparts B, E, H, and J.)
Production System
. This system includes measures and activities to control the manufacture of drugs and drug products including batch compounding, dosage form production, in-process sampling and testing, and process validation. It also includes establishing, following, and documenting performance of approved manufacturing procedures. (See the CGMP regulation, 21 CFR 211 subparts B, F, and J.)
Packaging and Labeling System
. This system includes measures and activities that control the packaging and labeling of drugs and drug products. It includes written procedures, label examination and usage, label storage and issuance, packaging and labeling operations controls, and validation of these operations. (See the CGMP regulation, 21 CFR 211 subparts B, G, and J.)
Laboratory Control System
. This system includes measures and activities related to laboratory procedures, testing, analytical method development, validation and/or qualification/verification, and the stability program. (See the CGMP regulation, 21 CFR 211 subparts B, I, J, and K.)
According to FDA, “The Quality System provides the foundation for the manufacturing systems that are linked and function within it.” Graphically, the scheme of systems looks like [1] (Figure 1.1):
This approach is commonly referred to as the six-system model and is still used today by FDA to conduct inspections of good manufacturing practice (GMP) facilities.
As stated in (6) earlier, FDA considers a firm's Laboratory Control System (LCS) to be a key element in CGMP compliance. Within the LCS are at least 10 additional sub systems or sub elements, which may include:
Laboratory Managerial and Administrative Systems (MS)
Laboratory Documentation Practices and Standard Operating Procedures (OP)
Laboratory Equipment (LE)
Laboratory Facilities (LF)
Method Validation and Method Transfer (MV)
Figure 1.1 FDA guidance for Industry Quality Systems approach to pharmaceutical CGMP regulations, September 2006 [1].
Laboratory Computer Systems (LC)
Laboratory Investigations (LI)
Data Governance and Data Integrity (DI)
Stability Program (SB)
General Laboratory Compliance Practices (CP)
These 10 sub elements of the LCS are not part of any guideline document, international council, or inspection convention. Instead they have been created by the author, to promote the establishment and maintenance of Quality Systems and sub systems, which demonstrate you are in control of your laboratory operations and thus in compliance with the CGMP regulations.
These 10 sub element topics constitute 10 chapters within this book. Each chapter will describe the critical functions of the LCS sub element so the reader understands what is expected from the US FDA and other Global Regulatory Agencies.
A listing of the primary Global Regulations, the Agencies that enforce them, and the international councils or inspection conventions that help to harmonize their efforts are listed in the succeeding text.
Regulations and Regulatory Bodies
The primary, globally significant, regulations related to the manufacturing, processing, packing, or holding of drugs include:
21 Code of US Federal Regulations Part 210 and 211 Current Good Manufacturing Practice Regulations
EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines
The major regulatory bodies or organizations that enforce the regulations or assist in harmonizing international regulatory efforts include:
US Food and Drug Administration (US FDA, United States)
European Medicines Agency
(
EMA
, European Union)
Medicines and Healthcare products Regulatory Agency
(
MHRA
, United Kingdom)
Health Canada (Canada)
Brazilian Health Regulatory Agency (ANVISA, Brazil)
Pharmaceuticals and Medical Devices Agency
(
PMDA
, Japan)
Therapeutic Goods Administration
(
TGA
, Australia)
World Health Organization
(
WHO
-International)
Central Drugs Standard Control Organization
(
CDSCO
, India)
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(
ICH
-International)
Pharmaceutical Inspection Convention
(
PIC
) and the
Pharmaceutical Inspection Co-operation Scheme
(PIC Scheme) (
PIC/S
-International)
There are numerous other country-specific bodies, which enforce their own laws related to the manufacturing, processing, packing, or holding of drugs. The reader is encouraged to consult the requirements of their own country's laws and regulations regarding the manufacture of pharmaceuticals.
Regulatory Guidance
Traditionally, Regulatory Agencies themselves have provided limited insight and assistance into how organizations operating within the pharmaceutical industry can comply with the regulations. However, over time, regulatory guidances and other instruments have arisen and evolved and today consist of a fairly large body of knowledge, which can be used by organizations to aid in compliance with the CGMPs.
When it comes to regulatory guidance for Quality Control (QC) Laboratories, the following documents may be helpful:
US FDA Compliance Programs to FDA staff, Chapter 56: Drug Quality Assurance 7366.002 Drug Manufacturing Inspections
US FDA Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations
ICH Harmonised Tripartite Guideline, Q1A to Q1F Stability
ICH Harmonised Tripartite Guideline, Q2 Analytical Validation
ICH Harmonised Tripartite Guideline, Q3A to Q3D Impurities
ICH Harmonised Tripartite Guideline, Q4 to Q4B Pharmacopoeias
ICH Harmonised Tripartite Guideline, Q6A to Q6B Specifications
ICH Harmonised Tripartite Guideline, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
ICH Harmonised Tripartite Guideline, Q8 Pharmaceutical Development
ICH Harmonised Tripartite Guideline, Q9 Quality Risk Management
ICH Harmonised Tripartite Guideline, Q10 Pharmaceutical Quality System
ICH Harmonised Tripartite Guideline, Q12 Lifecycle Management
ICH Harmonised Tripartite Guideline, Q14 Analytical Procedure Development
WHO Annex 2: Good Manufacturing Practices for Pharmaceutical Products: Main Principles
FDA Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations, September 2006
It should be noted that although not legally binding, violation of the principals of ICH Harmonised Tripartite Guideline, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7, are sometimes documented as findings by FDA.
Additional FDA and ICH guidelines exist and can be located at: https://www.fda.gov/drugs/guidances-drugs/all-guidances-drugs, https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html, and https://www.fda.gov/drugs/guidance-compliance-regulatory-information/drug-compliance-programs
Application of This Text
The remainder of “Laboratory Control System Operations in a GMP Environment” is dedicated to describing the critical functions of the LCS sub elements so the reader understands what is expected from the FDA and the Global Regulatory Agencies listed earlier. In addition, each chapter will present or link to tools, templates, checklists, and some of the Global Regulatory Agencies' guidance listed previously.
It should be noted that text is written for a broad audience. It is applicable to both Quality Control and Quality Assurance professionals in small, medium, and large companies within the pharmaceutical and biopharmaceutical industries. R&D personnel working in non-GMP environments will also benefit applying the organizational schemes and principals presented in this text.1 Also, foreign firms in China and India will find this book especially useful.
This book is particularly helpful for personnel who work in smaller companies because they often do not have the financial, personnel resources, and existing “corporate knowledge” that a large US- and European-based company may have and are therefore often left to “figure it out” on their own. In this respect the guide is particularly valuable in the example-templates and checklists it includes.
Overlap and Redundancy
As the reader progresses through this text, they will notice that some topics, notes, and clarifications are addressed more than once and in different locations within the book. This was done by the author on purpose to ensure that important topics are addressed appropriately and reinforced.
Additionally, the QC laboratory is a very complex and dynamic entity, which continually grows and evolves over time. This means that the 10 sub elements into with the LCS is divided (which is purely a matter of choice on the part of the author) can be reduced, modified, or expanded to address changes within the organization and the evolution of Regulatory Agency expectations and standard industry practices. This is why there is a “C” in CGMP: C means current, which is today, not yesterday.
Tools and Templates
The following are provided in electronic format in the Chapter 1 Appendix (www.wiley.com/go/Bliesner/LabControl_GMPEnvironment):
21 Code of Federal Regulations Parts 210 and 211 – Current Good Manufacturing Practice Regulations, Revised as of April 1, 2005
US FDA Compliance Programs to FDA staff, Chapter 56: Drug Quality Assurance 7366.002 Drug Manufacturing Inspections, October 31, 2017.
US FDA Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations, September 2006.
References
1
21 CFR Parts 210 and 211 Current Good Manufacturing Practice for Finished Pharmaceuticals.
2
US FDA (2017). Compliance Programs to FDA staff, Chapter 56: Drug Quality Assurance 7356.002 Drug Manufacturing Inspections.
Note
1
In June 2018 the ICH Assembly endorsed ICH Q14 “Analytical Procedure Development Guideline” and thus, by default, requiring a level of compliance with the GMPs by R&D laboratories.
2Components of the Laboratory Managerial and Administrative Systems Sub Element (MS)
Description of the Laboratory Managerial and Administrative Systems Sub Element
The Laboratory Managerial and Administrative Systems are those sub elements that provide the infrastructure for efficient and compliant operations of an analytical laboratory. It is sometimes difficult to directly relate items within this sub element to the Current Good Manufacturing Practices (CGMPs). However, deficiencies within this sub element, which cannot be directly attributed to the CGMPs, can lead to compliance failures. For example, 21 CFR Sections 210 and 211 do not specifically require that someone be assigned the duties of training manager. However, failing to have an individual responsible for training and consequently not having an effective training program can degrade the overall quality of data that is generated by laboratory personnel, and US Food and Drug Administration (US FDA) has cited companies for not having a training program for laboratory personnel [1].
The Laboratory Managerial and Administrative Systems sub element includes at least six individual topics. A laboratory that is in compliance with CGMPs should at least address each of these topics (as applicable). These topics include (i) Organizational Structure and Roles and Responsibilities, (ii) Training and Qualification, (iii) Laboratory Budgeting, Purchasing, and Requisition, (iv) Laboratory Administration and Operations, (v) Laboratory Chemicals, Solutions, Reagents and Supplies, and (vi) Laboratory Reference Standards and Solutions.
These six topics are listed within the text of the chapter along with some suggestions on what items should be addressed in each topic. The list of items under each topic is fairly comprehensive but may not be totally inclusive of all those components, which may constitute the sub element.
Contents of the Sub Element
The six topics mentioned earlier are presented in Table 2.1 in the form of questions related to each topic. For each topic, additional details, or “points to consider,” are offered along with notes and clarifications as appropriate. The questions, notes, and clarifications are all based on actual inspectional findings from Regulatory Inspectors or points that have been found to directly or indirectly impact compliant and efficient real-world Laboratory Control System operations.
It is envisioned that the below table may be used as a basis for:
Evaluating your own laboratory's managerial and administrative systems
Upgrading your own laboratory's managerial and administrative systems
Establishing your own laboratory's managerial and administrative systems if it is a new laboratory or if you are making substantial changes to an existing Laboratory Control System
Table 2.1 Components of the laboratory managerial and administrative systems sub element.
#
Laboratory managerial and administrative systems sub element topic
Notes and clarifications
2.1
Organizational Structure and
Roles and Responsibilities
2.1.1
Are current organization charts available for review and are they accurate?
Organizational charts will be one of the first things an auditor will request when your laboratory is being inspected. Make sure the document is current and correct in order to make a good first impression.
2.1.2
Is there a policy/procedure that defines the responsibility and authority of the
Quality Control
(
QC
) unit?
2.1.3
Have the responsibilities of each functional group and supervisor been clearly defined, including testing and operational requirements,
Standard Operating Procedure
s (
SOP
s), and all other critical functions?
2.1.4
Is an organizational structure in place which is properly staffed to assure that all required testing/monitoring and support activities are performed?
Section 211.25 Personnel qualifications of the Good Manufacturing Practices regulations states “(c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.” This applies to the laboratory and failing to meet this requirement is often the root cause of many issues which occur in poorly operated QC laboratories.
2.1.5
Is the span of control and authority assigned to the QC laboratory adequate to allow proper execution of these activities?
2.1.6
Is the ratio of supervisors to analyst appropriate? (A ratio of no more than 1 : 8 is recommended)
If a supervisor has to supervise more than eight employees directly, the effectiveness of their ability to do so decreases dramatically.
2.1.7
Are the roles and responsibilities for each position within the laboratory clearly defined?
2.1.8
Are the roles and responsibilities for each position in the organizational chart defined in formal, controlled, accurate, and current job descriptions?
Up until recently, job descriptions were considered the purview of the human resources department and therefore did not fall under the umbrella of GMPs. This has now changed, and the general expectation of regulatory agencies is that job descriptions should be maintained and controlled like any other GMP document.
2.1.9
Are signature authority, responsibility, and accountabilities appropriate and clearly defined?
2.1.10
Do systems exist to enhance communications, understanding, and working relationships between laboratory and
Quality Assurance
(
QA
) personnel?
A healthy, respectful relationship between QC and QA will do wonders for everyone's ability to manufacture, test, and, ship product. QC managers should encourage QA personnel to spend time in the laboratory and teach QA personnel as much about product testing and analytical techniques as they can.
2.1.11
Does a personnel performance evaluation system exist, which tracks laboratory personnel strengths and weaknesses and establishes a means to improve technical, administrative, and managerial skills?
Performance evaluation should not be a one-time-a-year event. A good leader will continually evaluate and assist their employees to become the best that they can be.
2.1.12
Does a master testing schedule or similar document(s) exist to ensure smooth and efficient work flow, and minimize laboratory personnel over-commitment?
2.1.13
Are current copies of CV's and resumes for all personnel, including consultants, available for review?
2.2
Training and Qualification
2.2.1
Have the educational, training, and work experience requirements for each laboratory position been clearly defined and do they reflect current standards in the industry?
2.2.2
Is the requirement for training and qualification clearly described in an SOP or similar document for all laboratory managers, supervisors, analysts, support, temporary staff, and consultants?
Training is defined as an activity designed to provide the skills and/or knowledge that individuals need to perform assigned job-related duties and responsibilities.Qualification is defined as the process, including documentation and approval, whereby a person is trained and demonstrates proof-of-proficiency in specified tests, tasks, procedures, or techniques.
2.2.3
Has a training and qualification curriculum been developed for each position that clearly identifies training requirements for all required SOPs and Policies, Test Methods, Safety Procedures, and the GMPs as well as all other internal and external courses or programs?
2.2.4
Is there a system in place (e.g. electronic, paper-based, or hybrid) to capture, track, and manage training and qualification of laboratory personnel?
Electronic training systems should have a set of standard file + curriculum for each unique position on the organizational chart. For example, the position for a laboratory technician responsible for glassware washing should be loaded into the training system as if it was a real person. It will include all the necessary SOPs required for the position, qualification tasks, safety training, etc.This “standard position” will serve as a template. It then lays the basis for an individual's training record, which will grow and change as the employee is trained and qualified in that position.
2.2.5
Does each employee have a training file or similar record within the training system?
2.2.6
Are the training histories for each individual employee kept current?
2.2.7
Have all laboratory personnel been properly trained and qualified?
This point seems obvious; however during auditing it is not unusual to see someone who was “thrown into a position” because of labor shortages, who has never been trained on the tasks they are preforming in the laboratory.
2.2.8
Are the training histories for each individual employee readily available for review?
2.2.9
Is SOP training conducted in a fashion other than “read and understand” as appropriate?
Unfortunately, organizations have a tendency to perform all SOP training in this fashion. It is not effective in many circumstances and the practice should be restricted to review of minor changes on previously trained-on procedures.
2.2.10
Are metrics, related to the execution of training, collected, analyzed, and used to determine the effectiveness of the employee training system in general?
2.2.11
Do the metrics used to evaluate training system effectiveness include the following:
Metrics can take many different forms; these are just a few suggestions.
2.2.11.1
Number of courses completed versus courses scheduled?
2.2.11.2
Percent of training that is overdue?
2.2.11.3
Evaluation of training course content by attendees?
2.2.11.4
Evaluation of instructor effectiveness by course attendees?
2.2.11.5
Evaluation of test questions to determine their appropriateness and effectiveness in evaluating knowledge?
2.2.12
Is there an analyst qualification program (e.g. proof-of-proficiency for laboratory skills) in place?
2.2.13
Has an individual been designated as the training coordinator or manager?
If the training manager or coordinator is not someone with a laboratory background, make sure they are supported by someone who has a science background with hands-on laboratory experience.
2.2.14
Is there evidence of management support for training and training programs?
2.2.15
Does a formal training budget exist?
2.2.16
Do vendor and consultant training records exist?
2.2.17
Is there evidence that newly hired employees are evaluated for skill level, competency, and proof-of-proficiency with respect to laboratory, supervisory, and managerial skills as appropriate?
One of the adages with respect to finding qualified personnel is we hire too quickly and fire too slowly. Take your time when hiring and verify, to the best of your organization's ability that who you are hiring truly does possess the education, training, and experience to do the job you need them to do.Also be aware that no matter how competent and experience a new hire is, it will most likely take them at least six months to come fully up-to-speed within your organization. And if you doubt this, you are fooling yourself.
2.2.18
Is there evidence that newly hired employees are evaluated for their language and literacy skills?
In culturally diverse workplaces, it is not unusual to encounter personnel who are not native speakers, readers, or writers in the primary language used at the facility. Since it is a GMP requirement that procedures exist and such procedures shall be followed, personnel should be evaluated for their ability to read, understand, and execute the SOPs for which are required to be followed in performance of their job responsibilities.
2.2.19
Is there a formal training schedule in place and is it being executed?
2.2.20
Is there evidence of employee re-training and re-qualification?
The GMPs in Section 211.25 (a) state “Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.” Although this section of the GMPs is targeted to GMP training, it should be expanded to cover the broader arena of job skills in general.
2.2.21
Do managers, supervisors, or training
