What is Validation in Pharma?
Validation in Pharma is the testing and documentation of evidence that a production process continuously and reliably outputs a product that meets all desired levels of quality and compliance. The process of validation follows a strict protocol which are documented instructions and tests which have been determined in the planning & design stages of the project. The combination of the individual protocols is known as the validation master plan. The master plan also defines the priority and order in which the validation must be carried out, as well as personnel responsible for each process.
Validation can be sub-categorised into 3 stages:
- Process Design
- Continued Process Verification
What is Process Design?
Process design is the initial stage of any validation protocol. Here, small scale production processes are designed and tested for their suitability to consistently produce a product that meet all necessary qualities. This stage would be carried out with a series of processes typically carried out in a laboratory and can be very experimental in nature, depending on the complexity of the drug. Once the process has been successfully carried out and each step carefully documented, the process design is ready to be sent onto the next stage. It is important to note that all conditions throughout the process must be recorded to be able to move onto the next stage.
Conditions which have to be recorded at this stage, as well as reasons why, may include:
Required temperatures are an important factor in the design of a process. Not only is the temperature itself identified here, but the method of heating/cooling will can also be identified. For example, if the temperature is between -40°C to 130°C, glycol might be used as the temperature controlling media. Equally, a P.F.P.E (Perfluoropolyether Fluorinated) based fluid, such as Galden, may be used for a higher temperature range between 55°C and 270°C.
Process pressure must be identified in order to accurately spec. the facility equipment. High pressure systems pose a huge risk to personnel and working environments. This is due to the high energy which is required to create such pressures. This is mostly evident in steam and gas under pressure. Steam, when under pressure can become highly corrosive. Steam at a relatively low pressure of 40 P.S.I has the ability to degrade steel over a relatively short period of time. Another pressure related risk is that of gases under pressure. Gas, unlike liquids, is compressible. If a tank contained 1m3 of nitrogen at atmospheric pressure (0 Barg), the volume would have to be doubled in order to double the pressure (1 Barg) inside the tank. Now, imagine a sudden release of this energy if the system were broken. The results could include a tank manway, lid or cap to be propelled, possible toward personnel in the area.
The viscosity of the media in process must be measured. There are many reasons for this, one being the selection of an agitation method as well as the addition of baffles. Agitators and baffles are an important addition to a tank/reactor as some designs offer a more aggressive agitation than others. All agitators are designed to agitate liquids, although different designs allow agitation of liquids with solids, liquids with gases or liquids with solids and gases. Baffles are a sort of disruptor to the fluid mass. Without a baffle, the fluid mass would essentially rotate with the agitator as one mass. By disrupting this swirling fluid, it greatly increases the efficiency of the agitation with controlled turbulences.
What is Qualification?
Qualification is the documentation of evidence that a specific facility, system or equipment is ready for intended use. It comprises of 3 main elements:
- Facility Design
- Qualification of Utilities & Equipment
- Process Performance Qualification (PPQ)
Facility design is where the small scale process designed in the previous stage is studied and, from it, a large scale commercial facility is designed. Facility design includes the selection of equipment, utilities, operating principles, technical specifications and the scale of the facility.
Qualification of utilities & equipment is the verification that all the requirements determined during the facility design stage match the physical specification of the equipment once it has arrived on site. The qualification of utilities & equipment can be broken down into 3 sub-categories:
- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)
When each of these 3 sub-categories have been individually qualified, you can move onto PPQ. PPQ combines the facility, equipment and utilities and personnel with the manufacturing process and process controls in order to produce a commercial batch, known as a PPQ Batch. The objective of this stage is to confirm the process design and the qualification of the individual components of the system. As such, PPQ is the method of testing all aspects of the facility as one, integrated system.
What is Continued Process Qualification?
The final stage of validation is continued process validation. This stage will last the entire duration of drug manufacturing and ensures that the system remains in the initial validated state. Failure to carry out this stage can result in damage/degradation of the equipment and compromised batches unsuitable for the market.
Continued Process Validation can be achieved by carrying out regular maintenance of equipment, product sampling and testing and, in Biopharma, equipment swabbing and cleaning. Apart from maintaining the facility at the validated state, CPV can also aid in building more effective planned/preventative maintenance schedules, which increases the longevity of the facility as a whole.
Activities which may be carried out in the CPV stage are:
Soft Part Change Out
This involves the replacement of gaskets, O-rings, valve diaphragms and rubber or plastic replaceable parts. Carrying out these activities does not only give a chance to replace parts that may be prone to disintegration or damage but it also allows for a general inspection of the state of the systems.
Maintenance personnel generally carry out mechanical inspections as part of a planned maintenance scheme. Such inspections allow for a detailed look at the condition of the facility equipment. Mechanical inspections can cover a wide range of conditions on the equipment including:
- Oil Levels and Conditions
- Surface Quality (Corrosion or Mechanical Damage)
- Filter Cartridge Replacement
- Inspect Secondary Components (Burst Discs, Steam Traps, Seals, Strainers)
- Test Operation of Limit Switches & Interlocks
- Drive Belts
- Torque Settings on Bolts
Surface Roughness Testing
Surface roughness is an important condition to monitor, particularly in the Biopharma industry. Surface roughness is generally read by measuring the microscopic peaks and troughs on the surface of the material of the equipment over a certain distance. The longer the distance of measurement the more accurate the reading will be. There are a number of values which can be adopted to measure the surface roughness, although the most popular unit used in industry is the Ra Value. The Ra Value is the average height of all the peaks and troughs measure over the set distance. The Ra Value measured in µm.
If the surface of an equipment is found to be out of tolerance the surface must be polished. A surface roughness which is out of tolerance may lead to bacteria lodging within the troughs which can lead to product and equipment contamination.
Equipment Swabbing & Testing
Clean room equipment in Biotech facilities are regularly swabbed for cleanliness to test for contamination. These activities require for maintenance personnel to work alongside process cleaning representatives. Maintenance personnel break lines and equipment in particular areas, as identified by process cleaning reps., to then be swabbed by the reps. Vessel entries are often required in order for the cleaning reps. to reach certain areas to be swabbed.