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Etid sou Pwosesis Validasyon nan seche filtre Nutsche ajite ("Twa-in-One")

Tan: 2023-02-27 Hits: 35

On the basis of in-depth understanding of the EU GMP and related guidelines, the validation process of Ajite Nutsche Filter Dryer (hereinafter referred to as “Three-in-One”) is studied, that is, through the qualitative and practical analysis of four confirmed practice results of the Ajite Nutsche Filter Dryer/"Three-in-One", to make it meet EU validation requirements. RESULTS AND CONCLUSION: The validation of Agitated Nutsche Filter Dryer was completed through a deep understanding of EU GMP requirements and an unerring instinct for international standards, of which the practical

Validation of Agitated Nutsche Filter Dryer is a documented procedure that proves the outcome of a particular process, method, or system will consistently comply with established acceptance criteria. Another related concept is “identification”. In fact, what Validation and Identification refer to are basically the same. It is generally believed that Validation is mainly for procedures (such as production processes, cleaning methods) and Identification is mainly for facilities and equipment (such as instruments and meters, auxiliary facilities, workshops, etc.), but they are often collectively referred to as “Validation”.

Generally, Validation can be classified: (1) according to validation objects, including product, process, production equipment, plant facility and analysis method; (2) according to validation methods, including pre-validation, synchronous validation, retrospective validation and revalidation.

2 Overview of Equipment Validation of Agitated Nutsche Filter Dryer

Equipment validation refers to the test and evaluation of validity of design, model selection, installation and operation and process adaptability of production equipment, and confirms that the equipment can meet the design requirements and technical specifications.

Both domestic and international GMPs and corresponding annexes have put forward clear requirements for equipment validation, stipulating that important changes that may affect drug quality should be verified.

Equipment validation is mainly for key ones, not all the equipment or instruments applied in production, but referring to the equipment that may have adverse effects on the quality of the produced drugs. In Guidance on Validation of Pharmaceutical Machinery (Equipment), it is clearly pointed out that all equipment related to pharmaceutical process, quality control, cleaning, disinfection and sterilization that directly or indirectly affect the quality of drugs must be verified. And other auxiliary pharmaceutical equipment or those that do not affect the quality of drugs may not be verified.

The purpose of equipment validation is to have documented evidence for all confirmed functions of pharmaceutical equipment, proving each section is really controlled, that is, the validation process and conclusions of the design, installation, operation and performance are required to be signed by the person in charge. Eventually, it is to evaluate the accuracy of the design, model selection, installation and operation of the production equipment and the applicability of the production process, so as to formulate and revise equipment operation and maintenance procedures, and to ensure all equipment that has direct contact with drugs or affects the quality of drugs has documents to clearly prove that they can meet the requirements of drug production.

3 Overview of Agitated Nutsche Filter Dryer (“Three-in-One”)

The agitated nutsche filter dryer (referred to as “Three-in-One”) is widely used in solid-liquid separation, solid washing and drying in pharmaceutical, chemical, pesticide, food and other industries. The equipment is called "Three-in-One" for short, because three processes, filtration, washing and drying, are completed in one device, in another word, the entire production flow, from the feeding of the crystalline solid-liquid suspension to the automatic discharge of the raw materials after drying, is completed in one container, which brings about reduction of API’s necessary production equipment, the workshop area, the labor intensity and the risk of drug contamination or confusion.

"Three-in-One" consists of the tank, stirring device, shaft end sealing device, lifting mechanism, hydraulic lifting unit, removable tank base, heating device, transmission mechanism, discharge valve, sampling valve, washing (cleaning) and sterilizing device, stirring and lifting travel indicator, display screen and manual operation device, hydraulic pump station, main electric control cabinet and other components, fully realizing the integration of machine, electric and instrument. The structure of “Three-in-One” is shown in Figure 1.

Non-1

Agitated Nutsche Filter Dryer /"Three-in-One" separates the crystallized solid-liquid mixture in a closed container by the pressure difference between the front and back of the filter cake, and completes filtering, cleaning, re-filtering, re-cleaning, filtering or pressing, drying and other processes in the same equipment. Both initial filtration and re-filtration after cleaning are through the filter cake, that is, under the pressure difference as the driving force, crystals and liquid in the solid-liquid mixed suspension passes through the porous sintered mesh, so that the crystals (particles) are intercepted on the filter medium, while the mother liquid passes through the medium. All processes of “Three-in-One”, including filtering, washing and drying, rely on the role of stirring paddles, its forward and reverse rotation.

At the current stage, foreign advanced pharmaceutical companies are working towards fully automatic control, hoping that the pharmaceutical process can be carried out in a closed system, because this can minimize the contamination of materials, which is exactly what Agitated Nutsche Filter Dryer/ "Three-in-One" can realize, the entire production process of sterile APIs to be completed in a closed environment.

4 Validation Content of Agitated Nutsche Filter Dryer

International standards, such as EU GMP, CGMP and WHO GMP all stipulate that equipment validation is generally divided into four sections: Design Qualification (DQ), Installation Qualification (IQ), Operation Qualification (OQ), and Performance Qualification (PQ).

4.1 Design Qualification (DQ)

Design qualification (DQ), also known as pre-validation, is the first step for pharmaceutical enterprises to carry out equipment validation. The enterprise checks the design and model selection of equipment used in production according to their own drug production process, from the aspects of equipment performance, set parameters and others, with reference to the equipment instructions, and the relevant department of the enterprise hands over a validation report afterwards, which needs to be reviewed and approved, and then pick the equipment supplier. DQ is the documental support that the equipment design can meet the URS and GMP requirements, it applies to two types of equipment: (1) fixed equipment, that is, equipment in use; (2) newly designed equipment, that is, the equipment newly designed and manufactured according to the user's requirements.

Design qualification is usually a pre-examination of the project design plan, including plan layout, water system, purification air-conditioning system, review of the applicability of the equipment to be ordered to the production process, and selection of suppliers.

The objects of design qualification include the adaptability of the production equipment in terms of model, specification, technical parameters, performance indicators, etc. and selection of the manufacturer, and it helps to finally confirm the ordered pharmaceutical equipment and its manufacturer and make documental records accordingly.

The development of quality management has gone through inspection quality management- process control - quality by design. At present, the viewpoint of quality management advocated internationally is that design is the key to quality. Design qualification is considered to be the key part of project and validation, because mistakes in design often lead to defects that are difficult to be remedied afterwards. In other words, well-considered design is the key to validation.

Agitated Nutsche Filter Dryer /"Three-in-One" is the key equipment in direct contact with drugs in the production of sterile cephalosporin APIs, which has a great impact on the process and drug quality, so design qualification is extremely important. DQ of Agitated Nutsche Filter Dryer /"Three-in-One" must take both the requirements of EU regulations and the process characteristics of sterile cephalosporin APIs into consideration to make sure that the equipment matches the technical parameters of production required. For example, if the equipment is used for the production of sterile drugs, then a) the environmental cleanliness level should be Class B, b) the material of equipment needs to be 316L; c) CIP/SIP is required, easy to clean and disinfect; d) quick-connect or flange connection should be applied, easy to disassemble; e) pulley is designed at the bottom of the equipment, and corresponding track is designed on the ground for easy maintenance. All structural and functional designs must be confirmed, and the relevant items are listed in detail, such as the working methods, the entire flow from feeding, filtering, washing, drying to discharging, and the functions, online cleaning, online sterilization, solid-liquid separation under pressure or vacuum and others based on process requirements, as shown in Table 1 and Table 2.

Table 1 Confirmation of Working

NoKondisyon pourezilta
WINON
DQ033Charge-in  
DQ034Filtration: Solid-liquid separation under vacuum or pressure  
DQ035Flat the filter cake:The mixing paddle rotates reversely to smooth the cracks on the filter cake surface to avoid short circuit of cleaning solvent along the cracks  
DQ036Mixing and cleaning: The rotating spray ball sprays the cleaning liquid evenly inside the container to achieve internal cleaning of the container and cleaning of the material.The up and down mixing of the stirring paddles mixes the filter cake with the cleaning solution, allowing the material to be fully washed.  
DQ037Drying: The stirring paddles rotate positive under vacuum to loosen the filter cake layer by layer. The heating system of the equipment evenly heats the wet filter cake, which accelerates the evaporation of the solvent and fully dries the material.  
DQ038Online Sampling:During the drying, material can be sampled and inspected through the plunger type sampling valve.  
DQ039Side discharge: After drying, the stirring paddles rotate in a positive direction, scraping loose and pushing the material to discharge from the side discharge port of the equipment  automatically.  
Deviation Detailskonklizyon
  
Confirmed by/DateReviewed by/Date

Table 2 Confirmation of Function

NoKondisyon pourezilta
WINON
DQ040Cleaning and serialization in place  
DQ041Filtration: Solid-liquid separation under vacuum or pressure  
DQ042Automatic discharge of the final product from the side discharge opening by means of an S-shaped paddle  
DQ043The clearance between the paddle and the bottom plate and cylinder is uniform, and the surface is smooth without scratches  
Deviation Detailskonklizyon
  
Confirmed by/DateReviewed by/Date

4.2 Installation Qualification (IQ)

Installation confirmation (IQ) is a series of activities to check the technical documents provided by the supplier, the equipment, spare parts and installation completion to confirm whether everything meets GMP, manufacturer standards and enterprise-specific technical requirements. It is the documentation of a variety of system inspections and technical data after the installation of equipment, of which the purpose is to check the equipment specifications, models, installation quality, and auxiliary facility layout. After the equipment is installed, it is to confirm that

a) the installation meets the requirements of the design and specifications;

b) documents attached along with the equipment are complete, including product drawings, list of spare parts, instrument calibration certificate and accessories, etc.;

c) inspection and the status of equipment are recorded in paper.

Technically, installation qualification includes two parts: (1) check whether the technical documents provided by the supplier are complete, whether products delivered are consistent with the list and the order contract; (2) check the installation of the equipment according to the process flow and installation drawings. The process of installation includes check and filing of technical data, inspection and acceptance of spare parts and installation completion. That is, to check (1) whether the documents and accessories attached along with the equipment are complete according to the IQ plan; (2) whether the on-site installation is carried out according to the drawings; (3) whether the public systems such as water, electricity and gas are properly connected; (4) whether the list of all valves and instruments is complete; etc.

“Installation Qualification” is different from “Installation”. Installation and commissioning of large and complex equipment is usually the obligation of the manufacturer before delivery. The manufacturer needs to perform the provisions of the contract, which is far from installation qualification.

Three parties are involved in the installation qualification of Agitated Nutsche Filter Dryer/ "Three-in-One", namely the manufacturer, the user, and the on-site construction contractor. These three parties must provide relevant materials on their respective responsibilities, which will be the cornerstone of IQ, including list of parts, material certification of pipeline valves, etc. It is to clarify the structure of the equipment system, and requires a complete plan and time schedule of equipment installation qualification, which needs the cooperation of the three parties.

The first step of installation qualification of "Three-in-One" is to check the unpacking list of the equipment. At this stage, it should be noted that regardless of the size of the parts, a detailed inventory must be carried out to ensure that the list is consistent with the parts in the box.

After the equipment is installed, the utility wires should be well connected, such as the electrical connection to operate the explosion-proof control box. The equipment has two control cabinets, which are respectively located on the upper platform and the lower part of the tank. According to the requirement of installation qualification, it is only necessary to take a preliminary inspection on the installation of the positive and negative poles of the power wiring and the button of the control box. The specific function qualification of the button will be carried out during the operation.

Equipment is generally installed by technical workers from pharmaceutical companies and manufacturers according to the designed construction drawings, and then the entire system is checked according to the drawings jointly provided by the manufacturer and the on-site construction contractor. At last, the site acceptance test (SAT) of the equipment is completed.

In addition to the above-mentioned items of installation qualification, it also needs to carry out necessary and simple confirmation of the mechanical parts of the equipment. The European Union's acceptance criteria for equipment refer to ASME. For example, ASME specifies neither the distance between the stirring paddle and the filter chassis or the distance between the stirring paddle and the tank wall shall be less than 6 mm. This is one of the items that need to be compared with the technical description of the equipment. Similar technical parameters need to be confirmed on site in turn.

4.3 Operation Qualification (OQ)

Operation qualification (OQ) refers to the no-load test of both each part and the whole installed equipment according to the draft standard of operating procedures to ensure that to some extents, the equipment operates well and meets the specified technical indicators. According to general operation qualification, both no-load and load tests should be carried out. Through such tests, the technical parameters and performance of operation will be checked and examined, and the capabilities, use functions, control functions, display functions, interlock function, protection function and voice index of pharmaceutical equipment will be verified and recorded in paper, which confirms that the equipment meets the requirements of production process and capacity.

Objects of Operation qualification (OQ) generally include: (1) pre-operation inspection, such as power supply voltage, safety grounding, various instruments, control elements and others; (2) calibration and check of test instruments for validation; (3) operation check: check the operation status, operation control, sealing status during operation, working noise and other items under no-load condition according to various standards, product types and operation instructions provided by the manufacturer that are specifically designed for the equipment; (4) operation control program: it can be checked and confirmed by automatic or semi-automatic operation program; (5) check and confirmation of mechanical and electrical safety performance and various technical indicators of equipment.

Plans of installation qualification and operation qualification can be either recorded in separate documents or combined into IOQ, because the two processes are continuous and uninterrupted, and it will be good to properly combine their documents and records, contributing to the clear and coherent reproduction of validation during quality tracking.

The operation qualification of "Three-in-One" is carried out after the installation qualification. It is a performance test without adding any production materials or blank materials, so as to ensure that the equipment can meet the specified technical indicators and run properly, and thus ensure the quality of the drugs produced.

For the "Three-in-One", the operation qualification mainly focuses on the following systems and mechanical parts of equipment, such as: heating system, hydraulic system, explosion-proof system, CIP, SIP, electrical system and sealing system, etc. Each system has its own standards and is strictly implemented according to the schedule. Taking a "Three-in-One" as an example, the key items and points of OQ mainly include:

4.3.1 CIP

There are four spray balls rotating by 360°in the "Three-in-One" , three of them are used to clean the tank and the rest one is used to clean the bellows. In the PQ process, when the cleaning program starts, the 4 spray balls can rotate by 360°to spray water. The FAT file needs to be checked to prove the online cleaning coverage.

4.3.2 Closed system

Since Steam is used in the "Three-in-One", a leak test must be carried out. "Three-in-One" uses a dry double-end mechanical seal. The airtightness of the equipment will be confirmed by testing the amount of gas maintained for a period of time.

4.3.3 Sistèm chofaj

The heating system of "Three-in-One" is mainly used for drying materials. There are five heating systems on the equipment, which are one on the catcher, two on the tank, one in the stirring paddle, and one at the bottom of the tank. During operation, the temperature is detected by the temperature sensor to confirm that the system runs normal.

4.3.4 Stirring Paddle

The operation of "Three-in-One" relies on the stirring paddle, which is the most important functional component, so it is necessary to confirm the rotation direction and frequency of the paddle. After the button of the explosion-proof operation control box is pressed, the stirring paddle will move accordingly, then this function will be confirmed.

Any deviation in the operation qualification process of the "Three-in-One" must be investigated and recorded in the deviation list, as shown in Table 3, Table 4, and Table 5.

Table 3 OQ-18 Deviation List

Deviation No.DetayOQ table  No.
1Abnormal motor operation during stand-alone runtime19
2Re-check the wires are correctly connected and the motor is rotating in the correct direction20

Table 4 OQ-19 Deviation List

devyasyonAbnormal motor operation during stand-alone runtime
rezolisyonRe-check the wires are correctly connected and the motor is rotating in the correct direction

Table 5 OQ-20 Deviation List

devyasyonFailure of Airtightness test
rezolisyonAfter checking the leaky points and replacing the rubber gasket between the connections, finally the test passed.

4.4 Performance Qualification (PQ)

Performance qualification (PQ) refers to the use of certain equipment or system to simulate the actual production situation to evaluate the adaptability. During the test, it is verified that the pharmaceutical process is completed with expected effects through observation, recording, sampling, inspection, collection and analysis of data, and it is determined that the equipment or system can meet the requirements of production, customers, GMP and others. In PQ process, both blank materials and materials actually used in production can be applied, but mainly blank materials.

The EU GMP guidelines clearly stipulate that performance qualification must be carried out after successful installation qualification and operational qualification. Although performance qualification is described as an independent section, it can be carried out together with operational qualification under appropriate circumstances.

Objects of performance confirmation generally include: (1) check of equipment performance under load operation using blank materials (such as starch); (2) check of equipment production capacity and indicators of processed materials; (3) check of equipment safety; (4) check of control system, including automatic or manual control devices and systems; (5) check of quality indicators of drugs produced by real materials , including internal quality, appearance quality, packaging quality, etc.; (6) challenging tests of equipment under load operation.

"Three-in-one" needs to complete three important processes in the whole production, filtering, washing and drying. The performance qualification mainly tests the mixing uniformity and drying humidity of the "Three-in-One", that is, the final humidity of the material must reach certain standard, showing the performance of the equipment. The result of this test is an indicator of the final output of Agitated Nutsche Filter Dryer /"Three-in-One".

According to the relevant regulations and guidelines of the EU GMP, the humidity of the dried material must reach 45% ± 1%, and the data received in the "Three-in-One" performance qualification test must meet this requirement. If there is any deviation, the relevant parameters must be modified and debugged, and then tested until the official requirements are met. Key points of humidity test: (1) humidity test shall be conducted in three batches; (2) The test time for each batch is 4 hours, and the interval between batches is 1 hour; (3) A total of 9 points (the selection of these 9 points is determined by the equipment department of the enterprise) are sampled and tested for humidity by the online sampling valve. Table 6 and Figure 2 show that this group of "Three-in-One" passed the humidity test of performance qualification.

Table 6 "ANFD" Performance Confirmation: Humidity

Time/h1234
Humidity  /%Point 165504845
Point 265494744
Point 365504745
Point 465514845
Point 565514744
Point 665494645
Point 765504745
Point 865504645
Point 965504844

The washing and drying function of “Three-in-One” is the result of the movement of the stirring paddle, and at the same time it is required that the material needs to be handled evenly, so the detection of uniformity of the material is also an important indicator in the PQ process. In general operation, starch and sodium chloride powder are used for mixing, and samples are taken at three points respectively placed in the upper, middle, and lower parts of the equipment, and each point is sampled for three times, with the interval as 1 hour, then uniformity in each sample will be tested (the measure of uniformity is RSD), the data are shown in Table 7 and Figure 3.

Table 7 "ANFD" Performance Confirmation: Uniformity

Time/h1234
RSD/%1.0000.8990.6450.630

信 图片 _20230221152708

5 Summary of Equipment Validation

Validation is a necessary proving process before the equipment is put into use, and it is also the guarantee of drug quality. First of all, the entire validation process must be well prepared in the early stage and carried out step by step according to design qualification, installation qualification, operation qualification and performance qualification. No step can be crossed, as it is very difficult to make up for it afterwards. Secondly, from the validation practice of “Three-in-one”, it is found that the four processes are all developed on the basis of user requirement specification (URS), so for successful validation, it is very important to discuss with the manufacturer to complete a high-quality URS. Design qualification is the confirmation of each item in the standard required by the user. Although URS is not mandatory in various regulations and standards, in the actual validation process, the importance of URS is emphasized, and pharmaceutical companies are required to provide detailed URS in compliance with regulations when submitting validation documents, which will provide a lot of data for follow-up work or directly become the template of IQ, OQ and PQ.

5.1 Summary of Design Qualification

According to the requirements of EU GMP for equipment, the design qualification is mainly based on the production requirements and plant conditions to formulate the type, size, material, model, connection method and others of the equipment, which must comply with international mechanical standards, among which ASME and ISPE (International Society for Pharmaceutical Engineering) are commonly used reference standards.

5.1.1 Production Process and Laws and Regulations of Quality Control

In the design qualification stage, it is necessary to clarify the requirements of the entire technological process and laws and regulations of quality control for materials and performance of equipment, so as to formulate a design qualification plan for the specified equipment. For example, "Three-in-One" completes processes of filtering, washing, and drying in API production in one single container, so it is required that the stirring paddles can take different actions. As “Three-in-One” is in contact with sterile cephalosporins, in order to meet the requirements of sterility, the entire equipment must realize online cleaning and online sterilization, which can be understood as the needs of the technological process.

5.1.2 Importance of Design Qualification

Design qualification is the first part of equipment validation. Actually, it is the confirmation and continuation of the URS, as well as the check and confirmation of all aspects of the equipment provided by the manufacturer, including functions, design, whether online cleaning and online disinfection are required, etc., in addition, especially details of material, model, manufacturer and other information of all valves, pipelines and equipment bodies. Design qualification is the cornerstone of the follow-up work and the key point of the whole validation procedure.

5.1.3 Attention to Details and Effective Way to Write Documents in Design Qualification

All items of "Three-in-One" can be presented in the attachments on file. In the list, they should be detailed to the internal structure of the equipment and various accessories. Here, it is necessary to note that accessories should be specified in detail regardless of size. Many manufacturers will focus on those important accessories when proceeding design qualification but ignore some smaller ones. Design qualification in the attachment on file requires the manufacturer to provide relevant information, and the writer then presents the documents provided in the form of an attachment. Since the writer of the design qualification document is not familiar with the equipment, this can reduce the workload and difficulty.

5.2 Summary of Installation Qualification

Installation confirmation is actually the whole process of check and confirmation of composition, parts, corresponding documents and good operation of the equipment after the supplier carries out FAT in its factory, and then disassembles and delivers it to the user's factory. The installation qualification is to assemble the equipment according to the drawings, then do some simple and necessary operation procedures. The user must pay attention to the inventory of the equipment parts and corresponding documents before assembly and compare the assembled system against the drawings to check the conformance. All work in the installation qualification stage needs to be accurately and timely recorded.

5.2.1 Installation qualification is about the document and site

Installation qualification is to check whether the equipment is installed correctly according to the drawings provided by the design institute and the manufacturer, that is, the equipment, the drawings and the site must highly match each other, and this is the prerequisite to ensure the normal operation of the equipment. The installation qualification is also the confirmation of the equipment design, the actual installation environment and the process. After the equipment is installed, various system inspections and documentation of technical data are carried out, such as single idling test of “Three-in-One” to confirm that the agitator is installed correctly without blade deviation, and the sealing test to confirm that the equipment is well sealed after installation, which can meet the needs of subsequent operation qualification.

5.2.2 Installation qualification essentially is about all files

Installation qualification is mainly to sort out various documents, such as unpacking list, spare parts list, material certification, model list, various qualification certificates of valves and gaskets, etc. How to deal with these documents is the focus of installation qualification. Taking the installation qualification of valves as an example, first, all the valves that appear in the large system need to be numbered, then it is necessary to check whether the installation position is the same as marked in the drawings, and finally check the final as-built drawings of the equipment with the site.

5.2.3 Installation confirmation is mainly for large systems

The equipment system here refers to the entire system from the first valve entering the installation room to the valve leaving the room, including the utility system and the entire equipment. Even it is usually called “equipment validation”, actually, it is not the validation of the equipment, but of the entire equipment system. Because during the general production, it does not only focus on the operation of a single piece of equipment, but the overall status of the public system and other auxiliary parts connected to the equipment, so in this stage, it must be implemented with a picture of equipment system.

5.2.4 General acceptance criteria for installation qualification

The general acceptance criteria for installation qualification are that all parts of the equipment delivered to the factory and all instruments and parts after installation conform to the agreement in the contract signed by the two parties and the content of the design qualification. For example, it should be noted that the inclination of the stirring paddle is specified in the initial design, and it should be measured after the installation at the construction site is completed to confirm that it meets the requirements. What’s more, the water, electricity, gas and other utilities of the equipment are installed in place to meet the requirements of operation.

5.3 Summary of Operation Qualification

The key to operation qualification is to check whether the installed equipment can meet the performance requirements in the normal production of the processed materials. Before OQ, it is necessary to clarify the performance parameters to be achieved by the equipment, and adjust the control system during the process, so that nothing abnormal happens under no-load and load conditions. Operation qualification is actually to trigger all the functions of the equipment again and again to examine the performance and the stability related. At each stage, all operations must be recorded, as well as important parameters. For example, there are five sets of "Three-in-One", and the materials they handle are different, so in the same external environment, the parameters they achieve are different, which need to be determined according to specific operating requirements.

5.3.1 Operating parameters vary from case to case

Due to the different products, the operating parameters required for the equipment will be different. For example, requirements for the rotation speed and paddle shape of crystallization tanks vary from one type of crystallization material to another. The specific parameter settings need to be determined according to the products, in other words, the confirmation of operation parameters is inseparable from the entire production process.

5.3.2 Validation of Online Cleaning System

The validation process of online cleaning system is not complicated. For example, in the performance qualification of "Three-in-One", when the cleaning program starts, four balls spray water and rotate by 360°, the operation qualification is completed. Regarding the confirmation of online cleaning coverage, since the manufacturer of “Three-in-One” has already carried out FAT in its factory, it is only necessary to review the relevant documents. If the documents provided by the manufacturer indicate that such tests have been carried out and the test items meet the requirements of relevant EU regulations, the coverage of online cleaning will be confirmed. When the coverage of online cleaning is not confirmed in FAT, then this project needs attention, and the cleaning scope must cover the areas where is the most difficult to clean in the equipment.

5.3.3 Sealing Test

For pressure vessels, the airtightness of the equipment is very important, and relevant test is a kind of on-site pressure test. There is no clear regulation of the quality control on the standard parameters of the airtightness test, but an agreed standard has been formed in the world. It is believed that if a fixed value is reached and maintained for 30 minutes, then the equipment is in compliance with the standard. Taking the airtightness test of "Three-in-One" as an example, first, purified water is poured into the tank. When 1/2 of the tank is filled, stop the water and feed with nitrogen. The amount of nitrogen is generally 0.3MPa., such state needs to be maintained for 30 minutes, and then use soapy water to check for leaks at each valve. Generally, the internal pressure of the tank will drop during pressure maintaining, which is also reasonable

5.4 Summary of Performance Qualification

The most critical part of performance qualification is the data search before the process. International standards are not the only aspects to be considered, but also various industrial standards with different applications, which makes it more difficult to determine parameter ranges and find related methods. Performance qualification is also the verification of the first three stages. Only equipment that is verified in strict accordance with design qualification, installation qualification and operation qualification can show performance parameters within the acceptable range during this stage, even if there are deviations, they won’t be big, only some small actions are needed.

5.4.1 Performance qualification is the verification of process flow

The performance qualification must be carried out after the quality research, so it is also the verification of the process flow. For the deviation in this stage, it has to be investigated, and the rectification plan will be proposed afterwards. It is likely to modify the process or set a more reasonable range of process parameters without affecting the quality of the final product, so as to achieve the perfect combination of equipment and process and get high-quality products. Performance qualification is the verification of the overall operation status and parameters associated with the production process. As we know, all quality control measures will be meaningless without combination of the process, so process qualification is the key to performance qualification and even equipment validation.

5.4.2 Requirements and acceptance criteria for performance qualification of test instrument

Performance qualification covers many test instruments and final acceptance criteria. All test instruments must be calibrated and checked in advance to guarantee the final test results. The final acceptance criteria should first be set by referring to the relevant pharmacopoeia and requirements of regulations, and then considering the chrematistics of verification object, parameters is set accordingly, which is also known as the acceptance criteria for performance qualification. These all is with a lot of work, especially the translation and understanding of English materials, but it is the cornerstone and key to the performance qualification.

5.5 Summary of Equipment Validation

All stages of equipment validation are closely related to the process flow, so the verification of the process flow is the key to the success of the equipment validation, and it must be carried out based on good technical research, so as to ensure the accuracy of validation and make it meaningful. Equipment validation is complex, and all items need the cooperation of multiple parties, including the supplier, the user and on-site construction contractor, so all parties must fully study and understand the relevant EU regulations on the requirements of such “Three-in-One” and what Validation is indeed.

Through the validation of “Three-in-One”, it is realized that especially in the installation qualification stage, all parts of the equipment are involved, careful verification on each of them. In the operation qualification stage, as various parameters related to the operation must be collected, it is necessary to study the working principle and mode of the equipment in advance, as well as the material objects handled by each equipment, then list the parameters to be recorded, and at last, make records when the equipment is no loaded.

In conclusion, the entire validation process of the equipment requires an accurate understanding of various relevant regulations and standards and the key points, which helps things to be completed in a standardized manner, documents to be done legally, and finally pass the EU audit. It is believed that through the in-depth study on regulations and processes of such equipment validation, more and more domestic pharmaceutical companies can go abroad, meanwhile, more and more equipment can reach the international advanced level in terms of hardware and software.

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