UNIT OPERATION / PRODUCTION PROCESS


Aseptic Process Equipment System Operation, Reducing Interventions and Product Risk

The dirtiest part of aseptic processing is people. All people shed skin cells continuously and these particulates contain viable microorganisms that can initiate growth of bacteria in the product. Gowning people provides protection to the product by creating a barrier. However, when you move in a gowned situation, the air outlet is in the neck area and this actually helps the person focus particles spewing in the direction he or she is looking.

Utilizing systems that run well all the time, using barriers or isolators on the machines and not have people intervening with process equipment is the key note to minimize risk due to any kinds of contamination.

Container shape can poses another issue. Tall narrow vials have a high center of gravity, small base profile can be very prone to tipping during transfers.

Certain areas in the manufacturing process needs specific monitoring since contamination may become evident. The first area is the drug development and clinical trial manufacturing which may be manual or very slow filling with small batch size. Purchasing area can also be a surprise in operation of production of equipment. Since, the goal of purchasing is to buy goods at the lowest cost, bonuses are based on how much can be saved. This result in glass that has not been annealed properly or glass that is slightly out of tolerance.

Stoppers have issues also. Mold “blow” can give a variation on flange thickness +/- 0.013 inch (0.3 mm). Trim die can cause non concentricity of bung with flange. These issues can cause stoppers to jam in the feeding systems. Machine-ability can be a problem due to not enough silicone or Teflon on surfaces or time since processing (sterilizing and siliconisation), hence silicone is absorbed into rubber and is not on the surface to provide lubricity. Stopper feeding systems have a realistic maximum output speed.

Operation philosophy needs to be evaluated for speed, container size (volume) and fill volume. There is a great difference in a 10 mL vial with 0.5 mL fill for a freeze dry product versus a 10 mL vial with a 10 mL liquid fill. In the latter case even the stopper size 13 mm or 20 mm can affect the nozzle outer diameter and inside diameter thus impacting the rate of filling. If the product is foaming or viscous, slowing down is the best option. The filling system needs to be clean, accurate and repeatable. It must meet the product requirements such as protein shear issues, nozzle size, side spry nozzles and the presence of air bubble in a cartridge or syringe.

Automation reduces product risk. It minimizes workers’ intervention. Similarly, for freeze dryer auto load and unload systems. Using reliable sensors and eject systems can keep the line running while sorting for missing stoppers or fallen vials.

For changeover, starwheels and guides should be identified and tied to a recipe matrix. No or minimal tools should be needed for changeover. Use doweled or keyed parts for correct alignment. Consider plastic change parts for lubricty and reduced particle generation.

Line layout is another area of consideration, hence area can be “U” or “L” shaped. One must consider the process equipment footprint with maintenance and changeover access as well as the space needed for material transfer for stoppers.