This document provides guidance on reporting and controlling degradation products in new drug products. It describes degradation products as impurities that arise from reactions between the drug substance and excipients or container closure materials. The summary should include a scientific rationale for evaluating degradation pathways and laboratory studies to detect degradation products. It should also describe reporting results from relevant batches, including degradation product levels and analytical procedures used. The selection of degradation products for product specifications should be based on those observed in batches made by the proposed commercial process. Qualification of degradation products involves acquiring safety data to establish their biological safety at specified levels.

1. IMPURITIES IN DRUG PRODUCTS
Vinit Gohel
2061615005
M.Pharma (Pharmaceutical Analysis)

2. Difference between Q3A(R2) and Q3B(R2)
Q3A(R2) - IMPURITIES IN NEW
DRUG SUBSTANCES
• This document is intended to
provide guidance for registration
applications on the content and
qualification of impurities in new
drug substances produced by
chemical syntheses and not
previously registered in a region or
member state
Q3B(R2) - IMPURITIES IN NEW
DRUG PRODUCTS
• This guideline addresses only those
impurities in new drug products
classified as degradation products
of the drug substance or reaction
products of the drug substance with
an excipient and/or immediate
container closure system
collectively referred to as
“degradation products” in this
guideline

3. Sources of impurities
sources of impurities
associated with api
organic
starting materials or
intermediateds
by products
degradation products
reagents ligands and
catalysts
enantiomers
impurities
inorganic
reagents ligands and
catalysts
heavy metals
other materials like
filler aids
residual solvents
class 1 (ccl4)
class 2 (methanol)
class 3 (acetic acid )
related to
formulation
method relation environment related
exposure to adverse
temp.
uv light
humidity
dosage form related
(water content ,
micobe groth , pH etc
impurities from
ageing
ingredient
interaction
functional group
degradation

4. Impurities & products that are not covered by this
guideline
• Arising from excipients
• Leaching from container closure system
• extraneous contaminants
• polymorphic forms & enantiomeric impurities
• biological/biotechnological products
• Peptides & oligonucleotides
• Radiopharmaceuticals
• fermentation products and semi-synthetic products derived therefrom,
herbal products, and crude products of animal or plant origin

5. Rationale for the reporting & control of
degradation products
• Summary should include scientific judgement of degradation pathway in
NDP (new drug product) and impurities arising from reaction between NDP
& excipient or container closure, or both
• laboratory studies conducted to detect degradation products in the new drug
product should also be included
• test results of batches manufactured during the development process and
batches representative of the proposed commercial process
• Identification of degradation product observed in stability studies conducted
at the recommended storage condition when present at a level greater than
(>) the identification thresholds.
A summary of unsuccessful efforts of the laboratory studies demonstrating to
identify degradation product should also be included when identification of a
degradation product is not possible.

6. Sometime degradation product present are not more than identification
thresholds but are suspected to be unusually potent , toxic producing , or
have significant pharmacological effect in low level. In this condition
analytical procedures should be developed for those substances.
In unusual circumstances, technical factors (e.g., manufacturing
capability, a low drug substance to excipient ratio, or the use of
excipients that are crude products of animal or plant origin) can be
considered as part of the justification for selection of alternative
thresholds based upon manufacturing experience with the proposed
commercial process.

7. Documentation of Analytical procedures
• Registration application should include documented evidence that the
analytical procedures followed have been validated and are suitable to
demonstrate specificity for the specified and unspecified degradation
products
• validation should include samples stored under relevant stress
conditions. When an analytical procedure reveals the presence of other
peaks in addition to those of the degradation products these peaks
should be labeled in the chromatograms and their origin(s) discussed
in the validation documentation

8. • In cases where the response factors are not close, this practice can still be
used if a correction factor is applied
• Reference standards used in the analytical procedures for control of
degradation products should be evaluated and characterized
• Acceptance criteria and analytical procedures, used to estimate identified or
unidentified degradation products, are often based on analytical
assumptions (e.g., equivalent detector response). These assumptions should
be discussed in the registration application.
• Differences between the analytical procedures used during development
and those proposed for the commercial product should also be included

9. Reporting degradation products content of
batches
• Analytical results should be provided for all relevant batches of the
new drug product used for clinical safety, stability testing & batches
that are representative of the proposed commercial process.
Quantitative results should be presented numerically, and not in general
terms
• degradation product at a level greater than the reporting threshold and
total degradation products observed in the relevant batches of the new
drug product, should be reported with the analytical procedures

10. • Result should be reported in following way
• Full justification should be provided if higher reporting threshold is
proposed
• Chromatograms with peaks labelled (or equivalent data if other analytical
procedures are used) from representative batches & chromatograms from
analytical procedure validation studies and from long-term and accelerated
stability studies, should be provided.
• Also if requested, applicant should ensure that complete degradation profile
(chromatogram) of every individual batches are available .
Result in % Number of decimal place
< 1.0% 2 (e.g. : 0.03% )
> 1.0% 1 (e.g. : 1.2%)

11. Things should be included for each batch of the new drug
product described in the registration application
• 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 used in the new drug product
• Storage conditions for stability studies

12. Listing of degradation products in specification
• While documentation list of all possible degradation products that are
expected to occur during mfg. process of commercial product at
recommended storage condition should be listed out
• The selection of degradation products in the new drug product
specification should be based on the degradation products found in
batches manufactured by the proposed commercial process.
• degradation products with specific acceptance criteria included in the
specification for the new drug product are referred to as "specified
degradation products“ . Specified degradation products can be
identified or unidentified.

13. • For unidentified degradation products, the procedure used and
assumptions made in establishing the level of the degradation product
should be clearly stated Specified unidentified degradation products
and referred by appropriate qualitative analytical descriptive label
( like unidentified A, unidentified with relative retention of 0.9)
• normal manufacturing variations are expected, significant variation in
batch-to-batch degradation product levels can indicate that the
manufacturing process of the new drug product is not adequately
controlled and validated

14. Qualification of degradation products
Qualification is the process of acquiring and evaluating data that
establishes the biological safety of an individual degradation product or
a given degradation profile at the level(s) specified
• The level of any degradation product present in a new drug product
that has been adequately tested in safety and/or clinical studies would
be considered qualified
• Higher or lower thresholds for qualification of degradation products
can be appropriate for some individual new drug products based on
scientific rationale and level of concern, including drug class effects
and clinical experience

15. • In some cases, reducing the level of degradation product (e.g., use of a
more protective container closure or modified storage conditions) to
not more than (≤) the threshold can be simpler than providing safety
data. Alternatively, adequate data could be available in the scientific
literature to qualify a degradation product.
• studies can be conducted on the new drug product or substance
containing the degradation products to be controlled, although studies
using isolated degradation products can sometimes be appropriate.

16. Safety studies should provide a comparison of results of safety testing of
the new drug product or drug substance containing a representative level
of the degradation product with previously qualified material, although
studies using the isolated degradation products can also be considered.
This guideline is not intended to apply during the clinical research stage
of development

17. References
• Q3A_R2 impurities in new drug substances
• Q3B_R2 impurities in new drug products
• Q3C_R6 impurities: guideline for residual solvents
👇🏽link to download guideline
https://www.ich.org/