In this chapter, the various components of facility qualification are illustrated by practical examples.

The general procedure to follow when carrying out qualifications is shown in chapter 6 Qualification.

1 Design qualification

All essential parameters for the subsequent use of pharmaceutical process equipment are defined in the specification (also known as user requirements). Together with the technical specification (the approved supplier specification), this is an important part of the design qualification (DQ). Checks are carried out throughout the remaining qualification modules (IQ/OQ) to verify whether the facility meets the requirements of the specification.

In the following, the specification for a washer is shown as an example:

Preliminary remark

This specification describes the minimum delivery scope for a facility that cleans, disinfects and dries equipment intended for use in the pharmaceutical industry. This document does not provide a comprehensive or complete description of the system to be delivered. Instead, it defines a minimum technical standard and refers to standards and specifications applicable in this case.

Direct references to standards and rules and regulations

The following standards and rules and regulations must be taken into consideration during the design and construction of automatic washers. This also applies to specifications not stated here that are relevant to the construction of the facility.

• EU GMP Guideline of good manufacturing practice for medicinal products
• Current Good Manufacturing Regulations and Guidelines (cGMP) of US Food and Drug Administration (FDA)
• European Pharmacopoeia
• DIN standards
• VDE guidelines
• VDI 2890: scheduled maintenance; instructions for the compilation of maintenance and inspection plans
• Trade association accident prevention regulations

Description of facility

• Functionality: automatic cleaning, drying and disinfection of pharmaceutical equipment. Cleaning is carried out using water with varying qualities to which cleansing agent is added depending on the programme step. The final rinse must be carried out using purified water.
• Description of procedure: A standard cleaning procedure as shown in figure 2 should be possible. The tenside-based cleaners are specified. Water and air temperatures must not exceed X °C.
• Accessories: washing baskets

Mechanical components

• Full drainage of machine and pumps; no exposed heating elements; variable partitioning of internal compartment
• Pharma-compliant version characterised by:
• use of material 316L for all surfaces and pipes coming into contact with fluids,
• use of diaphragm valves and tri-clamp connections,
• dead volume-free and fully drainable installation,
• prevention of mixup or reverse contamination and
• use of a validatable process control and machine documentation.
• 2 programmable liquid metering pumps for cleaning fluids with metering monitoring function.
• Drying with high-performance blower, HEPA filter in the drying circuit not required. Suction of drying air from production room including filtering in accordance with clean room grade D. Discharge of drying air via roof.
• Condensate drainage in venting line to prevent backflow contamination
• Dimensions
• Materials: washing compartment and inner face of door: 316L (alternatively 1.4401). Cladding material: 1.4301. The materials used for seals and tubes must correspond with the recommendations of the US Food and Drug Administration (FDA). Works certificates for the above materials must be included in the delivery.

Control

• Freely programmable control (microprocessor control or PLC). The programme should be structured in a modular fashion. Headings for the individual programme modules must be provided.
• Plain text display in the relevant language
• Display of washing programme, current programme step, temperature of washing compartment and remaining running time.
• It must be possible to print out the programmes and all their parameters (if required, printer to be connected).
• Self-diagnosis, programme and malfunction statistics
• The control should incorporate a memory that accommodates several (>10) wash programmes that may be called up individually.
• The machine must stop if the preset parameters are not complied with. The operator should then be provided with the reason why the process was cancelled. When the machine is restarted, the entire wash programme must be repeated.

Process monitoring

• Monitoring of the following process parameters with display option and limit value monitoring with alarm or machine stop.
• Temperature of rinsing water
• Pump pressure (circulatory pump)
• Drying temperature
• The sensors must be readily accessible and removable for calibration purposes (cable length) and it must be possible to calibrate these with the entire measurement chain.
• Dosage monitoring of detergent pumps
• Sampling tap for water samples
• Error display for important functions and utilities
• A connection that enables the machine to be regularly requalified must be provided. For example, a connection that can be used to log the progress of the relevant parameters during a rinsing cycle via an on-site chart recorder.

Supply of energy and utilities

• Connections for the following water types: purified water, 65 °C, connection to loop provided by installation location; drinking water both warm and cold.
• Drainage via open funnel siphon to prevent backflow contamination
• Electrical connection: 400 V/50 Hz
• Steam connection
• Connection to exhaust line provided by installation location

Constructional prerequisites

The equipment must be installed in a wash room. The particulate and microbiological loading of the room must correspond with clean room grade D. The nominal room temperature must be 20 °C +5/-2 °C, at 50% r.h.. Data on the required limits at the installation location (temperature, rel. humidity, electrostatic and magnetic influencing parameters) must be supplied.

Installation, start-up, acceptance tests

The scope of delivery includes:

• Free delivery and placing at site (supervision of placing as minimum)
• Complete assembly and start-up incl. test operation
• Instruction of operating personnel
• Necessary acceptance tests: the contract giver reserves the right to audit the manufacturing, programming and quality assurance at the premises of the contract acceptor.

The "pre-delivery check", otherwise known as the Factory Acceptance Test (FAT), at the manufacturer's premises guarantees the necessary manufacturing quality and ensures that the function tests are carried out.

The final acceptance, otherwise known as the Site Acceptance Test (SAT), by the contract giver takes place at the installation location once assembly and start-up have been completed and the operating personnel have been instructed. It must be verified that

• the delivery of the facility is complete and correct,
• the documentation is complete,
• the installation is correct,
• the cleaning and auxiliary programmes specified by the operator and also the safety devices are functioning faultlessly,
• the locks and alarms are functioning faultlessly,
• the installation and function of the measuring equipment is correct and
• the initial calibration of the sensors was carried out at the installation location (if carried out by contract acceptor)

The basis for the pre-delivery check and the site acceptance test is a reference programme to be compiled by the supplier according to the specifications of the contract acceptor containing all elements of the subsequent cleaning task. This programme also serves as the basis for carrying out function tests within the scope of the operational qualification.

Furthermore, three cleaning cycles with contaminated equipment are to be carried out to assess the success of the acceptance test using the following criteria:

• Visually clean / analytically clean
• Visually dry
• Surface quality of the materials washed
• Analysis of the cleansing agent residues (see chapter 8.E.2 Calculation of cleansing agent residues)

Documentation, validation, qualification

The technical documentation to be supplied for the purposes of qualifying the facility can be found in the basic documents table. (see figure 3, figure 4, figure 5).

2 Installation qualification

The basic structuring and detailed description of an installation qualification are not dealt with here. This information can be found in the chapter entitled Qualification. (See chapter chapter 6 Qualification.) Only the measures that must be carried out (partly using forms) during the installation qualification are listed below, using fluid bed equipment as an example. Computer validation measures are dealt with in chapter 9 Computer Validation.

Technical documentation

To complete the technical documentation, documents concerning the facility or its components must be available. These are required for the installation, operation and maintenance of the facility and must be checked as part of the installation qualification and documented in the form (see figure 3).

Operating procedures (SOPs)

The procedures required to operate the facility or its components must be checked (e.g. calibration, operating, maintenance and cleaning procedures). Attention must be paid to the personnel training documentation (see chapter 2.C Training). The form provides confirmation that the check has been carried out (see figure 4).

Risk analysis

The facility and its operating functions are assessed and tested during the risk analysis. Critical areas during operation, possible errors and causes of the various risks, as well as the steps that must be taken to minimise the risks, must be defined and recorded. The completed risk analysis must be included alongside the IQ report. (See chapter 6.B.6 Risk analysis.)

Facility components

The technical data of the facility or its components is to be checked against the functional specification and documented in the form. The available ID numbers of the individual facility components are registered during this check (see figure 5).

Terminal strip table

The electrical circuit diagram must be used to check whether the wiring of the facility's components is correct. A random check is sufficient. The circuits to be checked are specified in the form. If no deviations from the manufacturer's documentation are found during the check, the circuit diagram may be accepted. Where deviations are found, the circuit diagram must be reviewed. The results must be documented in the form (see figure 6).

Hardware installation

The system hardware must be checked by inspecting the hardware configuration, the wiring and the electrical supply. The results are documented in the form (see figure 7).

Input/output list

Checks must be carried out to verify that the control has been correctly connected to the functional modules and facility sensors, and this must be documented. If the manufacturer delivers an I/O list, a random check on 15 % of I/Os will suffice. If no deviations from the manufacturer's documentation are found during the check, the list may be accepted. If deviations are found, all I/Os must be checked. The results must be documented in the form (see figure 8).

Software installation

The software installation must be documented. The designation, type, name and version number (date) of the software must be noted. Similarly, the manufacturer and/or developer and the back-up system must be recorded. The results are documented in the form (see figure 9).

Initial cleaning

Once installation has been completed for the first time, facilities or their components must be thoroughly cleaned in accordance with the relevant operating procedures and confirmation provided to show that this has been carried out.

Inspection of utility connections

The connected loads of all utilities to and from the facility must be compared with the manufacturer's data. The connections must also be checked to make sure that they have been carried out correctly. The results must be documented in the form (see figure 10).

Safety devices and locks

A list of the safety devices and locks included with the facility or its components must be compiled with reference to the manufacturer's specifications. When qualifying the installation, checks must be carried out and documented to verify that all facilities are available. The actual function of the facilities is checked within the scope of the operational qualification. The results of the installation qualification are documented in the form (see figure 11).

Construction and assembly materials

Materials used in the facilities or any of their components that come into contact with raw materials, intermediate or final products, must be listed in the form (see figure 12).

Filter list

A list of the filters required for operation of the facility must be compiled. For sterile filters, copies of the test reports and the SOP used for implementation are also required. The filters are listed on the form (see figure 13).

Measuring and control points (M&C points)

A list must be compiled of the available M&C points that includes the numbers of M&C points, the relevant manufacturer, the date of the last calibration and the recalibration interval. The documentation of the last calibration must be included with the IQ report.

IQ - site acceptance test

A summary of the results obtained during the installation check is presented in the IQ site acceptance test . The results are checked using the form (see figure 14).

Deficiency report

Deviations identified during the installation qualification must be documented in the deficiency report. The operator defines the measures required to rectify the deficiencies or deviations; names the departments or persons responsible; specifies deadlines by which the deficiency must be rectified at the latest; and authorises implementation of the measures. Rectification of the deficiencies found must be documented in the form (see figure 14).

It must be ensured that changes made, as a result of rectifying deficiencies that have been determined, are assessed and documented in accordance with the established change control procedures, and also ensured that a requalification is carried out as required. The regulations governing requalification are laid down in the relevant operating procedures. (See chapter chapter 6 Qualification.)

3 Operational qualification

The basic structuring and detailed description of an operational qualification are not dealt with here. This information may be found in the chapter entitled Qualification (see chapter chapter 6 Qualification). Only the measures that must be carried out (partly using forms) during the operational qualification are listed below using fluid bed equipment for illustration purposes. Computer validation measures are dealt with in chapter 9 Computer Validation.

Testing equipment required for qualification

The testing equipment required to carry out the operational qualification (OQ) must be listed (see figure 15). It must be ensured that calibration can be traced back to the standards of the NIST (National Institute of Standards and Technology) or equivalent organisations. It must be checked that the time interval prior to recalibration has not been exceeded. Copies of the documents from the last calibration of the testing equipment used must be included with the equipment/qualification documents.

Calibrations

The quality-relevant MC points (measuring and control points) have been named. A copy of the compiled list can be found in the installation qualification report. The measuring circuits must be calibrated before the operational qualification is carried out. A copy of the calibration report is filed with the OQ report. (See chapter 4.G Calibration.)

Alarms

All alarms that respond to malfunctions in the facility must be checked by simulating the appropriate malfunctions. The type of simulation must be described in the form and documented. Care must be taken to ensure that only authorised personnel carry out these simulations.

Safety devices/locks

All safety devices in the facility must be checked to make sure that they are functioning correctly. "Safety devices" means all equipment that protects the operator from personal injury and the facility from improper handling. The tests must be documented with the aid of the form (see figure 16).

Flow rate test

The facility is started with a flow rate of 1000 mі/h without heating output and product (this corresponds with the minimum capacity). The air velocity is measured and recorded at three different measuring points. This measurement is then repeated with a flow rate of 3500 mі/h and 6000 mі/h. The values determined at the various measuring points are compared with one another and assessed. The analysis is documented using a form.

Flow rate control

A check must be carried out to verify that the flow rate is being controlled correctly using three different flow rates. This involves starting the facility with a flow rate of 1000 m³/h without heating output and product. This setting is maintained for 15 minutes. The flow rate is then increased to 3500 m³/h for a further 15 minutes and then finally to 6000 m³/h for 15 minutes. During this time the control must maintain a stable value that falls within the specified range. The tolerance values are specified in a form where the results are also documented.

Spray rate

The facility is to be prepared as if a product cycle was about to be carried out, it is started with a flow rate of 2000 m³/h without heating and product. The spray medium to be used is water. Measurements are carried out for 10 minutes with the minimum, 50 % and the maximum spray rates respectively. The spray quantity is determined by establishing the tare weight. The trial must be carried out three times for each spray rate which must not deviate by more than ±5 %. The tests are documented in the form.

Heat distribution

To check the heat distribution, the facility must be prepared as if a product cycle was about to be carried out and must be started with a flow rate of 3000 m³/h without a product load. The temperature is set at 50 °C. Following a five minute warm-up phase, the temperature is measured at 5 different points above the sieve screen for 10 minutes. None of the measured values may deviate by more than ±5 °C from the average value determined above the screen. The trial is repeated at 80 °C and 110 °C. The tests are documented in a form.

Temperature control

The temperature control is checked without a product with a flow rate of 5000 m³/h, at 50 °C, 80 °C and 110 °C respectively. After the five minute warm-up phase the temperature must settle down to a constant level which is maintained for 10 minutes. The same procedure is then carried out for temperatures of 80 °C and 110 °C respectively and the control checked. The deviations must not be more than ±5 °C from the preset value. The results must be documented. A printout of the plot must be included with the OQ report.

Screen masks

Checks must be carried out to verify whether the screen masks perform the functions they have been assigned. It must be ensured that the operational parameters can be modified within their assigned limits. It must be possible to store new formulations with the programmed operational parameters and call these up again. The temperature, humidity and pressure values displayed are checked during calibration. A hardcopy of each screen mask must be made and included with the form.

Equipment functions

This involves testing specific functions of the facility such as the "on/off" or "raise/lower" operator control elements. The decision as to which tests should be carried out is influenced by insights gained from the risk analysis (see chapter 6.B.6 Risk analysis). The tests are documented in a form.

Product cycle

To check the entire sequence of functions in context, a trial run is carried out with the product. The manufacturing instructions for the product must be used as the basis for the trial run.

The final product is checked in accordance with the relevant test procedure. The implementation and the test results must be documented (see figure 17). The product cycle data may be used for the performance qualification and validation.

Batch record

The recording of a batch starts when the process begins and ends when the container is lowered. It must be ensured that the process data entered and the measured values gathered are reproduced correctly in the batch record . To check this, the batch record for the test run described above must be recorded manually in the form. Once the trial has ended, the batch record which is generated automatically is compared with the manually recorded data. There must be no deviations.

Data backup

Checks must be carried out to determine how the system responds in the event of a power/utilities failure. It must be ensured that the operating data that has accumulated up to this point is not lost in the event of a sudden power/utilities failure. The facility must also be capable of continuing with the last process status following restoration of the power/utilities and final confirmation. There must be no deviations in the parameters set or the process data. The test is documented using the form.

Access protection

It must be demonstrated that unauthorised individuals cannot access the system and manipulate data. A check must be carried out to determine whether operational parameters can only be modified by authorised personnel. The analysis is documented using the form.

Deficiency report

Deviations identified during the operational qualification must be documented in the deficiency report. The operator defines the measures required to rectify the deficiencies or deviations; names the departments and/or persons responsible; specifies deadlines by which the deficiency must be rectified at the latest and authorises implementation of the measures. Rectification of the deficiencies identified must be documented.

It must be ensured that changes made, as a result of rectifying deficiencies that have been determined, are assessed and documented in accordance with the established change control procedures, and a requalification carried out as required.