drug degradation impurity in excipients

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

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.

ACKNOWLEDGEMENTS

Shawn Watson, Vice-president- Analytical R&D, LUPIN SOMERSET

Dr.Kurt Nielsen, President, LUPIN SOMERSET

LUPIN ANALYTICAL RESEARCH & DEVELOPMENT TEAM

Isabelle-Waters Corporation

AGENDA

CONCLUSIONSCONTROL OF

EXCIPIENT IMPURITIES

FDA PERSPECTIVES

CASE STUDIESSOURCES OF EXCIPIENTS

CRITICAL MATERIAL

ATTRIBUTES

CRITICAL ATTRIBUTES OF A DRUG PRODUCT

API

EXCIPIENTS

MANUFACTURING PROCESS

CONTAINER CLSOURE SYSTEM

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

API CHECK POINTS

SOURCE/

MANUFACTURER DMF QUALITY

RESIDUAL SOLVENTS

MORPHOLOGY AND

POLYMORPHISAMIMPURITIES

WHAT COULD GO WRONG IN A PRODUCT

Residual solvents

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.

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

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.

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.

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.

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.

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.

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.

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

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.

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

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.

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.

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

SS NH

NH

S

O

O

NH

N + OH2

FamotidineBenzaldehyde

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 calibration range of 200.00-5000.00 Da/sec)

80

108144

170

187

235

235

236

275

333343

419

421

424

424

503 998

Inte

nsity

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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

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

• 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.

Methylphenidate reacts with glycerin to form two positional isomers which were more than the MDD

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0.60

0.80

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1.20

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 Chrom atogram

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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

Inte

nsity

0.0

5000.0

10000.0

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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

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nsity

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NH

OO

CH3

NH

O+

O

CH3H

OH

OH OH

NH

OH

O

CH3

O+

OH

OH

H

-H+

-EtOHNH

O O

OH

OH

NH

O

O

OH

OH

H+

+NH

OHO

CH3

Methylphenidate

Glycerol

CASE STUDIES

6.902 Peak 1 - TQ 3: Product Scan 3: 436.50>(50.00-750.00) ES+, Centroid, CV=Tune CE=Tune

158.38186.63

187.25

238.81291.16

298.34381.57

436.22

Inte

nsity

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CASE STUDIES

Dehydrative cyclization of Buprenorphine in the presence

of citric acid forms a furanyl impurity

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 1445.99In

tensity

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Dexamethasone sodium reacts with sodium sulfite to form sulfonate adduct in the

parenteral formulation

CASE STUDIES

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

Project Name: ARD_Fluphenazine_Q2_2015Reported by User: Kishorekumar Hotha (khotha)

Report Method: Untitled Date Printed:

128 4/24/2015Report Method ID: 128

2:32:53 PM US/Central

Auto-Scaled Chrom atogram

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1

2

Name RTPurity1

Angle

Purity1

Threshold

Match1

Spect. Name

Match1

Angle

Match1

Threshold

Fluphenazine sulfoxide(454)

fluphenazine N Oxide(454)

3.682

4.425

PDA Result Table

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

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

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.

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.


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.


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.


EXAMPLES OF FDA DEFICIENCIES1. 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 futureapplications chemical changes and not just physical changes are studied during the pharmaceuticaldevelopment.

2. Please justify the functionality related characteristics of the release controlling(excipient name) in yourmodified release product, for example viscosity range. Please address what impact a lot with at the lowerend and higher endo of the range would have on the drug product critical quality attributes such asrelease profiles.

3. Due to the presence of carboxyl groups in the API there is a potential interaction with the glycerin in theformulation. Please demonstrate that the proposed analytical methods are suitable to identify andquantify 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 productshelf life. Your pharmaceutical development report has not addressed this topic though your API is anamine and lactose is the major excipient. Please provide the information regarding any pharmaceuticaldevelopment studies performed to rule out the formation of complex between API and lactose and tojustify the use of lactose in this formulation.


EXAMPLES OF FDA DEFICIENCIES Contd

5. You have used a certain grade of (excipient name) in your parenteralformulation, when the certificate of analysis from the supplier clearly indicatesthat this grade is not intended for use in parenteral dosage forms. Pleaseprovide justification

6. Please clarify why you have set the acceptance criteria for impuritiesin(excipient name) at much higher level than that of vendor’s acceptancecriteria

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 thevendor’s certificate of analysis. Please clarify.


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)

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.

• 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


Assess the risk to the performance of the drug product and implement a mitigation strategy


• 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

• 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

drug degradation impurity in excipients

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