1 - PrgRev01November2010ApplicantPart 1 135

LABORATORIO CHIMICO INTERNAZIONALE s.p.a.
QUALITY ASSURANCE DEPARTMENT

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COMMON TECHNICAL DOCUMENT Regulatory Department
APPLICANT PART
PRODUCT REVISED BY
PREGABALIN Quality Assurance
MODULE 3:
QUALITY
ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

CTD REV. 01 Technical Manager
3.2.S 1
PREGABALIN November 2010 (Qualified Person)

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3.1 TABLE OF CONTENTS OF MODULE 3
3.2 BODY OF DATA

3.2.S DRUG SUBSTANCE [Pregabalin, LABOCHIM]
Section Content Page
3.2.S.1 General Information [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.1.1 Nomenclature [Pregabalin, LABOCHIM] Applicant Part 2
3.2.S.1.2 Structure [Pregabalin, LABOCHIM] Applicant Part 4
3.2.S.1.3 General Properties [Pregabalin, LABOCHIM] Applicant Part 6
3.2.S.2 Manufacture [Pregabalin, LABOCHIM] Omissis–Applicant and 1

Restricted Parts
3.2.S.2.1 Manufacturer [Pregabalin, LABOCHIM] Applicant Part 2
3.2.S.2.2 Description of Manufacturing Process and Process Controls [Pregabalin, LABOCHIM] Omissis- Applicant and 4
Restricted Parts
3.2.S.2.3 Control of Materials [Pregabalin, LABOCHIM] Omissis- Restricted Part 7
3.2.S.2.4 Controls of Critical Steps and Intermediates [Pregabalin, LABOCHIM] Omissis- Restricted Part 9
3.2.S.2.5 Process Validation [Pregabalin, LABOCHIM] Omissis- Restricted Part 11
3.2.S.2.6 Manufacturing Process Development [Pregabalin, LABOCHIM] Omissis- Restricted Part 13
3.2.S.3 Characterisation [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.3.1 Elucidation of Structure and other Characteristics [Pregabalin, LABOCHIM] Applicant Part 2
3.2.S.3.2 Impurities [Pregabalin, LABOCHIM] Applicant Part 25
3.2.S.4 Control of Drug Substance [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.4.1 Specification [Pregabalin, LABOCHIM] Applicant Part 2
3.2.S.4.2 Analytical Procedures [Pregabalin, LABOCHIM] Applicant Part 5
3.2.S.4.3 Validation of Analytical Procedures [Pregabalin, LABOCHIM] Applicant Part 24
3.2.S.4.4 Batch Analyses [Pregabalin, LABOCHIM] Applicant Part 93
3.2.S.4.5 Justification of Specification [Pregabalin, LABOCHIM] Applicant Part 98
3.2.S.5 Reference Standards or Materials [Pregabalin, LABOCHIM] Applicant Part 1
3.2.S.6 Container Closure System [Pregabalin, LABOCHIM] Applicant Part 1
3.2.S.7 Stability [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.7.1 Stability Summary and Conclusions [Pregabalin, LABOCHIM] Applicant Part 2
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment [Pregabalin, LABOCHIM] Applicant Part 5
3.2.S.7.3 Stability Data [Pregabalin, LABOCHIM] Applicant Part 7

3.2.S 1

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3.2.S.1 General Information

3.2.S.1 1

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3.2.S.1.1 Nomenclature

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3.2.S.1 General Information [Pregabalin, LABOCHIM]
3.2.S.1.1 Nomenclature [Pregabalin, LABOCHIM]
INN : PREGABALIN
Chemical name : (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
Company code : PRG-00
CAS No. : 148553-50-8
Proprietary names : Lyrica

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3.2.S.1.2 Structure

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3.2.S.1.2 Structure [Pregabalin, LABOCHIM]
Characteristics : White to off white crystalline powder.
Structural Formula :
NH2
H
COOH
(s)
Molecular Formula : C8H17NO2
Molecular Weight : 159.18

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3.2.S.1.3 General Properties

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3.2.S.1.3 General Properties [Pregabalin, LABOCHIM]
Physical form : Pregabalin is a white or almost white crystalline powder.
SOLUBILITY TABLE
Solubility
Water Soluble
Alkaline solution (NaOH 1N) Soluble
Acidic solution (HCl 1N) Soluble
Ethanol (96%) Very slightly soluble
Chloroform Practically insoluble
Polymorphism : Crystal form was characterized by X-ray diffraction and FT-IR

spectroscopy. Based on the XRPD pattern the Pregabalin manufactured
by Labochim process is the polymorphic anhydrous form I ( crystal
form of the API contained in Lyrica 300 mg hard capsules)
Potential isomerism : Based on the structure of the product there are two potential optical
isomers : the (S)-(+) enantiomer ( Pregabalin ) and the (R)-(-)
enantiomer.
The purity of the (S)-(+) enantiomer is determined by preparing a
diastereoisomeric derivative and analyzing by HPLC ( enantiomeric
excess).
Melting range : Pregabalin melts between 193°C and 198°C ( DSC )
PS: The powder of Pregabalin is very coarse being around 60% <710 µ tested by
Alpine Airjet Sieving method.
Finer powder can be made available upon customer’s requirements.

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3.2.S.2 Manufacture

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3.2.S.2.1 Manufacturer

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3.2.S.2 Manufacture [Pregabalin, LABOCHIM]
3.2.S.2.1 Manufacturer [Pregabalin, LABOCHIM]
Manufacturer
LABORATORIO CHIMICO INTERNAZIONALE S.p.A.
Head office
The head office is located in:
Via Tommaso Salvini 10
20122 Milano, Italy
Manufacturing facility
The manufacturing facility is located in:
Via Benvenuto Cellini 20
20090 Segrate (Milano), Italy

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3.2.S.2.2 Description of Manufacturing Process and Process Controls

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3.2.S.2.2 Description of Manufacturing Process and Process Controls [Pregabalin, LABOCHIM]
MANUFACTURING SYNTHESIS ROUTE
STEP 1 = PREGABALIN CRUDE
O
NH2
NH2 1)NaClOaq
NaOH 30%
H
H
COOH
COOH (S)
(R) 2) HCl 33%
R(-) Monoamide Crude Pregabalin
STEP 2 = PREGABALIN
isopropyl alcohol NH2

NH2 water
H H
COOH COOH
(S) crystall. (S)
Crude Pregabalin Pregabalin

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3.2.S.2.2 Description of Manufacturing Process and Process Controls [Pregabalin, LABOCHIM]
MANUFACTURING PROCESS
Labochim Pregabalin is manufactured in two steps:
1st step: R (-) Monoamide reacts with a solution of NaClO and NaOH, with addition of
Na2SO3 and HCl to yield Pregabalin (crude).
2nd step: Pregabalin (crude) is purified to obtain Pregabalin (final active ingredient)

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3.2.S.2.3 Control of Materials

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3.2.S.2.3 Control of Materials [Pregabalin, LABOCHIM]
Omissis (Restricted Part for Authorities only).

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3.2.S.2.4 Controls of Critical Steps and Intermediates

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3.2.S.2.4 Controls of Critical Steps and Intermediates [Pregabalin, LABOCHIM]

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3.2.S.2.5 Process Validation

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3.2.S.2.5 Process Validation [Pregabalin, LABOCHIM]

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3.2.S.2.6 Manufacturing Process Development

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3.2.S.2.6 Manufacturing Process Development [Pregabalin, LABOCHIM]

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3.2.S.3 Characterisation

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3.2.S.3.1 Elucidation of Structure and other Characteristics

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3.2.S.3 Characterisation[Pregabalin, LABOCHIM]
3.2.S.3.1 Elucidation of Structure and other Characteristics [Pregabalin, LABOCHIM]
ACTIVE PHARMACEUTICAL INGREDIENT
PREGABALIN
NH2
H
COOH
(s)
mol.wt.159.18
The product is manufactured with the Labochim synthesis route described in section 3.2.S.2 Manufacture.
The final API is tested according to the method described in section 3.2.S.4 Control of Drug Substance.
Originally, an R&D sample was characterized as reference standard: it was named PRG0D001R (former
FG 1509) after being investigated by different techniques.
Currently a production batch has been characterized as reference standard.

It has been named PRG0M010R (former 108002).
The chemical structure has been investigated by the following techniques:
1. Infrared spectroscopy
2. 1H NMR spectroscopy
3. 13C NMR spectroscopy
4. Mass spectroscopy
5. DSC analysis
6. X-ray diffractometry
7. Elemental analysis
The characterization is reported in the following pages.

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3.2.S.3 Characterisation [Pregabalin, LABOCHIM]
IR SPECTROSCOPY OF PREGABALIN REFERENCE STANDARD PRG0M010R

(LABOCHIM FORMER BATCH 108002).
Instrument Perkin-Elmer Spectrum 100 spectrophotometer
The relevant IR spectrum as is enclosed in the following pages.

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IR SPECTRUM OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM FORMER

BATCH 108002)

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1
H-NMR SPECTROSCOPY OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM
FORMER BATCH 108002)
Instrument THERMO FOCUS

Solvent Deuterated water (D2O)
NH2
H
COOH
(s)
ppm H Multiplicity Group Assignment

0.81-0.84 6 multiplet 2 CH3-
1.15 2 doublet of doublet CH-(CH2)-CH-
1.59 1 multiplet CH3-CH-CH3
2.1-2.3 3 multiplet -CH2-COOH ; -CH-CH2-COOH
2.9-3.0 2 multiplet -CH2-NH2
The 1H-NMR spectrum of Pregabalin reference standard Labochim batch 108002 is enclosed in the
following page. The spectrum is consistent with the structure assigned to Pregabalin.

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H-NMR SPECTRUM OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM
FORMER BATCH 108002) page 1/2

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H-NMR SPECTRUM OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM

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C-NMR SPECTROSCOPY OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM

Solvent Deuterated water (D2O)
NH2
H
COOH
(s)
ppm Group Assignment

21.5 CH3
21.9 CH3
24.3 CH
31.6 CH
40.6 CH2
40.7 CH2
43.7 CH2
181.1 COOH

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C-NMR SPECTRUM OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM

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C-NMR SPECTRUM OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM

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MASS SPECTROSCOPY OF PREGABALIN REFERENCE STANDARD PRG0M010R

(LABOCHIM FORMER BATCH 108002)
The mass spectrum (EI+), reported in the following page, is consistent with the structure assigned to
Pregabalin reference standard Labochim batch 108002.
The molecular weight of Pregabalin is confirmed by (M+1)= 160.

The most prominent fragments and their possible structures are shown below.
m/z Fragment
160 Molecular ion(M+1)+
142 M-OH
The Mass Spectrum of Pregabalin Labochim batch 108002 is enclosed in the following page.

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MASS SPECTRUM OF PREGABALIN REFERENCE STANDARD PRG0M010R (LABOCHIM


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DSC ANALYSIS OF LABOCHIM OF PREGABALIN LABOCHIM PRODUCTION.
Differential Scanning Calorimetry (DSC) diagrams performed on the three Pregabalin validation batches
108001, 108002 ( current Reference Standard PRG0M010R) and 108003.
The DSC diagrams, obtained at a scan rate of 10°/minute, show for reference standard a single melt
endotherm around 197 °C.

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DSC ANALYSIS OF PREGABALIN VALIDATION BATCH 108001.

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DSC ANALYSIS OF PREGABALIN VALIDATION BATCH 108002 (CURRENT RS PRG0M010R).

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DSC ANALYSIS OF PREGABALIN VALIDATION BATCH 108003.

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X-RAY POWDER DIFFRACTOGRAMS OF PREGABALIN LABOCHIM PRODUCTION
In order to demonstrate the absence of polymorphism and the consistency of Labochim production
Pregabalin, an x-ray powder diffraction has been run on three different production batches. All the
supporting data are enclosed in the following pages:
- X-ray powder diffractograms of batches 108001, 18002, 18003 and PRG-0D001R
The translation from Italian into English of Politecnico University comment confirming the X-ray powder
diffractograms to be superimposible is enclosed as well.

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POLITECNICO OF MILAN: COMMENT ABOUT THE COMPARISON AMONG THE X-RAY POWDER
DIFFRACTOGRAMS OF PREGABALIN LABOCHIM BATCH PRG0M010R AND THREE VALIDATION
BATCHES OF CURRENT PRODUCTION.

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TRANSLATION FROM ITALIAN INTO ENGLISH OF POLITECNICO OF MILANO COMMENTS

ABOUT THE COMPARISON AMONG THE X-RAY POWDER DIFFRACTOGRAMS OF PREGABALIN
LABOCHIM BATCH PRG0M010R AND THREE VALIDATION BATCHES OF CURRENT
PRODUCTION.
Re.: identification, through XRPD, of the crystalline phases of 4 samples of Pregabalin batches 108001,
108002, 108003 and PRG 0D001R.
From the comparison among the diffractograms of samples in analysis and the ones in patent literature of
Pregabalin it is evident that:
− All four samples consist of the same crystalline phase.
− This crystalline phase is the same of Pregabalin described in patent CN1634869.
− From an update of scientific literature, it results also that the crystalline structure of this form
was resolved and described by X ray diffraction data of single crystal and this work was
published on: Acta Christ. C63, o306 (2007)
Note: four samples batches were formed by single crystals, having a coarser size than conventional
crystalline powders. For this reason, samples in analysis were properly milled.
4 diffractograms enclosed:, prg 108001, prg 18002, prg 18003 and prg 0D001R.

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X-RAY POWDER DIFFRACTOGRAM OF PREGABALIN LABOCHIM BATCH PRG-0D001R

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X-RAY POWDER DIFFRACTOGRAM OF PREGABALIN LABOCHIM BATCH 108001

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X-RAY POWDER DIFFRACTOGRAM OF PREGABALIN BATCH 108002 (CURRENT RS

PRG0M010R)

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X-RAY POWDER DIFFRACTOGRAM OF PREGABALIN BATCH 108003

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ELEMENTAL ANALYSIS OF PREGABALIN REFERENCE STANDARD PRG0M010R

(LABOCHIM FORMER BATCH 108002)
Instrument CARLO ERBA INSTRUMENTS ELEMENTAL ANALYZER 1108
Element C H N O
% calculated 60.45 10.76 8.80 20.10
% found 60.45 10.78 8.73 20.07
Analysis performed by an external laboratory (REDOX s.n.c. – Viale Stucchi 62/26 - 20052 Monza MI).
The elemental analysis is enclosed in the following page.

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ANALYSIS CERTIFICATE OF REFERENCE STANDARD PRG0M010R

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3.2.S.3.2 Impurities

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3.2.S.3.2 Impurities [Pregabalin, LABOCHIM]
ORGANIC IMPURITIES
The potential impurities detectable in Labochim Pregabalin are listed here below:
a. 3-carbamoylmethyl-5-methyl hexanoic acid , [ R(-)Monoamide ]
O
NH2
COOH
This impurity corresponds to the starting material of the synthesis process to manufacture the Pregabalin .
It represents a synthesis impurity and not a degradation product.
This impurity is kept under control by UPLC analysis used for the release.
b. 3-isobutyl glutaric acid

COOH
COOH
This impurity can be generated , as by-product , during the synthesis of crude Pregabalin.

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c. (S)-4-isobutyl-2-pyrrolidinone ( S-Lactam )
H
N
H
O
(s)
This impurity can be obtained by an intramolecular cyclization of the final product ( Pregabalin) as
described by the following scheme:
NH2 H
OH N
H H
(s) -H2O O
O (s)
Pregabalin
It represents a synthetic by-product impurity, as well as a degradation product.


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The certificate of analysis and spectra listed here below are enclosed in the following pages:
3-carbamoylmethyl-5-methyl hexanoic acid , [ R(-)Monoamide ]:

- IR spectroscopy of Labochim Reference Standard PRG 0D004I (former batch AN 719)
- 1H-NMR spectroscopy of Labochim Reference Standard PRG 0D004I
- UPLC chromatogram of Labochim Reference Standard PRG 0D004I
- certificate of analysis of Labochim Reference Standard PRG 0D004I
3-isobutyl glutaric acid:

- IR Spectroscopy of of Labochim Reference Standard PRG 0D002I (former batch BG 453)
- 1H-NMR spectroscopy of Labochim Reference Standard PRG 0D002I.
- MASS spectroscopy of Labochim Reference Standard PRG 0D002I.
- DSC of Labochim Reference Standard batch PRG 0D002I
- UPLC chromatogram of Labochim Reference Standard PRG 0D002I
(S)-4-isobutyl-2-pyrrolidinone ( S-Lactam ):
- IR spectroscopy of Labochim Reference Standard PRG 0D003I (former batch FG 1470)
- 1H-NMR spectroscopy of Labochim Reference Standard PRG 0D003I
- MASS spectroscopy of Labochim Reference Standard PRG 0D003I
- DSC of Labochim Reference Standard PRG 0D003I
- UPLC of Labochim Reference Standard PRG 0D003I

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IR SPECTROSCOPY OF PREGABALIN REFERENCE STANDARD LABOCHIM BATCH

PRG0D004I
The relevant IR spectrum is enclosed in the following page.

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IR SPECTRUM OF 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACID LABOCHIM

REFERENCE STANDARD PRG-0D004I

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1
H-NMR SPECTROSCOPY OF 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACID ,
[R(-)MONOAMIDE] LABOCHIM REFERENCE STANDARD PRG-0D004I
Instrument BRUKER AC 300

Solvent Dimethyl sulfoxide (DMSO d6)
O
NH2
COOH

0.83 6 doublet 2 CH3-
1.12 2 Doublet of doublet 2 CH3-
1.61 1 Multiplet CH3-CH-CH3
-CH2-COOH ; -CH-CH2-COOH
1.96-2.28 5 Multiplet
-CH2-CONH2
6.7 1 Broad singlet -NH2
7.2 1 Broad singlet -NH2
11.96 1 Broad singlet -COOH
The NMR, enclosed hereafter, is consistent with the structure assigned to 3-carbamoylmethyl-5-methyl
hexanoic acid , [ R(-)Monoamide ]
.

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H-NMR SPECTRUM OF 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACID LABOCHIM
REFERENCE STANDARD PRG-0D004I (page 1 of 4)

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1

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UPLC CHROMATOGRAM OF 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACID LABOCHIM

REFERENCE STANDARD PRG-0D004I (page 1 of 3_blank solution)

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REFERENCE STANDARD PRG-0D004I (page 2 of 3_resolution solution)

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REFERENCE STANDARD PRG-0D004I (page 3 of 3_standard solution)

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ANALYSIS CERTIFICATE OF 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACID LABOCHIM

REFERENCE STANDARD BATCH PRG-0D004I

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IR SPECTROSCOPY OF 3-ISOBUTYL GLUTARIC ACID REFERENCE STANDARD

LABOCHIM PRG-0D002I
The relevant IR spectrum is enclosed in the following page.

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IR SPECTRUM OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD BATCH

PRG-0D002I

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1
H-NMR SPECTROSCOPY OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE
STANDARD PRG-0D002I.

Solvent Deuterated chloroform (CDCl3)
COOH
COOH

0.96 6 doublet 2 CH3-
1.60-1.75 1 multiplet CH3-CH-CH3
2.24 2 doublet of doublet -CH2-COOH
2.45-2.55 2 doublet of doublet -CH2-COOH
2.55-2.65 1 multiplet -CH-CH2-COOH
The NMR, enclosed hereafter, is consistent with the structure assigned to 3-isobutyl glutaric acid.

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1
H-NMR SPECTRUM OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD
PRG-0D002I (page1 of 2)

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1
H-NMR SPECTRUM OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD
PRG-0D002I (page2 of 2)

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MASS SPECTROSCOPY OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE

STANDARD PRG-0D002I.
The mass spectrum (EI+), reported in the following pages, is consistent with the structure assigned to 3-
isobutyl glutaric acid.
The molecular weight of 3-isobutyl glutaric acid is confirmed by M+1= 189
m/z Fragment
189 M+1
171 M-OH
The mass spectrum of 3-isobutyl glutaric acid batch PRG-0D002I is enclosed in the following page.

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MASS SPECTRUM OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD PRG-

0D002I (page1 of 2)

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MASS SPECTRUM OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD PRG-

0D002I (page2 of 2)

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DSC ANALYSIS OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD

PRG-0D002I.
Differential Scanning Calorimetry (DSC) diagrams performed on 3-Isobutyl Glucaric Acid Labochim
Reference Standard batch number PRG-0D002I.
endotherm around 45 °C.

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DSC ANALYSIS OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD PRG-

0D002I

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UPLC ANALYSIS OF -ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE STANDARD PRG-

0D002I (page 1 of 3_blank solution)

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0D002I (page 2 of 3_resolution solution)

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0D002I (page 3 of 3_standard solution)

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ANALYSIS CERTIFICATE OF 3-ISOBUTYL GLUTARIC ACID LABOCHIM REFERENCE

STANDARD BATCH PRG-0D002I.

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IR SPECTROSCOPY OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM

To confirm the chemical structure of the product, IR spectrum of (S)-4-isobutyl-2-pyrrolidinone ( S-

Lactam ) Labochim Reference Standard batch PRG-0D003I has been carried out.
The relevant IR spectrum is enclosed in the following pages.

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IR SPECTRUM OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM REFERENCE

STANDARD PRG-0D003I

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1
H-NMR SPECTROSCOPY OF 3(S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-Lactam ) LABOCHIM

Solvent Dimethyl sulfoxide (DMSO d6)
O
NH2
COOH

0.87-0.90 6 2 doublets 2 CH3-
1.50-1.60 1 multiplet CH3-CH-CH3
1.92-2.0 1 Multiplet -CH-CH2-CO
2.35-2.55 2 Multiplet -CH2-CO
2.97 1 doublet of doublet -CH2-NH-
3.46 1 doublet of doublet -CH2-NH-
7.05 1 Broad singlet -NH
The NMR, enclosed hereafter, is consistent with the structure assigned to (S)-4-isobutyl 2-pyrrolidinone

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H-NMR SPECTRUM OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM

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MASS SPECTRUM OF (S)-4-ISOBUTYL 2-PYRROLIDINONE ( S-LACTAM) LABOCHIM

PRG-0D003I
The mass spectrum, reported in the following pages, is consistent with the structure assigned to (S)-
Lactam.
The molecular weight of (S)-Lactam is confirmed by M+= 141
m/z Fragment
142 M+1
141 M
111 M-(CH3CH3)
84 M- (CH3CH3CHCH2)
The mass spectrum of (S)-Lactam is enclosed in the following page.

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MASS SPECTRUM OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM


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DSC ANALYSIS OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM

REFERENCE STANDARD PRG-0D003I.
Differential Scanning Calorimetry (DSC) diagrams performed on S)-4-isobutyl-2-pyrrolidinone ( S-

Lactam ) Labochim Reference Standard batch number PRG-0D003I.
endotherm around 41-42 °C.

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DSC ANALYSIS OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM REFERENCE

STANDARD PRG-0D003I

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UPLC ANALYSIS OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM REFERENCE

STANDARD PRG-0D003I (page 1 of 3_blank solution)

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STANDARD PRG-0D003I (page 2 of 3_resolution solution)

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STANDARD PRG-0D003I (page 3 of 3_standard solution)

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ANALYSIS CERTIFICATE OF (S)-4-ISOBUTYL-2-PYRROLIDINONE ( S-LACTAM ) LABOCHIM

REFERENCE STANDARD PRG-0D003I.

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INORGANIC IMPURITIES
a. Salts
The salts potentially present in Labochim Pregabalin derive from the use of sodium sulphite in the
synthesis. Their potential presence is controlled by the Sulphated Ash test.
b. Catalysts
No catalysts are used in the manufacture of Pregabalin.
RESIDUAL SOLVENTS
The only solvent used by Labochim in the manufacturing process of Pregabalin is Isopropyl Alcohol that
belongs to Class 3 solvents (not more than 5000 ppm).
It is used in the final crystallization step and its limit on the Pregabalin API has been fixed to 2000 ppm.
Further justification can be found under section 3.2.S.4.5.

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3.2.S.4 Control of Drug Substance

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3.2.S.4.1 Specification

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3.2.S.4 Control of Drug Substance [Pregabalin, LABOCHIM]
3.2.S.4.1 Specification [Pregabalin, LABOCHIM]
PREGABALIN
NH2
H
COOH
(s)
C8H17NO2 CAS N° 148553-50-8 mol.wt.159.18
The substance Pregabalin is not included in any Pharmacopoeia.
Storage:
Store in well closed containers, protected from light.
Tests Specifications
Description White to off white crystalline powder. Soluble in
water and in alkaline and acidic solutions
Identification :
A) IR Spectrum Conforms to Pregabalin RS
B) UPLC The retention time of the major peak in the
chromatogram of the test solution correspond to that
of Pregabalin RS in the Resolution test.
C) Melting point (DSC)

193-198°C
pH Between 6.5 and 8 in a solution ( 1 g in 50 ml water)

Loss on drying Not more than 0.7%.
Water (K. Fisher) Not more than 0.5%
Heavy metals Not more than 20 ppm

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3.2.S.4.1 Specification [Pregabalin, LABOCHIM]
Tests Specifications
Related substances (UPLC):
-R(-)-3-carbamoylmethyl-5-
Not more than 0.1%.
methyl hexanoic acid
[ R(-)Monoamide ]
- 3-isobutyl glutaric acid Not more than 0.1%.
- (S)-Lactam Not more than 0.1%.

- each unknown impurity Not more than 0.10%.
- Total impurities Not more than 0.5%
Assay Not less than 98.0% and not more than 102.0% on
dried basis.
Enantiomeric excess (HPLC) Not less than 98.0%
Residue on ignition Not more than 0.1%
Limit of chloride Not more than 100 ppm
Residual solvents:
Isopropanol NMT 2000 ppm

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3.2.S.4.2 Analytical Procedures

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3.2.S.4.2 Analytical Procedures [Pregabalin, LABOCHIM]
TEST METHODS
Identification
a) IR spectrum: the infrared absorption spectrum is concordant with the reference spectrum of Pregabalin
RS.
b) In the test for the related substances the retention time of the major peak in the chromatogram of the
test preparation corresponds to that of Pregabalin RS in the chromatogram of the standard solution.
Melting point
(Equipment : Differential Scanning Calorimetry DSC 50 Shimadzu or equivalent sistem )
Charge an aluminum crucible with 2-4 mg of dry powder and close the crucible. Heat to 230°C at the rate
of 10°C/min.
Water
Determined by Karl Fisher on 0.5-1 g of Pregabalin.
Heavy metals
1.0 g of the substance to be examined are dissolved in 20 ml of water; 12 ml of this solution complies
with the limit test A for heavy metals (20 ppm). Prepare the reference solution using 1 ml of the lead
standard solution (10 mcg Pb/ml) R.
pH
Accurately weight 1 g of Pregabalin in analysis. Dissolve and dilute to 50 ml with water.
Limit of chloride
Accurately weight approximately 1500 mg of the substance being examined and transfer to a 100 ml
beaker. Dissolve in 50 ml of a mixture of 60 volumes of water , 39 volumes of methanol and 1 volume of
acetic acid. Titrate with 0.01 N silver nitrate, determining the end point potentiometrically. Perform a
blank determination , and make any necessary corrections. Each ml of 0.01 N silver nitrate is equivalent
to 0.3545 mg of chloride
Loss on drying
Dried 1 g of sample at 60°C at a pressure of 0.7kPa for 3 hours.

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Residue on ignition
Not more than 0.1%
Assay ( potentiometric)
Accurately weigh about 200 mg of the sample in analysis . Dissolve in 30-40 ml of acetic acid and titrate
with 0.1 N perchloric acid.
Each ml of 0.1 N perchloric acid is equivalent to 15.918 mg of Pregabalin.
Correct the assay with the value of loss on drying of the sample, applying the following formula: assay /
(100 – LOD) x 100.
Related substances
Apparatus and Conditions
Liquid chromatograph Acquity UPLC, or equivalent system.

Column Acquity UPLC BEH C18 1.7 μm, 2.1 x 50 mm
Column temperature 60°C
Preparatio of eluent A Dissolve 0.58 g of monobasic ammonium phosphate and 1.83 g of

sodium perchlorate in 1000 ml of water. Adjust with phosphoric acid
to a pH of 1.8.
Eluent B Acetonitrile
Gradient time (min) Eluent A Eluent B

0 80% 20%
0.6 80% 20%
2.0 95% 5%
3.0 95% 5%
3.2 80% 20%
5.0 80% 20%
Flow rate 0,6 ml/minute

Wavelength 215 nm
Volume injected 0.7 µl (partial loop with needle overfill)
Run time 5 min
Diluent 50% acetonitrile 50% water

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Sample solution :
In a 25 ml volumetric flask weight accurately about 700 mg of sample; make to volume with diluent.
Standard solution:
In a 50 ml volumetric flask weight accurately about 70 mg of each impurity :R (-) Monoamide RS ; S(+)
lattame ; 3-isobutyl glutaric acid ; Pregabalin RS and make to volume with diluent.
Transfer 1.0 ml of this solution in a 10 ml volumetric flask and make to volume with diluent.
Procedure
Inject three times 0,7 μl of standard solution and record the peak responses :
The resolution factor is not less than 3.
The RSD% for three injection is not more than 5.0%
Inject 0.7 μl of sample solution and record the peak responses.
Identify the impurities in the sample Vs standard solution and calculate the impurities content by
following formulas:
R (-) Monoamide : Wsa x Aca x 5__

Asa x Wc
S(+) lattame : Wsb x Acb x 5__

Asb x Wc
3-isobutyl glutaric acid: : Wsc x Acc x 5__

Asc x Wc
Where:
Wsa =Weight of R (-) Monoamide ( mg)
Wsb = Weight of S(+) lattame ( mg)
Wsc = Weight of 3-isobutyl glutaric acid ( mg)
Wc = Weight of sample ( mg)
Aca =Area R (-) Monoamide
Acb = Area of S(+) lattame
Acc = Area of 3-isobutyl glutaric acid
Calculate the content of each unidentified impurity in area%.

Calculate the total impurities amount by the sum of each impurity.

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Related Substances: typical chromatogram of blank solution

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Related Substances: typical chromatogram of standard solution

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Related Substances: typical chromatogram of sample solution.

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Enantiomeric Excess
Apparatus and conditions

Liquid chromatograph water Alliance equipped with Variable Wavelenght UV-VIS detector or
equivalent sistem
Column: Thermo Hypersil HyPurity C18 5 μm, 150 x 4,6 mm
Column temperature: 25°C
Buffer solution: Dissolve 10 g of triethylamine in 1000 ml of water.
adjust with phosphoric acid to pH 3 .
Mobile Phase: Prepare a filtered and degassed mixture of Buffer solution and
acetonitrile 60/40.
Flow rate: 2 ml/minute
Wavelength: 340 nm
Injection volume: 20 μl
Run time: 40 min
solution A
Transfer about 80 mg of Pregabalin in analysis , accurately weight , to a 10 ml volumetric flask , dissolve
and dilute to volume with water.
solution B
Transfer about 10 mg of Nα-(2,4-dinitro-5-fluoro-phenyl)-L-Valinamide , accurately weight, to a 10 ml
volumetric flask, dissolve and dilute to volume with acetone.
solution C
Transfer about 840 mg of Sodium hydrogen carbonate, accurately weight, to a 10 ml volumetric dissolve
and dilute to volume with water ( 1 M solution).
solution D
Transfer 1.0 ml of solution A, 2.0 ml of solution B, 0.4 ml of solution C in 5 ml volumetric flask.
Heat to 40°C and hold for 3 hours. Cool to 25°C and add 0.2 ml of 2 M hydrochloric acid.

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Procedure
Inject 20 μl of the solution D and record the peak responses: the first peak in the chromatogram is the
unreacted Nα-(2,4-dinitro-5-fluoro-phenyl)-L-Valinamide (excess reactant); the second peak is the
diastereomeric adduct of S(+) Pregabalin; the third peak is the diastereomeric adduct of R(-) Pregabalin.
Measure the areas of the second and third peaks. Using the response obtained from the UV detector and
calculate the enantiomeric excess by the formula:
AS - AR
Enantiomeric excess (%) = ------------------ x 100
AS + AR
AS = area of the diastereomeric adduct of S(+) Pregabalin , second peak
AR = area of the diastereomeric adduct of R(-) Pregabalin , third peak.

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Enantiomeric excess: typical chromatogram of blank solution

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Enantiomeric excess: typical chromatogram of sample solution

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Residual solvents
Apparatus and Conditions
Instrument Gas chromatograph Agilent 7890 equipped with HS G1888 or
equivalent system.
Detector Flame ionization
Column Fused silica, DB-624, 30m x 0.53 mm
Temperature 40°C for 7 minutes up to 150°C increasing 10°C/minute,
hold time 3 minutes
- Injector, 150°C
- Detector, 270°C
Carrier Helium (36 KPa, constant pressure)
Autosampler head space Agilent G1888 or equivalent sistem
Injection 1 ml of the gaseous phase
Split flow 26 ml/min
Standard Solution A
In a 200 ml volumetric flask transfer 4 ml of Isopropanol. Dissolve and dilute to volume with water. Isopropanol
d= 0.79 c = 15,8 mg/ml
Standard Solution B
In a 200 ml volumetric flask transfer 10 ml of the standard solution A. Dilute to volume with water, and
mix accurately. c = 790 µg/ml.
Standard Solution C
In a 200 ml volumetric flask transfer 10 ml of the standard solution B. Dilute to volume with water, and
mix accurately. c = 39,5 µg/ml
In a suitable bottle for head space transfer 10 ml of the standard solution C and close accurately- Prepare
5 bottles.
Each bottle contains 395 µg of Isopropanol.

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Test solution
In a suitable bottle for head space transfer 0.2 grams of Pregabalin in analysis and 10 ml of water. Close
the bottle accurately and shake to dissolution.
Each bottle must be heated to 60°C for 10 minutes before injecting.
System suitability
The retention time are approximately 2.9 minutes for Isopropanol.
The relative standard deviation, for 5 replicate injections of standard solution C is not more than 5%.
Procedure
Separately inject into the gas chromatograph 1 ml of gaseous phase taken from head space each of
standard solution C and the test solution.
Calculate the ppm of Isopropanol with the formula:
AECx 395
ppm Isopropanol : -----------------------
AES x W(g)
Where:
AEC is the area of Isopropanol in the chromatogram obtained with the test solution;
AES is the area of Isopropanol in the chromatogram obtained with the standard solution C;
W(g) is the weight in grams of Pregabalin in the test solution.

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3.2.S DRUG SUBSTANCE [Pregabalin LABOCHIM]
3.2.S.4 Control of Drug Substance [Pregabalin , LABOCHIM]
Residual Solvent: typical chromatogram of blank solution (1/2)

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Residual Solvent: typical chromatogram of blank solution (2/2)

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Residual Solvent: typical chromatogram of standard solution C (1/2)

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Residual Solvent: typical chromatogram of standard solution C (2/2)

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Residual Solvent: typical chromatogram of sample solution (1/2)

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Residual Solvent: typical chromatogram of sample solution (2/2)

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3.2.S.4.3 Validation of Analytical Procedures

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3.2.S.4.3 Validation of Analytical Procedures [Pregabalin, LABOCHIM]
The methods of analysis used for the final control of the product are described in sections “3.2.S.4.1
Specification” and “3.2.S.4.2 Analytical Procedures”.
The following methods have been validated:
1. UPLC method for the determination of related substances.

2. Forced Degradation study by UPLC.
3. GLC method for the determination of residual solvents.
4. Potentiometric method for the determination of assay.
5. HPLC method for determination of enantiomeric excess

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VALIDATION OF THE UPLC METHOD FOR RELATED SUBSTANCES
1 METHOD DESCRIPTION
Liquid chromatograph Acquity UPLC, or equivalent system.
Column Acquity UPLC BEH C18 1.7 μm, 2.1 x 50 mm
Column temperature 60°C
Preparatio of eluent A Dissolve 0.58 g of monobasic ammonium phosphate and 1.83 g of
sodium perchlorate in 1000 ml of water. Adjust with phosphoric acid
to a pH of 1.8.
Eluent B Acetonitrile
Gradient time (min) Eluent A Eluent B
0 80% 20%
0.6 80% 20%
2.0 95% 5%
3.0 95% 5%
3.2 80% 20%
5.0 80% 20%
Flow rate 0,6 ml/minute

Wavelength 215 nm
Volume injected 0.7 µl (partial loop with needle overfill)
Run time 5 min
Diluent 50% acetonitrile 50% water
Sample solution :
In a 25 ml volumetric flask weight accurately about 700 mg of sample ; make to volume with diluent.
Standard solution:
In a 50 ml volumetric flask weight accurately about 70 mg of each impurity :R (-) Monoamide RS; S(+)
lactam ; 3-isobutyl glutaric acid; Pregabalin RS and make to volume with diluent.
Transfer 1.0 ml of this solution in a 10 ml volumetric flask and make to volume with diluent.

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Procedure
Inject three times 0,7 μl of standard solution and record the peak responses:
The resolution factor is not less than 3.
The RSD% for three injection is not more than 10.0%.
Inject 0.7 ul of sample solution and record the peak responses:
Identify the impurities in the sample Vs standard solution and calculate the impurities content by
following formulas:
R (-) Monoamide : Wsa x Aca x 5__

Asa x Wc
S(+) lactam : Wsb x Acb x 5__
Asb x Wc
3-isobutyl glutaric acid: : Wsc x Acc x 5__

Asc x Wc
Where:
Wsa =Weight of R (-) Monoamide (mg)
Wsb = Weight of S(+) lactam (mg)
Wsc = Weight of 3-isobutyl glutaric acid (mg)
Wc = Weight of sample (mg)
Aca =Area R (-) Monoamide
Acb = Area of S(+) lactam
Acc = Area of 3-isobutyl glutaric acid
Calculate the content of each unidentified impurity in area%.

Calculate the total impurities amount by the sum of each impurity.

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2 VALIDATION
2.1 SPECIFICITY
The resolution factor obtained with the nearest peaks is:
R Pregabalin / R(-)monoamide = 5.2
Comments
The acceptance limit, resolution factor > 3, has been respected.
The analytical method is selective for all the impurities considered.
2.2 PRECISION
2.2.1 System precision
System precision was evaluated by performing six replicate injections of a solution containing Pregabalin,
R(-)monoamide, S(+)lactam and 3-isobutyl glutaric acid in a concentration equivalent to 0.05% w/w
related to the concentration of the sample solution described in the analytical method.
Average, standard deviation and relative standard deviation have been calculated on the areas and
retention times.
Sample PREGABALIN R (-)Monoamide

Area RT Area RT
S1 154 0.331 551 0.522
S2 157 0.329 553 0.522
S3 149 0.330 584 0.522
S4 174 0.330 576 0.522
S5 160 0.331 537 0.522
S6 164 0.332 542 0.523
Average S 159.67 0.331 557.17 0.522
Std. dev. 8.69 0.001 18.80 0
RSD% 5.44 0.32 3.37 0.08

3.2.S.4 28

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Sample S(+) lactam 3-isobutyl glutaric acid

Area RT Area RT
S1 2488 1.339 203 1.054
S2 2394 1.339 201 1.054
S3 2434 1.341 209 1.050
S4 2454 1.340 244 1.056
S5 2365 1.341 234 1.054
S6 2451 1.343 217 1.052
Average S 2431 1.341 218 1.053
Std. dev. 44.52 0.002 17.48 0.002
RSD% 1.83 0.11 8.02 0.20
Comments
The RSD% is within the acceptance limit (RSD% less than 10.0%) for both areas and retention times,
therefore the results obtained show good reproducibility of the retention times and good precision of the
responses.
2.2.2 Method precision

Method precision was performed on six preparation of the standard solution described in the analytical
method.
The response factors obtained with the relevant average, standard deviation and relative standard
deviation are reported in the following table.
S(+) lactam 3-isobutyl glutaric acid

Weight Area RF Weight Area RF
S1 70.78 mg 2542 35.91 S1 69.98 mg 316 4.52
S2 70.02 mg 2498 35.68 S2 70.15 mg 324 4.62
S3 70.63 mg 2509 35.52 S3 70.91 mg 331 4.67
S4 71.14 mg 2497 35.10 S4 71.47 mg 363 5.08
S5 70.34 mg 2511 35.70 S5 70.36 mg 340 4.83
S6 70.22 mg 2424 34.52 S6 71.70 mg 309 4.31
Average S 2496.8 35.41 Average S 330.5 4.67
Std. dev. 39.23 0.51 Std. dev. 19.30 0.26
RSD% 1.6 1.44 RSD% 5.8 5.66

3.2.S.4 29

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Pregabalin R (-)Monoamide
S1 70.39 mg 172 2.44 S1 70.17 mg 556 7.92
S2 70.27 mg 165 2.35 S2 70.04 mg 530 7.57
S3 70.96 mg 173 2.44 S3 70.56 mg 562 7.96
S4 70.68 mg 174 2.46 S4 71.15 mg 621 8.73
S5 70.19 mg 177 2.52 S5 70.42 mg 587 8.34
S6 71.63 mg 177 2.47 S6 70.71 mg 523 7.40
Average S 173 2.46 Average S 563.2 7.99
Std. dev. 4.43 0.06 Std. dev. 36.55 0.49
RSD% 2.6 2.33 RSD% 6.5 6.14
Comments
The RSD% calculated on the response factors obtained is within the acceptance
limit (RSD less than 10.0%).

3.2.S.4 30

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

2.3 INTERMEDIATE PRECISION
2.3.1 Intermediate system precision

System precision was repeated by a different analyst by performing six replicate injections of a solution
containing 0.05% w/w of Pregabalin, R(-)monoamide, S(+)lactam and 3-isobutyl glutaric acid related to
the concentration of the sample solution described in the analytical method. Average, standard deviation
and relative standard deviation have been calculated on the areas and retention times.
Sample PREGABALIN R (-)Monoamide

Area RT Area RT
S1 119 0.332 540 0.525
S2 120 0.332 542 0.524
S3 118 0.331 537 0.524
S4 118 0.330 539 0.523
S5 119 0.332 541 0.524
S6 117 0.332 539 0.525
Average S 118.5 0.332 539.67 0.524
Std. dev. 1.05 0.0008 1.75 0.0007
RSD% 0.89 0.25 0.32 0.14
Sample S(+) lactam 3-isobutyl glutaric acid

Area RT Area RT
S1 2567 1.358 268 1.067
S2 2562 1.359 262 1.064
S3 2565 1.359 267 1.065
S4 2568 1.354 268 1.066
S5 2564 1.355 267 1.062
S6 2566 1.357 269 1.062
Average S 2565.33 1.357 266.83 1.064
Std. dev. 2.16 0.0021 2.48 0.0021
RSD% 0.08 0.15 0.93 0.19

3.2.S.4 31

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Comments
The RSD% is within the acceptance limit (RSD less than 10.0%) for both areas and retention times,
therefore the results obtained show good reproducibility of the retention times and good precision of the
responses.
2.3.2 Intermediate method precision

Method precision was repeated by a different analyst on six preparation of the standard solution described
in the analytical method.
The response factors obtained with the relevant average, standard deviation and relative standard
deviation are reported in the following table.
S(+) lactam 3-isobutyl glutaric acid

S1 72.43 mg 2579 35.61 S1 72.55 mg 278 3.83
S2 71.27 mg 2524 35.41 S2 70.06 mg 233 3.33
S3 70.44 mg 2523 35.82 S3 70.07 mg 250 3.57
S4 70.23 mg 2542 36.20 S4 70.26 mg 248 3.53
S5 70.77 mg 2532 35.78 S5 70.82 mg 246 3.47
S6 70.06 mg 2561 36.55 S6 70.25 mg 270 3.84
Average S 2543.5 35.89 Average S 254.2 3.60
Std. dev. 22.37 0.41 Std. dev. 16.67 0.20
RSD% 0.88 1.15 RSD% 6.6 5.70

3.2.S.4 32

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Pregabalin R (-)Monoamide
S1 73.60 mg 164 2.23 S1 72.39 mg 570 7.87
S2 70.03 mg 151 2.16 S2 71.10 mg 535 7.52
S3 70.02 mg 149 2.13 S3 70.74 mg 536 7.58
S4 70.47 mg 160 2.27 S4 70.23 mg 537 7.65
S5 70.40 mg 159 2.26 S5 70.85 mg 563 7.95
S6 70.52 mg 159 2.25 S6 70.30 mg 547 7.78
Average S 157 2.22 Average S 548 7.72
Std. dev. 5.76 0.06 Std. dev. 15.13 0.17
RSD% 3.7 2.69 RSD% 2.8 2.19
Comments
The RSD% calculated on the response factors obtained is within the acceptance
limit (RSD less than 10.0%).

3.2.S.4 33

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

2.4 LINEARITY
The linearity study was carried out with standard solutions containing Pregabalin,
R(-)monoamide, S(+)lactam and 3-isobutyl glutaric in different concentrations (equivalent to 50% - 75%
- 100% - 125% - 150% of the concentration used for the routine calibration). Each solution has been
injected three times.
The concentrations, areas obtained, linearity curve and calculations of the linear regression for the
impurities under examination are illustrated in the following charts.
Solution Pregabalin
area 1 area 2 area 3 average area
L1 155 149 146 150
L2 224 224 222 223
L3 301 307 305 304
L4 391 394 394 393
L5 466 467 458 464
Solution % concentration against Pregabalin
specification limit μg / ml average area
L1 50% 14.206 150
L2 75% 21.309 223
L3 100% 28.412 304
L4 125% 35.515 393
L5 150% 42.618 464
PREGABALIN LINEARITY
500
450
400
350
300
Area
250
200
150 y = 11,2206x - 11,9333
2
100 R = 0,9982
50
0
0 5 10 15 20 25 30 35 40 45
ug/ml
Comments
Considering the coefficient of linear correlation (R2), which is very close to 1 (acceptance limit: NLT
0.995), a good correlation between the response and the concentration is confirmed.

3.2.S.4 34

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Solution R (-)Monoamide
L1 559 556 558 558
L2 852 855 850 852
L3 1109 1110 1108 1109
L4 1404 1407 1460 1424
L5 1736 1778 1729 1748
Solution % concentration against specification limit R(-)Monoamide

μg / ml average area
L1 50% 14.10 558
L2 75% 21.15 852
L3 100% 28.20 1109
L4 125% 35.25 1424
L5 150% 42.30 1748
R(-)MONOAMIDE LINEARITY
2000
1800
1600
1400
1200
Area
1000
800
600
400 y = 41,8629x - 42,4667

2
R = 0,9970
200
0
0 5 10 15 20 25 30 35 40 45
ug/ml
Comments

3.2.S.4 35

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Solution 3-isobutyl glutaric acid
L1 303 305 304 304
L2 451 459 445 452
L3 571 571 570 571
L4 742 738 758 746
L5 859 859 877 865
Solution % concentration against specification limit 3-isobutyl glutaric acid

L1 50% 14.21 304
L2 75% 21.32 452
L3 100% 28.42 571
L4 125% 35.53 746
L5 150% 42.63 865
3-ISOBUTYL GLUTARIC ACID LINEARITY
1000
900
800
700
600
Area
500
400
300
200 y = 19,9343x + 20,9333

2
R = 0,9960
100
0
0 5 10 15 20 25 30 35 40 45
ug/ml
Comments

3.2.S.4 36

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Solution S(+) lactam
L1 2517 2518 2513 2516
L2 3945 3871 3950 3922
L3 5537 5314 5345 5399
L4 6455 6455 6383 6431
L5 7943 8018 8007 7989
Solution % concentration against specification limit S(+) lactam

L1 50% 14.08 2516
L2 75% 21.12 3922
L3 100% 28.16 5399
L4 125% 35.21 6431
L5 150% 42.25 7989
S(+)LACTAM LINEARITY
9000
8000
7000
6000
5000
Area
4000
3000
2000 y = 191,1045x - 130,8667

2
R = 0,9963
1000
0
0 5 10 15 20 25 30 35 40 45
ug/ml
Comments
The response factor has been calculated (peak response divided by the concentration) and the values have
been individually compared with the average response factor obtained with standard solution L3 very
close to the standard solution used for the routine calibration.

3.2.S.4 37

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

The values obtained with the relevant graphic elaboration are reported in the following charts.
Solution Pregabalin
RF DRF%
L1 10.55 -1.42
L2 10.48 -2.15
L3 10.71 ---
L4 11.07 3.31
L5 10.88 1.57
PREGABALIN DRF%
20
15
10
5
0
-5 1 2 3 4 5
-10
-15
-20

3.2.S.4 38

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Solution S(+) lactam
RF DRF%
L1 178.67 -6.79
L2 185.67 -3.13
L3 191.69 ---
L4 182.67 4.70
L5 189.11 1.34
S(+)LACTAM DRF%
20
15
10
5
0
-5 1 2 3 4 5
-10
-15
-20

3.2.S.4 39

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Solution 3-isobutyl glutaric acid
RF DRF%
L1 21.39 6.54
L2 21.19 5.53
L3 20.08 ---
L4 21.00 4.58
L5 20.29 1.05
3-ISOBUTYL GLUTARIC ACID DRF%
20
15
10
5
0
-5 1 2 3 4 5
-10
-15
-20

3.2.S.4 40

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

Solution R(-)Monoamide
RF DRF%
L1 39.55 0.57
L2 40.30 2.47
L3 39.33 ---
L4 40.38 2.70
L5 41.32 5.06
R(-)MONOAMIDE DRF%
20
15
10
5
0
-5 1 2 3 4 5
-10
-15
-20
Comments
The DRF% obtained at the different concentrations for all the impurities considered are within the
acceptance limits (± 10%), therefore the method under validation is linear in the interval considered.

3.2.S.4 41

ITEM EDITED BY
APPLICANT PART
PRODUCT REVISED BY
3.2 BODY OF DATA

2.5 ACCURACY
The accuracy study was performed by evaluating the recovery obtained with the injection of three
solutions containing each impurity in different concentrations (50% - 100% - 150% of the specification
limits). The standard solution described in the method has been prepared and it was injected three times
to evaluate the system precision.
The results obtained are reported in the following charts.
Standard solution Area Area Area Area

S(+) lactam R(-)Monoamide 3-isobutyl glutaric acid Pregabalin
S1 27266 5896 3280 1746
S2 27413 5922 3276 1723
S3 27630 5954 3236 1705
Average S 27436 5924 3264 1725
Std. dev. 183.12 29.05 24.33 20.55
RSD% 0.67 0.49 0.75 1.2
Comments
Upon the evaluation of the data obtained, the RSD% calculated on the three injections of the standard
solution is within the acceptance limit of the system precision, therefore it can be used to calculate the
recovery for the three accuracy levels considered.
Pregabalin
A1
ug/ml ug/ml
R%
calculated theoretical
1 13.75 14.078 97.67
2 13.19 14.054 93.66
3 13.83 14.192 97.45
4 13.91 14.136 98.40
5 14.15 14.038 100.80
6 14.15 14.326 98.77
Average === === 97.83
Std. dev. === === 2.28
RSD% === === 2.33
Comments
The average recovery obtained for Pregabalin is within the acceptance criteria
(90%-110%).

3.2.S.4 42

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LABORATORIO CHIMICO INTERNAZIONALE s.p.a.

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.1 TABLE OF CONTENTS OF MODULE 3

3.2 BODY OF DATA

Section Content Page

3.2.S.1 General Information [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.2 Manufacture [Pregabalin, LABOCHIM] Omissis–Applicant and 1

3.2.S.3 Characterisation [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.4 Control of Drug Substance [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.5 Reference Standards or Materials [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.6 Container Closure System [Pregabalin, LABOCHIM] Applicant Part 1

3.2.S.7 Stability [Pregabalin, LABOCHIM] Applicant Part 1

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.2.S.1 General Information

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.2 BODY OF DATA

Chemical name : (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.

Company code : PRG-00

CAS No. : 148553-50-8

Proprietary names : Lyrica

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.2 BODY OF DATA

Characteristics : White to off white crystalline powder.

Molecular Formula : C8H17NO2

Molecular Weight : 159.18

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.2.S.1.3 General Properties

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.2 BODY OF DATA

Physical form : Pregabalin is a white or almost white crystalline powder.

Polymorphism : Crystal form was characterized by X-ray diffraction and FT-IR

Melting range : Pregabalin melts between 193°C and 198°C ( DSC )

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

ITEM / PRODUCT SECTION PAGE DATE APPROVED BY

QUALITY ASSURANCE DEPARTMENT

PREGABALIN Quality Assurance

3.2 BODY OF DATA