Drug degradation in presence of excipients and excipients impurities were discussed

1. DRUG DEGRADATION-REACTIVE
IMPURITIES IN EXCIPIENTS
KISHORE KUMAR HOTHA., Ph.D
ANALYTICAL TECHNOLOGY AND DEFORMULATIONS
LUPIN SOMERSET
Integrity*Team Work*Passion for Excellence*Customer Focus*Respect and Care*Entrepreneurial spirit

2. ABOUT LUPIN SOMERSET
LUPIN SOMERSET (Formerly Novel Laboratories Inc.) is a subsidiary of Lupin Pharmaceuticals Inc.,
specializing in difficult-to-develop, technology-driven specialty generics for the US market.
Analytical Technology and Deformulations is a specialized group in analytical research and development
which resolves complex analytical challenges in support of product submissions and commercial
products. The group’s responsibilities includes API Characterization, deformulation, impurity
identifications, and extractable and leachable studies.

3. ACKNOWLEDGEMENTS
Shawn Watson, Vice-president- Analytical R&D, LUPIN SOMERSET
Dr.Kurt Nielsen, President, LUPIN SOMERSET
LUPIN ANALYTICAL RESEARCH & DEVELOPMENT TEAM
Isabelle-Waters Corporation

4. AGENDA
CONCLUSIONS
CONTROL OF
EXCIPIENT
IMPURITIES
FDA
PERSPECTIVES
CASE STUDIES
SOURCES OF
EXCIPIENTS
CRITICAL
MATERIAL
ATTRIBUTES

5. CRITICAL ATTRIBUTES OF A DRUG PRODUCT
API
EXCIPIENTS
MANUFACTURING PROCESS
CONTAINER CLSOURE SYSTEM

6. DRUG
PRODUCT
Drug & Excipient
Chemical Structure
Impurity Profile
Physical form
Moisture content
Particle size
Surface area
Morphology
FORMULATION
Drug:Excipient ratio
Processing method
Mixing/milling
packing
ENVIRONMENT
Temperature
Relative humidity
Packaging
Light
Oxygen

7. API CHECK POINTS
SOURCE/
MANUFACTURER
DMF QUALITY
RESIDUAL
SOLVENTS
MORPHOLOGY
AND
POLYMORPHISAM
IMPURITIES

8. WHAT COULD GO WRONG IN A PRODUCT
Residual solvents

9. EXCIPIENTS
Excipients are generally multi-component systems
• Some components are added for functionality or processing aid
• These components may be*
• Necessary
• Desirable
• Harmless
• Undesirable
In this discussion, we define excipient impurities as the components (reactive) that are
detrimental to the drug product stability.

10. EXCIPIENTS CHECK POINTS
• Sources of generation
• Analytical methods for detection
• Stability upon processing and storage
• Potential reactions with the API
• Drug degradation often results from the reaction of API vs Excipient

11. EXCIPIENTS- RESIDUES
EXCIPIENT RESIDUE
Povidone, crospovidone, Polysorbate Peroxides
Magnesium stearate, fixed oils, lipids Antioxidants
Lactose Aldehydes, reducing sugars
Benzyl alcohol Benzaldehyde
Polyethylene glycol Aldehydes, peroxides, organic acids
Microcrystalline cellulose Lignin, hemicelluloses, water
Starch Formaldehyde
Talc Heavy metals
Dibasic calcium phosphate dehydrate Alkaline residues
Stearate lubricants Alkaline residues
Hydroxy propyl methyl/ethyl celluloses glyoxal
When developing drug product formulations, the effect of excipient residue interaction with
the drug substance must be considered.

12. EXCIPIENTS- RESIDUES
• Reducing sugars
• Aldehyde Impurities
• Hydro peroxide and Hydrogen Peroxide
• Trace Heavy Metals
• Organic acids
• Antioxidants used in excipients
All of these impurities could have a negative effect of the stability of the drug
product.

13. REDUCING SUGARS
• Generation during the manufacturing process where hydrolysis and
milling are commonly used
• Generated by long term exposure to heat and moisture in the following
excipients:
• Microcrystalline Cellulose (MCC)
• Starch
• Mannitol
Reducing sugars can be found in many commonly-used excipients.

14. ALDEHYDES
• Forms due to the break down of the polymeric chain of PEG
• Spray dried lactose contains furfuraldehyde
• Flavors uses benzaldehyde, Anthranilic acid for its aroma
Residual aldehydes are found in polymers and flavors.

15. PEROXIDES
• Peroxides are used to initiate the polymerization reaction
• Found in polymeric excipients such as povidone,
hydroxypropylcelluslose, crospovidone, Polysorbate
• Difficult to completely eliminate them from the final excipient
Even the highest quality excipients can contain trace levels of reactive oxidizers.

16. HYDROPEROXIDES IN COMMON PHARMACEUTICAL EXCIPIENTS
Pharmaceutical Analysis Chemistry, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 4, WP78-210, West Point, PA 19486
Even trace levels of oxidizers can affect the stability of drug products.

17. TRACE LEVEL METALS
• Metals are pervasive in pharmaceutical excipients at trace levels
• They are used as catalysts in the oxidation of the drug
products/excipients
• Trace metals can react with triplet oxygen with most organic molecules

18. TRACE LEVEL METALS
Wu et al., Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility, AAPS Pharm Sci Tech, 2011
Several metals can be found in well-known excipients from high quality vendors.

19. ORGANIC ACIDS
• Formic acid and its esters, acetic acid and monochloro acetic acid
are trace organic acid impurities that may be present in
pharmaceutical excipients
• Residual solvents from the synthesis and purification of the excipients
may go through further degradation to form organic acids

20. ORGANIC ACIDS/ALDEHYDES
poster presented at AAPS – Nov 2008. Authors: David Ferrizzi and Thomas P. Farrell.
Formic acid and formaldehyde are commonly found in widely-used excipients.

21. IMPURITIES FOUND IN PACKAGING COMPONENTS
• Na2O, SiO2, MgO, CaO from glass
• Styrene from Polystyrene
• Diethylhexylphthalate plasticizer from PVC
• Dioctyltin isooctylmercaptoacetate stabilizer from PVC
• 2 Mercaptobenzothiazole accelerator from rubber
• Furfural from rayon
Packaging components that have contact with the drug product may contain reactive impurities.

22. Famotidine reacts with cherry flavor components and forms an unknown impurity
NH2
NH
N
S
S NH
NH
S
O
O
NH2
NH
+
O
NH2
NH
N
S
S NH
NH
S
O
O
NH
N + OH2
Famotidine
Benzaldehyde
21.964 Unknow n Impurity - TQ 2: Product Scan 2: 424.00>(50.00-1000.00) ES-, Centroid, CV=Tune CE=Tune (Uncalibrated - 5000.0 is outside the ca
80
108
144
170
187
235
235
236
275
333
343
419
421
424
424
503 998
Intensity
0.0
2000.0
4000.0
6000.0
8000.0
10000.0
12000.0
14000.0
16000.0
18000.0
20000.0
22000.0
24000.0
26000.0
28000.0
30000.0
32000.0
34000.0
36000.0
38000.0
40000.0
m/z
100.00 200.00 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.00
CASE STUDIES

23. Parenteral formulations often contains benzyl alcohol, which can cause several degradation products over
time.
O
+
OH
2
O
O
Benzaldehyde Benzyl alcohol
Benzaldehyde Dibenzyl acetal
CASE STUDIES
Benzaldehyde dibenzyl acetal formed in the parenteral formulations due to benzaldehyde and benzyl alcohol

24. • Cetirizine contains carboxylic acid group and can form esters by reacting with sugars present in:
-Hydroxy Propyl Cellulose (HPC)
-Low Hydroxy Propyl Cellulose (Hyprolose or LHPC-31)
-Micro crystalline cellulose (MCC)
CASE STUDIES
The number of Hydroxyl groups plays an important role in the formation of the esters.

25. Methylphenidate reacts with glycerin to form two positional
isomers which were more than the MDDPlaceboPeak-1-PlaceboPeak-2PlaceboPeak-3PlaceboPeaPlaceboPeak-5-PlaceboPeak-6-PlaceboPeak-7-
PlaceboPeak-8-PlaceboPeak-9-
Unknown-1-16.0SpecifiedRRT0.SpecifiedRRT0.Ritalinicacid-16
ErythroIsomer-
MethylPheni
AU
0.00
0.20
0.40
0.60
Minutes
0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00
Zoom ed Chromatogram
Unknown-1-16.080
SpecifiedRRT0.75-16.205
SpecifiedRRT0.77-16.557
Ritalinicacid-16.941
ErythroIsomer-17.859
MethylPhenidate-21.255
AU
-0.020
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
Minutes
13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00
Zoom ed Chromatogram
AU
-0.020
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
Minutes
26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00
2.421 Impurity at RRT 0.75 - TQ 1: Product Scan 1: 294.20>(50.00-500.00) ES+, Centroid, CV=Tune CE=Tune
119.06
129.21146.23
171.45
174.27
192.47
219.05
293.41
294.30
367.47 478.98
Intensity
0.0
5000.0
10000.0
15000.0
20000.0
25000.0
30000.0
35000.0
40000.0
45000.0
50000.0
2.517 Impurity at RRT 0.77 - TQ 1: Product Scan 1: 294.20>(50.00-500.00) ES+, Centroid, CV=Tune CE=Tune
129.14
157.19
173.73
174.59 217.91
243.99
264.72
290.28292.25
293.89
294.78
382.42401.27 451.46469.34479.55
Intensity
0.0
2000.0
4000.0
6000.0
8000.0
10000.0
12000.0
14000.0
16000.0
18000.0
20000.0
m/z
100.00 120.00 140.00 160.00 180.00 200.00 220.00 240.00 260.00 280.00 300.00 320.00 340.00 360.00 380.00 400.00 420.00 440.00 460.00 480.00 500.00
N
H
OO
CH3
N
H
O
+
O
CH3
H
OH
OH OH
N
H
OH
O
CH3
O
+
OH
OH
H
-H+
-EtOHN
H
O O
OH
OH
N
H
O
O
OH
OH
H+
+N
H
OHO
CH3
Methylphenidate
Glycerol
CASE STUDIES

26. 6.902 Peak 1 - TQ 3: Product Scan 3: 436.50>(50.00-750.00) ES+, Centroid, CV=Tune CE=Tune
158.38
186.63
187.25
238.81
291.16
298.34
381.57
436.22
Intensity
0.0
20000.0
40000.0
60000.0
80000.0
100000.0
120000.0
140000.0
160000.0
180000.0
200000.0
220000.0
240000.0
260000.0
280000.0
m/z
100.00 200.00 300.00 400.00 500.00 600.00 700.00
CASE STUDIES
Dehydrative cyclization of Buprenorphine in the presence
of citric acid forms a furanyl impurity

27. 2.393 Impurity -1400-6GA - TQ 1: Product Scan 1: 572.30>(100.00-1500.00) ES+, Centroid, CV=Tune CE=Tune
181.25
393.90
473.70
555.06
571.32572.29
573.34
976.73 1227.14 1445.99
Intensity 0.0
10000.0
20000.0
30000.0
40000.0
50000.0
60000.0
70000.0
m/z
200.00 400.00 600.00 800.00 1000.00 1200.00 1400.00
Dexamethasone sodium reacts with sodium
sulfite to form sulfonate adduct in the
parenteral formulation
CASE STUDIES

28. S.No. Compounds X Y Z remarks Molecular Mass
1 Compound-1 - - O Fluphenazine 454
2 Compound-2 - O - Fluphenazine 454
3 Compound-3 O - - Fluphenazine 454
4 Compound-4 - O O Fluphenazine 470
5 Compound-5 O - O Fluphenazine 470
6 Compound-6 O O - Fluphenazine 470
7 Compound-7 O O O Fluphenazine 486
8 Compound-8 - - O Fluphenazine Decanoate 607
9 Compound-9 - O - Fluphenazine Decanoate 607
10 Compound-10 O - - Fluphenazine Decanoate 607
11 Compound-11 - O O Fluphenazine Decanoate 623
12 Compound-12 O - O Fluphenazine Decanoate 623
13 Compound-13 O O - Fluphenazine Decanoate 623
14 Compound-14 O O O Fluphenazine Decanoate 639
Untitled
Auto-Scaled Chrom atogram
Fluphenazinesulfoxide(454)-3.682
fluphenazineNOxide(454)-4.425
Fluphenazine-4.924
NNSTrioxide(640)-7.069
NNNSTetraoxide(656)-7.941
NNSTriOxide(640)-9.923NSDiOxide(624)-10.088
NNDioxide(624)-11.850
NNDioxide-2(624)-12.633
S-Oxide(608)-14.180
N1Oxide-1(608)-14.471
N-4oxide-1(608)-15.945
FluphenazineDecanoate-21.286
AU
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Minutes
4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00
Free radical oxidation of Fluphenazine Decanoate in the
parenteral injection forms several N-oxides which is due to
Hydrogen peroxide present in the sesame oil vehicle
CASE STUDIES

29. FDA PERSPECTIVE - CONTROL OF EXCIPIENTS
FDA asks only a single question pertaining to control of excipients in the
Quality Overall Summary in a Quality-based-Review :
"What are the specifications for the inactive ingredients and are they suitable
for their intended function?"
However, despite its apparent simplicity, the question is a poignant one and
relates to a critical question in the pharmaceutical development section,
2.3.P.2.2, which ensures the quality of the drug product and its performance.
Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology

30. FDA PERSPECTIVE - PERFORMANCE CHARACTERISTICS OF EXCIPIENTS
• One of the least understood questions in the QOS is perhaps the one in 2.3.P.2.2, where the sponsor is
asked to justify the selection of the "grade" of the excipients.
• Overwhelmingly, the response to this question is that the excipients are USP/NF grade.
• Another common response is the recital of the Handbook of Pharmaceutical Excipients with no specificity
to the intended use in the proposed drug product.
• Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology
This question in the QOS is intended to demonstrate the understanding of the perforance characteristics
(i.e., excipient performance or functionality related characteristics) of the excipients which may affect the
manufacturability of the drug product.

31. FDA PRESCPETIVE- PERFORMANCE CHARACTERISTICS OF EXCIPIENTS
The performance characteristics of excipient are based on their form and their physical properties.
solid excipient that is to be used in dry blending and direct compaction processes, the impact of
changing physical parameters such as bulk density, surface area, particle shape and size distribution
need to be evaluated and justified.
liquid excipients may be evaluated for variation in viscosity and pH; and polymeric excipients need to
be evaluated for the impact of changes in molecular weight distribution or viscosity, as applicable.
Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology

32. FDA PRESCPETIVE- COMPATABILITY STUDY
Justification for not performing excipient API compatibility studies based on the fact that
the formulation is similar to that of the reference listed drug has its flaws, too.
It is often found that based on the grade and supplier, the impurity and residual solvents
profile of the excipients may differ significantly.
The sponsors are encouraged to identify the impurities and residual solvents in
excipients which have the potential of adversely affecting the quality of the drug
product.
Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology

33. FDA PRESCPETIVE- GRADE OF EXCIPIENTS
Sponsors may need to avoid using a specific grade of excipient in certain formulations, if its use is
discouraged by the manufacturer of the excipient.
When the suppliers certificate of analysis (COA) clearly states that the grade is not intended for the
particular dosage form. This is a serious flaw and needs to be clearly justified.
An example of this is the avoidance of certain grades of mannitol in parenteral formulations based on
manufacturer's information.
Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology

34. EXAMPLES OF FDA DEFICIENCIES
1. We would like to point out that the premise of excipient compatibility studies is to ensure that there is no
adverse chemical reaction between the API and excipients. Thus we request that for your future
applications chemical changes and not just physical changes are studied during the pharmaceutical
development.
2. Please justify the functionality related characteristics of the release controlling(excipient name) in your
modified release product, for example viscosity range. Please address what impact a lot with at the lower
end and higher endo of the range would have on the drug product critical quality attributes such as
release profiles.
3. Due to the presence of carboxyl groups in the API there is a potential interaction with the glycerin in the
formulation. Please demonstrate that the proposed analytical methods are suitable to identify and
quantify any ester product that may be formed.
4. It is reported in literature that lactose reacts with primary amines to form adduct “amadori” complexes(
maillard reaction) under pharmaceutical manufacturing processes conditions as well as during product
shelf life. Your pharmaceutical development report has not addressed this topic though your API is an
amine and lactose is the major excipient. Please provide the information regarding any pharmaceutical
development studies performed to rule out the formation of complex between API and lactose and to
justify the use of lactose in this formulation.
Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology

35. EXAMPLES OF FDA DEFICIENCIES Contd
5. You have used a certain grade of (excipient name) in your parenteral
formulation, when the certificate of analysis from the supplier clearly indicates
that this grade is not intended for use in parenteral dosage forms. Please
provide justification
6. Please clarify why you have set the acceptance criteria for impurities
in(excipient name) at much higher level than that of vendor’s acceptance
criteria
7. We noted that your results of the analysis of impurities/physical attributes in(
excipient name) differs significantly from that of the results found in the
vendor’s certificate of analysis. Please clarify.
Reference: FDA Perspectives: Common deficiencies Description, composition and Excipients by Alok Srinivasan; Pharmaceutical technology

36. HOW TO CONTROL EXCIPIENT IMPURITIES
Chemical Modification –Practically impossible without
Pharmaceutical sponsor
Minimize impurities –Technically or economically within supplier
process capability? –Lot selection (frequency, process capability)
–User purification
Additives to suppress undesirable reactants –Transparency vs
trade secret –Need for common pharmacopoeial approach (IPEC)

37. EXCIPIENTS - WHERE IS THE PROBLEM
• Majority of Pharmaceutical Suppliers are Chemical Industry subsidiaries
• Small fraction of Parent Production
• Varying degrees of dedicated R&D
• Specifications-driven: less attention to the trace amounts of unknown
impurities
• Reactive impurity may be a problem for one product, not to be other
FDA expects drug product manufacturers to demonstrate control of excipient supply and material understanding.

38. • Predict/determine “soft spots” on the drug molecule
• Knowledge of potential reactive impurities in excipients (e.g. nature & source of impurities,
type of drug incompatibilities)
• Proactive excipient compatibility studies
HOW TO CONTROL EXCIPIENT IMPURITIES
Assess the risk to the performance of the drug product and implement a mitigation strategy

39. HOW TO CONTROL EXCIPIENT IMPURITIES
• The labelled or nominal entity may not be the cause of excipient-related API
degradation
• Understand your excipient manufacture and chemistry
• Use supplier excipient expertise
• Provide feedback to your suppliers:–They cannot ensure fitness for use if
user doesn’t provide criteria

40. • Many of the reported drug-excipient incompatibilities are due to impurities in excipients
• Understanding of sources of generation
• Analytical methods to assess the levels of these impurities is needed
• Knowledge of excipient impurities along with understanding of drug stability “soft spots”
and dosage form characteristics are essential for building product robustness
• Product design approaches (formulation, processing and packaging)
• Setting acceptance criteria for impurities in the excipients require strong collaboration
between product manufacturers and excipient suppliers
CONCLUSIONS