Surrogate testing (OEL)– the Methodology to perform the OEL Validation

Containment Solutions
As discussed in the earlier blog, Containment solutions are specifically designed to offer health protection and safety to working staff and eliminate environmental risks. I cannot emphasize enough to consider three critical factors while developing containment systems with process equipment integrations:

• Entry and Exit of Production Material: Protection from the potentially dangerous airborne particulate matter due to handling during the entry and exit.
• Manipulation: Interact with and manipulate the material during the manufacturing of a batch.
• Cleaning: Take prompt action to clean containment systems with minimal hands-on time and no risk of exposure to dangerous compounds. Avoid cross-contamination for operator safety and to avoid the risk of exposure to dangerous compounds.

In addition to the above, validation and testing are crucial to Containment solutions to evaluate its performance using a controlled/ regulatory approach.

The process of validating and defining the containment device according to the defined OEL level is known as surrogate monitoring. Surrogate monitoring is a stringent validation process to test whether the containment system is valid per the defined OEL category. While many companies across the world manufacture containment devices, only a limited number of these pass rigorous surrogate testing.

Containment Solutions Selection and Performance Process:
While selecting containment solutions for manufacturing a particular drug, it is essential to test the accuracy and effectiveness of equipment. This procedure involves creating an exhaustive list of the tasks to be carried out and setting a target based on performance (Containment Performance Target). The result is validated through a Factory Acceptance Test (FAT) performed at a manufacturer’s workshop and later at the customer’s site called Site Acceptance Test (SAT).

Methodology for Surrogate Monitoring:

• Validation Objective: To evaluate the effectiveness of containment solutions with the Active Pharma Ingredients (APIs) for its designed purpose, as per the ISPE guidelines.
• The evaluation to be performed using surrogate material like lactose, naproxen sodium, or paracetamol due to their physical properties, low toxic levels, samples even with low concentration can be quantified.
• The samples for iteration include background samples, personal breathing zone samples, area/static/emission samples, and swab samples.
• Air samples to be collected at the normal operator breathing zone and multiple emission sources that might be released/ dispersed from the isolator.
• Surface swab samples to be collected to identify surface contamination.
• A certified industrial hygienist selects a location for area/static/emission samples and swab samples.
• Primary calibrator and Sampling equipment capable of monitoring the flow rate in the range of 1 litre/min to 5 litres/min to be used for the surrogate monitoring.
• Instruments need to be calibrated using a primary calibrator (before and after each sample) to test the accuracy of volume air passed through the sample
• Other factors that may influence are temperature and relative humidity that required monitoring throughout the process.

The surrogate monitoring plan for containment validation of the equipment is summarised below inclusive of the proposed options and sampling locations:

The OEL validation aims to test whether the isolator is performing as intended and to carry out the desired tests required for various samples as per protocol. Each of these tests is carried out for at least 30 minutes.

Performance qualification procedure

Test instrument calibration status
We require a calibration certificate of the equipment and attach them.

Other accessories for test
We need to line-up other accessories required to conduct the test:

Sample test to be conducted
The table given below summarises the type of samples and the number of samples required to validate OEL containment solutions:

Blank sampling.
Blank samples are collected after a thorough cleaning of the test area and the equipment. The room condition is to be maintained by running the ahu for conducting this test, and a sample is taken before putting the surrogate material inside this area, called a blank sample. The media membrane is placed inside the holder, which is connected to the air sampler device and this entire unit to be kept near the isolator. The duration of this sampling procedure is a minimum of 30 minutes. This procedure is carried out to ensure that there is no contamination prior to the testing; else, the test would be deemed inaccurate.

Area sampling
For Area Sampling, air samples are collected at the particular equipment locations to test the discharge of the surrogate compound. The testing location includes the joints like front glass door, airlock glass door, glove ports, discharge port like active & passive valve joints & liner ports. A minimum of four sample tests is conducted.

The procedure is carried out by adding the surrogate compound(lactose/ sodium naproxen) to the running Isolator and carrying out tasks designed for the equipment. The sampling holder is placed with an air sampler at the selected places.

Operator breathing sample
The operator breathing sample carried out along with the area sampling. Here, the operator wears the air sampler around their waist and the media holder, near the nose.

This testing offers an insight into potential operator exposure to the surrogate under actual working conditions.

Swab sampling.
The swab sampling adds to the sampling techniques. As per standard procedure, the swab sample is conducted after carrying out the area & breathing samples. This is to check or measure contamination on the surface of the equipment and within the testing room.

Procedure

This swab kit consists of one bottle – wet solution (equal parts of methanol and water{ both HPLC grade }), swab sticks, amber glass vials, pair of gloves & a template having 10 cm x 10 cm opening area.

Determine the sample surface, place the template on the area, to record the vial id, surface type & date of collection.

Immerse the swab stick in the solution and ensure that the swab head is thoroughly wet and ensure excess solvent is drained from the swab before use. Use this swab head against the substrate surface to collect the sample. (ref. Below sketch)

Repeat this step using the opposite head of the swab, as shown in the above sketch. Place the swab head into the sample vial using cutting with the pliers or any cutting device, clip the swab handle to approximately 1” length, and put the cap of vials, the vial is now ready for an analytical test.