Bringing a product to market is a long and complex one, even more so when developing a sterile product, such as injections, ophthalmic preparations, irrigation fluids, dialysis solutions, among others. The only method for removing microorganisms without adversely affecting the product is sterile filtration, and those processes need to be assessed through filter validation to ensure that the filter used to eliminate any microorganisms is the right one.
To start with, it’s important to understand your product formulation and perform some preliminary compatibility studies, says Shelli Connelly, senior drug product consultant at DSI, a ProductLife Group company. This can be done by simply purchasing 47mm disc filters to test whether the filter will be compatible with the product. Companies that don’t know enough about their product can pick the wrong filter.
“If you're unsure or you don't have enough experience with preliminary compatibility studies, reach out to filter vendors and get them to do a filterability test upfront,” Shelli says. “They can pick out four or five different filters, looking at what your product formulation is, and do a quick study to help you pick the right filter before you start.”
The next big question is what size filter to pick. Filter size typically relates to the batch size and the bio-load during the formulation process. You need information about the product formulation to make this decision. For example, is it more viscous? Is it going to clog your filter?
“The majority of injectable sterile products are going to be 10 inches or smaller,” Shelli says. “If you have a 100- or 200-liter batch, normally you are using a four-inch or six-inch filter.”
Types of Filters
While in the past disk and filters contained in stainless steel housings were more commonly used, the move today is toward disposable filters, which are robust, come ready-to-use, and eliminate the risk of failure or setup problems. However, some products that require heat during filtration need a jacketed stainless steel filter housing so disposable filters can’t be used for those products.
Once a filter is selected, the next step is a sterilization process. Shelli says that if you’re using a sterilizing filter at 0.2 microns, you must run it through some type of sterilization process, either autoclave or gamma irradiation, which will depend on what the manufacturing facility has in place or prefers.
The sterility assurance and validation process should be done either before or in conjunction with registration batches since it is a requirement for regulatory filing.
“For commercial products, if you change the batch size and go bigger, or make any other change, or if your filter parameters change in any way, you will have to go back and revalidate your filter validation in support of the product,” Shelli says.
However, when it comes to pre-use filter testing, Shelli argues that it’s generally unnecessary since filter manufacturers integrity test all their filters, so filter failures are extremely rare.
“Each filter is integrity tested to show that it meets its minimum bubble point requirements based on what the vendor has provided,” she says, adding that the purpose of a bubble point test is to put pressure on the upstream side of the filter to allow air to get through the pores. “The bubble point value is in relation to the micron size of the filter. For the 0.2micron filters, it's normally around 50 psi.”
One important consideration with integrity testing is to pay attention to the calibration data produced by the tester because it could impact your filter values.
The Validation Process
At the start of the process, a filter validation vendor sends an information product sheet to the manufacturer to get the information they need, including how the filter is sterilized, the batch size, flow rate per minute of the solution, temperature requirements (cold, room temperature), whether an intermittent filtration is planned and for how long or whether it will be continual filtration, for example from tank to tank or bag to bag. All this information is necessary for the vendor to perform the validation successfully.
“One word of caution is that if you are uncertain of what your batch sizes are going to be from a commercial standpoint, do a worst-case scenario to give yourself some wiggle room,” Shelli says. “You might start out thinking your batch is only going to be 200 liters, but a year later you have a blockbuster product and have to scale up to 400 liters. In that case, you will have to repeat your filter validation and that is not cheap. If you think intermittent filtration will be 24 hours, then validate for 36 to 48 hours. Don't validate your process at a set batch size, give a range. It will save you time and money in the long run.”
Filter validation is carried out in conjunction with other validation processes, such as media fills where aseptic manufacturing procedures are tested to ensure they are adequate to prevent contamination during drug production. It’s important to ensure the filter validation and media fill program are in alignment. Workspace parameters for filter validation must either match or exceed from an aseptic media perspective so they can work in sync.
“When selecting a filter, choose the right membrane from a media perspective,” Shelli says. “Make sure you're picking a membrane that's water-based but also focus on whatever type of connections you're using for the product to ensure your connections for your media are the same.”
Filter Validation in the Submission Process
Today, the top four filter validations that are being done are bacterial retention, compatibility, product bubble point, as well as extractables, which regulators are increasingly demanding since it helps to identify, quantify, and assess that the product-contact materials won’t adversely affect the product’s safety.
“With extractables, most of the vendors use almost a worst-case scenario solvent stream where you're at low and high pH's, and they're using solvents to ensure that nothing is getting extracted off the filter and into your product,” Shelli says. “Vendors can do this easily because they have all the data to assess worst-case scenarios.”
Partnership is key with filter validation and finding a partner with experience in properly evaluating and documenting each element is important to a successful outcome. Failure or missteps can lead to costly delays in getting your product to market.