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Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.

Abstract Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 ?C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 ?C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 ?C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations.
PMID
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Authors

Mayor MeshTerms

Excipients

Freeze Drying

Keywords
Journal Title pda journal of pharmaceutical science and technology / pda
Publication Year Start
%A Zhou, Rong; Schlam, Roxana F.; Yin, Shawn; Gandhi, Rajesh B.; Adams, Monica L.
%T Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.
%J PDA journal of pharmaceutical science and technology / PDA, vol. 66, no. 3, pp. 221-235
%D 05/2012
%V 66
%N 3
%M eng
%B Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 ?C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 ?C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 ?C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations.
%K Calorimetry, Differential Scanning, Chemistry, Pharmaceutical, Excipients, Freeze Drying, Freezing, Mannitol, Sucrose
%P 221
%L 235
%Y 10.5731/pdajpst.2012.00861
%W PHY
%G AUTHOR
%R 2012.......66..221Z

@Article{Zhou2012,
author="Zhou, Rong
and Schlam, Roxana F.
and Yin, Shawn
and Gandhi, Rajesh B.
and Adams, Monica L.",
title="Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.",
journal="PDA journal of pharmaceutical science and technology / PDA",
year="2012",
month="May/Jun",
volume="66",
number="3",
pages="221--235",
keywords="Calorimetry, Differential Scanning",
keywords="Chemistry, Pharmaceutical",
keywords="Excipients",
keywords="Freeze Drying",
keywords="Freezing",
keywords="Mannitol",
keywords="Sucrose",
abstract="Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 {\textdegree}C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 {\textdegree}C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 {\textdegree}C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations.",
issn="1948-2124",
doi="10.5731/pdajpst.2012.00861",
url="http://www.ncbi.nlm.nih.gov/pubmed/22634588",
language="eng"
}

%0 Journal Article
%T Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.
%A Zhou, Rong
%A Schlam, Roxana F.
%A Yin, Shawn
%A Gandhi, Rajesh B.
%A Adams, Monica L.
%J PDA journal of pharmaceutical science and technology / PDA
%D 2012
%8 May/Jun
%V 66
%N 3
%@ 1948-2124
%G eng
%F Zhou2012
%X Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 ?C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 ?C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 ?C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations.
%K Calorimetry, Differential Scanning
%K Chemistry, Pharmaceutical
%K Excipients
%K Freeze Drying
%K Freezing
%K Mannitol
%K Sucrose
%U http://dx.doi.org/10.5731/pdajpst.2012.00861
%U http://www.ncbi.nlm.nih.gov/pubmed/22634588
%P 221-235

PT Journal
AU Zhou, R
   Schlam, RF
   Yin, S
   Gandhi, RB
   Adams, ML
TI Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.
SO PDA journal of pharmaceutical science and technology / PDA
JI PDA J Pharm Sci Technol
PD May/Jun
PY 2012
BP 221
EP 235
VL 66
IS 3
DI 10.5731/pdajpst.2012.00861
LA eng
DE Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Excipients; Freeze Drying; Freezing; Mannitol; Sucrose
AB Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 ?C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 ?C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 ?C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations.
ER

PMID- 22634588
OWN - NLM
STAT- MEDLINE
DA  - 20120528
DCOM- 20160422
IS  - 1948-2124 (Electronic)
IS  - 1079-7440 (Linking)
VI  - 66
IP  - 3
DP  - 2012 May-Jun
TI  - Investigation of freeze/thaw-related quality attributes of a liquid
      biopharmaceutical formulation: the role of saccharide excipients.
PG  - 221-35
LID - 10.5731/pdajpst.2012.00861 [doi]
AB  - Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly
      employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein
      formulations. During the thawing of a protein-containing formulated bulk drug
      substance conducted prior to a drug product (DP) filling operation, a white,
      crystalline precipitate was observed. In addition, upon thawing, vial breakage
      was observed for filled DP that had been previously frozen at -40 degrees C. To
      investigate the causes of both phenomena, the freeze/thaw behavior of the
      formulation components was studied. Multiple physical characterization
      techniques, including differential scanning calorimetry (DSC), electrical
      resistance measurements, thermomechanical analysis (TMA), and powder X-ray
      diffraction (PXRD), were utilized to characterize the formulations. The PXRD
      pattern of precipitate collected from thawed bulk was consistent with that of a
      mannitol control. An exothermic transition observed by DSC, a sharp increase in
      electrical resistance detected via resistivity measurements, and the onset of
      volumetric expansion of the frozen matrix evident in the TMA curve offer evidence
      that the frozen mannitol solution undergoes transitions at or near the vial
      breakage temperature (-22 to -23 degrees C) observed during warming. In addition,
      osmolality measurements taken from fractionated aliquots of frozen samples
      indicated that non-uniform concentration gradients contributed to precipitation
      of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 
      10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L
      and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw
      properties of the tonicity adjustor, mannitol, alternative saccharide excipients,
      including sorbitol, sucrose, and trehalose, were evaluated at isotonic
      concentrations over a temperature range of -80 to 25 degrees C using
      physical-chemical techniques and visual observation. Neither precipitation nor
      vial breakage was observed for the alternate saccharides. Recommendations for
      saccharide selection are provided based on storage conditions and scale
      considerations for liquid biopharmaceutical formulations. LAY ABSTRACT:
      Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly
      employed as stabilizers, cryoprotectants and/or tonicity adjusters in protein
      formulations. During thawing of formulated bulk drug substance, a white,
      crystalline precipitate was observed. In addition, upon thawing, vial breakage
      was observed for filled drug product that had been previously frozen at -40
      degrees C. To investigate the causes of both phenomena, multiple physical
      characterization techniques were utilized to characterize the formulations. The
      powder X-ray diffraction pattern of precipitate collected from thawed bulk was
      consistent with that of a mannitol control. Upon linking the detrimental behavior
      to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative
      saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated
      at isotonic concentrations over a temperature range of -80 to 25 degrees C using 
      physico-chemical techniques and visual observation. Neither precipitation nor
      vial breakage was observed for the alternate saccharides. Recommendations for
      saccharide selection are given based on storage conditions and scale
      considerations for liquid biopharmaceutical formulations.
FAU - Zhou, Rong
AU  - Zhou R
AD  - Department of Drug Product Science & Technology, Bristol-Myers Squibb, One Squibb
      Drive, New Brunswick, NJ 08903.
FAU - Schlam, Roxana F
AU  - Schlam RF
FAU - Yin, Shawn
AU  - Yin S
FAU - Gandhi, Rajesh B
AU  - Gandhi RB
FAU - Adams, Monica L
AU  - Adams ML
LA  - eng
PT  - Journal Article
PL  - United States
TA  - PDA J Pharm Sci Technol
JT  - PDA journal of pharmaceutical science and technology / PDA
JID - 9439538
RN  - 0 (Excipients)
RN  - 3OWL53L36A (Mannitol)
RN  - 57-50-1 (Sucrose)
SB  - IM
MH  - Calorimetry, Differential Scanning
MH  - Chemistry, Pharmaceutical
MH  - *Excipients/chemistry
MH  - *Freeze Drying
MH  - Freezing
MH  - Mannitol/chemistry
MH  - Sucrose/chemistry
EDAT- 2012/05/29 06:00
MHDA- 2016/04/23 06:00
CRDT- 2012/05/29 06:00
AID - 66/3/221 [pii]
AID - 10.5731/pdajpst.2012.00861 [doi]
PST - ppublish
SO  - PDA J Pharm Sci Technol. 2012 May-Jun;66(3):221-35. doi:
      10.5731/pdajpst.2012.00861.
TY  - JOUR
AU  - Zhou, Rong
AU  - Schlam, Roxana F.
AU  - Yin, Shawn
AU  - Gandhi, Rajesh B.
AU  - Adams, Monica L.
PY  - 2012/May/Jun/
TI  - Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.
T2  - PDA J Pharm Sci Technol
JO  - PDA journal of pharmaceutical science and technology / PDA
SP  - 221
EP  - 235
VL  - 66
IS  - 3
KW  - Calorimetry, Differential Scanning
KW  - Chemistry, Pharmaceutical
KW  - Excipients
KW  - Freeze Drying
KW  - Freezing
KW  - Mannitol
KW  - Sucrose
N2  - Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 ?C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 ?C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 ?C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations.
SN  - 1948-2124
UR  - http://dx.doi.org/10.5731/pdajpst.2012.00861
UR  - http://www.ncbi.nlm.nih.gov/pubmed/22634588
ID  - Zhou2012
ER  - 
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