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:

1. Quality System
2. Facilities and Equipment System
3. Materials System
4. Production System
5. Packaging and Labeling System
6. 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:

1. Laboratory Managerial and Administrative Systems
2. Laboratory Documentation Practices and Standard Operating Procedures
3. Laboratory Equipment Qualification and Calibration
4. Laboratory Facilities
5. Methods Validation and Technology Transfer
6. Laboratory Computer Systems
7. 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 ingredients (APIs) 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:

1. Laboratory Managerial and Administrative Systems
2. Laboratory Documentation Practices and Standard Operating Procedures
3. Laboratory Equipment
4. Laboratory Facilities
5. Method Validation and Method Transfer
6. Laboratory Computer Systems
7. Laboratory Investigations
8. Data Governance and Data Integrity*
9. Stability Program*
10. 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.

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.

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:

1. 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.)
2. 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:
   1. Buildings and facilities along with maintenance.
   2. 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.
   3. 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.)
3. 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.)
4. 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.)
5. 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.)
6. 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)

  

• 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.  1 21 CFR Parts 210 and 211 Current Good Manufacturing Practice for Finished Pharmaceuticals.
2.  2 US FDA (2017). Compliance Programs to FDA staff, Chapter 56: Drug Quality Assurance 7356.002 Drug Manufacturing Inspections.