Transcript Intro to GMP - Nuclear Sciences and Applications

FDG and its intended regulation
by FDA in the USA: Points to
Ponder
Pradeep K. Garg, Ph.D.
Director, PET Center
Wake Forest University Health Sciences
Winston Salem, NC; USA
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PET Center
Three major domains:
 Radiopharmaceutical area: Chemist
 Imaging and data acquisition:
Technologist
 Reading scans and reporting: Physician
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Radiopharmaceuticals
Among several choices:
FDG is widely accepted and dominates the
market share
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FDG regulations
In US:

Expectation is to be compliant with
cGMP
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FDA requiring CMC
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FDA differentiates between small and
large manufacturers
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cGMP
current Good Manufacturing Practices
Broad coverage, covers four major areas

Safety

Purity
Strength
Quality
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CMC: The full form
Chemistry, Manufacturing, and Controls
Section
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CMC
CMC covers following points:
A. Drug product component and quantitative
composition
B. Controls for components/raw materials
C. Reference standards
D. Manufacturing and testing facilities
E. Manufacture of drug substance
F.
Manufacture of drug product
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CMC (contn..)
G.
H.
I.
J.
K.
L.
Containers/closures
Controls for the finished dosage form
Analytical test procedures
Microbial Validation
Stability and Batch Records
Vials and outer packaging labels
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A. Drug product component and
quantitative composition
Drug substance:
1.
i.
ii.
iii.
Name/description: 2-Deoxy-2[18F]fluoro Dglucose, FDG.
Composition/mL: 10-20mCi at 9:30AM (EOS)
Composition/batch: 100-250mCi at 9:30AM (ESO)
Other ingredients:
2.
i.
ii.
iii.
Name/description: Sodium chloride injection,
USP
Composition/mL: 1 mL
Composition/batch: 10-12 mL
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B. Controls for components /
raw materials
1.
2.
3.
4.
Organic substrates:
Target material (radioactive fluoride)
Other ingredients
Reagent
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B.Controls for components and
raw materials (contn)
1.
Organic substrates:
i.
Component name: 1,3,4,6-Tetrafluoro
methanesulfonyl-D-mannopyranose (triflate)
ii. Supplier: Name and address
iii. Is this further purified: yes/no, if yes, how?
iv. Acceptance specs: Tests and criteria
i.
Appearance, Identity (nmr, ir), Purity (mp hplc).
v. COA
vi. Identity test: test procedure and criteria in SOP
vii. Storage condition: refrigerator, room temp, dry
glove box,..
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B.Controls for components and
raw materials (contn)
2.
Target Material (O-18 water):
i.
ii.
iii.
iv.
v.
vi.
Name of Material
Manufacturer/supplier
Specifications
Identity test to release lot: as attachment
COA
Recycled: yes/no, if yes:
i. Procedure as attachment
ii. Acceptance specs
vii. *If F-18 purchased: supply all this info on it
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B. Controls for components
and raw materials (contn)
Reagent, solvents, gases, columns, and
other auxiliary
3.
Name
ii. Supplier
iii. Grade, quality, COA, and acceptance
criteria
The above info is needed for all materials used
in the manufacturing
i.
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B. Controls for components
and raw materials (contn)
Other ingredients (may not apply)
4.
i.
ii.
iii.
iv.
Name
Purpose
Manufacturer
Specifications
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C. Reference standards
Items:

2-Fluoro-2deoxy-D-glucose

2-Chloro-2deoxy-D-glucose
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Kryptofix 222
On each of these items, supply:
i.
ii.
iii.
Name of these standards
Suppliers info
Specifications, COA, acceptance criteria
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D. Manufacturing and testing
facilities
1.
2.
3.
Name of PET facility and address
Contact person name
Contact person phone number
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E. Manufacture of drug
substance
Batch formula: Name, function, and
quantities of each component
1.
i.
ii.
Triflate; used as a precursor, 10 mg
F-18 fluoride, radioisotope, 100-2000mCi
Radionuclide production
2.

F-18 produced at site? Yes/no ; if yes:
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Cyclotron
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make and model, operating parameters, specifications on
target body (volume, material, windows info, acceptance
criteria on windows and body…)
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E. Manufacture of drug
substance (contn)
3.
Synthesis and purification of drug
i.
Synthesis and purification equipment

Description of equipment, its components, acceptance
criteria, flow diagram: an attachment

Synth and purifi. Unit: make and model
ii. Synthesis and purification operation
Step wise description, amount of reagents, solvents,
acceptable yields: an attachment
iii. In process control
Number of azeotropic evaps, temp for heating precursor,
delivery rates, pressure for air and gases, hydrolysis
temp, time for each steps, etc: a master production and
control record section
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E. Manufacture of drug
substance (contn)
Post synthesis procedures:
4.
ii.
Set up of synthesis units, cartridges
Cleaning and purging procedures
iii.
Provided as an attachment
i.
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F. Manufacture of drug
products
Production operation
1.
General procedures provided as an attachment
Master production and traceable control records
provided as an attachment
Reprocessing of drug product
2.
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Yes/no, if yes, circumstances (Attachment)
Packaging and labeling
3.

Detail descriptions as an attachment
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G. Containers and closures
Using USP Type 1 glass, grey butyl
stopper, and aluminum crimp seal
1.
i.
ii.
iii.
Manufacturer name and address
Catalog number and description
DMF # (attachment #)
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H. Controls for finished dosage
1.
Sampling procedure

Produced as multidose or aliquot in
multiple vials

If multi-vials, sampling procedure to assure
unbiased representation
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H. Controls for finished dosage
(contn)
2.
Regulatory specs, procedures and
testing schedules

Provide:

Test, acceptance criteria, procedure, and test
schedule
Each batch should meet these criteria during
entire shelf life
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H. Controls for finished dosage
(contn)
Regulatory specs (itemized)
1. Appearance
2. Radionuclide identity
3. Radiochemical identity
4. Radionuclide purity
5. Radiochemical purity
6. Radiochemical impurities
7. Assay (concentration)
8. Specific activity
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H. Controls for finished dosage
(contn)
9.
10.
11.
12.
13.
14.
15.
pH
K222 concentration
Residue solvents
Chloro-deoxy glucose
Membrane filter integrity
Bacterial endotoxins
Sterility
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I. Description of Analytical test
procedures
For each (major) tests described,
provide:
1.

Test, STP #, Attachment #, Page number
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J. Microbial validation
Includes procedures that ensure sterility
1.
i.
ii.
iii.
iv.
v.
vi.
vii.
In manufacturing facility
Synthesis box and its components
Facility environmental controls
Clean room
Aseptic techniques
Final filtration
Finished product microbial testing
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K. Stability and batch data
1.
2.
3.
Expiration dating period
Stability data (a curve)
Post approval commitment

Annually, minimally one batch tested for
the following tests

List these tests
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L. Vials and outer label

Copies of proposed vial description and
outer packaging and label

As an attachment
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PET Center
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Scanner
Cyclotron
Chemistry Laboratories
Radiopharmacy
Offices
Personnel
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Scanner
Several options, but does not necessarily
affects our task at hand:
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CTI-Siemens HR+
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GE Advance
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CTI CT/PET
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GE CT/PET
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Philips PET and CT/PET
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Cyclotron
Is an important factor in preparing
this document
Several to choose from:
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CTI RDS 111; 11 MeV
GE 10MeV or 18.5 MeV
IBA (various)
Others…
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Medical Cyclotron
Are deutrons as common and important?
• Acceleration Capability
• Particle
• + v/s –ve ions
• Single particle (Protons) v/s dual particles
(proton & deuteron)
• Energy
• Nuclear Reaction
• Target Material and Design
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Isotope Production
Issues may not be pertinent to FDG book,
but would impact on what document we
prepare
 Small Medical Cyclotron (<15 MeV)
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C-11
N-13
O-15
F-18
 Large Cyclotron (>15 MeV)
 Br-75, Br-76
 Ga-68
 I-122
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Cyclotron Target Yields
These factors would influence the details
for the document
 Dependent on:
1. Nuclear Reaction
2. Target Design
Physical (silver, tantalum, HP, LP, HV)
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Radiochemistry Laboratories
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Hot Cells
Fume Hoods
Laminar flow Hood
HPLC
GC
Synthesis Modules
Dose drawing station
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Other Issues
We may want to emphasize on radiation
safety factor as guidance (FDA does not
cover it)
 Radiation Exposure from 1 mCi unshielded
 General Nuclear Medicine clinic
 0.02 – 0.22 mR/h at 1 meter
 PET clinic
 0.58 mR/h at 1 meter (5.8 R/h at 1 cm)
 Patient handling
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