TABLE OF

CONTENTS
Cyclotron Quality Control
1. Particle accelerator 29. Radionuclide Identification
2. Main Parts 32. pH
4. KFSH&RC Cyclotrons 33. Radiochemical Purity
5. Our Isotopes 34. Osmolality
6. Safety system 34. Packaging Inspection
35. Enviromental Monitoring
Radiochemistry 36. Raw materials testing
7. Hot Lab
8. Bulk Processing Quality Assurance
10. Calculation & formulation 37. Final Approval of Radio-
pharmaceuticals
38. Raw materials control
Radiopharmacy 39. Control of Documents
11. GMP
39. Incident reporting
13. Aseptic Technique & Gowning
40. Audits
16. Depyrogenation & Sterlization
40. Customer Satisfation
18. Packaging
41. Mangement Reveiw
19. Raw Materials

PET Research & Development

21. Introduction 42. Development of Radiotracers
23. PET Radioisotopes 45. Common Equipment
25. Manufaturing
27. Theraputic Radiotracers
28. Packaging
 1. CYCLOTRON SECTION
1.1. Introduction to Particle Accelerators:
A radioactive substance can be formed by bombarding a
stable substance with charged particles in a linear or circu-
lar type accelerator. The tools most frequently used are cir-
cular accelerators, also called cyclotrons. But whatever the
technology used, the same type of radionuclide is formed
by the bombardment of an identical target with the same
type of charged particles.

The cyclotron is one of the earliest types of particle vac-

celerators and is still used as the first stage of some large
multi-stage particle accelerators. Lawrence and M.S Living-
ston invented the cyclotron in 1930.

1
CYCLOTRON SECTION
1.2. Main parts of the Cyclotron:

Vacuum: Particles can only be accelerated inside a

relatively high vacuum & ultra-high vacuum.

Ion source:
Produces ionized particles (protons) for accelera-
tion.
These can be of a negative charge, similar to
what we have in C-30 & RDS-111, or they can be of
a positive charge like the CS-30 cyclotron.

Acceleration force (RF):

Alternating Radio Frequency (RF) is used to pull/
push ions to higher velocities within a magnetic
field that contains the ions.

2
CYCLOTRON SECTION
Main coil:
The magnetic field forces the particles to travel in a
spiral path.

Thus, in a cyclotron, charged particles of low mass,

such as protons, are accelerated in a circular trajec-
tory until they reach high energy. These particles are
used to bombard a specific target which may be solid,
liquid, or gaseous, transforming it into radioactive
material. Unlike a reactor, a cyclotron is ideal when the
radioisotope formed is an element different from the
cold isotope serving as the target.

Thus Fluorine 18, a positron emitter, is formed from

Oxygen 18, a stable isotope available in the form of
a water molecule, in liquid form, and Iodine 123, a y
emitter, is produced from Xenon 124, a stable gaseous
isotope. At the end of the process, the radioactive el-
ement can easily be separated from the cold element
that served as a target.
In a cyclotron, the particles are accelerated in a circu-
lar electromagnetic field under a high vacuum.

When these particles reach a suitable speed, the

beam is directed outside the field onto the target to
be irradiated. The operation hardly lasts a few hours.
The irradiated target is extracted from the cyclotron
to be treated by radiochemists in such a way as to
separate the radioactive elements from the residual
cold matter. Products obtained via a cyclotron have
extremely high specific activity. The products are vir-
tually pure, but the quantity of material available can
be counted in millionths of a milligram.

3
CYCLOTRON SECTION
 1.3. Cylotrons in KFSHRC :

TCC CS-30 IBA C-30 RDS-111

Acceleration
Positive Negative Negative
type

Proton ( H+) Proton( H-) Proton ( H -)

Particle
Deuteron
H-3
H-4
(27 MeV Proton) 15 to 30MeV 11 MeV
Energy (15 MeV Deuteron)
(35 MeV H-3)
(15 H-4)
Solid Solid -
Targets Liquid Liquid Liquid
Gas Gas Gas
Reaction Internal/External External External
Current 100 µA 250 µA Single/Dual 60 µA Single/Dual
Protection Wall-Shiela d Wall-shield Self-shielded
Running mode Manual mode Auto/manual-mode Auto/manual-mode
installed 1981 2010 2006

4
CYCLOTRON SECTION
1.4. Isotopes Produced By Cyclotrons at C&RD:

5
CYCLOTRON SECTION
1.5. SAFETY SYSTEMS OF THE CYCLOTRONS FACILITY:

In addition to the self-safety system which op-

erates the PLC technology included in each cy-
clotron, the facility is equipped with a radiation
monitoring system that can
detect the radiation levels inside the rooms or
corridors.

Safety first:

ALARA (As Low As Reasonably Achievable) is a

safety principle designed to minimize radiation
doses and releases of radioactive materials. More
than merely best practice, ALARA is predicated
on legal dose limits for regulatory compliance.

Following the safety guidelines by wearing the

TLD, lab coat, shoe & head cover will ensure your
safety.

6
CYCLOTRON SECTION
2. RADIOCHEMISTRY SECTION

2.1. Summary of Hot Cells Laboratory:

2.1.1. Hotcells:

Hot cell components:

• Hot cell unit.
• Manipulators.
• Liquids hot waste drain.
• Air filtration & circulation.
• Lead glass window.
• Conveyor belt.
• Dose calibrator and balance.
• Target sending & receiving
unit.
• Glassware transfer unit.
• Cell control panel.
Hot waste disposal:
• Liquid hot waste.
• Solid hot waste.
• Used copper targets.

Fume hood cabinet.

Chemicals storage.

7
RADIOCHEMISTRY SECTION
2.1.2. Recovery & electroplating laboratory:

Recovery: Collect the enriched target material

from several used targets to be reused in the next
electroplating. Electroplating process: depositing
the enriched material on the copper plate using
an electrolytic cell.

• Recovery process.
• Electroplating solution preparation.
• Electroplating unit.
2.1.3. Iodine-123 concentration unit.
Components and procedures.

2.2. Radiochemical Bulk Processing:

8
RADIOCHEMISTRY SECTION
Production and Processing of New Isotopes fol-
lowed by chemical separation steps of the new
isotope from target enriched material.

1- Thallus chloride (201Tl Cl): (t1/2

=73.05hrs;E=167KeV)
Tl-203(P,3N), Pb-201 Tl-201

2- Gallium citrate C6H567GaO7: (t1/2 =78.2 hrs. ;

E=300.2KeV)
Zn68(P,2N), Ga-67

3- Rubidium chloride 81RbCl: (t1/2 =4.28 hrs. ;

E=191KeV)
Kr81 (p,N)Rb-81 Kr81m(t1/2 =13.1 seconds)

4- Sodium iodide-123 NaI-123: (t1/2 =13.2 hrs. ;

E=159KeV)

I- Gas target(Xe-124): Xe-124(P ,Pn)Xe-123

I-123
II- Solid target (Te-124): Te-124(P, 2N) I-123

9
RADIOCHEMISTRY SECTION
2.3. Calculations & Formulation:

- Activity @ calibration:
A=A.e- t
=0.693/(t 1/2)
- Yield :
Activity @EOB
yield=
Dose

- Time of electroplating:
Faradays Constant x Wt(mg) x n(Valence state)
plating time(h)= Atomic.Wt x Current(Amp) x 60 x 60

At.Wt x Current (Amp) x Plating time x 60 x 60

Wt(mg)= n(Valence state) x Faradays Constant

- Efficiency of electroplating:

Amount of deposit x 100

Current efficiency= Theoretical amount

10
RADIOCHEMISTRY SECTION
3. RADIOPHARMACY SECTION:
3.1. Good Manufacturing Practices: standards and requirements.
3.1.1. Definition:
The GMP regulations establish minimum stan-
dards for the manufacturing of medicinal prod-
ucts to assist in preventing adulteration. Patients
expect that each batch of medicines they take
will meet quality standards so that they will be
safe and effective.
GMPs provide systems that assure proper design,
monitoring, and control of manufacturing pro-
cesses and facilities. Adherence to the GMP reg-
ulations assures the identity, activity, quality, and
purity of radiopharmaceutical products.
3.1.2. Importance:
• Government requirement
• Ensures product Quality as a result of compre-
hensive “Quality by Design” concept
• Reduces rejects and recalls
• Maintain manufacturing consistency
• Satisfied customers
• Entity image and reputation
Radiopharmaceuticals must be manufactured under conditions
and practices required by the GMP regulations to assure that
quality is built into the design and manufacturing process at every
step.

11
RADIOPHARMACY SECTION
3.1.3. Ten principles of GMP lifestyle:
Those are ten good manufacturing principles that
we believe will help in achieving a “GMP lifestyle”
in our Cyclotron department.
1. Writing step-by-step procedures and work instruc-
tions.
2. Carefully following written procedures and instruc-
tions to prevent contamination, mix-up, and errors.
3. Accurately document work using Document Man-
agement System
4. Validating our work by following a Master Valida-
tion Plan.
5. Integrating productivity, product quality, and em-
ployee safety into the design and construction of our
facility and equipment.
6. Properly maintaining our facilities and equipment.
7. Clearly defining and demonstrating job confidence.
8. Protecting our products against contamination, by
making cleanliness and hygiene daily
9. Building quality into our products by systematically
controlling our components and product-related pro-
cesses, such as manufacturing, packaging, labeling,
testing, distribution, and marketing.
10. Conducting planned and periodic audits for com-
pliance and performance using the Audit Management
System.

12
RADIOPHARMACY SECTION
3.2. Aseptic Technique, including gowning
The aseptic technique means using practices and
procedures to prevent contamination from patho-
gens. Sterile compounding involves the dilution,
mixing, and dispensing of various products using
an aseptic technique. Failure to follow the proto-
col of the aseptic technique may lead to micro-
bial contamination of the radiopharmaceutical
product.
3.2.1. Aseptic garbing, Hand washing, and gloving:
1. Washing forearms and hands using an appropri-
ate antimicrobial agent.
2. Personnel may cleanse their hands or gloves
with sterile 70% isopropyl Alcohol (IPA).
3. A sterile gown and a pair of sterile gloves.
4. They should wear close-toed shoes because of
the potential of injury by needles or broken glass-
es. Also, they need to place disposable shoe cov-
ers over close-toed shoes.
5. Head covers and face mask.
Technicians must assess their physical appear-
ance for any violations. These violations are in-
cluding and are not limited to:
• Wearing cosmetics, hair spray, perfumes, artifi-
cial nails, or nail polishing
• Wearing jewelry including body piercing not
covered with a gown and mask
• Dirty and long fingernails and not closely
trimmed
• Presence of weeping sores, rash, sunburn, or
respiratory infection

13
RADIOPHARMACY SECTION
Personnel protective equipment (PPE) is used to
minimize the risk of contamination of a sterile com-
pounding area and the Compounded Sterile Prepara-
tion (CSP)s. Cleaning the hood bench, preparation of
dispensing machine and vials labeling should follow
the precautions of aseptic technique.
3.3. Radiopharmaceutical calculations.
In the process of radioactivity, an unstable isotope
changes until a stable state is reached, and in the
transformation, it emits energy in the form of radi-
ation. Individual radioisotopes differ in the rate of
radioactive decay, but in each case, a definite time is
required for half of the original atoms to decay. This
time is called the half-life of the radioisotopes. Each
radioisotope, then, has a distinct half-life.

The rate of decay is always a constant fraction of

the total number of undecomposed atoms present.
Mathematically, the rate of disintegration may be ex-
pressed as follows:

Where N is the number of undecomposed atoms at

time t, and is the decay constant or the fraction
disintegrating per unit of time. The constant may be
expressed in any unit of time (reciprocal sec, min, or
hours)
The exponential decay law

14
RADIOPHARMACY SECTION
In which N is the number of atoms remaining at
elapsed time t, N0 is the number of atoms orig-
inally present (when t=0), is the decay constant
for the unit of time in terms of which the interval
t is expressed, and e is the base of the natural
logarithm 2.71828

Units of radioactivity
The quantity of radioisotope activity is expressed
in absolute units, (total number of atoms disinte-
grating per unit time). The basic unit is the curie
(Ci), the quantity of a radioisotope in which 3.7 X
1010 (37 billion) atoms disintegrate per second.
Also, millicurie (mCi) 10-3 Ci, microcurie (µCi)
10-6 Ci, and nanocurie or millimicrocurie (nCi)
10-9 Ci.
The international system (SI) unit for radioactivity
is the becquerel (Bq), defined as 1 disintegration
per second. Because (Bq) is so small, it is more
convenient to use multiples of the unit such as Ki-
lobecquerel (kBq) 103 Bq, mega becquerel (MBq)
106 Bq, and gigabecquerel (GBq) 109Bq
1 Ci = 3.7 X 1010 Bq = 3.7 X 104 MBq
1 Bq = 2.7 X 10-11Ci
1 MBq = 2.7 X 10-5 Ci = 2.7 X 10-2 mCi = 0.027
mCi = 27 mCi

Example: A thallous chloride Tl 201 injection has a

labeled activity of 550 microcurie (mCi). Express
this activity in terms of mega becquerels.

550 uCi = 0.55 mCi

1 mCi 37 MBq
0.55 mCi MBq X = 20.35 MBq

15
RADIOPHARMACY SECTION
Example: The disintegration constant of a radio-
isotope is 0.02496 day-1. Calculate the half-life of
the radioisotope.

= 0.693/0.02496 day-1= 27.76 or 27.8

days
For example, the half-life of 198Au is 2.7 days.
Calculate the disintegration constant.
2.7 days = 0.693/
= 0.693/2.7 = 0.2567 day-1
3.4. Cleaning and disinfection of work areas
Bacterial and fungal spores are one of the most
pervasive and resilient microorganisms on earth.
By definition, a sterile environment is 100% free
of all microorganisms, including spores. Disin-
fection methods may slow, disrupt or hinder the
proliferation of microorganisms; however, disin-
fection is not considered sporicidal.
Sterilization describes a process that destroys or
eliminates all forms of microbial life and is carried
out in healthcare facilities by physical or chemi-
cal methods. Steam under pressure, dry heat, EtO
gas, hydrogen peroxide gas plasma, and liquid
chemicals are the principal sterilizing agents used
in healthcare facilities. When chemicals are used
to destroy all forms of microbiologic life, they can
be called chemical sterilants. These same germi-
cides used for shorter exposure periods also can
be part of the disinfection process (i.e., high-level
disinfection).
Disinfection describes a process that eliminates
many or all pathogenic microorganisms, except
bacterial spores, on inanimate objects.
16
RADIOPHARMACY SECTION
3.5. Depyrogenation and Steam Sterilization

3.5.1. Steam Sterilization

Autoclaving with Steam is the method of choice for most

applications. The presence of moisture with heat denatures
proteinaceous materials. Saturated steam enters the cham-
ber, condenses on the product, and imparts latent heat en-
ergy to the product. As temperature/pressure is increased,
the time required to kill is significantly reduced.

3.5.2. Depyrogenation

Heat is produced by electrical heating coils. Introduced

into the chamber at atmospheric pressure. Fans circulate
the heated air. The process consists of heat up, exposure,
and cool down. The temperature in the chamber is raised to
approximately 300F (150C). Dry heat is not as efficient as
steam. The mode of kill is an oxidation process rather than
coagulation. It is the preferred method for depyrogenation
of glassware in the pharma industry

17
RADIOPHARMACY SECTION
3.6. Assay measurement using dose calibrators.

An ionization chamber is an instrument constructed to

measure the number of ions within a medium.
Ionization chambers are used in nuclear medicine to deter-
mine the exact activity of radioactive doses administered to
patients. Such devices are called ‘radioisotope dose calibra-
tors’.

Measurements are carried out utilizing the interaction be-

tween radiation and substances. Geiger Muller (GM) count-
er survey meters and ionization chambers utilize the ioniza-
tion between radiation and gas atoms. NaI (Tl) scintillation
survey meters utilize excitation with substances.

It is essential to perform the following test procedures

correctly since patient safety is highly dependent upon the
reliability of this instrument.

18
RADIOPHARMACY SECTION
Test Required Frequency

Accuracy At installation, then weekly thereafter

Constancy At installation, then daily thereafter
Linearity At installation, then annually thereafter
Geometry At installation; after repair or moving the instrument

3.7. Packaging of radiopharmaceutical products.

3.7.1. Primary Packaging Materials.

Borosilicate Glass: Glass has good radiation-resistant prop-

erties, although often radiation will cause discoloration.
Forms of glass, such as lead glass, are used heavily in the
radioactive products manufacturing industry (it is the yel-
low-colored glass windows on hot cells. Glass can usually
tolerate KGy of absorbed dose.

Halobutyl rubber: Commonly rubber stoppers on sterile

products are made from halo (chloro or bromo) butyl rub-
ber. Published data and my own experience show 25 KGy
is acceptable but 50 KGy and the material shows signs of a
breakdown in physical properties.

3.7.2. Secondary Packaging Materials

The secondary packaging for Radiopharmaceuticals and

radioactive medical devices is always the shielding. They
must be approved by International Atomic Energy Agency
(IAEA) standards. Read about Type A package require-
ments for more information. All radioactive products are
class VII dangerous goods.

19
RADIOPHARMACY SECTION
3.8. Raw materials preparation and management.
The pharmaceutical industry needs utmost care and preci-
sion in each aspect of the field ranging from collecting the
raw materials to getting the final product ready for supply
in the market.

3.8.1. Radiopharmaceuticals production chain

The raw materials used in the pharmaceutical industry are

categorized into 3 major types. They are:

- Raw Materials of Excipients

- Raw Materials of Radioisotopes
- Raw Materials for Packaging

The pharmaceutical raw materials used for excipients in-

clude solvents and other carriers which can carry the actual
drug. This excipient should not affect the chemical features
of the Radioisotope. Raw materials used for pharmaceutical
packaging include plastic & polymers, glass, paper, alumi-
num foil, and paper boards, etc.

3.8.2. What is inventory management?

Inventory management is the process of keeping track of

all the goods your company has in stock.

20
RADIOPHARMACY SECTION
Forms of inventory

Note: the first row is the same color and font as all other
rows.

Other items you need for the sake of the

Consumablest production work, such as PPEs, syringes or
plastics, etc.

Materials that can be used in the radio-

Raw materials pharmaceutical formula, such as copper
and components sulfate, ammonium sulphate, sodium thio-
sulfate, and mIBG, etc.

Work-in-progress Items in the process of becoming finished

products, such as the silica columns used
stock as part of Tc-99m generators

Finished goods Products that are completed and ready to

be sold, such as 5.0 mCi TI-201 Inj. vial.

21
RADIOPHARMACY SECTION
 4. PET SECTION:

A PET Radiopharmaceutical (also known as PET Radio-

tracer) is a positron-emitting radiopharmaceutical used in
positron emission tomography. Each radiotracer consists of
a positron-emitting isotope (radioactive tag) bound to an
organic ligand (targeting agent). The ligand component of
each radiotracer interacts with a target, resulting in a char-
acteristic distribution of the tracer throughout the tissues.

Positron-emitting isotopes are short-lived. Four posi-

tron-emitting radioisotopes are considered biological trac-
ers: Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18. 11C
(t1/2 20.4 min), 15O (t1/2 2.1 min), and 13N (t1/2 10 min) are
referred to as the essentials of life. Fluorine-18 (110 minutes
half-life) is the most widely used. Other positron emitters
include Gallium-68, Iodine-124, and Copper-64.

22
PET SECTION
4.1. Introduction to Positron Emission Tomography
(PET).
PET is a noninvasive diagnostic technique that provides
images of the distribution of radiopharmaceuticals labeled
with positron-emitting radionuclides inside the body, there-
by making it possible to visualize different physiological or
physiopathological processes in vivo.

Positron emitters decay by emitting a positively charged

electron (the positron B+) which travels a short distance
before encountering an electron the two particles annihilate
to produce two 511-keV gamma rays which are emitted at
180° to each other and these are detectable using a Posi-
tron Emission Tomography (PET) imaging camera. Modern
PET cameras are now coupled with CT to give accurate
anatomical details, as well as enable the identification of
tumors even smaller than 1cm.

4.2. Production of PET Radioisotopes

PET radioisotopes are produced in cyclotrons. A cyclotron

is a particle accelerator. It is an electrically powered ma-
chine that produces charged particles in an ion chamber in
the center of the machine. These particles are focused onto
a ‘target’ or starting material and the bombardment causes
the production of the desired radioisotope. Below are the
principal nuclear reactions employed to produce various
PET isotopes:

23
PET SECTION
24
PET SECTION
4.2.1. Common PET Radioisotopes
The most suitable positron-emitting radionuclides for use in
PET studies are 11C, 13N, 15O, and 18F. The first three have
a short radioactive half-life, which limits their possibility
for use in centers located far from the isotope production
site. In contrast, 18F is more suitable for distribution since
it is more stable as a radioisotope. This feature has caused
labeling with 18F to be the most widely-used option in the
manufacture of radiopharmaceuticals labeled with posi-
tron-emitting radionuclides for PET.

Fluorine (18F)

The best radionuclide for clinical application in routine

diagnostic PET procedures is 18F. The 18F positron-emit-
ting energy is only 0.64 MeV – the lowest of all the positron
emitters used in PET. This implies lesser patient radiation
exposure and improved diagnostic image resolution. Fur-
thermore, 18F decay does not involve the emission of gam-
ma radiation that can interfere with photon detection or of
particles (Beta- or Alpha) that may constitute an increase
in the dose of radiation received by the patient. The radio-
active half-life of 18F (110 minutes) permits the transport
and distribution of 18F-labeled radiopharmaceuticals to sat-
ellite centers and hospitals distant from the production site.
This half-life makes it possible to complete complex syn-
theses and PET protocols with a duration of several hours,
thereby allowing pharmacokinetic studies and analyses of
metabolites.

25
PET SECTION
4.3. Manufacturing of PET Radiopharmaceuticals

PET Radiopharmaceuticals are manufactured according to

guidelines on ‘’Current Good manufacturing practices of
Radiopharmaceuticals’’. Sterile Disposable kits and phar-
maceutical-grade materials are used in PET radiopharma-
ceutical production. PET Radiopharmaceuticals are man-
ufactured in cleanrooms (Grade B and C) and dispensed
aseptically in (Grade A) cells or hoods. Manufacture of the
PET radiopharmaceuticals is generally automated because
of the high activities needed. Automated synthesizers
(Tracer lab Mx and Neptis, etc.) are used for manufacturing
various PET radiopharmaceuticals (FDG, FCH, and FDOPA,
etc.). Automated synthesizers provide highly reproducible
synthesis operation and compliance with cGMP.

26
PET SECTION
4.4. PET Radiopharmaceuticals manufactured at KFSHRC
PET radiotracers are a class of new Radiopharmaceuticals
with high target specificity and affinity. 18F-labeled PET
tracers have wide applications in major clinical areas (On-
cology, Neurology, Cardiology, etc.).

4.4.1. Fluorine [18F] labeled PET Radiotracers

Fluorine is the most electronegative element in the peri-

odic table. When bound to carbon, it forms the strongest
bonds in organic chemistry, and this makes fluorine substi-
tution attractive for the development of pharmaceuticals.
Fluorination (18F) is possible by electrophilic or nucleophilic
methods. Electrophilic Fluorine (Elemental F2) has disad-
vantages and limitations. Nucleophilic radio fluorination
is widely used for the manufacturing of PET radiotracers.
Manufacturing of PET radiotracers Fluorodeoxyglucose
[18F]-FDG, Fluorocholine [18F]FCH, and Fluoro-L-DOPA
[18F]-L-DOPA follows similar kinds of steps. Various 18F-la-
beled PET Radiotracers have been synthesized by radio
fluorination of various precursors using K18F/Kryptofix or
TBA (tetrabutylammonium) as the nucleophilic fluorinating
agent.

The synthesis of 18F-FDG takes place through nucleophil-

ic substitution (SN2-type reaction) with the 18F- ion on a
mannose-derived precursor, mannose triflate (1,3,4,6-tet-
ra-O-acetyl-2-O-trifluoromethanesulfonyl-b-D-mannopyra-
nose).

27
PET SECTION
4.4.2. Ammonia [13N-NH3]

The radioactive half-life of 13N is only 9.97 minutes, which

precludes its use in applications involving complex synthet-
ic processes. The incorporation of 13N into organic mole-
cules is not as direct as in the case of C or F and makes its
use for diagnostic purposes practically unviable. For this
reason, 13N-labeled radiopharmaceuticals are exclusively
limited to 13N-NH3.

4.5. Theranostic Radiotracers Manufactured at KFSH&RC

Theranostics is a combination of the terms therapeutics

and diagnostics. Theranostics is the term used to describe
the combination of using one radioactive drug to identify
(diagnose) and a second radioactive drug to deliver thera-
py to treat the main tumor and any metastatic tumors.

4.5.1. The diagnostic phase of theranostics

68
Ga-DOTATATE is a PET radioactive diagnostic drug that
targets Somatostatin receptors (SSTR2).68Ga-DOTATATE
is injected into a patient’s vein and travels throughout the
bloodstream to all organs and tissues of the body. If the pa-
tient has a neuroendocrine tumor with SSTR2 on the tumor
cell membranes, the 68Ga-DOTATATE will bind to the SSTR2
and the tumor will light up on a PET scan.

28
PET SECTION
4.5.2. The therapeutic phase of theranostics
Once neuroendocrine cancer is diagnosed using a 68Ga-DO-
TATATE PET scan, the 68Ga can be replaced with another
radionuclide, such as Lutetium-177 (177Lu) or Yttrium-90
(90Y), that can target and kill tumor cells that have SSTR2
on their membranes.

These theranostic drugs will enable doctors to personalize

treatment based on the very specific type of cancer and
the specific tumor cell membrane proteins that each pa-
tient may have.

4.6. Packaging and Transportation of PET

Radiopharmaceuticals
PET Radiopharmaceuticals (multi-dose vials) are labeled
and packaged in compliance with regulations. As part of
packaging regulations the inner container and outer shield-
ing are labeled with radiation symbol, Radiopharmaceutical
name, dosage units, and volumes at calibration time. All ra-
dioactive packages include radioactive l, ll, or lll labels with
Transport Index (T.I.) Number.

Radiation-safe packaging is an obvious requirement during

the transport of radioactive pharmaceuticals. Type A pack-
aging is an international regulation issued by the Interna-
tional Atomic Energy Agency (IAEA). Transportation of
radiopharmaceuticals or radioactive materials must strictly
comply with IAEA standards.

29
PET SECTION
 5. QC SECTION:
Quality Control (QC) is a procedure or set of procedures
intended to ensure that a manufactured product or per-
formed service adheres to a defined set of quality criteria
or meets the requirements of the client or customer.

5.1. Radionuclide Identification:

Shelf-life The shelf-life (expiry period) of a radiopharma-

ceutical preparation depends principally on the physical
half-life of the radioisotope, the radiochemical stability, and
the content of longer-lived Radionuclidic impurities in the
preparation under consideration. Many radiopharmaceutical
preparations contain radioisotopes with very short half-
lives and such preparations therefore have very short shelf-
lives. Such preparation requires an expiry date and time to
be indicated. For example, technetium-based preparations
and positron emission tomography (PET) preparations
are normally intended to be used within less than 12 hours
(some within minutes) of preparation.

30
QC SECTION
• At the end of the expiry period, the radioactivity will have
decreased to the extent where insufficient radioactivity
remains to serve the intended purpose or where the dose
of an active ingredient must be increased so much that
undesirable physiological responses occur. Furthermore,
chemical or radiation decomposition may have reduced
the radiochemical purity to an unacceptable extent. More-
over, the Radionuclidic impurity content may be such that
an unacceptable radiation dose would be delivered to the
patient.

• The shelf-life of a multi-dose radiopharmaceutical prepa-

ration, after aseptic withdrawal of the first dose, will also
depend on microbiological considerations. For radiophar-
maceutical preparations containing radioisotopes with
long half-lives, microbiological considerations may take
precedence over those based on the physical half-life of
the radioisotope. For example, once the first dose has been
aseptically withdrawn from a multi-dose container of an
iodine-containing injection, the container should be stored
at a temperature between 2 - 8 °C and the contents used
within 7 days.

5.2. Half-life Measurement:

• The activity must be sufficiently high to allow detection

during several estimated half-lives. This is measured using
an ionization chamber, a Geiger-Muller counter, and a scin-
tillation counter of a semiconductor detector.

31
QC SECTION
• Formula for half-life calculation is given below:

5.3. Radionuclidic Purity:

Radionuclidic purity is the ratio, expressed as a percentage

of the radioactivity of the desired radionuclide of the total
activity of the source. For Fluorine-18, the radionuclidic pu-
rity is expressed in terms of gamma emissions 511 and 1022
KeV as a percentage of total radioactivity.

32
QC SECTION
5.6. pH:

The pH test is one of the requirements for releasing radio-

pharmaceuticals as a final product. It might be measured
either with a pH meter or with pH paper.

pH specification for PET products is between 4.5-7; for

other radiopharmaceuticals as well, the pH range should be
within the physiological human body pH.

A pH meter may also be required for other purposes for

testing reagents and other raw materials.

5.7. Radiochemical Purity:

Radiochemical purity is the proportion of the total activity

of a specific radionuclide in a specific chemical or biolog-
ical form. Radiochemical purity is assessed by a variety
of analytical techniques such as liquid chromatography,
thin-layer chromatography, paper chromatography, and
electrophoresis. During or after separation, the distribu-
tion of radioactivity on the chromatogram is determined.
Different measuring techniques are used depending on the
nature of the radiation and the chromatographic technique.

33
QC SECTION
HPLC Method:
HPLC (High-Performance Liquid
Chromatography) can be used both
to measure radiochemical purity
in quality control testing as well as
for the assay of active components.
Moreover, HPLC is useful for valida-
tion studies and the development of
new products.

TLC Method:
TLC is used for both determining the radiochemical identity
and radiochemical purity of finished products. The radioac-
tivity scanner is used for quantitative measurement of the
radioactivity distribution corresponding to the individual
spots on TLC. The TLC plate can be developed in a glass jar
or a developing tank. The TLC scanner can be either a gas
proportional counter or a NaI detector mounted so that the
entire plate is scanned.
GC Method:

GC (Gas Chromatography) is utilized for

quantitation and identification of the resid-
ual solvents (ethanol, acetonitrile, and other
components) in various PET products. The
test is performed with a gas chromatograph
equipped with a flame ionization detector
(FID) and appropriate column (capillary or
packed column).
A computer with software to identify and
quantitate the residual solvents is a useful
feature and is generally supplied with the
equipment.

34
QC SECTION
5.8. Osmolality:

Osmolality is the measure of

solute concentration per unit
mass of solvent. Ideally, the
isotonic range is 250 - 350
mOsm/kg. The equipment
should be calibrated with
known standards before using.

5.9. Final Package Inspection:

Conforms to the packaging
prescribed for each product;
reserve samples are
maintained.

5.10. Sterility Test (Direct Inoculation Method):

To test the effectiveness of sterilization for Radiopharma-

ceuticals and Raw Materials that render them to be sterile.
Two types of media are used:

• FTG (Fluid Thioglycolate Medium); Incubation at 30 – 35

°C for 14 days.
• TSB (Tryptic Soy Broth Medium): Incubation at 20 – 25 °C
for 14 days.

35
QC SECTION
5.11. Pyrogenicity:
Pyrogen is any substance or agent that tends to cause a
rise in body temperature, such as some bacterial toxins. The
product must be pyrogenic, or NMT 175 EU/max. injection
volume.

This test is based on the formation of a gel clot by LAL re-

agent in the presence of endotoxins. That formation of the
gel can be inspected manually or with the use of a device
called an endotoxin test reader. Alternately, an automated
method employing Endosafe equipment may be employed
which is a very reliable and sensitive method for endotoxin
detection and quantification.

5.12. Environmental monitoring:

Periodic monitoring of production clean areas (clean-
rooms, anterooms, and laminar flow cabinets) for viable
and non-viable contamination after cleanup and sanitation
is vital as these tests are important in achieving product
compendia requirements for both particulate matter and
sterility.

5.12.1. Equipment and materials:

- Petri dishes containing Sabouraud Dextrose Agar (SDA).
- Petri dishes containing Sheep Blood Agar (SBA).
- Rodac contact plates.
- Air particulate counter.
- Microbiological air sampler.

36
QC SECTION
5.13. Raw materials:
Quality Control carries out testing of all incoming raw ma-
terials, including packaging and process materials such as
syringes, needles, vials, stoppers, etc. to ensure that they
meet the specifications as per USP (United States Pharma-
copeia) and other regulatory requirements. For each item,
there are instructions on how to deal with the items from
receiving to releasing stage.
Each item has a specific Item Code, and each incoming
consignment is given a unique Lot Number, for traceability
purposes.

5.14. Equipment and instruments:

In QC a wide range of techniques and equipment are used
for a variety of purposes, such as:
Gas Chromatography, High-Performance Liquid Chroma-
tography, Thin Layer Chromatography, Multi-Channel Ana-
lyzer, liquid particle counter, pH meter, melting point appa-
ratus, spectrophotometer, Osmometer, Dose Calibrator, etc.

37
QC SECTION
 6. QUALITY ASSURANCE SECTION:

Quality Assurance (QA) is an all-encompassing, indepen-

dent unit, which assumes authority and responsibility for

day-to-day implementation and maintenance of the Quality

Management System of the C&R Department. QA is respon-

sible for ensuring that all radiopharmaceutical products

manufactured are of the desired quality and specifications,

following the guidelines of good manufacturing practices

as laid out by the local regulatory authority (SFDA). This is

done by ensuring that all production operations are car-

ried out by following processes that have been validated,

approved, and documented. Additionally, QA ensures that

all materials used in the production of any batch have been

qualified. Similarly, QA ensures that all equipment used in

production and testing is qualified and calibrated. Also, all

analytical methods should have been validated.

38
QUALITY ASSURANCE SECTION
Many critical functions and operations generally fall
under the umbrella of QA, which include:

6.1. PREPARATION OF DOCUMENTS FOR ROUTINE PRODUCTION

QA is responsible for issuing batch records, QC records,

and labels for routine radiopharmaceutical production. QA
ensures the correctness of lot numbers, manufacturing,
calibration, and expiration dates, as well as correct infor-
mation on product labels. Additionally, QA ensures that the
current versions of all forms and records are used in batch
manufacturing. Detailed instructions are provided in SOP #
11-02-002 and 11-02-003.

6.2. FINAL APPROVAL AND RELEASE OF RADIOPHARMA-

CEUTICAL PRODUCTS
All records are brought to QA at the end of production and
testing for review. QA reviews all records for correctness
and accuracy, assures that all processes have been carried
out as per approved procedures, and approves the product
for release for patient use. The steps involved in the release
of products are outlined in SOP # 07-02-001.
6.3. RAW MATERIALS CONTROL
QA ensures that all materials used in radiopharmaceutical
production are of the required specifications and quality.
All QC testing records (and preparation records, if any) are
brought to QA, who reviews all records for correctness and
accuracy, assures that all preparation and testing have been
carried out as per approved procedures, and releases the
material for patient use. QA also issues the requisite labels.
The steps involved in the release of products are outlined in
SOP # 05-02-002. QA is also responsible to ensure that all
materials are acquired from approved vendors which have
been qualified and that these materials have been validated
and found to be fit for purpose, as per SOP # 05-03-001.

39
QUALITY ASSURANCE SECTION
6.4. CONTROL OF DOCUMENTS
QA is responsible for the management of all official doc-
uments within the C&R Department, as per SOPs # 01-02-
001 to 01-02-006. Control of Documentation includes:

• Review and approval of new standard operating proce-

dures (SOPs), batch production records, and testing re-
cords;
• Revision and approval of existing standard operating
procedures (SOPs), batch production records, and testing
records;
• Ensuring that copies of only the current SOPs are avail-
able at the points of use;
• Maintaining document indices, numbering system, and
revision numbers, as well as historical documents;
• Managing electronic storage, scanning, archiving, and dis-
posal of documents (SOPs # 11-04-001 and 11-04-002).
6.5. INCIDENT REPORTING AND MANAGEMENT
QA is responsible for reviewing and control of all untoward
incidents that may occur during the routine operations of
the C&R department, as per SOPs # 07-02-003 to 07-02-
004 AND 11-03-001 to 11-03-006). These include:
• Non-conforming (rejected) products;
• Other non-conformities;
• Process deviations;
• Production delays, shortages, and cancellations;
• Product rework;
• Product recalls and disposal;
• Customer complaints.
QA follows up on the timely and effective implementation
of the corrective and preventive actions that have been
planned in response to untoward incidents and maintains
records.

40
QUALITY ASSURANCE SECTION
6.7. AUDITS AND INSPECTIONS
QA is responsible for planning, organizing, and conducting
periodic internal audits and inspections of all the sections
of the C&R department, as per SOP # 13-01-001. These au-
dits are carried out to ensure the effective implementation
of our Quality Management System as well as the GMP, and
to identify gaps and deficiencies, if any. Corrective actions
are planned to address any deficiencies found; QA then fol-
lows up to ensure timely and effective closure of the action
plans. Records are maintained.
QA is also responsible for coordinating with external bodies
(BSI auditors for maintenance of ISO 9001:2015 QMS and
SFDA inspectors for implementation of GMP) to provide
the necessary support for their periodic audits and inspec-
tions. QA devises action plans and prepares a report in
response to the inspection findings.

6.8. TRENDING AND DATA ANALYSIS

QA carries out statistical analysis of gathered data to main-
ly ensure that Quality Objectives are being met. Data anal-
ysis is also carried out to observe any trends in production
parameters or product specifications. Process, production,
and shipping success rates are gauged through effective
data analysis, as outlined in SOP # 11-01-001.

6.9. CUSTOMER SATISFACTION MONITORING

QA carries out periodic customer surveys as per SOP # 13-

01-004 to gauge their level of satisfaction and to address
their concerns, if any. Action plans are made based on the
feedback received from customers. In addition, QA is also
involved in addressing any product quality or delivery-relat-
ed complaints that are received from customers.

41
QUALITY ASSURANCE SECTION
6.10. TRAINING AND CONTINUING EDUCATION
QA is responsible for overseeing the induction and training
of new employees and trainees. QA recommends training
programs for the growth of existing staff members and also
organizes short training programs and presentations for
continuing education of C&RD staff. Training records of em-
ployees/trainees are maintained by QA. Training guidelines
are provided in SOPs # 02-02-004 and 02-02-005.

6.11. PRODUCT QUALITY REVIEW

To fulfill GMP requirements, QA plans the annual prod-
uct quality review of all radiopharmaceutical products, to
ensure their continued suitability, and to address specific
product-related issues, if any. PQRs are carried out as per
SOP # 13-01-006.

6.12. MANAGEMENT REVIEW

QA plans and organizes the annual Management Review
as per SOP # 13-01-002 to ensure that the department’s
Quality Management System is effectively implemented to
ensure maximum customer satisfaction and that its quality
objectives are successfully being achieved. Action plans are
devised to address any issues or deficiencies observed.

42
QUALITY ASSURANCE SECTION
 7. RESEARCH AND DEVELOPMENT SECTION:

7.1. Development of radiotracers in research:

A radioactive tracer is a chemical compound in which one

or more atoms have been replaced by a radioisotope. Mon-

itoring its radioactive decay, a radiotracer can be used to

explore the mechanism of chemical reactions. They are also

used for flow visualization through different technologies,

such as Single Photon Emission Computed Tomography

(SPECT) and Positon Emission Tomography (PET).

There is an increasing role for PET and SPECT in oncology,

particularly as a component of early-phase clinical trials. As

a non-invasive functional imaging modality, PET and SPECT

can be used to assess both the pharmacokinetics and phar-

macodynamics of novel therapeutics by utilizing radiola-

belled compounds.

43
RESEARCH AND DEVELOPMENT SECTION
Any biological target that is present at increased or de-
creased levels in cancer cells can be visualized by PET and
SPECT. Ideally, the target should be as specific as possi-
ble for the disease process, and consideration should also
be given to the clinical information that might be gleaned
from imaging the target or pathway. The development of a
targeted radiotracer involves the synthesis of an extensive
library of potential compounds for a particular target, with
the expectation that only a few imaging agents will suc-
cessfully progress to clinical PET and SPECT studies. This
library can contain several analogs of the parent compound
that have a known affinity for a target and often may be
based on previously known compounds.

The researcher groups interested in the potential tracers

must have a subnanomolar or nanomolar affinity for the
physiological target to not interfere with normal biological
function. Other desirable characteristics of radiotracers for
somatic tumors include:

• high specificity and/or selectivity.

• high plasma clearance and low plasma protein binding.
• neutral and hydrophilic to enhance elimination and reduce
effective (radiation) dose.
• Limited or measurable metabolism and amenable to ki-
netic modeling.
• low toxicity.
• good in vivo stability because of low metabolic clearance.

44
RESEARCH AND DEVELOPMENT SECTION
Our areas of expertise in radiotracer research include:

• Development of new radiotracers, including the produc-

tion such as (18FLT, 18F-choline, 18F-DOPA, 68Ga-DOTA-PS-

MA, and 177Lu-DOTA-PSMA).

• Radiolabelling by way of radiolabeled synthons.

• Metal ligand conjugation, conjugate evaluation, and radio

metal labeling development.

• Modifying pharmaceutical structures and synthesizing

small compound libraries for enhancing and optimizing

radiotracer properties including absorption, distribution,

metabolism, clearance, and toxicity.

• Development of automated procedures for production.

Our capability includes the opportunity to undertake radio-

labeling development for the following targets:

• small molecules and peptides.

• particles: nanoparticles to macroparticles of polymers.

45
RESEARCH AND DEVELOPMENT SECTION
7.2. Common equipment used in radiotracer development:

7.2.1. Thin-layer chromatography (TLC).

TLC is a chromatography technique used to separate
non-volatile mixtures. Thin-layer chromatography is per-
formed on a sheet of glass, plastic, or aluminum foil, which
is coated with a thin layer of adsorbent material, usually
silica gel, aluminum oxide (alumina), or cellulose. This layer
of adsorbent is known as the stationary phase.
After the sample has been applied to the plate, a solvent
or solvent mixture (known as the mobile phase) is drawn
up the plate via capillary action. Because different ana-
lytes ascend the TLC plate at different rates, separation is
achieved.
After the experiment, the spots are visualized. Often this
can be done simply by projecting ultraviolet light onto the
sheet; the sheets are treated with a phosphor, and dark
spots appear on the sheet where compounds absorb the
light impinging on a certain area. Chemical processes can
also be used to visualize spots; anisaldehyde, for example,
forms colored adducts with many compounds, and sulfuric
acid will char most organic compounds, leaving a dark spot
on the sheet.

46
RESEARCH AND DEVELOPMENT SECTION
7.2.2. High-Performance Liquid Chromatography (HPLC).
High-Performance Liquid Chromatography (HPLC) is a form
of column chromatography that pumps a sample mixture
or analyte in a solvent (known as the mobile phase) at high
pressure through a column with chromatographic packing
material (stationary phase). HPLC can separate, and identify
compounds that are present in any sample that can be dis-
solved in a liquid in trace concentrations as low as parts per
trillion. Because of this versatility, HPLC is used in a variety
of industrial and scientific applications, such as pharmaceu-
tical, environmental, forensics, and chemicals.

7.2.3. NanoScan PET/CT camera (Pre-clinical studies).

The nanoScan PET/CT small animal in vivo imager offers
user-friendly imaging and the broadest range of supported
applications in one simple-to-use, high-end PET/CT system.
The nanoScan PET/CT is equipped with an imaging technol-
ogy that is widely considered to have the most advanced
PET and CT detector construction, data processing, and
reconstruction chain in the industry.

7.2.4. Cell harvester.

The harvester is used worldwide for various glass fiber fil-
tration applications, for example, cell proliferation assays,
membrane or precipitate collection, or receptor-ligand
complex collection. Swiss precision, design, and quality
manufacturing go into all instruments.

47
RESEARCH AND DEVELOPMENTSECTION
7.2.5. Dose calibrator.
An ionization chamber is an instrument constructed to
measure the number of ions within a medium. It usually
consists of a gas-filled enclosure between two conduct-
ing electrodes (the anode and the cathode). When gas
between the electrodes is ionized by any means, such as
by gamma rays or another radioactive emission, the ions,
and dissociated electrons move to the electrodes of the
opposite polarity, thus creating an ionization current that
may be measured. Each ion essentially deposits or removes
a small electric charge to or from an electrode, such that
the accumulated charge is proportional to the number of
like-charged ions. Ionization chambers are used in nuclear
medicine to determine the exact activity of radioactive dos-
es administered to patients. Such devices are called ‘radio-
isotope dose calibrators’.

7.2.6. Chemical Rotavapor.

A rotary evaporator (or rotavap) is a device used in chem-
ical laboratories for the efficient and gentle removal of
solvents from samples by evaporation. When referenced in
the chemistry research literature, a description of the use
of this technique and equipment may include the phrase
“rotary evaporator”, though use is often rather signaled by
another language (e.g., “the sample was evaporated under
reduced pressure”).

Rotary evaporators are also used in molecular cooking for

the preparation of distillates and extracts.

48
RESEARCH AND DEVELOPMENTSECTION