Peer-Reviewed Technical Note: Quality by Design in Freeze-Drying - Pharmaceutical Technology

Latest Issue

Latest Issue
PharmTech Europe

Peer-Reviewed Technical Note: Quality by Design in Freeze-Drying
Cycle design and robustness testing using advanced process analytical technology.

Pharmaceutical Technology
Volume 32, Issue 10, pp. 88-93

Freeze-dry microscopy (FDM). Collapse temperatures (T c) were determined using a "FDCS 196" freeze-drying stage (Linkam Scientific Instruments, Surrey, UK) and an "Axio Imager" microscope (Zeiss, Göttingen, Germany). Images were captured with a 1.3 MPix digital camera and analyzed using "LinkSys" (Linkam) software. The protocol applied was a standard procedure reported in the literature (7, 8). Onset of collapse for the sucrose was determined as follows:

50 mg/mL: T c = –34°C

100 mg/mL: T c = –32 °C

200 mg/mL: T c = –32 °C.

Scanning electron microscopy (SEM). Lyophilized samples were broken into pieces, fixed on aluminum stubs and then carefully gold-sputtered at 20 mA/5 kV (Hummer JR Technics) for about 30 s. Cake morphology was then examined using an Amray 1810 T scanning electron microscope (SEMTech Solutions, CITY, MA) at 20 kV.

Results and discussion

Figure 1
Cycle design by manometric temperature measurement. Figure 1 illustrates the cycle recipe obtained for 50 mg/mL sucrose. The recipe is optimized for the type of excipient, individual T c of the product, and container system. Note that T s was automatically lowered by the software after about 6 h to account for a continuous increase in T p toward the end of primary drying, caused by an increase in R p (see Figure 4). Product temperature at the sublimation interface did not exceed the collapse temperature during primary drying (see Figure 3 and Table I). A freeze-drying cycle may be denoted as "optimized" when T p is maintained just below T c (i.e., 2–3 °C) during primary drying to avoid structural loss (9). For the SMART cycle, total primary drying time during this run was 1136 min and the cycle recipe in primary drying as follows: –39 °C (60 min), –18 °C (358 min), –23 °C (718 min). The endpoint of primary drying was determined using MTM and based on the total difference between the calculated Pice value by MTM (nonlinear regression analysis of the pressure rise data) and the chamber pressure, P c. A representative determinant of the endpoint of primary drying is crucial for testing robustness as described in this article. Once all ice has been removed, the pressure rise in the chamber during an MTM measurement is based on leaks and additional heat transfer to the product. Thus, the "fitted" vapor pressure of ice obtained from the MTM procedure equals that of the chamber pressure (see Figure 1) (3–5).


blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
| Weekly

What role should the US government play in the current Ebola outbreak?
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Jim Miller Outsourcing Outlook Jim MillerCMO Industry Thins Out
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerFluorination Remains Key Challenge in API Synthesis
Marilyn E. Morris Guest EditorialMarilyn E. MorrisBolstering Graduate Education and Research Programs
Jill Wechsler Regulatory Watch Jill Wechsler Biopharma Manufacturers Respond to Ebola Crisis
Sean Milmo European Regulatory WatchSean MilmoHarmonizing Marketing Approval of Generic Drugs in Europe
FDA Reorganization to Promote Drug Quality
FDA Readies Quality Metrics Measures
New FDA Team to Spur Modern Drug Manufacturing
From Generics to Supergenerics
CMOs and the Track-and-Trace Race: Are You Engaged Yet?
Source: Pharmaceutical Technology,
Click here