12.1: Principles of Quality Assurance (QA) and Quality Control (QC)

Biotech Focus

In the fall of 2004, the US experienced a severe influenza vaccine shortage due to a production issue at Chiron Corporation's Liverpool, England plant. FDA and British inspectors at the plant revealed violations of "good manufacturing practices" leading to contamination of vials of the vaccine with the bacteria Serratia marcescens. Inspectors identified potential errors in the filling of the vials, possibly compromising the sterility of the vaccine. The FDA concluded that none of the Chiron vaccine was safe for distribution in the US and a recall was issued of over a million doses of the vaccine shipped to the US. This recall effectively halved the expected US supply of influenza vaccine, necessitating a shift in vaccination recommendations and priority groups.

Read about the Fluvirin recall here.

Introduction

Because biotechnology products impact human health, quality is not optional it is essential. From therapeutic proteins to gene therapies, the integrity of biotechnology products (and services) must meet the highest standards. To ensure standards are met, biotechnology facilities rely upon quality assurance (QA) and quality control (QC) (Figure \(\PageIndex{1}\)). Through QA, product quality is built into the process from design to delivery, with an emphasis on identifying defects and errors before they happen. If they do, companies can use QC procedures to correct. As such, both QA and QC are integral components of a biotechnology company's production of safe and effective products.

Figure \(\PageIndex{1}\): QA versus QC. Quality assurance (QA) is proactive and process oriented and involves process improvement, monitoring, documentation, audits and training. Quality control (QC) is reactive and product oriented and involves product sampling, lab testing, verification, inspection, and customer feedback. Both emphasize the release of high-quality products, improvement of processes and procedures, increase of efficiency, safety and efficacy, and the reduction of costs. (QA vs. QC by Patricia Zuk, CC BY 4.0)

Learning Objectives

Quality assurance (QA) and quality control (QC) are used by biotechnology companies to identify errors before they happen or to correct them when they do. At the end of this page, you will be able to:

• Define QA and QC and distinguish between them
• Compare and contrast major features of QA and QC
• Explain the major principles of QA and QC
• List the different types of QA and QC
• Explain the role of ISO standards in QA and QC
• Explain the ISO 9000 family of standards
• Explain the purpose of ICH guidelines in pharmaceuticals
• Explain the major categories of ICH guidelines
• Explain the difference between a standard and a specification
• Discuss the roles of QA and QC in biotechnology manufacturing

Quality Assurance (QA) vs. Quality Control (QC)

QA and QC are often confused with one another. While they are related to one another and are both used in product development, they are distinct processes. QA is a systematic approach that ensures all processes involved in the production, testing, and documentation of manufactured products are conducted in accordance with defined standards, specifications, and regulations. QA is process-oriented and pro-active. It focuses on preventing errors before they occur. The mantra for QA is "right the first time". QC reviews the quality of all factors involved in production. It is the process of testing and inspection that is used by manufacturers to identify defects or deviations from specifications in raw materials, in-process samples, and final products. QC is product-oriented and reactive. It ensures that outputs meet established quality standards and, when they don't, identifies where and when errors occurred. Table \(\PageIndex{1}\): below summarizes the focus, purpose, responsibilities, and activities of QA and QC.

Table \(\PageIndex{1}\): Quality Assurance vs. Quality Control

Feature	Quality Assurance (QA)	Quality Control (QC)
Focus	The process of making a product (from design to delivery)	the product being made
Purpose	Prevention of defects before production (proactive)	Identification and correction of defects during or after production (reactive)
Activities	Documentation, audits, training, SOPs	Testing, sampling, inspection
Responsibility	Quality Assurance department	Quality Control department

Major Principles of Quality Assurance

1. Compliance with Regulatory Standards: QA ensures that all products and processes meet regulatory requirements set by regulatory agencies
2. Document Control: QA ensures that all procedures are properly documented in Standard Operating Procedures (SOPs), which must be approved, regularly reviewed, and archived
3. Change Control: Any proposed changes to materials, methods, or equipment must go through a formal change control process, including risk assessment and justification for the change
4. Training and Qualification: QA is responsible for ensuring all personnel are properly trained according to internal and external regulations (e.g., Occupational Health and Safety) and their training is documented and regularly updated
5. Auditing and Self-Inspection: QA is responsible for conducting internal and external audits that help verify compliance with standards and specifications and uncover opportunities for improvement
6. Corrective and Preventive Action (CAPA): QA oversees CAPA systems that investigate the root causes of deviations from standards and specifications and implements actions to prevent recurrence of these deviations

Types of QA

• Product QA: focuses on ensuring that the final product meets the specified requirements and standards
• Process QA: focuses on ensuring that the processes used to create the product or service are efficient, effective, and consistent
• Functional QA: focuses on ensuring that the product functions as intended and meets all functional requirements
• Supplier QA: focuses on ensuring that the suppliers of materials or components meet the required quality standard

Major Principles of Quality Control

1. Raw Material Testing: All raw materials must be verified for identity, purity, and potency before use in production
2. In-Process Control (IPC): QC requires the monitoring of processes while they are being performed (i.e., real-time monitoring) in order to ensure that critical parameters remain within acceptable ranges
   • prevents defects and errors by maintaining process conditions within predefined limits
   • e.g. bioreactor conditions during fermentation processes
3. Acceptance Sampling: Inspection of a random sample taken from a production batch to decide whether the whole batch meets quality standards
   • identifies defects in products as they are being made
   • samples (and the entire batch) are either accepted or rejected
   • e.g. extraction of a sample from a bioreactor
4. Final Product Testing: QC performs tests for material identity, potency, purity, sterility, and stability
   • goal is to detect and remove defective items before they reach the customer
   • e.g. laboratory analysis of a drug
5. Analytical Method Validation: All analytical methods used in QC must be validated to demonstrate accuracy, precision, sensitivity, and reproducibility
   • method validation is mandatory to meet standards set by regulatory authorities like the FDA
   • e.g. validation of quantitative QC methods used to assay drug purity and safety
6. Stability Testing: QC must ensure products remain effective and safe throughout their shelf life by conducting short-term and long-term stability studies
7. Batch Release and Certificate of Analysis (CoA): QC provides the final evaluation of product quality before a "batch" of product is released
   • includes a signed CoA with key test results

Quality Management Systems

In biotechnology, QA and QC ensure that each product is made in accordance with regulations set by agencies like the FDA, USDA, or the European Medicines Agency (EMA). To ensure this, a biotechnology company employs some type of quality management system (QMS). A QMS is a highly structured framework that helps an organization deliver a high-quality product (or service) in a consistent manner. The QMS defines and documents all processes, procedures, and responsibilities involved in manufacturing a product (or providing a service).

Biotechnology facilities will use one (or both) of the following QMS:

• GMP (Good Manufacturing Practice)
  • a QMS that applies to the manufacturing, processing, and packaging of regulated products, such as pharmaceuticals, medical devices, and foods
  • ensures that products are produced to consistently meet all quality standards and are safe for use
  • emphasizes comprehensive documentation of all manufacturing processes, batch records, and product testing in order to ensure traceability and regulatory compliance
• GLP (Good Laboratory Practice)
  • a QMS used in the research and development labs of biotechnology companies
  • ensures the credibility and reliability of scientific data
  • establishes standards for the conducting of a study and the collection, analysis and reporting of its data
  • emphasizes adherence to protocols, documentation, and quality control measures to ensure that research findings are accurate and reproducible

ISO Standards in QA and QC

Every company promises an unwavering commitment to quality. However, how does a company provide proof of this commitment? Companies can assure their customers of the quality of their practices and processes using standards established by the International Organization for Standardization (ISO). Founded in 1947, the ISO has over 170 member countries and publishes new standards and revisions to existing standards on a regular basis. As of 2024, there are over 24,000 ISO standards that cover virtually every industry and sector. Some of the major categories of ISO standards cover quality management systems, environmental management systems, information security, occupational health and safety, food safety, medical devices, and laboratory competence. In QA, ISO's promote principles such as continual improvement and a commitment to safety and quality. They encourage documentation, monitoring, and evaluation of processes to prevent defects and errors. In QC, ISO standards are used to define calibration requirements for equipment, specific testing methods, and the criteria used to accept or reject a product. They help organizations develop a structured approach to inspection and testing, so that non-conforming products can be detected and dealt with.

The following ISO standards are used frequently in biotechnology QA and QC:

• ISO 9001 – Used to create and implement a QMS
• ISO 22000 - Used for Food Safety Management Systems
• ISO 2859 - Used for QC sampling procedures
• ISO 17025 – Used for testing and calibration of laboratories
• ISO 13485 – Used for a QMS for medical devices
• ISO 19011 – Guidelines for auditing management systems

ISO 9001 is part of the ISO 9000 "family" of standards. The ISO 9000 family includes three main standards: ISO 9000, ISO 9001, and ISO 9004. ISO 9001 is the standard that helps organizations develop and implement a robust QMS like GMP or GLP. The most recent ISO 9001 version is called ISO 9001:2015. Companies achieving this certification are permitted to display a logo on company materials like letterhead, labels, and their website (Figure \(\PageIndex{1}\)). This specific ISO is the only one in the ISO 9000 family that is "certified" through an external ISO audit - a systematic, independent, and documented process for evaluating whether an organization's management system, such as their QMS, complies with the requirements of a specific ISO standard. Companies will seek "ISO 9001 certification" in order to improve their product and service quality, enhance operational efficiency, and support continuous improvement of their processes. This certification can also boost customer satisfaction and confidence and increase market share because it assures customers that the product they are purchasing has a defined level of quality. In certain instances, companies cannot realistically enter a market without ISO 9001 certification. In contrast to ISO 9001, the ISO 9000 and ISO 9004 standards are not certified through an audit. Rather, companies will use ISO 9000 to learn the basic concepts, principles, and terminology important to ISO 9001 certification. If desired, companies can also follow the standards outlined in ISO 9004 in order to go beyond ISO 9001 compliance to achieve long-term success. Because of this, ISO 9000 and ISO 9004 are applicable to any organization regardless of size, industry, or location, whereas ISO 9001 is used by companies that have established a QMS.

Figure \(\PageIndex{2}\): The ISO 9001:2015 logo. (ISO 9001-2015 by Юкатан, CC BY-SA 4.0)

ICH Guidelines

For pharmaceutical companies, products must be deemed as safe, effective, and of high quality. Moreover, the production, testing, and regulatory processes used in QA and QC must be consistent across major global markets. In short, these processes must be "harmonized". As a result, pharmaceutical companies also follow ICH guidelines. These guidelines are internationally harmonized standards developed by the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use. The ICH was founded in 1990 and its members include regulatory authorities (e.g., FDA, EMA, PMDA) and industry groups. The goal of ICH guidelines is to "harmonize" pharmaceutical regulations across the U.S., EU, Japan, and more recently, Canada, China, and Brazil. ICH guidelines focus on reducing duplication in drug development, testing, and approval processes. They are recognizes by regulatory agencies worldwide and are often required for drugs that are entering the global market.

ICH guidelines are divided into five categories:

1. Q – Quality Guidelines: focuses on chemistry, manufacturing, and controls
   • examples: Q1 (stability testing), Q8 (pharmaceutical quality system)
2. S – Safety Guidelines: focuses on preclinical safety and toxicology studies
   • examples: S1 (carcinogenicity), S2 (genotoxicity), S6 (biotechnology products - i.e., preclinical safety)
3. E – Efficacy Guidelines: focuses on clinical studies and pharmacology
   • E6 (Good Clinical Practice), E8 (general considerations for clinical trials), E9 (statistical principles)
4. M – Multidisciplinary Guidelines: focuses on topics that cross multiple categories
   • M1 (medical terminology), M4 (common technical document), and M9 (biopharmaceutical classification system)
5. R – Recently Revised/Implemented Guidelines: introduces updated versions of older guidelines

Quality Standards and Specifications

The terms standard and specification are used frequently in QA and QC. A standard might require or refer to a specification, while a specification might comply with or be derived from a standard. So, while standard and specification are related, they are not the same thing. A standard is a broad, consensus-based document that provides the guidelines or rules for a process and product (or service). A standard covers terminology, general principles, and "best practices" and is often applied across an organization or industry. Because of this, the scope of a standard is broad and general. For example, a standard might stipulate that the base of a light bulb be "made of conductive metal". Another example of a standard is the ISO 9001 standard used in a QMS. This standard defines what a QMS should include, but not how every company must implement it.

A specification is a more detailed, technical document that defines the exact requirements for a product, material, or process. It is often used in manufacturing and engineering. The specification tells a user exactly what the product must be and must do. The scope of a specification is narrow, detailed, and technical. For example, with regards to the light bulb, the specification might stipulate that the conductive metal contain 30 to 40% copper. Lastly, specifications might differ from company to company, but a standard does not change.

Integration of QA and QC in Biotechnology Manufacturing

In biotech manufacturing, QA and QC are deeply integrated into every stage of the process to ensure that biopharmaceutical products are safe, effective, and comply with regulatory standards (e.g., FDA, EMA, ICH). They are embedded in all stages of product development. For example, during upstream processing, QA oversees process validation, while QC tests cell lines and growth media. During downstream processing, QC ensures the purity and integrity of a product. Regulatory agencies like the FDA (and the European Medicines Agency/EMA) require comprehensive QA and QC documentation as part of new drug applications and the licensing of new biologics. Failures in QA or QC can result in clinical trial delays, product recalls, or regulatory action that can result in large fines. Table \(\PageIndex{2}\) below gives several examples of how QA and QC work together in biotechnology manufacturing.

Table \(\PageIndex{2}\): Roles of QA and QC In Biotech

Phase	QA Role	QC Role
Design and Development	Implement quality manufacturing systems (QMS) like Good Manufacturing Practices (GMP) or Good Laboratory Practices (GLP) early in development Develops standard operating procedures (SOPs) Oversees design controls	Validates analytical test methods Performs initial raw material testing Supports method development with data
Raw Material Control	Approves qualified suppliers Reviews material handling procedures	Tests incoming raw materials (e.g., media, buffers) Ensures material identity, purity, and sterility
Upstream and Downstream Processing	Audits the compliance of processes to SOPs and batch records Approves change controls and Corrective and Preventive Actions (CAPAs)	Performs in-process testing (e.g., cell viability, metabolite levels) Monitors critical quality attributes (CQAs) Conducts environmental monitoring in clean rooms
Product Testing and Release	Reviews and approves batch records and QC data for release Ensures data integrity and traceability Manages product disposition decisions	Conducts release testing of products (e.g., potency, purity, sterility) Confirms compliance with product specifications Performs stability testing (short-term)
Validation and Continuous Monitoring	Oversees the development of strategies for process validation Implements quality risk management (QRM) principles Ensures systems remain qualified and calibrated	Collects and analyzes validation data Performs trend analysis (e.g., control charts) Performs and supports long-term stability studies

Key Concepts

Both QA and QC are integral components of a biotechnology company's production of safe and effective products. Some important concepts to remember are:

• QA is proactive; QC is reactive - QA focuses on preventing defects, QC focuses on detecting them
• QA is process-based and focuses on the processes and systems that create the product (or service)
• QC is product-based and tests the final product before it is released
• Biotechnology manufacturers use a quality management system (QMS), like GMP or GLP as part of their QA and QC practices
• QA and QC are conducted using a set of standards established by the International Organization for Standardization (ISO).
• ISO 9001 is the current ISO standard used for the QMS
• Pharmaceutical companies will also use International Council for Harmonisation (ICH) guidelines to ensure that the production, testing, and regulatory processes used in QA and QC are consistent for pharmaceuticals entering the global market

Glossary

 

Audit - a systematic, independent, and documented process for evaluating whether an organization's management system complies with the requirements of a specific ISO standard

Batch - a specific quantity of material or product produced during a single manufacturing cycle under uniform conditions; identified by a batch number and must meet defined quality criteria

Documentation - the systematic process of creating, organizing, and maintaining written records that describe processes, procedures, decisions, designs, and results

Good Manufacturing Practice (GMP) - a system of regulations and guidelines used in pharmaceuticals, biologics, medical devices, and food, that ensure products are consistently produced and controlled according to quality standards; enforced by regulatory bodies

Good Laboratory Practice (GLP) - a quality system concerned with ensuring the integrity, reliability, and reproducibility of laboratory data

International Organization for Standardization (ISO) - an independent, non-governmental international organization that develops and publishes voluntary global standards

ISO standards - internationally recognized guidelines published by the International Organization for Standardization (ISO) in order to provide best practices, technical specifications, and requirements for quality, safety, and efficiency across industries

ISO 9001 - the standard that helps organizations develop and implement a QMS like GMP or GLP

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) - an international organization that develops guidelines to ensure safe, effective, and high-quality medicines are developed and registered efficiently and properly

Quality assurance (QA) - a set of planned and systematic activities implemented in a quality system to ensure that quality requirements for a product or service are fulfilled

Quality control (QC) - the operational techniques and activities used to fulfill requirements for quality, typically through sampling, measurement, and testing

Quality Management System (QMS) - a highly structured framework that helps organizations deliver a high-quality product (or service) in a consistent manner

Product testing - the process of evaluating a product's performance, quality, safety, and compliance with relevant standards, regulations, or customer requirements before it is released to the market or approved for use

Standard Operating Procedure (SOP) - a detailed, written instruction describing how to perform a routine or repetitive activity in a consistent and controlled way; ensures compliance, training, quality, and safety

Standard - a documented general agreement containing technical specifications, guidelines, or criteria that can be used consistently by an industry to ensure that materials, products, processes, or services are fit for purpose

Specification - a detailed and exact statement of technical requirements, including measurements, tolerances, materials, and methods for a product, service, or process; defines what is acceptable or expected and is used for quality control, purchasing, and regulatory compliance