Description of Radiopharmaceuticals with their Regulatory Aspects and full GMP of Radiopharmaceuticals

1. REGULATORY ASPECTS OF
RADIOPHARMACEUTICALS
Presented By:
ABHISHEK S KERALLI
1st M Pharm,
Pharmaceutical Regulatory Affairs,
Dept. of Pharmaceutics,
JSSCP, Ooty.
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J S S C O L L E G E O F P H A R M A C Y, O O T Y.
An ISO 9001:2015 Certified Institution,
Accredited ‘A+' Grade by NAAC.

2. CONTENTS
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 Introduction
 Definition
 Types of Radiopharmaceuticals
 Regulatory requirements for
Clinical studies
 Regulatory requirements for safety
evaluation
 GMP
 GRP
 Safety precautions
 Labelling
 Comparison of Various Countries & their
Guidelines
 References

3. INTRODUCTION
 Radiopharmaceuticals are unique medicinal formulations containing radioisotopes which are
used in major clinical areas for diagnosis and/or therapy.
 This licensing includes compliance both with regulations governing pharmaceutical
preparations and with those governing radioactive materials. Additional regulations may apply
for issues such as transportation or dispensing of radiopharmaceuticals.
 Each producer or user must be thoroughly cognizant of the national requirements pertaining
to the articles concerned. Regulations concerning pharmaceutical preparations include the
application of current Good Manufacturing Practices (cGMP).
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4. DEFINITIONS
 Radionuclide
Nuclides having an unbalanced combination of neutrons and
protons that convert spontaneously to either a stable or unstable arrangement of
neutrons and protons with a constant emission of radiation are known as
radionuclides. depicts the typical process of the transmutation of parent radionuclide
into daughter radionuclide.
 Radiopharmaceuticals
A Radiopharmaceutical is a medical product in a ready-to-use form
suitable for human use that contains a radionuclide. The radionuclide is integral to the
medicinal application of preparation, making it appropriate for one or more diagnostic
or therapeutic applications. 4

5. 5
Radiopharmaceutical
Radionuclide Part
-Radiochemical Purity
-Radionuclide Purity
Pharmaceutical Part
-Organoleptic property
-Sterility
-pH
-Chemical Purity

6. TYPES OF RADIOPHARMACEUTICALS
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Therapeutic
Radiopharmaceuticals
Therapeutic Radiopharmaceuticals are
radio stickered molecules that
specifically deliver a therapeutic dose of
ionizing radiation by localizing in the
specific organ and destroy
malfunctioned cells. This is also termed
as Radionuclide Therapy (RNT).
Diagnostic
Radiopharmaceuticals
Diagnostic Radiopharmaceuticals are
tracers for monitoring or manifestation of
disease in humans. These tracers
contain a short-lived isotope that is
typically linked to a ligand or carrier.

7. DESIGN OF NEW RADIOPHARMACEUTICALS
 General considerations
1. Preparation should be simple, easy and reproducible and should not
alter the desired property of the labelled compound.
2. Optimum conditions of temperature, pH, ionic strength and molar
ratio should be established and maintained for maximum efficacy of
the radiopharmaceuticals.
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8. FACTORS INFLUENCING THE DESIGN OF NEW
RADIOPHARMACEUTICALS
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Compatibility
Charge of the molecule
Size of the molecule
Protein binding
Solubility
Stability

9. REGULATORY REQUIREMENTS FOR CLINICAL STUDIES
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Pre-clinical
Studies Clinical
Studies

10. PRE-CLINICAL STUDIES
 Currently, there is no ICH or FDA regulatory guidelines that expressly outlines
the considerations for pre-clinical studies of Radiopharmaceuticals.
 Specific guidelines should be framed separately in the contest of performing
the pharmacological studies for the medical imaging agent so that risk-to-
benefit ratio is determined.
 Pre-clinical studies involve parameters which measure the in vivo stability of
radionuclide, its bio-distribution profile and toxicological evaluation.
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11.  Frequency of dosing of Therapeutic Radiopharmaceuticals are generally
multiple and also at a longer dose than Diagnostic Radiopharmaceuticals.
 Due to these fact that toxicological and safety issues are important
regulatory challenges.
 Thus there is a requirement for separately drafting the guidelines on pre-
clinical studies of both Diagnostic and Therapeutic Radiopharmaceuticals.
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12. CLINICAL STUDIES
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Precursor Used as a Starting Material
Toxicological Profile of Radiopharmaceuticals
Geno-toxicity Profile of Radio-diagnostics
Reproductive Toxicity Profile of Radiopharmaceuticals
Dosimetry Profile of Radiopharmaceuticals

13. REGULATORY REQUIREMENTS FOR SAFETY
EVALUATION
 Potential Drug/disease state interaction with radiopharmaceuticals may result
in the wrong visualization of pathophysiological changes during diagnosis and
eventually result in lesser/excess of irradiation of organ during therapy.
 These adverse reactions give false positive results. False-positive reactions
can be characterized as any imaging appearance due to the physiological or
pathological accumulation of radiopharmaceuticals.
 Flow chart below depicts various pathological conditions that hamper the
diagnosis of the current disease.
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SURGERY
URINARY
INTUBATION
CHEMOTHERAPY
OTHER RADIATION
THERAPY
DISEASED STATE
X-RAY or
PET/SPECT/GAMMA
SCINTIGRAPHY
ALTERED IMAGE
APPEARANCE
SYNTHETIC DRUGS

15.  Adverse reaction events occur due to diseased state and from the
standard dose which is used for prophylaxis, diagnosis or therapy of
disease.
 In India, these events are not easily detectable due to underreporting
or lack of proper surveillance under Pharmacovigilance program. The
bio-distribution and pharmacokinetic of radiopharmaceuticals gets
altered due to the pathological condition or the drugs results in false
positive result.
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16. GMP FOR RADIOPHARMACEUTICALS
As we all know Radiopharmaceuticals Production is still on a relatively small
scale & implementing the cGMP guidelines and it involves taking care of
several aspects.
In USA, [PET(Positron Emission Tomography) Drug Product =
Radiopharmaceuticals]
 Radiopharmaceuticals cGMP regulation is effective from Dec 12,2011.
 Starting on this date, FDA will require submission of NDA or ANDA for any
Radiopharmaceutical for clinical use.
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17. HISTORY OF CGMP FOR RADIOPHARMACEUTICALS IN USA
Public meeting - Feb 19, 1999
Preliminary draft regulation - Sept 21, 1999
Public meeting - Sept 28, 1999
Preliminary Draft Proposed Rule - Apr 1, 2002
Draft Guidance PET Drug Product cGMP - Apr 1, 2002
Public meeting on PET cGMP - May 21, 2002
Issuance: Proposed Rule/Draft Guidance - Sept 20, 2005
cGMP Final Rule - Dec 10, 2009
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18. OBJECTIVES IN DEVELOPING CGMP FOR PET DRUGS
Safeguards to assure safety, identity, strength, quality and
purity of PET Drugs;
Quality built into production process;
Sufficient facilities to accommodate all PET production, without
any of the unreasonable regulatory burden;
Various mechanisms to proactively identify potential problems,
eliminate them, and promote continuous improvement.
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19. MAJOR ELEMENTS IN PET DRUG CGMPS
Personnel and Resources (21 CFR
Part 212.10)
Quality Assurance (212.20)
Facilities and Equipment(212.30)
Control of Components,
Containers, and Closures(212.40)
Production and Process
controls(212.50)
Laboratory Controls(212.60)
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Drug Product Controls and
Acceptance criteria(212.70)
Packaging and Labelling
Controls(212.80)
Distribution
Controls(212.90)
Complaint
Handling(212.100)
Record Keeping(212.110)

20. Personnel and Resources
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 Sufficient number of qualified and trained personnel to reform their
assigned tasks.
- Facilities where few individuals are employed, one individual can be assigned
to perform both production and QA tasks.
 Sufficient resources including equipment and facilities to produce a
quality PET Drug.

21. Quality Assurance
 Person or Organizational element responsible for the duties relating to
quality control.
 Oversees production operations to ensure that a quality PET drug is
produced.
 Examines and approves or rejects components, containers, closures
and the finished PET drug.
 Approves or rejects procedures and/or specifications.
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22. Quality Assurance, contd…..
 Reviews production records for accuracy and completeness.
 Ensures that investigations have been conducted and corrective
action is taken.
 It’s possible for certain part of the QA function to be at a centralized
off-site location, however batch release must be signed off on-site by
a responsible QA individual.
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23. Facilities and Equipment
 Equipment: should be clean, suitable for its intended purposes,
properly installed and maintained.
 Facilities: should be adequate to assure the orderly handling of
materials and equipment, prevent mix-ups and contamination of
equipment and the PET drug.
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24. Control of Components, Containers, and Closures
 Procedures for the handling of Components.
 Establish the appropriate specifications, and examine each lot upon
receipt with established specifications.
 Each lot must meet all established specifications to be used in
production.
 Instead of full testing, a COA may be accepted provided that the PET
center establishes the reliability of test results.
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25. Production and Process Controls
 Ensures consistent and quality production.
 Establish written procedures, master and batch production and control
records.
 Include inspection of the production area and all equipment for
suitability and cleanliness before use.
 Process verification results must be documented when the production
batch is not fully verified through finished product testing.
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26. Production and Process Controls, contd…..
 Prepare batch production and control record for each batch of PET
drug produced.
 Batch record should include the critical production steps and test
results.
 Deviations from established procedures must be investigated and
documented.
 The process must be validated.
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27. Laboratory Controls
 Follow written procedures and document each laboratory test results.
 Analytical methods should be suitable, sensitive, specific, accurate
and reproducible.
 Control the identity, purity and quality of reagent solutions and
supplies used in testing procedures.
 All testing equipment must be suitable for its intended purpose and
capable of producing valid results.
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28. Laboratory Controls, contd…..
 Test records
- A complete description of the sample received
- A reference to the method used
- Raw data; including charts, graphs and calculations
- Results: pass or fail acceptance criteria
- Initials or signature of the person performing the test
 Program to assess the stability of a PET drug, including suitable
storage conditions, use of reliable and specific test methods and
expiration dates/times. 28

29. Drug Product Controls & Acceptance Criteria
 Sterility testing must be performed but need not be completed prior to drug
product release.
- Must begin < 30 hours after completion of PET drug production
 Establish procedures for release:
- Complete laboratory testing and review data
- Release authorized by designated person
 Each batch must meet its established acceptance criteria prior to release
- If product does not meet acceptance criteria: reject product; conduct the investigation
and take corrective action if any problems are identified.
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30. DP Controls: Conditional Release [212.70(f)]
 Conditional release applies, if one finished product test cannot be
completed due to an analytical equipment malfunction, when the
following conditions are met:
- Prior history must demonstrate that the final release of the product will meet
the established specifications.
- Immediate CA against the malfunctioning analytical equipment.
- The performance of the product identity, purity and specific activity must be
verifiable.
- No additional batch can be released until the problem is corrected.
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31. Packaging and Labelling Controls
 Packaging and shipping containers should protect against damage
during storage, handling, distribution and use.
 In part, the label should also contain the product name, strength,
batch number, date/time prepared, expiration date/time.
 Operations should be controlled to prevent mix-ups.
 Label must be legible.
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32. Distribution Controls
 Drug products should be shipped according to the labelling conditions.
 Establish and follow procedures if the drug is distributed or shipped.
 Keep adequate distribution records
- The chain of distribution of each batch of product must be readily determined
to permit its recall if necessary.
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33. Complaint Handling
 Establish procedures to handle complaints pertaining to the quality and labelling, or possible
adverse reactions.
- A written record of each complaint, the investigational findings, and follow-up must be maintained.
- A drug returned due to a complaint must be destroyed.
- CA should be taken immediately if there is reason to believe that an adulterated drug was implicated
in complaint.
 Written complaint records must include
- Drug name, strength
- Batch number
- Date and nature of complaint
- Response to complaint
- Findings of investigation, follow-ups if.
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34. Record Keeping
 Maintain records at location that is reasonably accessible.
 Keep records for 1 year from the date of drug product release.
 Records include:
- Composition and quality,
- Production operations, batch records, and OOS
- Distribution and complaints.
 Records: legible and readily available for review and copying by FDA.
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35. GRP FOR RADIOPHARMACEUTICALS
Production of radio pharmaceuticals is therefore a bit more complex than normal
pharmaceuticals. Good Radiation Practices (GRPs) and Good Manufacturing Practices
(GMPs) should be strictly followed during manufacturing and dispensing operations.
1. Strict personnel hygiene.
2. Avoidance of risk methodology.
3. Operations only in the recommended zones of hot Lab.
4. Proper techniques of distance and shielding.
5. Isolated storage , refrigeration of radionuclides and labeled compounds.
6. Trial run using dummy or inactive source.
7. Adequate washing facilities including showers.
8. Proper in service training of qualified personnel.
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36. 9. Drawing out a manual of standardized procedures of safe handling and step by
step processing, testing and waste disposal of radio active compounds.
10. Facilities of minimizing radiation levels, removal of surface and air borne
contaminants.
11. Calibration and maintenance of instruments for radioactivity measurements.
12. Provision of appropriate personnel monitoring and protective devices.
13. Periodic inspection of protective devices for wear and tear and performance.
14. Establishment of well understood emergency procedures.
15. Proper documentation system is required by law.
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37. SAFETY PRECAUTIONS
 Radiation Safety is a term applied to concepts requirements, technologies and
operations related to protection of people against the harmful effects of
ionizing radiation.
Safe Handling of Radio Isotopes :
1. GRP needs to be strictly followed for operations with unrelated sources to
reduce the chances of getting unwanted and avoidable radiation exposure.
2. It is necessary to mark the area in which the radio active work is carried out
and it should be monitored regularly at periodic intervals.
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38. 3. Unnecessary movements of persons or materials should be avoided in the
hot laboratory or radio pharmacy.
4. All the radiation workers must wear suitable protective clothing and
radiation monitoring devices, Surgical gloves is necessary.
5. When not in use, the radionuclides must be kept in sealed containers.
6. The area should be surveyed regularly for both contamination and
exposure hazards.
7. Work areas should be covered with a plastic, glass or stainless.
8. Tray with absorbent paper should be use to catch any spills and to prevent
the spread of contamination.
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39. 9. Do not pipette by mouth.
10. Wash hands thoroughly.
11. Radioactive materials should never be touched with hand but handled with
forceps or suitable instrument.
12. Do not eat, drink and smoke in areas where unsealed radionuclides are
stored.
13. The radiation survey meter should be used to ensure safety of worker and
public.
14. Survey an wipe test suggested action levels are
For unrestricted area 0.25 mR/hr. (mille Roentgens)
For restricted area 20 mR/hr. 39

40. LABELLING OF RADIOPHARMACEUTICALS
 The label on the outer package should include:
 a statement that the product is radioactive or the international symbol of
radioactivity.
 The name of the radiopharmaceutical preparation: The preparation is for
diagnostic for therapeutic use
 The total radioactivity present
 Name of the drug product and product code
 The name of radio nuclide
 The name of manufacturer or the company
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41.  Route of administration
 The expiry date
 The batch (lot) number
 For Solutions, the total volume
 The radioactivity per unit dose
 The amount of radioactivity at dispatch time
 In case of cold kits
- The direction of preparing and
- A statement of shelf life of the prepared radio pharmaceutical and
- The radiation dose that the patient would receive,
 Any special storage requirements with respect to temperature and light,
 The name and Concentration of any added microbial preservative. 41

42. LABELLING COMPARISON OF RADIOPHARMACEUTICALS &
PHARMACEUTICAL
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44. COMPARISON OF VARIOUS COUNTRIES & THEIR
GUIDELINES
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• Clinical Trial Imaging Endpoint Process Standards
Guidance for Industry
• Compounding and Repackaging of
Radiopharmaceuticals by Outsourcing
• Microdose Radiopharmaceutical Diagnostic Drugs :
Nonclinical Study Recommendations – Sept 2017
US –
USFDA
• Guidance on Clinical Evaluation of Diagnostic
Agents: Committee for Medicinal Products for
Human Use – July 2009
• Guideline on the Acceptability of Names for Human
Medicinal Products Processed through the
Centralized Procedure – May 2014
EU –
EMA

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• Radioisotope Handling Facilities
– Aug 2015
• Security of Radioactive Material
During Transport – Jan 2008
INDIA –
AERB
• Cleaning Validation Guidelines
– Jan 2008
• Guidance Document for Clinical
Trial Sponsors: Clinical Trial
Applications – May 2013
CANADA
– Health
Canada

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• IAEA consultation meeting on
Harmonization of Health
Regulations related to
Radiopharmaceuticals – Nov
2018
• Widely available for public
consultation using the IAEA
and WHO mailing list and
public web posting – Mar 2019
WHO –
IAEA

47. ADVANTAGES & DISADVANTAGES
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 Used as Both diagnostics and
therapeutics.
 Most common to cure cancer.
 Can treat multiple disease sites.
 Widely available mode of
treatment.
 Can provide fast onset of relief.
 Can produce some allergic
reactions.
 It has a radiation risk.
 Nuclear medicine tests are not
recommended for pregnant women
because unborn babies have a
greater sensitivity to radiation than
children or adults.
Advantages Disadvantages

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49. REFERENCES
 https://www2.rsna.org/re/twotopicimagingworkshoppresentations/Index%20Files/Perrella.pdf
 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=212
 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=212&showFR=1&subpartNode=21:4.0.1.1.12.6
 https://www.snmmi.org/files/docs/PET%20Drugs%20Webinar.pdf
 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070306.pdf
 https://eanm.org/publications/guidelines/5_EJNMMI_Guidance_cGRPPfulltext_05_2010.pdf
 https://humanhealth.iaea.org/HHW/NuclearMedicine/Conferences/IPET2015/Presentations/Tuesday/07_Parallel_Session_1b/04_Suleiman.p
df
 http://www.rjlbpcs.com/article-pdf-downloads/2018/19/256.pdf
 http://www.eurekaselect.com/node/151473/article/radiopharmaceuticals-regulations-current-scenario-and-the-way-forward
 https://www.eanm.org/publications/guidelines/gl_radio_phct_259_853.pdf
 https://www.who.int/medicines/publications/pharmacopoeia/Radgenmono.pdf
 https://www.researchgate.net/publication/318787094_Radiopharmaceuticals_Regulations_Current_Scenario_and_the_Way_Forward
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