Qualification and Validation (Q&V)
Qualification Definitions
Qualification is the verification through documented activities that an instrument, process equipment, or process facility involved in manufacturing and quality control of medicinal products is properly designed and installed and operates within predefined specifications.
Objective of qualification regulation
The purpose of qualifying process equipment or analytical instruments is to verify suitability for the intended use and to ensure that equipment, devices or facilities meet their specifications and the associated acceptance criteria.
FDA statutory and regulatory GMP requirements
Federal Food, Drug, and Cosmetic Act (FDC Act)
The regulatory basis for Good Manufacturing Practice (GMP) is the Federal Food, Drug, and Cosmetic Act (FDC Act). The GMP requirements are codified by the FDA of the Code of Federal Regulations (CFR) Title 21 Food and Drugs: CFR Title 21 parts 210 and 211:
Part 211 Current good manufacturing practice in manufacturing for finished pharmaceuticals.
Regulatory FDA requirements
The FDA requires that the medicinal product meet the safety aspects, and the identity, strength, purity, and quality specifications which it states to have, as required by section 501(a)(2)(B) of the act.
Food, Drug, and Cosmetic Act (FDC Act) Section 501 (a) (2)(B)
A drug is deemed adulterated if its manufacturing, processing, packing, or holding method do not conform to cGMP to ensure safety, quality, and purity.
(a) Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act provides that a drug (including a drug contained in a medicated feed) shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirement of the act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
Process Line and Process Facility Qualification
Process line and process facility qualification (e.g. Sterile Fill Line Equipment) for sterile pharmaceutical manufacturing is one of the most critical assets. For aseptic manufacturing in compliance with cGMP, EU GMP Guide Annex 1, FDA guidance, and ISO 14644 principles are applicable.
Qualification Acitivities
Qualification is part of validation. Equipment, instruments, systems, and devices are qualified, processes, procedures, and analytical methods are validated. The legal responsibility for qualified equipment lies within the manufacturer.
Qualification Phases
Qualification is a multilevel process consisting of four main qualification phases: DQ, IQ, OQ, and PQ
Design Qualification (DQ)
Definition
The Design Qualification (DQ) verifies the functional and operational specifications through documented activities and that the specified design of the process equipment, process facility, instrument or device is suitable for the intended purpose.
Objective
The selection and purchase of a new instrument, process equipment, or process facility shall follow a documented decision process. The decision is based on the needs related to the intended purpose.
General DQ requirements
I Planning
- Design stage
- URS, FS
- System Classification
- Risk Assessment
II Procurement
III Suppliers Work
- FAT
- SAT
Installation Qualification (IQ)
Definition
IQ verifies through documented activities that the process equipment is delivered as designed and specified, according to the URS and that the equipment is properly installed and assembled in the designated environment.
Objective
The IQ verifies the correct implementation of the requirements defined in the design qualification (DQ) during the assembly and installation of the equipment. The verification of the installation qualification (IQ) is basically performed on the basis of the previously devised URS.
General IQ requirements
- Conformity checks with order (instrument, material, documentation)
- Check for damage
- Check for required medial supply (connections, environmental conditions)
- Check of correct instrument installation and assembly
General IQ activities
- Instrument delivery
- Description
- Utilities/Facility/Environment
- Assembly and installation
- Software installation, network, and data storage
- Installation verification
Operational Qualification (OQ)
Definition
OQ verifies through documented activities that the process equipment, process facility, or analytical instrument operates within its specified operational specifications and acceptance criteria as designed and installed.
About OQ
- OQ follows the IQ
- OQ verifies the URS
- FAT and SAT should be incorporated into testing activities to avoid retesting
Performance Qualification (PQ)
Definition
PQ verifies through documented activities that the process equipment, process facility, or analytical instrument operates consistently and reproducibly within predefined performance specifications and acceptance criteria under actual conditions of use.
About PQ
PQ therefore verifies the fitness for purpose of the process equipment or process facility under actual conditions of use.
User Requirements Specification (URS)
The user requirements refer to the laboratory needs and the technical and operational requirements of the system. The system specification describes a solution that will satisfy the needs of the users.
Specifications must solve every part of the problem described in the requirements document and must trace back to the user requirements. Requirements and specifications must be testable.
The URS is an essential regulatory GMP requirement. The devise of a thorough and intelligent URS is of utmost avail as the URS influences directly the outcome of the qualification activities.
General URS instructions
- Description of the analysis, test method, system
- Description of the intended use of the equipment
- Description of functional specifications
- Description of operational specifications
- Description of environmental specifications
- Safety aspects
System Classification
To determine the extent of qualification the systems are classified into categories depending on their complexity and the criticality on its intended use.
Group A includes the simplest standards devices and instruments such as magnetic stirrer or vortex mixer which are used without measurement capability. Their handling is simple and self-explanatory. The quality of product and process will not be affected by this category and therefore qualification activities require only the basics.
Group B includes instruments which are more complex and provide a measurement capability or a condition that may affect a measurement, for example a pH meter and oven or incubator. These instruments may have firmware but are not software-controlled. The extent of qualification activities depends on criticality regarding critical quality attributes (CQAs) and critical process parameters (CPPs) which shall be analyzed by a risk assessment.
Group C includes complex analytical instruments with software-controlled measurements and analysis such as HPLC, mass spectrometer or flow cytometer. This category requires the highest quality standards. Their qualification is elaborate and labor-intensive. It also includes the computerized software validation (CSV) which is even more challenging and demanding.
Instrument Calibration
Calibration is a test procedure for determining the output and input variables, i.e. the measured value and the corresponding true or correct value using a reference standard to identify the deviation of a test device (e.g. test instrument or analytical instrument).
FAT
For complex process line or process facilities the framework is extended to include functional specifications (FS) and factory acceptance testing (FAT). FAT is performed by and at the vendor’s location. The primary objective is to ensure that the system meets the functional and operational specifications as devised in the URS. FAT may include all activities from commissioning to qualification (DQ, IQ, OQ). FAT should be incorporated into the qualification operations where possible.
SAT
Site acceptance testing (SAT) includes analytical instrument installation, process equipment installation and start-up which are normally undertaken in IQ and OQ. The equipment is retested when installed at the manufacturing site by the vendor. Some of the SAT activities may be satisfied and do not need to be repeated by the manufacturer. The documentation can be incorporated into the qualification process.
Specifications and acceptance criteria
Specifications are part of the laboratory controls. The quality control unit is responsible for the establishment of scientifically sound and appropriate specification standards, sampling plans, and test procedures.
To ensure that products meet their specifications, a diverse repertoire of analytical instruments, process equipment and process facility for the production and quality control of biopharmaceuticals is required.
Validation parameters and acceptance criteria are part of the specifications. Specifications aim to assure compliance with GMP.
The regulatory FDA requirements are stated in the code of federal regulation 21 CFR § 211.160 General requirements.
- Specification, validation parameters and the acceptance criteria represent the core element of any qualification or validation plan.
- Specifications must be established before qualification or validation is performed.
- When establishing specifications, expertise from drug development, drug manufacturing and quality control should be incorporated into validation and qualification processes.
Risk Assessment and Risk Analysis
Manufacturers of biotechnological-derived medicinal products are required to follow risk-based approaches in their GMP compliance operations. Annex 15 of the EU GMP Guide states that a quality risk approach should be applied throughout the product life cycle.
The risk assessment identifies and provides scientific knowledge about potential quality risks. Quality risks associated with biotechnological-derived products are highly dependent on the manufacturing process, the protein itself and the manufacturing facility and environment.
The objective of risk assessment is to identify all the potential risks and to implement control and mitigation activities to minimize all the potential risks where possible.
The assessment shall follow the impact of potential risks in terms of quality, safety and efficacy of the product as well as other risks to health, human and environment.
The evaluation of the risk assessment should be knowledge-based on current scientific knowledge and the accumulated experience during drug development, preclinical development, quality control and manufacturing processes.
Critical quality attributes (CQAs) and critical process parameters (CPPs) play the key role within your risk assessment..
Summary
Qualification and validation activities are part of good manufacturing practice (GMP). The use of qualified instruments and process equipment is mandatory because it is required by regulatory authorities. The purpose of Q&V is to contribute to customers’ confidence and that the instruments and equipment perform suitably according to their intended purpose.
Qualification and validation operations require compliance with predefined specifications and GMP regulations to ensure the quality and reliability of manufacturing processes with regard to the quality, safety and efficacy of medicinal products.
For GMP-related environments such as the pharmaceutical industry and treatment centers for ATMPs, qualification and validation are essential GMP requirements to verify GMP compliance.