Issues Related to Non-PET

Radiopharmaceutical General Chapters

& Monographs
Issues Related to Non-PET
Radiopharmaceutical General Chapters
& Monographs
Joseph C. Hung, PhD, BCNP
Mayo Clinic
Joseph C. Hung, PhD, BCNP
Mayo Clinic
USP General Chapters
USP General Chapters
Non-PET Radiopharmaceuticals
Non-PET Radiopharmaceuticals
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permission of author.
USP General Chapters Related to Non-
PET Radiopharmaceuticals
USP General Chapters Related to Non-
PET Radiopharmaceuticals
<371> Cobalamin Radiotracer Assay
<797> Pharmaceutical Compounding
Sterile Preparations
<821> Radioactivity
<1165> Radiopharmaceutical Quality
Control Assurance and Compounding
<371> Cobalamin Radiotracer Assay
<797> Pharmaceutical Compounding
Sterile Preparations
<821> Radioactivity
<1165> Radiopharmaceutical Quality
Control Assurance and Compounding
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USP General Chapters
USP General Chapters
General Chapters numbered <1000, also
termed General Tests and Assays, are
considered enforceable (i.e.,
compliance is required).
General Chapters numbered <1000, also
termed General Tests and Assays, are
considered enforceable (i.e.,
compliance is required).
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permission of author.
USP General Chapters
USP General Chapters
General Chapters numbered > 1000,
also termed General Information
Chapters, are considered interpretative
(i.e., suggested guidance).
General Chapters numbered > 1000,
also termed General Information
Chapters, are considered interpretative
(i.e., suggested guidance).
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permission of author.
USP <371> Cobalamin Radiotracer Assay
USP <371> Cobalamin Radiotracer Assay
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permission of author.
USP <797> Pharmaceutical
Compounding Sterile Preparations
USP <797> Pharmaceutical
Compounding Sterile Preparations
Radiopharmaceuticals
Dispensing
SCA
Immediate-use provision
Radiopharmaceuticals
Dispensing
SCA
Immediate-use provision
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FAQs about USP <797>
FAQs about USP <797>
Prepared by Joe Hung and Jim Ponto.
To be posted on SNM Web site once the
draft is approved by SNM COP and SNM
leadership.
Prepared by Joe Hung and Jim Ponto.
To be posted on SNM Web site once the
draft is approved by SNM COP and SNM
leadership.
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permission of author.
USP <821> Radioactivity
USP <821> Radioactivity
Definitions, special considerations, and
procedures with respect to the
Pharmacopeial monographs on
radioactive drugs are set forth in this
chapter.
Definitions, special considerations, and
procedures with respect to the
Pharmacopeial monographs on
radioactive drugs are set forth in this
chapter.
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permission of author.
Radionuclidic Identification
Radionuclidic Identification
The radioactive half-life is readily
determined by successive counting of a
given source of the radionuclide over a
period of time that is long compared to
its half-life.
The radioactive half-life is readily
determined by successive counting of a
given source of the radionuclide over a
period of time that is long compared to
its half-life.
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European Pharmacopeia (EP)
European Pharmacopeia (EP)
General Monograph
Radiopharmaceutical Preparations
General Monograph
Radiopharmaceutical Preparations
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Radionuclidic Identification
Radionuclidic Identification
The same source is measured in the
same geometrical conditions and at
intervals usually corresponding to half
of the estimated half-life throughout a
time equal to about three half-lives.
The same source is measured in the
same geometrical conditions and at
intervals usually corresponding to half
of the estimated half-life throughout a
time equal to about three half-lives.
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General Chapter
General Chapter
<821> Radioactivity
Determine half-life at intervals
corresponding to half of the estimated
half-life throughout a time equal to
about three half-lives.
<821> Radioactivity
Determine half-life at intervals
corresponding to half of the estimated
half-life throughout a time equal to
about three half-lives.
USP Monographs
USP Monographs
Non-PET Radiopharmaceuticals
Non-PET Radiopharmaceuticals
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USP Monographs Related to Non-PET
Radiopharmaceuticals
USP Monographs Related to Non-PET
Radiopharmaceuticals
63 monographs

99m
Tc (26)

111
In (7),
131
I (7)

123
I (4)

57
Co (2),
51
Cr (2),
125
I (2),
32
P (2),
133
Xe (2)

14
C(1),
58
Co (1),
67
Ga (1),
81m
Kr (1),
153
Sm (1),
89
Sr (1),
201
Tl (1),
127
Xe (1),
90
Y (1)
63 monographs

99m
Tc (26)

111
In (7),
131
I (7)

123
I (4)

57
Co (2),
51
Cr (2),
125
I (2),
32
P (2),
133
Xe (2)

14
C(1),
58
Co (1),
67
Ga (1),
81m
Kr (1),
153
Sm (1),
89
Sr (1),
201
Tl (1),
127
Xe (1),
90
Y (1)
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Not Yet FDA Approved
Not Yet FDA Approved
Chromium Cr 51 Edetate Injection
Iobenguane I 123 Injection
Chromium Cr 51 Edetate Injection
Iobenguane I 123 Injection
USPs
USPs
SAPFA (Standards for
SAPFA (Standards for
Articles Pending FDA Approval)
Articles Pending FDA Approval)
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Not Commercially Available in U.S.
Not Commercially Available in U.S.
22 non-PET radiopharmaceuticals that
are currently listed in USP are no longer
commercially available in the U.S.
market due to economic reasons.
22 out of 63 = 35%
22 non-PET radiopharmaceuticals that
are currently listed in USP are no longer
commercially available in the U.S.
market due to economic reasons.
22 out of 63 = 35%
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permission of author.
Not Yet Listed in USP
Not Yet Listed in USP
Iodine I 131 Tositumomab Injection
(Bexxar)
Iodine I 131 Tositumomab Injection
(Bexxar)
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USP Monographs
USP Monographs
According to Section 501 of the Federal
Food, Drug, and Cosmetic Act, assays
and specifications in monographs of
the USP constitute legal standards.
According to Section 501 of the Federal
Food, Drug, and Cosmetic Act, assays
and specifications in monographs of
the USP constitute legal standards.
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permission of author.
Assays & Specifications
Assays & Specifications
USP Monographs
Package Inserts
USP Monographs
Package Inserts
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permission of author.
Deficiencies of Package Inserts
Deficiencies of Package Inserts
Hung JC, Ponto JA,
Hung JC, Ponto JA,
Gadient
Gadient
KR, et al.
KR, et al.
J Am Pharm Assoc.
J Am Pharm Assoc.
2004; 44:30
2004; 44:30
-
-
35
35
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Deficiencies of Package Inserts
Deficiencies of Package Inserts
31 package inserts were evaluated
Absent or incomplete directions
Restrictive directions
Inconsistent directions
Impractical directions
Vague directions
31 package inserts were evaluated
Absent or incomplete directions
Restrictive directions
Inconsistent directions
Impractical directions
Vague directions

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Deficiencies of USP Monographs?
Deficiencies of USP Monographs?
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permission of author.
Technetium Tc 99m Albumin Aggregated Injection
Technetium Tc 99m Albumin Aggregated Injection
Radiochemical Purity
Place a measured volume of Injection,
appropriately diluted, such that it provides a
count rate of about 20,000 counts per minute,
about 25 mm from one end of a 25- 300-mm
strip of chromatographic paper (see
Chromatography 621 ), and allow to dry.
Develop the chromatogram over a period of
about 3 to 4 hours by ascending
chromatography, using dilute methanol (7 in 10),
and air-dry.
Radiochemical Purity
Place a measured volume of Injection,
appropriately diluted, such that it provides a
count rate of about 20,000 counts per minute,
about 25 mm from one end of a 25- 300-mm
strip of chromatographic paper (see
Chromatography 621 ), and allow to dry.
Develop the chromatogram over a period of
about 3 to 4 hours by ascending
chromatography, using dilute methanol (7 in 10),
and air-dry.
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permission of author.
Technetium Tc 99m Albumin Aggregated Injection
Technetium Tc 99m Albumin Aggregated Injection
Protein concentration
Test preparationTransfer 2.0 mL of Injection to a suitable centrifuge tube, and centrifuge
at about 2000 rpm for 5 to 10 minutes. Decant the supernatant, and add 2.0 mL of Sodium
Chloride Injection to wash the centrifuged aggregate. Centrifuge again at 2000 rpm for 5 to
10 minutes, decant the supernatant, and add 2.0 mL of Sodium Chloride Injection.
Standard preparationTo a second test tube add 2.0 mL of a solution containing 2.0 mg of
Albumin Human per mL in 0.9 percent sodium chloride solution.
ProcedureTo a third test tube add 2.0 mL of Sodium Chloride Injection to provide a blank.
To each of the three tubes containing the Test preparation, Standard preparation, and blank,
add 4.0 mL of biuret reagent TS, mix, and allow to stand for 30 minutes, accurately timed,
for maximum color development. Additional mixing or slight heating may be required to
dissolve the aggregated albumin completely, but the Test preparation, Standard preparation,
and blank are to be treated identically. Determine the absorbances of the solutions from
the Test preparation and the Standard preparation in 1-cm cells at the wavelength of
maximum absorbance at about 540 nm, with a suitable spectrophotometer, against the
blank. Calculate the quantity, in mg, of aggregated albumin in each mL of the Injection
taken by the formula: 2(AU / AS)
in which AU and AS are the absorbances of the solutions from the Test preparation and the
Standard preparation, respectively. The protein concentration is not more than 1 mg, as
aggregated albumin, per 37 MBq (1 mCi) of Tc 99m at the time of administration.
Protein concentration
Test preparationTransfer 2.0 mL of Injection to a suitable centrifuge tube, and centrifuge
at about 2000 rpm for 5 to 10 minutes. Decant the supernatant, and add 2.0 mL of Sodium
Chloride Injection to wash the centrifuged aggregate. Centrifuge again at 2000 rpm for 5 to
10 minutes, decant the supernatant, and add 2.0 mL of Sodium Chloride Injection.
Standard preparationTo a second test tube add 2.0 mL of a solution containing 2.0 mg of
Albumin Human per mL in 0.9 percent sodium chloride solution.
ProcedureTo a third test tube add 2.0 mL of Sodium Chloride Injection to provide a blank.
To each of the three tubes containing the Test preparation, Standard preparation, and blank,
add 4.0 mL of biuret reagent TS, mix, and allow to stand for 30 minutes, accurately timed,
for maximum color development. Additional mixing or slight heating may be required to
dissolve the aggregated albumin completely, but the Test preparation, Standard preparation,
and blank are to be treated identically. Determine the absorbances of the solutions from
the Test preparation and the Standard preparation in 1-cm cells at the wavelength of
maximum absorbance at about 540 nm, with a suitable spectrophotometer, against the
blank. Calculate the quantity, in mg, of aggregated albumin in each mL of the Injection
taken by the formula: 2(AU / AS)
in which AU and AS are the absorbances of the solutions from the Test preparation and the
Standard preparation, respectively. The protein concentration is not more than 1 mg, as
aggregated albumin, per 37 MBq (1 mCi) of Tc 99m at the time of administration.
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Sodium Pertechnetate Tc 99m Injection
Sodium Pertechnetate Tc 99m Injection
Chemical Purity
Aluminum
ALUMINUM STANDARD SOLUTIONDissolve 35.17 mg, accurately weighed, of
aluminum potassium sulfate dodecahydrate in water to make 1000.0 mL. Each
mL of this solution contains 2 g of Al.
PROCEDUREPipet 10 mL of Aluminum standard solution into each of two 50-mL
volumetric flasks. To each flask add 3 drops of methyl orange TS and 2 drops
of 6 N ammonium hydroxide, then add 0.5 N hydrochloric acid, dropwise, until
the solution turns red. To one flask add 25 mL of sodium thioglycolate TS, and
to the other flask add 1 mL of edetate disodium TS. To each flask add 5 mL of
eriochrome cyanine TS and 5 mL of acetate buffer TS, and add water to volume.
Immediately determine the absorbance of the solution containing sodium
thioglycolate TS at the wavelength of maximum absorbance at about 535 nm,
with a suitable spectrophotometer, using the solution containing the edetate
disodium TS as a blank. Repeat the procedure using two 1.0-mL aliquots of
Injection. Calculate the quantity, in g per mL, of aluminum in the Injection
taken by the formula: 20(TU / TS)
in which TU and TS are the absorbances of the solution from the Injection and
the solution containing the aluminum standard, respectively. The concentration
of aluminum ion in the Injection is not greater than 10 g per mL.
Chemical Purity
Aluminum
ALUMINUM STANDARD SOLUTIONDissolve 35.17 mg, accurately weighed, of
aluminum potassium sulfate dodecahydrate in water to make 1000.0 mL. Each
mL of this solution contains 2 g of Al.
PROCEDUREPipet 10 mL of Aluminum standard solution into each of two 50-mL
volumetric flasks. To each flask add 3 drops of methyl orange TS and 2 drops
of 6 N ammonium hydroxide, then add 0.5 N hydrochloric acid, dropwise, until
the solution turns red. To one flask add 25 mL of sodium thioglycolate TS, and
to the other flask add 1 mL of edetate disodium TS. To each flask add 5 mL of
eriochrome cyanine TS and 5 mL of acetate buffer TS, and add water to volume.
Immediately determine the absorbance of the solution containing sodium
thioglycolate TS at the wavelength of maximum absorbance at about 535 nm,
with a suitable spectrophotometer, using the solution containing the edetate
disodium TS as a blank. Repeat the procedure using two 1.0-mL aliquots of
Injection. Calculate the quantity, in g per mL, of aluminum in the Injection
taken by the formula: 20(TU / TS)
in which TU and TS are the absorbances of the solution from the Injection and
the solution containing the aluminum standard, respectively. The concentration
of aluminum ion in the Injection is not greater than 10 g per mL.
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Sodium Pertechnetate Tc 99m Injection
Sodium Pertechnetate Tc 99m Injection
Chemical Purity
Aluminum
Chemical Purity
Aluminum
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Technetium Tc 99m Sestamibi Injection
Technetium Tc 99m Sestamibi Injection
Radiochemical Purity
Constitute each of 4 vials with 1 mL
(1875 187.5 MBq, or 50 5 mCi) of
Sodium Pertechnetate Tc 99m
Injection.
Radiochemical Purity
Constitute each of 4 vials with 1 mL
(1875 187.5 MBq, or 50 5 mCi) of
Sodium Pertechnetate Tc 99m
Injection.
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USP General Notices
USP General Notices
Confusion of compendial standards
with release tests and with statistical
sampling plans occasionally occurs.
Compendial standards apply at any
time in the life of the article from
production to consumption.
Confusion of compendial standards
with release tests and with statistical
sampling plans occasionally occurs.
Compendial standards apply at any
time in the life of the article from
production to consumption.
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USP General Notices
USP General Notices
Tests and assays in this Pharmacopeia
prescribe operation on a single
specimen, that is, the singlet
determination, which is the minimum
sample on which the attributes of a
compendial article should be
measured.
Tests and assays in this Pharmacopeia
prescribe operation on a single
specimen, that is, the singlet
determination, which is the minimum
sample on which the attributes of a
compendial article should be
measured.
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USP General Notices
USP General Notices
Some tests require multiple dosage
units are in fact the singlet
determinations of those particular
attributes of the specimen.
Some tests require multiple dosage
units are in fact the singlet
determinations of those particular
attributes of the specimen.
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Deficiencies of USP Monographs
Deficiencies of USP Monographs
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Apparatus
Apparatus
High-Pressure Liquid Chromatography
(HPLC)
Packing L1 column?
High-Pressure Liquid Chromatography
(HPLC)
Packing L1 column?
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Technetium Tc 99m Albumin Aggregated Injection
Technetium Tc 99m Albumin Aggregated Injection
Radiochemical Purity
Place a measured volume of Injection,
appropriately diluted, such that it provides a
count rate of about 20,000 counts per minute,
about 25 mm from one end of a 25- 300-mm
strip of chromatographic paper (see
Chromatography 621 ), and allow to dry.
Develop the chromatogram over a period of
about 3 to 4 hours by ascending
chromatography, using dilute methanol (7 in 10),
and air-dry.
Radiochemical Purity
Place a measured volume of Injection,
appropriately diluted, such that it provides a
count rate of about 20,000 counts per minute,
about 25 mm from one end of a 25- 300-mm
strip of chromatographic paper (see
Chromatography 621 ), and allow to dry.
Develop the chromatogram over a period of
about 3 to 4 hours by ascending
chromatography, using dilute methanol (7 in 10),
and air-dry.
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permission of author.
Biological/Physiological Distribution
Biological/Physiological Distribution
A physiological distribution conforming
to the requirements will assure
appropriate distribution of the
radioactive compounds to the intended
biological target in humans and limits
its distribution to non-target areas.
A physiological distribution conforming
to the requirements will assure
appropriate distribution of the
radioactive compounds to the intended
biological target in humans and limits
its distribution to non-target areas.
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Biological Distribution
Biological Distribution
20 USP monographs
17 monographs for radioactive drugs
(85%)
3 monographs for non-radioactive
drugs
20 USP monographs
17 monographs for radioactive drugs
(85%)
3 monographs for non-radioactive
drugs
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permission of author.
Biological Distribution
Biological Distribution
16
99m
Tc-labeled drug monographs
Technetium Tc 99m Albumin Aggregated
Injection
Technetium Tc 99m Disofenin Injection
Technetium Tc 99m Exametazime Injection
Technetium Tc 99m Mebrofenin Injection
Technetium Tc 99m Medronate Injection
Technetium Tc 99m Oxidronate Injection
Technetium Tc 99m Sulfur Colloid Injection
16
99m
Tc-labeled drug monographs
Technetium Tc 99m Albumin Aggregated
Injection
Technetium Tc 99m Disofenin Injection
Technetium Tc 99m Exametazime Injection
Technetium Tc 99m Mebrofenin Injection
Technetium Tc 99m Medronate Injection
Technetium Tc 99m Oxidronate Injection
Technetium Tc 99m Sulfur Colloid Injection
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Biological Distribution
Biological Distribution
16
99m
Tc-labeled drug monographs (cont)
Technetium Tc 99m Pentetate Injection
Technetium Tc 99m Pyrophosphate Injection
Technetium Tc 99m Succimer Injection
Technetium Tc 99m Sulfur Colloid Injection
16
99m
Tc-labeled drug monographs (cont)
Technetium Tc 99m Pentetate Injection
Technetium Tc 99m Pyrophosphate Injection
Technetium Tc 99m Succimer Injection
Technetium Tc 99m Sulfur Colloid Injection
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Biological Distribution
Biological Distribution
1 non
99m
Tc-labeled drug monograph
Iodohippurate Sodium I 123 Injection
1 non
99m
Tc-labeled drug monograph
Iodohippurate Sodium I 123 Injection
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Biological/Physiological Distribution
Biological/Physiological Distribution
Why is not required for each
monograph of radiopharmaceutical?
Why is not required for each
monograph of radiopharmaceutical?
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Appearance
Appearance
68 monographs
68 monographs
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permission of author.
Appearance
Appearance
Technetium Tc 99m Red Blood Cells Injection
Clarity and color of solution
Observe the appearance and color of the
supernatant diluted plasma obtained in
the Radiochemical purity test procedure.
The diluted plasma is clear and has a
colorless to a very slight pink or yellow
appearance. Samples that produce a
distinctive red coloration are not
acceptable for administration.
Technetium Tc 99m Red Blood Cells Injection
Clarity and color of solution
Observe the appearance and color of the
supernatant diluted plasma obtained in
the Radiochemical purity test procedure.
The diluted plasma is clear and has a
colorless to a very slight pink or yellow
appearance. Samples that produce a
distinctive red coloration are not
acceptable for administration.
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Appearance
Appearance
Chromic Phosphate P 32 Injection
Chromic Phosphate P 32 Injection
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Appearance
Appearance
<797>
Direct visual inspection of
radiopharmaceutical CSPs containing high
concentrations of doses of radioactivity
shall be conducted in accordance with
ALRA.
Leaded glass
<797>
Direct visual inspection of
radiopharmaceutical CSPs containing high
concentrations of doses of radioactivity
shall be conducted in accordance with
ALRA.
Leaded glass
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Technetium Tc 99m Tetrofosmin Injection
Technetium Tc 99m Tetrofosmin Injection
pH
8.3-9.1 (USP monograph)
7.5-9.0 (package insert)
pH
8.3-9.1 (USP monograph)
7.5-9.0 (package insert)
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USP General Notices
USP General Notices
Every compandiel article in commerce
shall be so constituted that when
examined in accordance with these
assay and test procedures, it meets all
the requirements in the monograph
defining it.
Every compandiel article in commerce
shall be so constituted that when
examined in accordance with these
assay and test procedures, it meets all
the requirements in the monograph
defining it.
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USP General Notices
USP General Notices
On the basis of such assurances
[process validation studies & in-
process controls], the analytical
procedures in the monograph may be
omitted.
On the basis of such assurances
[process validation studies & in-
process controls], the analytical
procedures in the monograph may be
omitted.
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permission of author.
General Chapter
General Chapter
<1165> Radiopharmaceutical Quality
Control Assurance and Compounding
Process validation data
Frequency of testing
In-process testing
Timing of QC test completion
<1165> Radiopharmaceutical Quality
Control Assurance and Compounding
Process validation data
Frequency of testing
In-process testing
Timing of QC test completion
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