Stuart R. Gallant, MD, PhD

Parenteral products require sterility whether they are liquid vials, lyophilized vials, or prefilled syringes.  This week’s post on Pharmatopo addresses sterilely filed products of all types, but the focus is on lyophilized vials for reconstitution with water for injection or with sterile saline.

Filling Supplies

Note:  Pharmatopo has received no compensation from any vendor mentioned in this post.

Vials vary in numerous subtle ways, as shown in the figure above.  Share your part numbers and drawings with your vendors and contract manufacturers to be sure that there is no confusion about your precise configuration.  Contract manufacturers may need significant lead times, and your project may incur extra charges if your vial is not standard for their filling line; confirm vial configuration prior to signing with a particular contract manufacturer.  Here are some things to think about as you select your vial, stopper, and cap:

• Stocks:  Decades ago, pharmaceutical companies had to advance order filling supplies many months in advance.  Currently, the major suppliers, such as Schott (schott.com), carry inventories of their most commonly ordered products.  Talk to your customer representative to clarify lead times on various order sizes.  Generally, it is not a problem to order multiples of 10,000 vials for immediate delivery, but larger orders still need to be ordered in advance.
• Glass Type:  There are three types of glass commonly used for pharmaceutical containers:
  • Type I:  Used in glass vials, prefilled syringes, cartridges, ampoules, and other configurations and known as “neutral” glass, Type I glass is a borosilicate glass with good chemical resistance and low reactivity with the product.  In addition, there are subtle variations of glass composition and finish within the Type I category.
  • Type II:  Used in infusion bottles, Type II glass is treated on its internal surface to reduce ion exchange.
  • Type III:  Used in syrup bottles and tablet containers, Type III glass is a soda-lime glass.
• Glass Treatment:  In filling lyophilized products, it is not uncommon for some filling solutions to climb the sides of the containers; this can leave a residue on the vial wall after lyophilization is completed.  Schott’s EVERIC [1] vials receives a hydrophobic inner coating during manufacture that prevents the lyophilization solution from climbing the vial walls and allows vials to shed any drops which fall on their sides due to splashing.
• Blowback:  There are three configurations of the vial mouths (see drawing above), European blowback, American blowback, and no blowback.  Blowback configurations hold the stopper in place while it travels along the filling line from the lyophilizer to the capper.  Frequently, Pharmatopo has seen higher inventory levels of the no blowback vials—so you may need to order what is at hand, rather than what is ideal—the number of stoppers that pop out are typically quite small.  Discuss this topic with your contract manufacturer.
• Stopper Polymers:  Stoppers are commonly manufactured of either chlorobutyl or bromobutyl with chlorobutyl more commonly used in the US and bromobutyl more commonly used in the EU.  Bromobutyl is commonly used in prefilled syringes, so making the vial to syringe transition is smoother with bromobutyl.  Both materials have the same durometer, both can be steamed, and both tolerate up to about 10 punctures if a multidose vial is to be employed.  The pH ranges are broad for both (chloro:  pH 3 to pH 10, and bromo:  pH 4 to pH 10).  West Pharma (www.westpharma.com) is a vendor to consider for stoppers and for caps.
• Ready to Use or Ready to Sterilize Stoppers:  Following steaming, sterilized stoppers can have variable amounts of water.  Gamma irradiation can leave stoppers sticky.  Ready-to-use bags of stoppers are a convenience, but more than that they have a consistent, low moisture level—ready-to-use is often the best way to go, but other presentations are valid options.  Check with the manufacturing engineer to understand which configurations the manufacturing line accepts.
• Caps:  Caps come in a variety of colors to allow products to be easily distinguished and to help prevent two products from the same company from being confused.  Because labeling occurs days, weeks, months, or years after inspection, ensuring the identity of the product is a concern.

Drug Product Inspection

Prior to discussing the filling process itself, here are some observations about drug product inspection following filling and prior to release testing.  By addressing inspection first, some of the important aspects of filling will be illuminated.  After removal from the lyophilizer, the vials are capped and held at the specified storage temperature.  Some issues to consider during visual inspection include:

• Groups of vials in their secondary packaging are brought to the inspection room for 100% visual inspection.  Although automated vial inspection is more widespread, commonly vials are inspected manually by trained personnel.  Inspectors must be provided with appropriate breaks to avoid fatigue.
• Defects are stratified as:
  • Critical:  missing stopper; defective cap; penetrating defect of the vial; product on stopper
  • Major:  particulate matter observed; major vial defect; cake collapse; low or high fill level; stopper or vial defect not affecting container integrity
  • Minor:  cosmetic deficiencies of vial, cap, or cake
• Because some of the inspection defects can be judgement calls, the sponsor is always advised to prepare a memo describing what constitutes acceptable drug product, including a representative set of photos to provide examples to the inspectors.  This memo should offer reassurance to the inspectors and ensure that visual inspection is consistent with the sponsor’s intentions and with process development data supporting the drug product.
• Product on stopper is a subject of concern because the vial seal depends on the contact between the stopper and the vial and also because the area of contact between the stopper and the vial is not completely visible to the inspectors due to the presence of the cap.  In the figure above, the regions of the Land seal (red) and the plug seal (blue) are depicted, along with region which is visible to inspection.  It is important that inspectors differentiate between product on stopper and loose grains of lyophilization cake which may become detached from the lyophilization cake and migrate to the stopper region.
• Container Closure Integrity Testing (CCIT):  Product on stopper (POS) has been reported for some formulations to represent a problem for seal integrity [2].  This type of report is used to justify POS being categorized as a critical defect.  CCIT can be used to demote POS to a lower category.  This approach culls POS vials from the manufacturing process during process development or during early GMP manufacturing runs and submits them to CCIT—a reassuring report which finds integrity of the seal in spite of POS observation can be used to justify the lower categorization for POS defect.
• Release and Stability Testing:  Following completion of visual inspection, vials are selected for release testing and for stability studies.
• Reconstitution Instructions:  For friable lyophilization cakes, it is important to make clear in the reconstitution instructions that a variety of drug product appearances are possible, including a single intact cake, a fragmented cake, or even fine powder.  The handling history will be important in defining the product appearance—vials subjected to vibration in shipment are more likely to have fragmented or finely divided drug product at the time of reconstitution.

Drug Product Manufacture

The filling parameters should be extensively investigated during process development using a laboratory mockup of the filling station.  Once the preferred filling parameters have been locked in, either an engineering run or a full GMP run is the next step, depending on risk tolerance.  Generally, proceeding directly to a GMP run will result in less manufacturing expense.  If the filling parameters fail to produce releasable vials, additional development work is required.  The filling cycle for sterile lyophilized products includes the following steps:

• Startup:  The line speed and filling parameters may receive final adjustments during the process of startup.  Skilled, experienced manufacturing and engineering personnel are important during scale up because they will be sensitive to unusual or atypical operating conditions along the filling line.  A high-speed, high-resolution camera placed at a viewing window in the vicinity of the filling station can provide valuable real-time feedback on filling performance.  Keep the camera available throughout the run to document any problems that develop and to get a good look at the needles as the run progresses, looking for any problems that develop 1000s of cycles into the run.
• Filling Cycle:  The needle typically dips down into the vial as it begins vial filling; the needle may rise during filling, then, when flow stops, the pump may suck back a small amount of solution to pull any drop on the end of the needle back into the inside of the filling needle (see illustration above).
• Filling Parameters:  Each vendor has a unique set of filling parameters that control their machine(s).  Some important parameters to investigate during process development and during line startup are:
  • Humidity and Airflow:  The humidity of the air and the flow of air in the vicinity of the filling station have an important effect on the operation—though they are not easily changed.  Manufacturing air is typically relatively dry, and the downflow of air common at the filling station can contribute to the formation of a dry crust (beard) at the tip of the needle as residual filling solution evaporates.  The beard can in turn be a nexus of dripping as the manufacturing run continues.
• • Needle Cut and Material:  Needles are available in a range of diameters, cuts (straight, angle, basket), and materials (stainless steel, PEEK, polypropylene, PTFE).  Stainless steel is the most widely available due to its durability and easy machinability.  PTFE is an excellent surface because of its ability to shed liquid, but it must be coated onto a stronger material such as steel, and PTFE coating is a specialized technology that has not been widely adopted to date.  The bottom line is that a range of needle cuts, diameters, and material should be evaluated during process development with at least hundreds of cycles performed on the most promising configurations before the final selection can be made—ideally this configuration is a common stocked item with a needle vendor, rather than an exotic custom needle with long lead times.  If time is limited, focus efforts on straight-cut, stainless steel needles in diameters easily ordered from preferred needle and tubing set vendors.
  • Operating Parameters:  There are two sources of information for operating parameter selection.  First, the manufacturing personnel and engineering staff will have a set of parameters that generally work well for the filling machine.  This will be around 100 individual speeds, heights, rates, and other variables.  Second, there are a small number of parameters that should be extensively investigated in process development (see illustration above):
    • Distance needle moves down at start of filling and distance needle move up during filling.
    • Duration of dispensing and length of suck back.
    • Line speed—ideally line speed is fast in order to minimize run time, but it is more important to make acceptable vials.  Starting at a slower line speed may be necessary.
• Sampling:  Generally, vials can be pulled from the line at various sampling points to verify that each manufacturing step is running successfully.  This is good practice both at the beginning of the run and at intermediate points during the run.  The needles should be surveilled to be sure that bearding is not occurring as the run advances.  Watch out for drips on the vial side which could lead to product-on-stopper failures during inspection.
• Maintenance:  Filling lines perform perhaps 10,000 cycles of operation per clinical lot manufacture and perhaps 100,000s of cycles per commercial lot—line maintenance is crucial.  Review with the engineering staff what maintenance is performed on the line and confirm that that schedule aligns with the filling machine vendor recommendations.  A line malfunction during a manufacturing run can be difficult to repair without compromising sterility, and losing a lot to poor maintenance is heartbreaking.
• Staffing:  Consider paying to have the maintenance engineer for the filling machine vendor attend the first engineering or GMP run of a new drug product.  CMO plant engineers wear many hats, and it is hard for them to know the equipment as well as a full-time maintenance engineer.  The equipment vendor’s engineer will likely spot things that engineering staff may miss—it’s cheap insurance when the only cost is travel time and an hourly fee.

Conclusions

Lyophilization is a form of parenteral drug product designed to remove problems from the supply chain—by making the drug product more stable, greater assurance of delivery of patient doses of high quality is possible.  To get that benefit, careful process development, including development of the filling process and careful planning of the manufacturing runs, must occur to ensure easy and consistent manufacturability.  Once the hard work has been done, the project and the company will reap the benefits.

[1] www.schott-pharma.com/en/products/vials/everic-lyo

[2] Mehta, S.B., et al.  “Product on Stopper in a Lyophilized Drug Product: Cosmetic Defect or a Product Quality Concern?,” J Pharm Sci. 2018 Jun;107(6):1736-1740.

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