For factories, facilities and equipment, maintain the confirmation status through routine monitoring, maintenance and calibration procedures, plans and implementation; Determine whether it is necessary to reconfirm or the degree of reconfirmation by regularly evaluating the daily data and facilities and equipment confirmation data.
For cleaning, the maintenance of verification status should include the trend analysis of environmental monitoring data; When necessary, carry out residue detection on the surface of equipment that directly contacts materials (Article 197-VI of the new GMP); Preventive maintenance and calibration of equipment (including cleaned equipment and equipment used for cleaning).
In a word, the principle of risk management should be adopted, and the verification state maintenance tools should be selected according to actual needs.
The new GMP article 140 emphasizes that the implementation of confirmation and verification should be documented, recorded and targeted. It is clearly required that the design of the plant, facilities and equipment should meet the expected use and GMP requirements, the construction and installation should meet the design standards, the operation should meet the design standards, and its performance can meet the standards under normal operation methods and technological conditions; The production process can continuously produce products that meet the expected use and registration requirements according to the specified parameters.
Design Confirmation (DQ) is the first step in the verification of newly built or rebuilt factories, facilities and equipment, which mainly includes all kinds of verification work and documents to confirm that the design scheme of facilities, systems and equipment reaches the expected goal.
According to the appendix of the new GMP confirmation and verification, enterprises need to provide "User Requirements Statement (URS)" to suppliers in the form of documents.
Generally speaking, the customer requirements document (URS) is the inspection standard for design confirmation. This is the basis for the success of the verification work, and only with URS can the verification activities be carried out purposefully.
In the URS provided to suppliers, enterprises should clearly put forward their own requirements (expected uses) for the use of relevant laws and regulations such as factories, facilities and equipment according to the needs of products and processes. Try to pre-examine the design scheme and explanatory materials of the factory buildings, facilities and equipment "provided" by the supplier to avoid irreparable congenital defects caused by design mistakes.
The User Requirements Specification (URS) reviewed and approved by the person in charge of production quality should try its best to achieve: each requirement has specific standards; Each demand can be tested or confirmed to confirm whether the goods provided by the supplier meet their own needs; Every requirement is clear and achievable; Track each requirement through design and testing.
During the design verification, we should pay attention to the key points related to quality. Such as material quality, safety assessment, environmental protection issues, space requirements and use requirements; Whether the design is easy to clean/clean and check; Whether to introduce harmful materials and parts that need to be replaced.
At present, there is not a universally recognized design confirmation mode in the industry. In practical work, if we follow the relevant national regulations on medical buildings and equipment from the beginning of the project implementation and keep all the materials that meet these regulations, we will basically meet the inspection requirements of the new GMP for design confirmation. If the equipment is customized, it is even more necessary to strengthen design confirmation.
In addition, in the design confirmation stage, change management should be strengthened, any changes in the original design should be recorded, and relevant factors should be adjusted adaptively.
IQ (Installation Verification) refers to the inspection of various systems and the documentation of technical data in order to prove that newly-built or renovated factories, facilities and equipment meet the design requirements.
The enterprise shall inspect and record the factory buildings, facilities and equipment according to the user's needs and the technical requirements in design confirmation. Installation confirmation at least includes: according to the latest engineering drawings and technical requirements, check whether the installation of equipment, pipelines, public facilities and instruments meets the design standards; Collect (archive) drawings, equipment lists, certificates and material certificates, manuals or operation and maintenance manuals provided by suppliers; Make necessary calibration for corresponding instruments and meters; According to the technical data provided by suppliers and the actual situation of enterprises, engineers and technicians draft standard operating procedures such as operation, cleaning, calibration and maintenance.
Operational Confirmation (OQ) refers to the trial operation, verification and documentation to prove that newly-built or renovated factories, facilities and equipment can operate normally within the expected range of design requirements.
Operation confirmation at least includes: formulating operation test items according to the design standards of facilities and equipment; The test/test shall be carried out under one or a group of operating conditions, including the upper and lower limits of equipment operation. If necessary, the "worst condition" shall be adopted for confirmation, and the test shall be repeated enough times to ensure reliable results; In the process of operation confirmation, the operating procedures such as operation, cleaning, calibration and preventive maintenance should be revised and improved, and relevant personnel should be trained.
Installation confirmation and operation confirmation can generally be completed by suppliers and enterprises. The completion of operation confirmation is equivalent to allowing the factory buildings, facilities and equipment to be officially "released" for use. ?
PQ is a kind of trial operation, verification and documentation to prove that the installed and connected factories, facilities and equipment can operate effectively and stably (with good reproducibility) according to the approved production methods and technical requirements of products.
Performance verification is to test every key control system (such as temperature control, pressure control and mixing control) and all key parameters (such as temperature, pressure and mixing speed) that affect product quality by using production materials, confirmed substitutes or simulated products. The content of performance verification scheme includes parameter introduction, test conditions and methods, test frequency and standards, etc. , and should evaluate the sampling frequency required during the test.
In the performance confirmation stage, for preparation products, in order to prove that the equipment can meet the ability of commercial production, some blank products will be produced before formal production. For APIs, it is difficult to use so-called blank materials in production. Some companies will run solvents or water to imitate the API process (using water instead of materials, combined with debugging work). You can also use materials used in routine production for performance confirmation, and define this batch of products as process verification batch and equipment performance confirmation batch (the enterprise bears the risk of economic loss caused by batch failure).
Confirm that the working process should be logical and systematic. In general, URS is proposed to suppliers first, followed by DQ, IQ, OQ and PQ. In some cases, we can consider combining performance verification with operation verification or process verification, but it should be fully explained that the sampling frequency of performance verification process needs to be evaluated.
Factories and facilities (including air purification system, compressed air system, water production system, etc.). It should be confirmed before the equipment is put into normal production, because the production equipment should be used within the confirmed parameters (see article 83 of the new GMP). Documents related to verification include standard operating procedures, acceptable standards, operation manuals, etc. Confirmation shall be carried out according to the approved scheme, and the confirmation result shall be recorded and reflected in the confirmation report.
If the confirmed object is already in use, it should be confirmed according to the actual situation: installation status inspection (IQ), equipment operation parameter inspection test (OQ) and process matching test evaluation (PQ).
Confirmation is a prerequisite for process verification, and the confirmation of plant, facilities and equipment should be included in the verification master plan.
The main goal of process verification (PV) is to confirm that the designed production process can continuously produce products that meet the expected use and registration requirements according to the specified process parameters.
Before the drug goes on the market, the process verification must be completed and meet the set requirements. The new GMP especially emphasizes that the applicability of new product prescriptions or production processes should be verified before adoption, so as to ensure that "products that meet the expected use and registration requirements can always be produced" (see article 14 1). The "intended use and registration requirements" here refers to meeting the drug efficacy, safety and quality standards.
Process verification is based on the understanding of product and process knowledge obtained from R&D process, so as to identify and pay attention to the key quality attributes of products (including identification, physical and chemical properties, properties, content, purity, granularity, microbial limit, crystal form, etc.). ), key process parameters, and the range of key process parameters in daily production and process control. The first process verification of new production formula or production process should cover all specifications of the product.