Preparing sterile products requires manufacturers to control microbial quality. Sterility and endotoxin content are critical because failure to properly manage them can seriously harm, or even kill, patients. Manufacturers use various means to sterilize products, but depyrogenation-a process whereby fever-inducing materials are eliminated from materials, components, and equipment-is largely restricted to dry-heat methods or cleaning and rinsing. Dry heat is appropriate for heat-resistant glass or stainless steel items. For other materials, however, depyrogenation is accomplished by cleaning and rinsing surfaces.

Large pieces of equipment such as tanks and permanent piping customarily undergo cleaning in place (CIP). Cleaning requires various chemical agents, including strong acids and bases. Although these agents remove pyrogens, the magnitude of this removal is rarely quantified (1). The last step in cleaning these items is often a rinse with water for injection (WFI). Samples for cleaning validation, and sometimes for routine verification, may be tested for endotoxins.

 Small equipment that cannot be cleaned in place such as filling needles, pumps, and utensils is commonly cleaned with milder agents. Use of these agents ensures the safety of the personnel who perform much of the cleaning process. Small items are sometimes cleaned in parts washers that achieve conditions similar to those in CIP. The final rinse of these materials is always performed with WFI. Depyrogenation of equipment surfaces is not the prime objective of these processes, however. Given the diversity of equipment materials and cleaning processes, expectations for depyrogenation are varied. Some of these processes may achieve depyrogenation effectively; others are less effective. 

Elastomeric materials used in the manufacturing process or as part of primary packaging also require depyrogenation. The problem with these items is that their surfaces may adsorb and retain pyrogenic materials. Reproducible recovery of known endotoxin challenges from these surfaces is not easy; results are highly variable. During production, these items may be exposed to pyrogenic materials that differ substantially from the purified endotoxin used in laboratory evaluations.

A primary technique for controlling endotoxins is rinsing surfaces with warm WFI. This technique can sometimes be supplemented with clean steam and air to dislodge pyrogenic materials. Glass containers, for example, can be treated this way. Results, however, are often less than stellar. Private discussions with industry scientists reveal that the level of reduction is typically not more than 1–2 logs. That reduction is often accomplished using purified endotoxin at high initial concentrations (2).

 Thus, a considerable amount of residual endotoxin remains on the surface after the validation exercise. Going from 106 to 103 endotoxin units (EU) per component represents a 3-log reduction. This process leaves 1000 EU on an item’s surface, but the expected limit for a depyrogenated item may be as low as 0.25 EU. To support the expectations for a validated removal by washing, manufacturers must often use surfactants and other agents to aid in endotoxin removal. When preparing elastomeric materials, it is essential to monitor their incoming endotoxin content, wash them with WFI, and dry them thoroughly. Interactions between elastomeric materials and endotoxin are reportedly strong enough to preclude effective removal by rinsing (2).

Injectable drugs must be pyrogen-free. Depyrogenation by rinsing is an important part of production processes. Our ability to demonstrate effective depyrogenation by rinsing is hampered by the materials and processes we use. Manufacturers must use methods that remove pyrogens efficiently and ensure patients’ safety. 

1. PDA, “TR #7–Depyrogenation,” (PDA, Philadelphia, PA, 1985).

2. J. Agalloco – Personnel Communications – 1982 to present.

Articles

In the Mixer

Preparing sterile products requires manufacturers to control microbial quality. Sterility and endotoxin content are critical because failure to properly manage them can seriously harm, or even kill, patients.

Depyrogenation by Dilution

To ensure an effective treatment, a patient often must take equal doses of an active pharmaceutical ingredient (API) at regular intervals. Powder-in-capsule dosage forms must maintain a consistent ratio of API to excipients as well as a consistent amount of each ingredient. Pharmaceutical manufacturers must therefore achieve content and fill-weight uniformity.

Producers of powder-in-capsule dosage forms face several obstacles to reaching these goals, however. One major challenge is filling capsules with powders having poor flow properties or that are highly cohesive. Karl-Heinz Seyfang, division leader of pharmaceutical services at Harro Höfliger Packaging Systems (Allmersbach im Tal, Germany), says that filling capsules with those kinds of powders is particularly challenging at fill weights of less than 10 mg. The challenge results from the variance introduced by the confinement step, which separates the dose from the bulk powder. To overcome this problem, Harro Höfliger equips its capsule-filling machines with a vacuum-drum filling system. This system doses powders at low fill weights by using a vacuum to draw the powder from a small hopper into bores on the drum. 

Reuben Zielinski, senior director of technical operations at Catalent Pharma Solutions (Somerset, NJ), remarks that his greatest challenge is ensuring smooth material flow at high encapsulation-machine speeds. Zielinski says maintaining good flow requires vibratory action, but notes that this technique can reduce capsules’ content uniformity. “For this reason, we run our encapsulation machines only as fast as the gravity feed will allow,” he explains.

Another potential threat to content uniformity is powder segregation, Seyfang observes. To be certain that segregation has not occurred, a capsule-filling machine “must be equipped with process analytical technology devices such as a near-infrared spectrometer, a UV–vis spectrometer, or other technologies to verify API content.” Zielinski says Catalent takes samples throughout the capsule-filling process, according to company testing protocols, to monitor content uniformity. 

A powder’s physical properties are not the only influences on content and fill-weight uniformity, however. Zielinski points out that manufacturers must consider the properties of their production machinery. He names the thickness of the encapsulator’s dosing disk as an example.

  “We have found that the machined tolerances on dosing disks can affect the fill-weight accuracy,” he explains. Because the diameters of the disk’s through-holes accommodate standard capsule sizes, the dosing disk’s thickness determines the accuracy of capsule fill weights.

  After they are filled, capsules must be checked. In addition to having the proper dosing system, Seyfang notes, a capsule-filling machine “must include an appropriate tare and gross check-weighing system to neutralize capsule-shell weight variance.” He recommends encapsulators that weigh capsules both before and after filling.

  Yet weight-checker data should not necessarily be taken at face value. Zielinski cautions that a manufacturing plant’s inherent vibrations affect the location of the weight-checker. “These vibrations cause displacements that in turn can cause an abnormal amount of rejected capsules because of the sensitivity of the load cells,” he says.

  Manufacturers achieve content and fill-weight uniformity by taking into account several factors. Filling equipment must operate precisely at high speeds and must also be validated to ensure that capsules meet label claim specifications. Also, facilities produce dosage forms of consistent quality when equipment operators are well trained and experienced. The facility environment must be monitored, as well: temperatures must be kept within 15–25 °C and relative humidities should be maintained within 35–55% to enable good powder flow. Attention to critical details such as these helps produce uniform and effective products for end users.

Production Lines

To ensure an effective treatment, a patient often must take equal doses of an active pharmaceutical ingredient (API) at regular intervals.

Consistent Capsule Filling

Optima Group Pharma
    Nested syringe filler operates at high speed

 
      The “H10-16” nested syringe-filling and -closing machine from Optima Group Pharma (Green Bay, WI) provides high-speed operation and on line fill-weight checking. Uwe Kellermann, vice-president of pharmaceutical applications for the company, says, “In the 160-nest configuration, the [unit’s] output is 960 syringes/min.” He adds that the device processes six tubs per minute, regardless of the nest configuration.

        The H10-16 machine is equipped with a proprietary in-process control (IPC) system. The IPC system performs fill checks by removing one row of syringes, weighing it before and after filling, and providing automatic feedback to the filling system. This nondestructive method allows companies to use or sell all tested syringes.
        In addition, the unit incorporates a robot that removes the “Tyvek” cover and layer from tubs before filling and closing.
    Kellermann observes that the device accommodates various fill systems, including peristaltic pumps.	

Sono-Tek
          Spray dryer collects small particles


       At INTERPHEX Puerto Rico, Sono-Tek (Milton, NY) unveiled its “SonoDry 1000” spray-drying system. Luis Abarca, director of Sono-Tek’s ultrasonic coating solutions business, explains that the system’s dual-cyclone design “efficiently collects fine particles with high yields to create small batches of spray-dried particles from aqueous or solvent feeds.”

        Abarca adds that the nonclogging high-frequency ultrasonic nozzle is core of the system’s technology. The nozzle is available in four frequencies to create customized droplet sizes at low flow rates. The 120 kHz nozzle, for example, creates a median drop size of 18 µm in water.

Featured products from this issue of Equipment & Processing Report

Equipment and Processing Report-02-20-2008

Depyrogenation by Dilution

Consistent Capsule Filling

February 2008 Editor's Picks