bace - Regulatory Compliance and Quality Systems Overview

Drug Development

Complex process involving preclinical research, an Investigational New Drug (IND) application, clinical trials, FDA review, and post-market safety monitoring.

Goal of Drug Development

To bring safer, more efficient treatments to patients quickly after thorough medical evaluation.

Critical Steps in Drug Development

Five steps: Discovery and Development, Preclinical Research, Clinical Research, FDA Review, and Post-Market Monitoring.

Step 1: Discovery and Development

Research begins in a lab to identify promising compounds for development.

Methods of Drug Discovery

New disease insights, molecular compound testing, unanticipated effects of existing treatments, and new technologies.

Information Gathered During Discovery Phase

Absorption, distribution, metabolism, excretion, benefits, mechanisms, dosage, administration methods, side effects, and effectiveness compared to similar drugs.

Step 2: Preclinical Research

Drugs undergo lab and animal testing to assess basic safety and toxicity.

Toxicity

The potential of a drug to cause serious harm or adverse effects, assessed during preclinical and clinical trials.

Types of Preclinical Research

In vitro (test tube) and in vivo (animal) studies.

FDA Requirements for Preclinical Research

Must follow Good Laboratory Practices (GLP) as outlined in 21 CFR Part 58.1.

Purpose of Preclinical Studies

Provide detailed information on dosing and toxicity levels.

Outcome of Preclinical Studies

Researchers decide whether a drug is safe enough for testing in humans.

Step 3: Clinical Research

Drugs are tested on humans to ensure they are safe and effective.

Clinical Research Phases

Phase 1, Phase 2, Phase 3, and Phase 4.

Phase 1

Focuses on safety, involves 20-100 participants, lasts less than a year, and determines dosage and drug interaction in humans.

Phase 2

Focuses on safety and efficacy, involves about 300 participants, and lasts a few months to a year.

Phase 3

Focuses on treatment efficacy and side effects, involves 300-3000 participants, and lasts 1-3 years.

Phase 4

Post-market monitoring of benefits and risks, involves thousands of participants, and lasts many years.

Protections for Clinical Trial Volunteers

Developers must report serious side effects and follow strict protocols to minimize risk.

New Drug Application (NDA) Filing

Requires adequate data from two large, controlled clinical trials.

Step 4: FDA Review

Thorough review of all submitted data to decide if a drug is safe and effective for marketing approval.

New Drug Application (NDA)

Presents the full story of the drug, including preclinical and clinical data, safety, efficacy, labeling, and more.

FDA Review Team Process

Decides whether an NDA is complete and makes a decision within 6-10 months.

NDA Review Outcomes

Approval for marketing, additional studies required, or rejection with an option for appeal.

Labeling

Describes approval basis and how to best use the drug.

Step 5: Post-Market Safety Monitoring

FDA monitors the safety of drugs and devices after public release.

Purpose of Post-Market Monitoring

Collect safety information that was not fully available during clinical trials.

FDA Actions During Post-Market Monitoring

Add warnings, adjust usage instructions, or implement other measures for safety issues.

Limitations of Clinical Trials

Do not provide complete safety information; ongoing monitoring is needed after approval.

Regulatory Compliance

The process of following laws, regulations, and standards that apply to an organization's industry and operations to ensure legality and ethical practices.

Purpose of Regulatory Compliance

Ensures biotechnology-derived products are safe, effective, and manufactured to high standards.

Key Regulatory Bodies in the United States

The Food and Drug Administration (FDA) oversees biotechnology products under the Federal Food, Drug, and Cosmetic Act (FDCA), Biologics Control Act, and FDA guidelines.

Key Regulatory Bodies in the European Union

The European Medicines Agency (EMA) regulates biotechnology products under EU legislation from the European Commission.

Key Regulatory Bodies in Other Regions

Includes agencies like the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the National Medical Products Administration (NMPA) in China.

Biologics

Products such as vaccines, blood products, gene therapies, and monoclonal antibodies that are under stringent regulatory oversight.

Pharmaceuticals

Drugs produced through biotechnological methods, including recombinant proteins and biosimilars.

Medical Devices

Products intersecting biotechnology, such as in vitro diagnostics and implantable devices.

Preclinical Research

Research phase requiring approval for animal studies and adherence to specific guidelines.

Clinical Trials

Conducted according to Good Clinical Practice (GCP) standards, requiring approvals from regulatory authorities and ethics committees.

Marketing Authorization

A rigorous process of submitting safety, efficacy, and manufacturing data for regulatory review to gain product approval.

Good Laboratory Practice (GLP)

Regulates the management and conduct of preclinical laboratory studies.

Good Clinical Practice (GCP)

Ensures clinical trials are designed, conducted, and reported ethically and scientifically.

Good Manufacturing Practice (GMP)

Ensures consistent production and quality control of biotechnology products.

Good Distribution Practice (GDP)

Regulates the proper handling, storage, and distribution of biotechnology products.

Role of the FDA in Marketing Authorization

Reviews extensive data on safety, efficacy, and manufacturing practices before approving biotechnology products for the market.

Compliance in Biotechnology

Essential for legal operation and to protect public safety in biologics, pharmaceuticals, and medical devices.

Examples of Biotechnology Product Categories

Biologics, pharmaceuticals, and medical devices.

Good Practices Framework

GLP, GCP, GMP, and GDP form the foundation of regulatory compliance standards in biotechnology.

Good Manufacturing Practices (GMP)

A system to ensure healthcare products like drugs and medical devices are consistently produced and controlled according to quality standards.

Purpose of GMP

Ensures the safety, identity, potency, purity, and quality of regulated healthcare products.

Current Good Manufacturing Practices (CGMP)

Refers to GMP standards that evolve over time to reflect the latest technological and scientific advancements.

Scope of CGMP

Covers starting materials, premises, equipment, staff training, and personal hygiene to ensure product quality.

Importance of Written Procedures

Essential for documenting every process that could impact the quality of the final product.

Proof of Compliance

Requires systems that provide documented evidence that correct procedures are followed consistently in manufacturing.

Aspects Regulated by CGMP

Includes production methods, starting materials, facility standards, equipment maintenance, and staff hygiene.

Key Components of GMP

Focuses on safety, consistency, and quality assurance at each step of the manufacturing process.

Training (Subpart B: Organization and Personnel)

Employees must have the education and experience necessary for their roles. Training ensures employees are skilled in their tasks and CGMP requirements. Training records must be documented, as well-trained personnel are less likely to make mistakes.

Documentation and Recordkeeping (Subpart J: Records and Reports)

Ensures an "easy-to-follow" trail for products, components, equipment, and processes at any point in time, facilitating traceability and accountability.

Written Procedures (Subpart J: Records and Reports)

Pharmaceutical CGMP requires at least two dozen document types, such as Standard Operating Procedures, Batch Records, Test Records, and Equipment Cleaning Records, to standardize processes and ensure consistency.

Control and Identification of Materials (Subpart E: Components, Containers, and Closures)

Knowledge of the receipt, origin, identity, status, location, storage, and distribution of materials is essential. Even trash must be labeled as "trash."

Communication (Subpart B: Organization and Personnel)

Effective communication is required to notify personnel of changes in procedures, processes, specifications, or equipment. Written procedures provide the foundation for strong communication systems.

Label Controls (Subpart G: Packaging and Labeling Control)

Frequent inspection and accountability are mandated for labels and labeling operations. Incorrect labeling can pose serious risks to consumers. Labels must include information such as expiration dates, lot numbers, storage instructions, and more.

Contamination Controls (Subpart F: Production and Process Controls)

Regulations ensure the quality, purity, and safety of products through cleaning procedures, pest control, air-quality monitoring, high-purity water systems, and the use of food-grade lubricants.

Change Control (Subpart I: Laboratory Controls)

Changes in specifications, standards, or procedures must be documented, evaluated, approved, and communicated. Investigations into deviations and corrective actions are required when issues arise.

Maintenance and Calibration (Subparts C and D: Buildings, Facilities, and Equipment)

Equipment must be properly maintained and calibrated to ensure accuracy and functionality. Processes can only be reliable if equipment is in good condition.

Validation (Subpart I: Laboratory Controls)

Validation provides documented evidence that processes perform as intended. Required validations include computer systems, sterile processes, and testing methods.

Upstream Processing

Initial stages of production focusing on the growth and maintenance of cells or organisms that produce the target product, including cell culture, fermentation, and harvesting.

Cell Line Development

Selection and engineering of cell lines or microorganisms capable of producing the target product, followed by screening and characterization for productivity and stability.

Cell Culture

Processes involving media preparation, inoculation of bioreactors, and cultivation under controlled conditions like temperature, pH, and dissolved oxygen to ensure cell growth and product expression.

Fermentation

Operation of bioreactors or fermenters to cultivate microorganisms for product production, with optimization to maximize yield and efficiency.

Process Optimization and Scale-Up

Fine-tuning of growth conditions to improve product yield and transitioning from laboratory-scale to production-scale while maintaining quality and consistency.

Harvesting

Collection of cells or biomass containing the product using techniques such as centrifugation or filtration to separate cells from the culture medium.

Downstream Processing

Post-production stages focused on purifying, formulating, and preparing the final product, including removal of impurities and ensuring product quality.

Cell Disruption

Breaking open cells to release intracellular products using mechanical, chemical, or enzymatic methods if the product is not secreted.

Clarification

Separation of cell debris and particulates from the product-containing solution using centrifugation or filtration.

Purification

Separation of the product from impurities using methods like affinity chromatography, ion exchange chromatography, or ultrafiltration.

Formulation

Combination of the product with stabilizers, preservatives, or other excipients to create the final product formulation, including buffer preparation.

Sterilization

Ensuring the product is sterile and free of microbial contamination through methods like filtration or heat.

Filling and Packaging

Processes for filling the final product into containers like vials or syringes and packaging to ensure stability and regulatory compliance.

Quality Control Testing

Extensive testing of the final product for attributes like potency, purity, sterility, and safety to meet quality standards and regulatory requirements.

Research and Development (R&D)

Responsible for discovering and developing products with commercial value, including process development, raw material and equipment determination, production planning, product characterization, and method development for testing.

Key Responsibilities of R&D

Characterize product properties (e.g., composition, strength, purity, safety), identify applications, and develop manufacturing and testing methods.

Example R&D Job Titles

Research Scientist, Biochemist, Molecular Biologist, Research Associate.

Manufacturing/Production

Responsible for producing the product, including preparation of materials, operation and monitoring of equipment, implementing corrective actions, and routine calibration and maintenance.

Key Responsibilities of Manufacturing/Production

Ensure smooth operation of production processes and equipment to consistently produce high-quality products.

Example Manufacturing/Production Job Titles

Manufacturing Technician, Production Manager, Process Engineer, Production Planner.

Quality Control (QC)

Ensures product identity, safety, purity, and stability by testing products and raw materials and performing environmental monitoring within the facility.

Key Responsibilities of QC

Test raw materials, monitor the facility environment, and verify product quality against established standards.

Example QC Job Titles

Quality Control Analyst, QC Scientist, Analytical Chemist, Microbiologist, QC Technician.

Quality Assurance (QA)/Regulatory Affairs

Ensures compliance with CGMP, oversees documentation, audits, vendor qualifications, validation plans, and has authority to release or reject materials and product lots.

Key Responsibilities of QA/Regulatory Affairs

Review and approve documentation, oversee audits, manage training, and ensure regulatory compliance across systems and processes.

Example QA/Regulatory Job Titles

Quality Assurance Specialist, Regulatory Affairs Specialist, Compliance Officer, QA Auditor.

Additional Departments in Larger Companies

Clinical Development, Project Management, Business Development, Finance & Accounting, Human Resources, Legal & Intellectual Property, Marketing.

Role of Larger Departments

Support end-to-end processes from research and development to production, quality control, and market commercialization.

Research and Development (R&D)

Responsible for discovering and developing products with commercial value, including process development, raw material and equipment determination, production planning, product characterization, and method development for testing.

Key Responsibilities of R&D

Characterize product properties (e.g., composition, strength, purity, safety), identify applications, and develop manufacturing and testing methods.

Example R&D Job Titles

Research Scientist, Biochemist, Molecular Biologist, Research Associate.

Manufacturing/Production

Responsible for producing the product, including preparation of materials, operation and monitoring of equipment, implementing corrective actions, and routine calibration and maintenance.

Key Responsibilities of Manufacturing/Production

Ensure smooth operation of production processes and equipment to consistently produce high-quality products.

Example Manufacturing/Production Job Titles

Manufacturing Technician, Production Manager, Process Engineer, Production Planner.