For the production process, effective measures are taken to monitor deviations from the validated product registration process that may occur in daily production and to assess the need to take measures for prevention or correction to ensure that the process is under monitoring; process data related to product quality in daily production is collected and analyzed on an ongoing basis to determine the status of the product's key quality attributes as they are under control throughout the process; quality defects Complaints, OOS data, deviations, yield fluctuations and other trend analysis. This is done through annual reviews of product quality and evaluates whether the process is in a controlled state.
For plant, facilities, and equipment, the state of validation is maintained through routine monitoring, maintenance, and calibration procedures, planning, and implementation; and the need for, or extent of, revalidation is determined through periodic evaluations of routine data and facility and equipment validation data.
For cleaning, maintenance of validation status should include trend analysis of environmental monitoring data; residue testing of equipment surfaces in direct contact with materials, if necessary (Article 197-6 of the new version of the GMP); and preventive maintenance and calibration of equipment (both cleaned equipment and equipment used for cleaning).
In short, the principle of risk management should be used to select the calibration status maintenance tools according to the actual needs.
Article 140 of the new GMP emphasizes that the implementation of confirmation and validation should be documented, recorded and targeted. Requirements for plant, facilities and equipment designed to meet the intended use and GMP requirements, constructed and installed in accordance with the design criteria, operation in accordance with the design criteria, under normal operating methods and process conditions, its performance can continue to comply with the standard; in accordance with the specified parameters, the production process can be continuous production of products in line with the intended use and the requirements of registration.
Design Qualification (DQ) is the first step in the validation of new or modified plants, facilities and equipment, and consists primarily of a variety of validation efforts and documentation that confirms that the design plans for facilities, systems and equipment meet the intended objectives.
According to the appendix of the new GMP validation and verification, companies are required to first provide a User Requirements Specification (URS) in the form of a document to the supplier.
In general, the customer requirements document (URS) is the test standard for design confirmation. It is the basis for successful verification, and with the URS, verification activities can be targeted.
In the URS provided to the supplier, the company should clearly state its own requirements for the use of plant, facilities, equipment, etc. (intended use). As well as requirements for compliance with other relevant laws and regulations based on product and process needs. As far as possible, the supplier "provides" the plant, facilities, equipment, design plans and description of the material for pre-approval, to avoid irreparable inherent defects caused by design errors.
After the production quality and other relevant responsible person to review and approve the user requirements specification (URS) to be as far as possible: each requirement has specific criteria; each requirement can be tested or confirmed to confirm that the supplier to provide the physical meet their own needs; each requirement is clear, can be achieved; through the design and testing of the tracking of each requirement.
During the design confirmation process, we should focus on key points related to quality. Such as material, safety assessment, environmental protection, space requirements, usage requirements, etc.; whether the design is easy to wash/clean and inspect; whether it introduces hazardous materials and parts that need to be replaced.
There is no universally accepted design validation model in the industry. In practice, if national regulations for medical buildings and equipment are followed from the beginning of a project, and a full set of information complying with those regulations is maintained, the new GMP test for design validation is largely satisfied. If the equipment is customized, there is a greater need to strengthen the design confirmation.
In addition, during the design confirmation phase, change management should be strengthened to document any changes to the original design and adaptively adjust the relevant factors.
Installation (IQ) refers to a variety of system checks and technical data documents that demonstrate that new or modified plant, facilities and equipment meet design requirements.
Enterprises shall accept and document the acceptance of plant, facilities and equipment in accordance with user requirements and the technical requirements in the design confirmation. The confirmation includes at least: checking whether the installation of equipment, piping, utilities and instrumentation is in accordance with the design standards according to the latest engineering drawings and technical requirements; collecting and organizing (archiving) drawings, equipment lists, various certificates and material certificates, instructions or operation and maintenance manuals provided by the suppliers; carrying out necessary calibrations of the corresponding instrumentation; and engineers drafting the operation, cleaning, and maintenance manuals according to the technical data provided by the suppliers and the enterprise's The engineer drafts the standard operating procedures for operation, cleaning, calibration and maintenance according to the technical information provided by the supplier and the actual situation of the enterprise.
Operation Qualification (OQ) is the commissioning, validation, and documentation of new or modified plants, facilities, and equipment to demonstrate that they can operate normally within the expected range of design requirements.
Operational validation includes, at a minimum, the development of an operational test program based on the design criteria for the facility and equipment; tests/trials should be conducted under one or a set of operating conditions, including the upper and lower limits of the equipment's operation, and, if necessary, using the "worst-case scenarios" for validation, and the tests should be repeated a sufficient number of times to ensure that the results are reliable; in the operational validation process, the operation, cleaning and maintenance should be performed in the same manner as for the equipment. During the confirmation process, operating procedures for operation, cleaning, calibration and preventive maintenance should be revised and improved, and training should be provided to relevant personnel.
Installation and operational confirmation can generally be accomplished by both the supplier and the company***. Completion of the operational verification is equivalent to the formal "release" of the plant, facility and equipment for use.
Performance Qualification (PQ) is the commissioning, verification, and documentation of installed and connected plant, facilities, and equipment to demonstrate that it will operate efficiently and consistently (with good reproducibility) in accordance with approved production methods and product specifications.
Performance validation is the testing of each critical control system (e.g., temperature control, pressure control, stirring control) and all critical parameters affecting product quality (e.g., temperature, pressure, stirring speed) using production materials, confirmed substitutes, or simulated products. The performance confirmation program includes parameter descriptions, test conditions and methods, test frequency and criteria. The sampling frequency required during testing should be evaluated.
In the performance confirmation stage, for formulation products, in order to verify whether the equipment can meet the commercial production capacity, some blank products will be produced before formal production. For APIs, it is difficult to use so-called blank material in production. Some companies will run solvents or water to mimic the API process (replacing the material with water in conjunction with a trial run). It is also possible to use materials used in formal production for performance confirmation, defining the batch as both a process validation batch and an equipment performance confirmation batch (the company bears the risk of economic loss due to batch failure).
The confirmation process should be logical and systematic. Typically, the URS is presented to the supplier first, followed by the DQ, IQ, OQ, and PQ. In some cases, performance confirmation can be considered in conjunction with operational confirmation or process validation, but the need to evaluate the sampling frequency of the performance confirmation process should be adequately addressed.
Workshop and facilities (including air purification systems, compressed air systems, water systems, etc.). Should be confirmed before the equipment, equipment confirmation should be completed before putting into normal production, because the production equipment should be used within the parameters of the confirmation (see the new GMP Article 83). Documents related to validation include standard operating procedures, acceptable standards, operating manuals, etc. Confirmation shall be performed in accordance with the approved program, and the results of the confirmation shall be documented and reflected in the confirmation report.
If the object of confirmation is already in use, it shall be confirmed according to the actual situation:Installation status check (IQ), equipment operation parameter checking and testing (OQ), and process matching test evaluation (PQ).
Confirmation is a prerequisite for process validation, and confirmation of plant, facilities and equipment should be included in the overall validation plan.
The main objective of process validation (PV) is to confirm that the designed manufacturing process is capable of continuously producing a product that meets the intended use and registration requirements in accordance with the specified process parameters.
Before a drug can be marketed, the process validation must be completed and meet the set requirements. In particular, the new GMP emphasizes that before adopting a new product prescription or manufacturing process, the applicability of routine production should be verified to ensure that "it is always possible to produce a product that meets the requirements for its intended use and registration" (see Article 141). Intended use and registration requirements" means compliance with efficacy, safety and quality standards.
First, process validation is based on the understanding of the product and process knowledge gained from the R&D process, focusing on identifying and focusing on the key quality attributes of the product (which may be considered in terms of identification, physicochemical properties, nature, content, purity, particle size, microbial limits, crystalline form, etc.). , key process parameters, and the range of key process parameters in routine production and process control. The first process validation of a new manufacturing prescription or production process should cover all specifications of the product.