Wyeth Carolina Uses PAT to Monitor an Oxygen-Sensitive New Parenteral

Close teamwork, and incorporating validation criteria into the FAT test, helped Wyeth’s team meet a tight drug approval and commercialization timeline.

By Vivianne Y. Colón, John E. Walsh, and Dave Bertsch, Wyeth Pharmaceuticals, Inc.

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One of our key products at Wyeth Carolina is a new parenteral that is highly sensitive to oxygen and can degrade from continued exposure. During manufacture, great care must be taken to prevent oxygen ingress. Thus, for example, the lyophilized product is sealed under partial vacuum in a nitrogen atmosphere. During the vacuum break cycle, nitrogen is back-flushed into the lyophilization chamber to 860 mb pressure and the stopper is then set.

Last year, our team saw an opportunity to use Process Analytical Technology (PAT) to expand our capabilities to monitor oxygen with this product. PAT’s overall goal, as defined by FDA, is to design, analyze and control manufacturing by measuring critical quality and performance attributes during manufacturing. If designed right, a PAT application would allow us to monitor and control a critical product attribute and ensure the safety and efficacy of the drug from manufacture through distribution and sale.

There are many possible ways that air can enter a vial before sealing or capping. A stopper can stick to the lyophilizer shelf (due to shelf finish, defective stoppers, stopper siliconization, or defective stopper finish material) and become unseated when the shelf rises, or it can become partially dislodged during manual transfer from the lyophilizer to the sealing area. The vial can be defective, cracked, or out of specification.

Air ingress can increase headspace pressure in the vial by up to 1 atmosphere, causing oxygen content in the product to increase to 3%, well above acceptable levels. (The pressure value reference used is 1,013 mb at sea level. The 3% value is based on available headspace volume and ingress of 173 mbar of air.) To prevent this from occurring, we needed some way to monitor oxygen levels within the vial headspace.

A non-destructive technology

The traditional method of doing this is through a destructive laboratory analysis involving gas chromatography. Since we had used this test successfully for batch release and it met all component testing requirements, we had no intention of replacing it. However, we knew that we needed a technology to support our oxygen monitoring efforts. Other technologies were available, but each had its own limitations:
  • Dye-leak tests
  • are not suitable for 100% in-line inspection.

  • Pressure decay tests
  • offer a leak detection limit of less than 5 microns.

  • Pressure decay, dye leak and helium tests
  • require that the container leak at time of measurement.

  • Spark tests
  • might impact product.

  • Moisture/pressure tests
  • may prove inaccurate since moisture amounts can vary between lots.
After evaluating the alternatives, we opted for a new technology based upon laser technology and Frequency Modulation Spectroscopy. The automated oxygen analyzer we chose was the Wilcomat R4 VR, manufactured by Wilco AG (Wohlen, Switzerland).

We had a very tight timeline for the project, and had to meet target dates for FDA approval and product launch. Wilco’s technology offered a number of benefits, while the vendor had domain experience, good technical support, and documentation and validation experience.

Wyeth Carolina bought the Wilcomat machine as an in-line inspection that could identify and/or measure critical material or process attributes for each lot of product. The Wilcomat machine met the required definitions of PAT, since it is a process analyzer system and provides non-destructive measurements that deliver information on critical product attributes. The ability to measure relative attribute differences within each lot provides useful product information for process control and/or process feedback.

Our team decided to install the analyzer in the packaging area, to inspect for oxygen content in that part of the plant, rather than immediately after vial sealing. We had two very practical reasons for doing this:
  • We wanted to inspect the product as late as possible in the process, so that we could maximize inspection opportunities and remove any defects that might be introduced during the sealing process (e.g., cracks under the seal finish);

  • Space was limited in the sealing area, so there wasn’t enough room to allow a complete cosmetic and oxygen content inspection to be performed.
The machine is a four-head station precision tester. Each head contains a laser unit that passes a laser beam through the upper headspace area of each vial as shown in Figure 1 (to access the figures accompanying this article, click the Download Now button at the end of the page).

Frequency Modulation Spectroscopy uses a modulating wavelength-calibrated low-energy laser beam (whose midpoint was tuned at approximately 760 nm, the absorption frequency of oxygen), which is directed through the vial’s headspace. The laser beam detects changes in this energy when increased levels of oxygen molecules are detected within a container. The principle behind this measurement is that the energy from the laser diode changes the laser wavelength. The comparison, peak to amplitude, changes with variation of oxygen content (Figure 2, accessible by clicking the Download Now button at the end of this article).

During each vial inspection, the laser transmission power is monitored. If it is below or above set levels, the data result is deemed “unknown,” and the vial is directed to a special collection area for evaluation and possible re-testing. Transmission errors can result from laser beam impairment or blockage (i.e., when powder particles are on the vial wall). The pre-set level includes a safety factor so that the minimum transmission limit is above the minimum molecule sampling point required for accuracy.

The oxygen analyzer used at Wyeth Carolina, the Wilcomat R4 VR. Photo courtesy of Wilco AG.

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