a brief knowledge about degradation product introduction to degradation and its type important key points are noted with specific example

1. RATIONALE FOR THE REPORTING
AND CONTROL OF DEGRADATION
PRODUCTS.
PRESENTED BY
T MANIKANDAN
M PHARM
PHARM ANALYSIS
1

2. CONTENTS
• INTRODUCTION
• DEGRADATION PRODUCTS.
• RATIONALE FOR REPORTING AND CONTROL OF DEGRADATION
PRODUCTS.
• ANALYTICAL PROCEDURE
• REPORTING DEGRADATION PRODUCTS
• LISTING OF DEGRADATION PRODUCTS
• QUALIFICATION OF DEGRADATION PRODUCTS.
• EXAMPLES.
2

3. INTRODUCTION
RATIONALE
 Identification and characterisation of all degradation products.
Essential for achieving the quality in pharmaceutical products.
 Development for patient safety.
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4. DEGRADATION PRODUCTS:
Unwanted chemicals that develop during the manufacture,
transport, and Storage of drug products.
Affect the efficiency of pharmaceutical products.
--light
--temperature
-- pH
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5. TYPES OF DEGRADATION PRODUCTS
PHYSICAL DEGRADATION
PRODUCTS
CHEMICAL DEGRADATION
PRODUCTS
MICRO BIOLOGICAL
DEGRADATION PRODUCTS
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6. RATIONALE FOR THE REPORTING AND
CONTROL OF DEGRADATION PRODUCTS.
Degradation products observed during manufacture and/or stability
studies.
It should be -sound scientific appraisal of potential degradation
pathways.
Impurities arising from the interaction with excipients and/or the
immediate container closure system.
A rationale should be provided for exclusion of those impurities that
are not degradation products (e.g., process impurities from the drug
substance and impurities arising from excipients). 6

7. Laboratory studies conducted to detect degradation products.
Any degradation product observed in stability studies – recommended
storage condition should be identified - at a level greater than (>) the
identification thresholds.
Analytical procedures should be developed for degradation products
which are:
--potent
--toxic
-- pharmacological effects. 7

8. ANALYTICAL PROCEDURES
I. The registration application - documented evidence (analytical procedure have
been validated –detection and quantification of degradation products).
II. Analytical procedure should be validated to demonstrate – specified and
unspecified degradation product.
III. For validation, the samples should be stored under stress condition like
1.Light
2. Heat
3. Humidity
4. Acid base hydrolysis
5. Oxidation
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9. REPORTING DEGRADATION PRODUCTS
CONTENT OF BATCHES
1.Clinical safety and stability testing.
2.Quantitative results should be presented numerically, and not in general
terms such as “complies”, “meets limit”.
3. Below 1.0%, the results should be reported to the number of decimal places
(e.g., 0.06%) in the applicable reporting threshold
4. Above 1.0%, the results should be reported to one decimal place (e.g., 1.3%).
5. Degradation products should be designated by code number (e.g.. Retention
time). 9

10. For each batch of the new drug product, the documentation should include:
• Batch identity, strength, and size
• Date of manufacture
• Site of manufacture
• Manufacturing process
• Immediate container closure
• Degradation product content, individual and total
• Use of batch (e.g., clinical studies, stability studies)
• Reference to analytical procedure used
• Batch number of the drug substance
• Storage conditions for stability studies
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11. LISTING OF DEGRADATION PRODUCTS IN
SPECIFICATION
Specification should contain a- list of degradation products.
Characterise the degradation products -- stability studies, knowledge of
degradation pathways, product development studies, and laboratory studies.
Selection of degradation product should be based on the degradation products
found in batches.
Specified degradation products can be identified or unidentified.
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12. NEW DRUG PRODUCTS SPECIFICATION SHOULD
INCLUDE:
•Each specified identified degradation product
• Each specified unidentified degradation product
• Any unspecified degradation product with an acceptance
criterion of not more than (≤) the identification threshold.
• Total degradation products.
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13. QUALIFICATION OF DEGRADATION PRODUCT
• Qualification : acquiring and evaluating data that establishes the
biological safety of an individual degradation product.
• Degradation product present in a new drug product – adequately
tested in safety and/or clinical studies –qualified.
• Degradation products that are also significant metabolites present
in animal and/or human studies are generally considered qualified.
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14. • Degradation products could be considered qualified at levels higher
than those administered in safety studies based on a comparison
between actual doses given in the safety studies and the intended dose
of the new drug product.
• Justification of such higher levels should include consideration of
factors such as:
(1) the amount of degradation product administered in previous safety
and/or clinical studies and found to be safe.
(2) the increase in the amount of the degradation product.
3) other safety factors. 14

15. THRESHOLD FOR DEGRADATION PRODUCTS
IN NEW DRUG SUBSTANCE
Reporting Thresholds
Maximum Daily
Dose
Threshold
≤1g 0.1%
>1g 0.05%
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16. Identification threshold
Maximum daily
dose
Threshold
<1mg 1.0%
1mg-10mg 0.5%
>10mg – 2g 0.2%
>2g 0.10% 16

17. Qualification threshold
Maximum daily
dose
Threshold
<10 mg 1.0%
10mg-100mg 0.5%
>100mg-2g 0.2%
>2g 0.15%
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20. EXAMPLE
Sample : IBUPROFEN
Organism : Trametes versicolor
Method : NMR
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21. IDENTIFICATION OF DEGRDATION PRODUCTS
OF IBUPROFEN
• To demonstrate the ability of T.versicolor to minearalise IBU , cultures were
spiked with 5mg/L to calculate the isotopic ratios.
• Identification of metabolites of IBU by T.versicolor in the liquid medium was
achieved by NMR.
21`

22. IBUPROFEN
2 hydroxy ibuprofen 1hydroxy ibuprofenPhase 1
Phase
2
1,2 dihydroxy
ibuprofen
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23. PROCEDURE:
• 4 extracts at different experiment times were analysed by NMR.
• Experiment times : 0 min, 60 min, 150 min & 7 days.
• At 0 min, uninoculated sample is taken.
• In first phase (after time = 60 min & 150min) two main metabolites – 2
hydroxy ibuprofen , 1 hydroxy ibuprofen were detected.
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24. • Appearance of the metabolites was accompanied by progressive decrease in
IBU SIGNALS.
• In second phase after the 7 days of experiment, 1,2 dihydroxy ibuprofen was
observed as the main metabolite.
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25. REFERENCES
i. ICH guidelines Q3B(R2) impurities in new drug products – Europen
Medicinal Agency.
ii. Ernest Marco-Urrea, Miriam Perez-Trujillo,Teresa Vicent, Gloria
Caminal, Identification of degradation products of ibuprofen by
Trametes versicolor, chemosphere 74 (2009)765-772.
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