Scope of validation and qualification
In the medical and pharmaceutical industries, software supports numerous manufacturing and business processes. Software validation makes it possible to confirm, by way of testing and by providing objective evidence, that the software specification is consistent with the user’s requirements and intended use and the implemented solution consistently satisfies predefined assumptions. Software should be subjected to validation wherever it is used for supporting regulated processes and wherever it replaces manual operation. Software must not cause any deterioration in product quality, limit the process controls or quality assurance.
We do software validation regarding, among others:
- SAP systems
- LIMS systems
- cloud solutions (SaaS Solution)
- SCADA (RMS, BMS) systems
- GMP processes supporting tools (testing, including test automation, change control processes, documentation management)
SAP System, SD (Sales and Distribution), SCM (Supply Chain Management), FICO (Financial Accounting and Controlling) modules.
The scope of SAP system support includes operations as well as project implementation. The main task within the operations was to maintain the system in the validated state. The principal tool used to this end is the change control process, which guarantees that all the changes are properly evaluated, documented and tested prior to being implemented on the production server. Last year we conducted about 3,000 change requestes.
One of the projects conducted was validation as part of the SAP implementation in new sites. An updated, validated solution was migrated, and additional modifications were performed. As a result of the process, several dozen User Requirement Specifications and more than a hundred functional and technical specifications were updated. Several regression tests were performed in regard to the migrated solution, albeit in a limited scope. New modifications were fully tested (unit tests, system tests, user acceptance tests).
The implementation was successful and the main SAP system was expanded by further 3 implementations. The work was all conducted on the basis of a Validation Plan and a Risk Analysis conducted beforehand. Finally, the work was summarised in the Validation Report.
Process installations and utilities, such as purified water or compressed air supply installations, require qualifications as they have a serious impact on the quality of the finished product and on proper operation of the manufacturing equipment. The qualification of process installations and utilities is understood as ensuring that the equipment, installations and supporting systems are capable of continuous and stable operation within the specified limits and tolerance.
We do installation validation regarding, among others:
- Heating, Ventilating and Air Conditioning (HVAC) - most often in combination with the qualification of cleanrooms and warehouses
- Purified Water (PW, HPW) and Water for Injections (WFI) installations
- Compressed gas installations (compressed air, nitrogen)
- Steam installation (for manufacturing, for HVAC)
A Purified Water (PW) supply installation where the water is produced by the reverse osmosis and electro-deionisation method.
The scope of the qualification included the following components: a raw water preparation station, a purified water production station (RO+EDI), a distribution loop with a buffer tank, a distribution sub-loop for the laboratory, a SCADA monitoring and control system, procedures: sanitization, alert and emergency.
During the qualification process, the design qualification (DQ) was performed with the system designer while the installation qualification (IQ) and the operational qualification (OQ) with the supplier. At the OQ stage, the sanitization procedure was tested.
The process qualification (PQ) was divided into 3 stages, in accordance with the sampling plan and schedule. During the PQ qualification, the quality of water was tested in terms of physiochemical and microbiological properties. The tests were conducted on the basis of the monograph for purified water (PW) according to the European Pharmacopoeia.
At the first stage of the process qualification, purified water was qualified for use in the manufacturing process and at the second stage of qualification, alert and intervention limits were set for individual parameters. At the third stage of the process qualification, the final Qualification Report was produced. Following this stage, the set alert and intervention limits were reviewed again and a schedule of preventive sanitization was created.
Laboratory Installation Qualification
Process Installations and Utilities such as purified water installations or laboratory gas installations (such as argon, helium and nitrogen) have a critical influence on the results of laboratory analyses and the proper operation of laboratory equipment. The qualification of laboratory installations and utilities is understood as ensuring that the equipment, installations and supporting systems are capable of continuous and stable operation within the specified limits and tolerance.
We do laboratory installation validation regarding, among others:
- Heating, Ventilating and Air Conditioning (HVAC) – most often in combination with the qualification of cleanrooms and warehouses – including also local exhaust hoods, laminar flow areas, infeed windows, etc.
- Purified Water (PW, HPW) and Water for Injections (WFI) installations
- Compressed gas installations (laboratory gasses)
- Steam installations (for stability chambers, HVAC)
A laboratory gas installation – synthetic air, argon, helium, nitrogen.
The scope of qualification included: a pressure reduction station with cylinder connection panels, a distribution installation – a separate one for each gas, procedures – cylinder connection.
During the qualification process, the DQ was conducted with the system designer while the IQ and OQ with the supplier. At the OQ stage, the cylinder connection procedure was tested.
Given the existing technical capabilities (no possibility to test the parameters of the gases), the Process Qualification (PQ) was performed with a limited scope and consisted of verification of the supplier audit results and of the certificate provided by the supplier.
When PQ was completed, the final Qualification Report was produced, summarising all the qualification work.
Qualification of Rooms
In the pharmaceutical and medical industries, rooms are used, among other things, for manufacturing processes, laboratory tests and storage of raw materials and finished products. During the design process of new facilities and the modernisation of the existing buildings, beginning from the conceptual phase one has to take into account the requirements related to the obligation to meet the good manufacturing practices. To ensure safety of the products, before the rooms are commissioned, a proof of the fulfilment of the relevant GMP requirements must be obtained.
We perform the rooms qualification with regard to:
- manufacturing and laboratory cleanrooms in A, B, C and D zones based on ISO14644-1
- airlocks for people and goods,
- special facilities (stability rooms, high dust content rooms, etc.)
Rooms qualification is most often conducted together with HVAC qualification. Environment testing (temperature, humidity, particulate measure, air flow, etc.) is done as HVAC testing.
The individual installations in the premises are qualified in the form of installation-specific qualification, for example compressed air, purified water, nitrogen, steam, etc.
The qualification of manufacturing, storage and laboratory rooms as well as airlocks in clean zones.
In connection with the building of a new plant, all the rooms identified during risk assessment as critical were subject to full qualification. The cleanrooms were divided by organizational divisions and a separate qualification was performed for each such division.
All in all, 5 separate processes were conducted. Each time a Qualification Plan and relevant reports were produced. The DQ was conducted with the architect whereas the IQ and the OQ with the general contractor. The scope of testing excluded environment checks and the tests of individual installations as those were qualified as separate processes.
At the Rooms OQ stage only the operation of access control systems and cross-locks in the airlocks were verified.
The final rooms qualification report contained references to all the related qualifications of the individual installations. The closing of the rooms qualification report required that the reports of the related qualifications were successfully closed.
Qualification of Manufacturing Equipment
The proper operation of the manufacturing equipment is critical for the assurance of product quality and process stability.
The GMP requirements stipulate that the manufacturing process must be performed on qualified equipment before it can be validated. The qualification of manufacturing equipment is understood as ensuring that the manufacturing equipment and supporting systems are capable of continuous and stable operation within the specified limits and tolerance.
We perform the qualification of manufacturing equipment with regard to:
- manufacturing equipment (capsule filling machines, tablet presses, mixers, granulators, fluidising towers, reactors, driers, scales, etc.)
- packaging machines (tube filling machines, bottling machines, blister packaging machines, carton packaging machines, labelling machines, OCR and OCV, etc.)
- accessories (mills, pumps, conveyors, printers, etc.)
- complete production lines
The project consisted in the preparation of a complete validation of a dry form packaging line with controlled humidity of ≤20% rH, consisting of a thermo-forming blister packaging machine, carton packaging machine, overwrapper (bundler) and palletiser.
The validation consisted of 3 stages and included:
- qualification of the installation of machinery and of the controlled humidity maintenance installation,
- operational qualification, covering also connected computerised monitoring systems, control and data storage systems according to the data integrity management recommendations by the FDA,
- performance qualification by means of a series of tests verifying if each component of the packaging line meets the expected performance requirements and the selection of the most appropriate parameters for the validation of the packaging process.
In spite of the complexity of the project due to the necessity to ensure controlled humidity and meet tight deadlines, the production line was commissioned on time.
Qualification of Laboratory Equipment
The proper operation of laboratory equipment is critical for the assurance of correct results of tests and analyses.
An item of laboratory equipment must be qualified before it is used for analytical tests. The qualification of laboratory equipment is understood as ensuring that the laboratory equipment and supporting systems are capable of continuous and stable operation within the specified limits and tolerance.
We perform the qualification of laboratory equipment with regard to:
- fume hoods
- laminar flow cabinets
- stability chambers
A laminar flow cabinet with an A clean zone in the surroundings of the B zone.
The scope of qualification included the following components:
- air handling unit,
- control and measurement system.
As it was legacy equipment, the DQ was limited to verifying if the equipment was still capable of satisfying the basic legal requirements according to the technical documentation. At the IQ stage, the available technical documentation was verified and the correctness of installation confirmed. The OQ and PQ qualifications were combined in one stage during which all the measurements concerning air quality and the laminarity of flow were taken and the control and monitoring system was tested.
Validation of Manufacturing Process
Because, in the pharmaceutical and medical industries, it is the patient who bears the consequences (including in extreme cases the loss of health or life) of the use of a defective product, before a process is released for use in serial production, one must make sure that the process delivers a product which is compliant in terms of quality in a stable and consistent manner. Validation provides documented evidence of that.
The extent of our involvement in the validation of a manufacturing process is agreed in detail with the client on each occasion and it may comprise:
- validation approach consultancy
- preparation of risk analysis and identification of critical parameters of the process, sampling plan, etc.
- performance of a comprehensive validation process.
Owing to the specific nature of the validation of manufacturing processes (access to technology, laboratory data, etc.), we expect full commitment of the client’s Quality Control and Production function at all times.
Soft capsule manufacturing process.
The validation of the manufacturing process included, among other things, the following aspects:
- determination of the process-critical parameters at the stage of each operation (input formation, hull formation, capsule filling, drying)
- evaluation of the qualification status of all the equipment involved in the process
- evaluation of the manufacturing documentation - necessary specifications, technology instructions, production report template, etc. as well as staff training,
- analysis of product for consistence with the specification on different stages
A sampling plan (inspection stages, number of samples) was prepared on the basis of a risk analysis, taking into account the components listed above.
The validation was performed on 3 production batches. For each batch, statistical test results were prepared and the process capability ratios: Cp (a measure of scattering of a given feature in relation to the tolerance field) and Cpk (a measure of shift of the mean value of a given feature compared with its nominal value and tolerance limits) were determined.
The validation confirmed that the processes ran in a stable way and the finished product was consistent with the specification.
Validation of Cleaning Process
The validation of the cleaning process is applied to ensure that the cleaning process removes from the equipment all residues of active pharmaceutical components of the product, the cleaning agents used in the cleaning process and microorganism. All residues are removed down to a predefined level in order to ensure that the product quality is not jeopardised by contaminated equipment or waste from the previous product, so as to avoid cross-contamination. Such measures are required by the Good Manufacturing Practice (GMP).
We perform the validation of cleaning processes in regard to:
- automated CIP processes
- manual methods – verification of procedures, instructions, training
- cleaning of the manufacturing and laboratory equipment
- development of a cleaning procedures management strategy
Owing to the specific nature of the validation of cleaning processes (access to technology data, laboratory data, etc.), we expect full commitment of the client’s R&D, Quality Control and Production functions at all times.
Cleaning of the production line.
The work was commenced by analysing the products for their therapeutic action and solubility in water (selection of representative products). For each product, we calculated the maximum allowed amount of contaminants (MAC) which are allowed to be present on the surface of the equipment following the production line cleaning process.
In the case of the plant and equipment which had no contact with active substances or were dedicated to one product, the cleaning validation was limited to the testing for any residual detergents or microbiological contaminants.
Based on the validation tests, we verified:
- the maximum time which may lapse from the end of manufacturing to the commencement of the cleaning procedure;
- the maximum time which may lapse from the end of the cleaning procedure to the use of the equipment in manufacturing;
- the maximum duration of one product campaign.
During the validation process, we verified all the procedures for the cleaning of the production line components which came into direct contact with the product.
Validation of Analytical Methods
Analytical methods are used for testing the qualitative properties of pharmaceuticals in laboratories. Depending on the type of analytical method used, evaluated are such qualities as accuracy, precision, specificity, consistency, reproducibility, linearity, scope, stability, detection limit and quantitative limit. The aim of validation of an analytical method is to provide a documented proof that it is fit for purpose by verifying and documenting the evaluation of said characteristics of the analytical method.
We perform the validation of analytical methods in regard to:
- Chromatographic methods
- Spectroscopic methods
- Electrochemical methods
Validation of an analytical method using High Performance Liquid Chromatography (HPLC) to determine the limit of determination and the limit of detection of the compounds included in the mixture.
What was validated was a new method of identification of the detection limit for a mixture of compounds by means of HPLC.
The first stage comprised defining the parameters to be tested and the acceptance criteria. Then a plan of validation experiments was prepared and the characteristics of the equipment specified. After the basic requirements were satisfied, samples of model materials and reagents necessary for the experiments were prepared.
When the experiment was completed, the raw data was processed mathematically and all the parameters considered in the method validation were calculated:
- Method scope
- Detection limit
- Determination limit
The last stage included preparation of the SOP for the examinations to be carried out with the validated method, definition of the revalidation criteria, and creation of the validation report.
Validation of Medical Products
Medical products should give patients, users and third parties a high level of protection and achieve the effectiveness assumed by the manufacturer. The validation of medical products will provide documented proof that the supplied goods are compliant in terms of quality and the manufacturing process is stable and consistent.
Welding of bands for the preventive therapy against deep vein thrombosis.
The validation included a process of welding two layers of foil with a PVC tube, which formed the welded product, then sewn around with laminate and packaged. The product was manufactured on 9 rotating welders simultaneously. The manufacturing line had a capacity of 25,000 products per one production shift. Determination of the optimum process parameters for each welder separately and validation of the welding process made it possible to launch production. Thanks to the stable and high quality of the products, the process was characterised by there being no uncontrolled interruptions.
Maintenance of the validated state is no less important than the validation itself. Upon the completion of proper validation and the launch of production, the object of validation / qualification moves into the state of operation and maintenance. This means that from that moment one should take care that none of the activities performed should cause the loss of the validated state.
The most common causes of the loss of the validated state are:
- breakdowns and repairs,
- changes implementation,
- amendments to laws and standards.
What is also connected with the operation and maintenance state is also withdrawal from use. The stage of withdrawal from use is also incorporated into the validation life cycle and requires taking appropriate action.
The most frequent processes at this stage include:
- incident management
- change management
- periodic inspections (APR, regarding the equipment, the installations, etc.)
- revalidation and re-qualification
We perform the following, among other things, as part of the maintenance of the validated state:
- we develop relevant procedures and instructions
- we conduct training and implementations as per the instructions mentioned above
- we take active part in the incident management and change control processes (we review and assess changes , supervise scheduled actions, perform validation activities – for example, preparation of documentation and testing)
- we perform periodic inspections
- we do revalidation and re-qualification (to the extent identified in the risk assessment)