~teloo -...

I ' , ,

F.No. 4-14/97-DC (Pt CRBIOI l

From The Drug Controller General (India) Directorate General of Health Services

L Nirman Bhawan, New Delhi

Dated: The 5th October, 2007

To .· / CH1lical_~esea~C:~~ ~ ~ioscie~c~s~I) Pv~. Ltd., • ~ § §§j i1 • C3(AJ, 1''1rst .l''loor, HUUA comerc1a1 comp1ex, J. 1

Tarnaka, Secunderabad-500 017,A.P. ~7 2GO"r ILJ % ~O~· J

I" v o}. Sub: Bioavailability/Bioequivalence Study for new drug formulation ;

Regarding.

Ref: Your letter dated 10.02.2007 .

Dear Sir,

This Directorate will continue to accept the bioavailability/bio

equivalence protocols and the report of the studies with the new drugs from

your laboratory, initially for one year subject to the condition that specific

protocol for conducting BE/BA studies be got approved by Institutional

ethics committee and then from this Directorate on case to case basis.

Yours Faithfully,

IA. ~teloo I For Drugs Controller General (I)

T.C. SAGL!K BAKANL!GI

llay ve Eczaclhk Genet Mildilrlttgu Say1 : B.!O.O.iEG.O.l l.00..DI Konu: Denetim

HOSN() ARSAN ILA<;!LARI A.$. Ayazaga koyU yolu 80570

Mas!ak!ISTANBUL

06~Id1U!!'J

Denetimini gen;:ekle~tirdigimiz, Hindistan' in Hyderabad kentinde bulunan CRBIO (Clinical Research and Biosciences Pvt. Ltd.) Biyoe~deg:erlik Merkezi· talebiniz ilzerine 17.06.2008-19.06.2008 tarihleri aras1nda flay A~ttrmalan Hakkmdak.i Y6netmelik. Farmas6tik M'Ostahzarlann Biyoyararlantm ve Biyoe§degerliginin Degerlendirilmesi Haklo.ndaki Ye:>netmelik ve lyi Klinik Uygulamalan Kdavuzu ve iyi Laboratuar Uygulamalan Kdavuzu hOk.funlerine gare denetleruni§ olup, istenilen dilzettmelerin yaptld11t1na dair yaztlann1z kayitlanrruza. altnnu§tlr. A§ag1da adresi belirtilen tesise ili§kin lyi Klinik Uygulama1an Kdavuzu ve lyi Laboratuar Uygulamalan Kllavuzu ko§ullan dogrultusunda biyoyararlantm ve biyoe¢egerlik fah~malanrun yapdmas1 uygun bulunmillitur.

• CRB!O Clinical Research and Biosciences (I) P_Vf. LTD. Cl (A). RUDA ·Commercial Complex Tamaka, Hyderabad-500017, India

Bakanhg1m1ztn gerek. gordu~ zamanda merkezi denetleme yetkisine sahip oldugunun bilirunesi,

SOz konusu merkezin klinik ve analitik ktsunlan ile ilgili yaptlan de~i~ilclikler hakk1nda haztrlanacak. raporun Genel MU.di.irlU~i.lmtlz.e gOnderilmesi gerekmektedir.

Bilginizi ve sOz konusu merkeze yukanda belirtilen hususlann iletilmesi hususunu rica ederim.

co,. s". E. i>oo s". A. s~ .sn. S. o~

s •. ~· $'14' SA. JJ, OiµitJ,..,

os.Qi.o9 c;..c.

<;ankln Cad. 57 D1~kap1- Ulus %060 ANKARA Telefon: (0312) 309 11 41 - 309 70 94 Faks: (0312) 309 71 18 Ag,: www.iegm.gov.tr

F.No.4-14/97-DC Pt (CRBIO) Directorate General Of Health Services Office of Drug Controller General (India)

(Drugs Control Section)

M/s RA Chem Pharma LTD, Clinical research and Bioscience Division C3(a), First floor, HUDA Commmercial Complex Tarnaka ,Securandrabad-500017

FDA Bhawan Katia Road, New Delhi-110002.

Dated f 6 APR 2010

Sub:- Approval of Bioavailability/Bioequivalence Study-regarding.

Sir,

This Directorate will continue to accept the bioavailability/bio-equivalence protocols and the report of the studies with the new drugs from your laboratory subject to the condition that specific protocol for conducting BE/BA studies be got approved by Institutional ethics committee and then from this Directorate on case to case basis and also simultaneously there will be inspection by COSCO, sub-zone, Hyderabad for compliance.

Copy to:-Asstt. Drugs Controller (I}, Central Drugs Standard Control Organization, Sub Zonal Offices, Air Cargo Complex, S.P. Road, Hyderabad, (ANDHRA PRADESH)

Yours faithfully,

~ (A. B. MTEKE)

Joint Drugs Controller (India)

Beige No/Reference No: 11

T.C. SAtLIK BAKANLltl~ ILAC VE ECZACILIK GENEL M0D0RL0li0,

[06.04.2011 - 07.04.2011] tarlhinde diizenlenen denetim sonucuda,

Bu beige ile;

CRBIO

CRBIO C3 (A) HUDA Commercial Complex Tarnaka Hyderabad-500017 /Hindistan

Biyoyararlamm/Biybe§deAerlik ~l1~malann1n Klinik ve Biyoanalitik bolumumln fyi Klinik Uygulamalan ilkeleri

~er~evesinde yiirutiild'ilAfinu onaylar.

Bu beige [24/06/2014] tarihine kadar ge~erlidir.

THE MINISTRY OF HEALTH OF TURKEY, GENERAL DIRECTORATE OF

PHARMACEUTICALS AND PHARMACY,

On the basis of the inspections carried on [06.04.2011- 07.04.2011]

Hereby approve that; clinical and bioanalytical parts of the Bioavailability/Bioequivalence studies conducted by;

CRBIO

CRBIO C3 (A) HUDA Commercial Complex Tarnaka Hyderabad-500017 /India

according to the principles of Good Clinical Practices in compliance with the related legislation.

This document is valid until [24/06/2014].

Yeri ve TarihVPlace and Date of Issue Ankara, [24/06/2011 J

~~-> . Saim KERMAN Gene! MndUr

To

F.t-Jo.4-14/97-DC PT (Cf~B!Ql Directorate General of Health Services

Office of Drug Controller General (India) (Drugs Control Section)

M/s. RA Chem Pharma Ltd.,

FDA Bhawan, Kotla Road, New Delhi-110002. Dated n 9 AUG 201'2.

1st & 2nd Floor, Block No. C-3(a), C3(b), B-3(FF),C-4 & 0-4, HUDA Commercial Complex, · Tarnaka, Secunderabad, AP.

Sub:- Renewal of Approval of Bioavailability/Bioequivalence Study Centre of M/s. RA Chem Pharma ltd., 1st & 2nd Floor, Block No. C-3(a), C3(b), B-3(FF),C-4 & 0-4, HUDA Commercial Complex, Tarnaka, Secunderabad, AP- regarding.

Ref: This office even letter no 4-14/97-0C Pt (CRBIO) dated 16th April, 2010. ·

Sir, Please refer to your letter dated 17/01/2011 received by this Directorate vide diary

no 2548 dated 18/01/2011 on the above subject.

As per documentation submitted by you, this Directorate will accept the protocol and bioavailability /bioequivalence study reports of New Drugs from your laboratory having a Clinical facility of 72 Beds and Bio-analytical facility at 1st & 2nd Floor, Block No. C-3(a), C3(b), B-3(FF),C-4 & 0-4, HUDA Commercial Complex, Tarnaka, Secunderabad, subject to following conditions:-

1. The study centre should ensure that the whole Informed Consent Process shoul<;I be documented through Audio- Video means maintaining the principle of confidentiality.

2. Specific protocol for conducting BE/BA studies with new drug formulation should be . cleared by Institutional Ethics Committee and then got approved from this office on case to case basis.

3. After one year there will be assessment of performance of the said study center for continued acceptance of reports.

Copy to: Dy. Drugs Controller (I), Central Drugs Standard Control Organisation, Zonal Office, Air Cargo Complex, S.P. Road, Hyderabad, (Andhra Pradesh).

Yours faithfully,

(Dr. G. . Singh) ·Drugs Controller Gene al (India)

DEPARTMENT OF HEALTH & HUMAN SERVICES

VIA UPS

September 24, 2012

R. Sirish Kumar, Director RA Chem Pharma Limited Rajbhavan Rd Hyderabad, INDIA

Dear Mr. Kumar :

Public Health Service

Food and Drug Administration Silver Spring, MD 20993

We are enclosing a copy of the Establishment Inspection Report (EIR) for the inspection conducted at your premises, RA Chem Pharma Limited, C3 Huda Complex, Hyderabad, INDIA, by the United States Food and Drug Administration (FDA) from March 26, 2012, to April 3, 2012.

The Agency has concluded that this inspection is closed under 21 CFR 20.64(d)(3). We are therefore releasing a copy of the EIR for the inspected establishment to you. The EIR being provided to you comprises the narrative portion of the report; it reflects redactions made by the Agency in accordance with the Freedom of Information Act (FOIA) and Title 21, Code of Federal Regulations, part 20. However, this does not preclude you from requesting, and possibly obtaining, any additional information provided under FOIA.

The documents provided to you under FDA's FMD-145 Program have not been reviewed for public disclosure, and may contain confidential commercial information (e.g., applicant protocol information) and/or patient information (e.g., patient initials) that you already know in your capacity. FDA would normally redact this type of information before allowing the EIR's public disclosure. If you were to disclose this information to others, you would be responsible for ensuring that sensitive information is adequately protected.

If you would like a copy of the EIR that has been reviewed by FDA and redacted for public disclosure, you will need to submit a FOIA request specifically asking for a publicly disclosable version.

Mr. Kumar Page 2

If you have any questions about the released information, please contact me by letter at the address given below.

Sincerely,

William H, Taylor, Ph.D Director, Division of BEGLPC Office of Compliance Center for Drug Evaluation and Research Food and Drug Administration Building 51, Room 5364 10903 New Hampshire Avenue Silver Spring, MD 20993

Enclosure: Establishment Inspection Report (narrative portion only)

To

4-14/201318A,,BE/30 (RACHEM). Directorate General of Health. S.e.rvices

Office ofDrug ColltroHer General {India) (Drugs Coritrol.Section) ·

Mis. RA Chem Pharma Ltd., Plot No. 26 & 27, Technocrat Industrial Estate, Balanagar,. Hyderabad 500 037.

FDA Bhawan, Kotla Road, New Delhi -110002. Dated,

Sub:- Approval of Bioavailability/Bioequiva!ence Study Centre of M/s. RA Chern Pharma Ltd., Plot No. 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad 500 037 - regarding (Due to change of premises).

Sir, Please refer to your letter no. NH dated 30/11 /2011 and joint inspection report

received by this officevide diary No. 4892 dated 23/01/2013 on the above subject.

As per documentation submitted by you, this Directorate will accept the protocol and bioavailability /bioequivalence study reports of New Drugs from your laboratory having a Clinical facility of 114 Beds and Bio-analytical facility at Mis. RA Chem Pharma Ltd., Plot No, 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad 500 037, subject to following conditions:-

1. The study centre should ensure thatthe whole Informed Consent Process should be documented through Audio- Video means maintaining the principle of confidentiality.

2. Specific protocol for conducting BE/BA studies with new drug formulation should be cleared by Ethics Committee and then got approved from this office on case to case basis.

3. After one year there will be assessment of performance of the said study center for continued acceptance of reports.

Copy to: Deputy Drugs Controller (India), COSCO, Zonal office, Hyderabad,

Yours faithfully,

(D,. kSl"gh) Drugs Controller Ge?eral (India)

CDSCO BHAVAN, Beside T.B. & Demonstration Centre, S.R. Nagar, Hyderabad - 500038

T.C. SAGLIK BAKANLIGI

Turkiye i la~ ve T1bbi Cihaz Kurumu

iyi Klinik UyguJamalar Uyum Belgesi Good Clinical Practice Certificate of Compliance

T.C. SAGLIK BAKANLIGI, TURKiYE iIAc;: VE TIBBi CiHAZ KURUMU,

05-07 Nisan 2013 tarihinde ger~ekle~tirilen denetim sonucunda,

Bu beige ile; RA Chem Pharma Ltd. Clinical Research

& Biosciences Division (CRBIO)

Plot-No. 26&.27, Technocrat Industrial Estate, (TIE), Balanagar, Hyderabat-

500037, INDIA

Adresinde Faaliyet gosteren merkezin Biyoyararlamm/Biyoe~degerl ik <rah~maJarm m

klinik ve biyoanalitik boliimiiniin "iyi Klinik UyguJamalan Kilavuzu" ilkelerine

gore ilgili mevzuat <rer<revesinde yiiriitiildiigunii onaylar.

Bu beige merkezin ilgili mevzuat hiikiim]erine uygunlugunu siirdi.irmesi halinde io.06.2016

tarihine kadar gelj:erlidir.

Beige No/ReferenceNo: 2013-BED098-008

THE MINISTRY OF HEALTH OF TURKEY, TURKISH MEDICINES & MEDICAL

DEVICES AGENCY,

On the basis of the inspections conducted on 05-07 April 2013

Hereby approve that; clinical and bioanalytical part of the Bioavailability/Bioequivalence

studies conducted by; RA Chem Pharma Ltd. Clinical Research &

Biosciences Division (CRBIO)

Plot-No. 26&.27, Technocrat Industrial Estate, (TIE), Balanagar, Hyderabat-500037,

INDIA

according to the principles of Good Clinical Practices in compliance with the

related legislation.

This document valid until io.06.2016 on condition that the center continue to

compliance with the related legislation.

l0.06.2013

urum B~karn

BIRO PENGAWALAN FARMASEUTIKAL KEBANGSAAN NATIONAL PHARMACEUTICAL CONTROL BUREAU

KEMENTERIAN KESIHATAN MALAYSIA MINISTRY OF HEAL TH, MALAYSIA

PROGRAM KOMPLIANS PUSAT KAJIAN BIOEKUIVALENS COMPLIANCE PROGRAMME FOR BIOEQUIVALENCE CENTRE

NO. SIJIL CERT. NO.

KGCPIBE 201309

Nama Pusat Kajian Bioekuivalens Name of Bioequivalence Centre

Alam at Address

Tapak Klinikal Clinical Site

Tapak Bioanalitikal Bie'-analytical Site

Tarikh Pemeriksaan Date of Inspection

RA Chem Pharma Ltd Clinical Research & Biosciences Division (CRBio)

Plot No: 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad, 500037, Andhra Pradesh, India

Plot No: 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad, 500037, Andhra Pradesh, India

25th - 30th August 2013

Pusat Kajian Bioekuivalens tersebut di atas telah disenaraikan di dalam Program Komplians Pusat Kajian Bioekuivalens, Biro Pengawalan Farmaseutikal Kebangsaan , Kementerian Kesihatan Malaysia. Sijil ini sah bagi tiga (3) tahun dari tarikh sijil ini dikeluarkan. The above mentioned Bioequivalence centre is included in the National Pharmaceutical Control Bureau, Ministry of Health Malaysia Compliance Programme for Bioequivalence Centre. This certificate is valid for three (3) years from the date of this certificate issued. ->

Date: 1 oth December 2013 Direc harmacy Regulatory, ational Pharmaceutical Control Bureau ,

Ministry of Health Malaysia

To

4-14/2013/BA-BE/30 (RACHEM) Directorate General of Health Services

Office of Drug Controller General (India) (Drugs Control Section)

FDA Bhawan, Kotla Road, New Delhi -110002.

M/s. RA Chem Pharma Ltd., Clinical Research & Biosciences Division, Plot No. 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad 500 037

Dated :

2 2 JAN 2015

Sub:- Renewal of Approval of Bioavailability/Bioequivalence Study Centre of Mis. RA Chem Pharma Ltd., Clinical Research & Biosciences Division, Plot No. 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad 500 037 -regarding (Due to change of premises).

Sir, Please refer to your letter no. DCGl/FA/001-14 dated 8/01/2014 received by

this office vide diary no. 1035 dated 09/01/2014 on the subject stated above. As per documentation submitted by you, this Directorate will accept the

protocol and bioavailability I bioequivalence study reports of New Drugs from your laboratory having a Clinical facility of 114 Beds and Bio-analytical facility at "Mis. RA Chem Pharma Ltd., Clinical Research & Biosciences Division, Plot No. 26 & 27, Technocrat Industrial Estate, Balanagar, Hyderabad 500 037" subject to following conditions:-

l. The study centre should ensure that the whole Informed Consent Process should be documented through Audio-Video means maintaining the principle of confidentiality.

2. Specific protocol for conducting BE/ BA studies with _new drug formulation should be cleared by Institutional Ethics Committee and then got approved from this office on case to cases basis.

3. After one year there will be assessment of performance of said study centre for continued acceptance of protocol & reports in this regard.

Yours faithfu lly,

"'~ . (Dr. V. G. Somani)

Joint Drugs Controller (India)

Copy to:-Deputy Drugs Controller (India), COSCO, Zonal office, Hyderabad, COSCO BHAVAN, Beside T.B. & Demonstration Centre, S.R. Nagar, Hyderabad - 500038

DEPARTMENT OF HEAL TH ANO HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

DISTRICT OFFICE ADDRESS AND PHONE NUMBER

Division of Generic Drug Bioequivalence Evaluation Office of Study Integrity and Surveillance (OSIS) 10903 New Hampshire Avenue, Bldg 51, Room 5330 Silver Spring, !\.ID 20993 Phone: (301}496-3393

Industry lnfonnation: www.fda.gov/oc/industry NAME AND TITtE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

TO: A. Kiran Kumar, Head-Operations

FIRM NAME STREET ADDRESS

DATE(S} OF INSPECTION

120ct- l60ct20 l5

FEINUMBER

3009291635

RA Chem Pharma Ltd. Plot #26 & 27, Technocrat Industrial Estate Cl1E) CllY, STATE AND ZIP CODE

Balanagar, Hyderabad. AP 500037, INDIA

TYPE OF ESTABLISHMENT INSPECTED

Bioequivalence testing facility

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAL OBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OOJECTION REGARDING AN OBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVF ACTION IN RF.SPONSE TO AN OBSERVATION, YOU MAY DISCUSS TtiE OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S) DURlNG THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA 'T THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM (I) rt'/E} OBSERVED:

The observations were made during the inspection of studies ~ l I. Not all aspects of experiments were recorded accurately. Specifically,

a) For the sample analysis of- in study# . - records show that calibration curve and QC nominal concentrations were changed for calculations but there is no justification and record of these changes in control forms i.e. sample batch processing, extraction steps checklist and project data check up forms. b) For sample analysis of- in study# records show changes of unknown samples to QC and QC to unknown samples. There is no justification and explanation for these changes in control forms. c) In study # - there is no simple retrieval form to confirm that sample - was retrieved from the freezer for reanalysis. The sample retrieval form documents that sample - was taken out of the freezer for reanalysis instead of sample-d) Failure to record events that are necessary to reconstruct studies. Specifically, volumes of subject plasma samples and internal standard solutions during subject sample analysis for studies on sample batch processing forms.

2. Failure to identify the root-cause of high internal standard (JS) variability observed during bioanalytical runs. Specifically, the IS signals of subject samples in following runs are consistently different from those of calibrator and QC samples in the same run, suggesting that the QC samples did not represent subject samples to demonstrate accuracy:

SEE REVERSE OF THIS PAGE

FORM FDA 483 (9/08)

EMPLOYEE(S) NAME ANO TITLE \Print or Type)

INSPECTIONAL OBSERVATIONS

DATEISSUEO

10/16/2015

Page 1of1

The observations of objectionable conditions and practices listed on the front of this form are reported:

1. Pursuant to Section 704(b) of the Federal Food, Drug and Cosmetic Act, or

2. To assist firms inspected in complying with the Acts and regul-ations enforced by the Food and Drug Administration.

Section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 USC 374(b)) provides:

"Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other establishment, and prior to leaving the premises, the officer or employee making the inspection shall give to the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed by him which, in his judgement, indicate that any food, drug, device, or cosmetic in such establishment (1) consists in whole or in part of any filthy, r.:trid, or decomposed substance, or (2) has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health. A copy of such report shall be sent promptly, to the Secretary."

FORM FDA 483 (9/08)

Response to USFDA Inspectional Observations (483s)

Date(s) of Inspection 12 Oct 2015 to 16 Oct 2015

Name of Inspector(s)

Site Inspected

Type of Inspection

Studies Inspected

RA Chem Phanna Ltd, Clinical Research & Biosciences Division, Plot No 26 & 27, TIE, Balanagar, Hyderabad, Telangana, India- 500037. FBI Number - 3009291635

Study Integrity and Surveillance audit

Date of receipt of 16

Oct 2015

Observations

Date of Response 05 Nov 2015

Submitted by A. Kiran Kumar (Head Operations)

Clinical Research and Biosciences Page 1 of9

Plot N('. 26 & 27. Technocrat Industrial Estate, Balanagar, Hyderabad-500 037. A.P., INDIA. Tel:-:-Q 1 40 44758595, Fax: +9 l 40 44 758596, web : www.crbio.co.in


1. Observation: Not all aspects of experiments were recorded accurately. Specifically,

a) For the sample analysis of Subject records show that calibration curve and QC nominal concentrations were changed for calculations but there is no justification and record of these changes in control forms i.e. sample batch processing, extraction steps checklist and project data check up forms.

CRBio Response: We acknowledge the agency's observation. In this case the analyst had imported the sequence from Method Validation sequence, - batch ID and created the sequence for subject number . run on the same LCMSMS system on 17 Jan 2015. The analyst inadvertently missed to change the calibration curve and QC sample concentrations in the batch sequence.

However, during the data review on 19 Jan 2015, it was identified and the reviewer made respective changes in the nominal concentrations of CC and QC (captured in audit trial from serial no. 11 to 21 ). The sequence summary report was printed thereafter. We acknowledge that making a comment or note has been missed here. Referred below are the arinexures showing the actual nominal concentrations.

Refer Annexure I (Bioanalytical Project Report: , page 33 of 106 and 40 of 106) for the actual nominal concentrations of the study.

Refer Annexure II (Subject I audit trail in study# correcting the CC and QC concentrations.

) for the changes made towards

Refer Annexure-III (Method Validation Report (Version: 00) page 21of59 and 22 of 59) for nominal concentrations used during method validation.

Please refer to the changes that have been made in the calibration curve standards and QC nominal concentrations from incorrect value to correct values:

Standard/QC ID

STD5 STD6

STD7

STD8

Nominal Concentration of Nominal Concentration of Project Validation(incorrect value) Sample analysis( correct value)

7.158 7.157

20.451 20.449

40.902 40.897

90.892 90.883

151.487 151.471 114.359 114.165

60.610 60.507

CHEM PHARMA LTD Page 2 of9

inical Research and Biosciences

ocrat Industrial Estate, Balanagar, Hyderabad-500 037. A.P., INDIA. 40 44758595, Fax: 1-9140 44758596, web: www.crbio.co.in

Response to USFDA lnspectional Observations (483s)

Corrective and Preventive Action:

We will ensure that the template from the previous validation experiments or studies will not be

used for the subject sample analysis hereafter and justification is documented appropriately for any

relevant changes/corrections/modifications made during the run to the sequence in the ''Audit Trial

Event Record" and filed along with the raw data.

In case of any change/correction/modification (for example correction of nominal concentration,

sample type, sample ID, correction of vial position, rack position, file name etc.) during or after

completion of the run or during review, the justification shall be documented in the "Audit Trial

Event Record" and other controlled forms as appropriate.

Procedure to document the justification for changes/corrections/modifications made during the run

is incorpo~ated as section no 6.10 "Changes/modification/Corrections" of SOP~. "Project Sample Analysis" effective from 02 Nov 2015.

Training on "Good Documentation Practices" has been imparted to the study personnel. Please

refer to some of the annexures supporting the corrective and the preventive actions:

Refer Annexure IV (Training Attendance on Good documentation practice) for training attendance

on GDP.

Refer Annexure V (SOP No. - "Project Sample Analysis" effective from 02 Nov 2015

with attachments and Training Attendance) for revised SOP and SOP training details.

b) For sample analysis of Subject . in study# records show changes of unknown samples to QC and QC to unknown samples. There is no justification and explanation for these changes in control forms.

CRBio Response: We acknowledge the agency 's observation. In Study - , Subject • the value (sample

type) of unknown sample in row 98 was changed to QC at 11:48hrs on 06 Nov 2012 by the analyst

during the addition of samples to sequence but immediately he realized the error within one minute

at 11 :50 hrs on 06 Nov 2012 and corrected the sample type to unknown from QC.

In another event, sample type in row 20 was corrected to unknown sample from QC. Sample type

of row 20 and row 98 prepared before the acquisition shows correct sample type (unknown).

for the changes made towards

Page 3 of 9

Plot No. 26 & 27. Technocrat Industrial Estate, Balanagar, Hyderabad-500 037. A.P., INDIA. Tel:+<-11 4044758595, Fax; +9140 44758596, web: www.crbio.co.in

llll;J=DC I


Since the mistake was realized during the run, the analyst changed the sample type online, without making a note of the same in the Instrwnent log book or on the raw data sheet.


For all the future studies, in case of any change/correction/modification (for example correction of nominal concentration, sample type, sample ID, correction of vial position, rack position, file name

etc.) during or after completion of the run or during review, the justification shall be documented in the "Audit Trial Event Record "and other controlled forms as appropriate and filed along with the raw data.

Procedure to document the justification for changes/corrections/modifications made during the run

is incorporated as section no 6.10 "Changes/modification/Corrections" of SOP No."Project Sample Analysis" effective from 02 Nov 2015.

Training on "Good Documentation Practices" has been imparted to the study personnel.

Kindly refer to the annexures pertaining to the attendance records and SOP.

Refer Annexure IV (Training Attendance on Good documentation practice) for training attendance on GDP.

Refer Annexure V ''Project Sample Analysis" effective from 02 Nov 2015 with attachments and Training Attendance) for revised SOP and SOP training details.

c) Instud~ there is no sample retrieval form to confirm that sample 111111 was retrieved from the freezer for reanalysis. The sample retrieval form documents that sample 111111 was taken out of the freezer for reanalysis instead of sampe-

CRBio Response: We admit the documentation lapse. The Sample ID- was identified under repeat code-E as per the respective repeat analysis SOP by the reviewer and the same was captured in corresponding data checkup form and authorization for repeat analysis document.

Refer Annexure VII (Project Data Checkup Form and Authorization for Repeat Analysis Form) for

correct repeat sample IDs.

The Deep freezer usage logbook also shows the retrieval of sample ID - and restoring it back.

Refer Annexure VIII (Deep Freezer logbook) for retrieval and restorage entries.

However in the sample retrieval form and in the sequence sheet, the sample ID was captured wrong

as nstead o- by the analyst. Analyst has failed to correct the sample ID in the sample retrieval fo · t have communicated orally to the custodian during the issue and receipt of

""" the sam e.. '-1 (' ~ A

CJ 37 ° ~ \-\~o- . . HEM PHARMA LTD 11 .

('--P_e10 oi: · 1cal R~se1\rch and Biosciences ~- ... ~

Plot N0. 26 & 11,i, _ ocrat Industrial Estate, Balanagar, Hyderabad-500 037. A.P .. INDIA.

Page 4 of9

Tel:+Ql 40 44758595, Fax: +914044758596, web : www.crbio.co.in


The same was overlooked by the reviewer also.

We acknowledge the documentation error and will ensure that training to all the study personnel will be imparted on GDP periodically and all the crucial activities like repeat analysis will be

closely monitored by a second level check before initiating the repeat analysis hereafter.

However as there was ambiguity in the documentation, pharmacokinetic analysis has been

performed to assess the impact on the study outcome and the results are as follows:

BE Summary Results Sample ID- Concentration changed to Initial Value (before repeat)

Within reference SD and CV BE Criteria

Point 95% Upper BE

Parameter SDwr% CVwr % Estimate Bound

Cmax 32.5 33.4 95% Upper Bound should be

100.85 -0.064502 Yes Less than or equal to Zero

AUCO-t 31.4 32.2 95% Upper Bound should be

104.84 -0.052595 Yes Less than or equal to Zero

AU CO-inf 29.3 30.0 Normal BE limits should be

102.91 -0.048369 Yes 80.00 to 125.00

Normal BE Limits for AUCO-inf as CVwr=30%

Parameter Point

· 90o/o CI Lower 90% CI Upper Estimate

AU CO-inf 102.72% 94.12% 112.11%

BE Summary Results -Sample ID- Concentration changed to Zero

Within reference SD and CV BE Criteria

Point 95% Upper BE

Parameter SDwr'Yo CVwro/o Estimate Bound 95% Upper Bound should

Cm ax 32.5 33.4 be Less than or equal to 100.85 -0.064502 Yes Zero

95% Upper Bound should

AUCO-t 31.4 32.2 be Less than or equal to 104.89 -0.052489 Yes Zero

AU CO-inf 29.3 30.0 Normal BE limits should

102.97 -0.048338 Yes be 80.00 to 125.00

Normal BE Limits for A UCO-inf as CV wr=30%

Parameter Point

90°/o CI Lower 90% Cl Upper

94.18% 112.16%


inical Research and Biosciences


From the above results, it is clear that considering the original value (before repeat) of Sample ID - or considering the value as zero did not alter the final conclusion of bioequivalence. Regardless of whether repeat value based on application of our repeats SOP or only when original value was used, the final pharmacokinetic results easily met all required confidence interval BE criteria.


SOP No. - · "Project sample analysis" is revised to incorporate procedure for verification of sample retrieval request for all identified repeat samples and incurred sample reanalysis samples to avoid such documentation errors in request forms.

As per section 6.8.3 to 6.8.5 of SOP No. - · all the samples identified under repeats from the source data will be listed in the "List of Individual Samples" by the analyst and the same will be verified by the other study personnel or IQC against the repeat sample authorization form to avoid documentation errors.

Training on "Good Documentation Practices" has been imparted to the study personnel. Also attached are the annexures pertaining to the attendance record and SOP.

Refer A.nnexure IV (Training Attendance on Good documentation practice) for training attendance on GDP.

Refer Annexure-V (SOP No. - , "Project Sample Analysis" effective from 02 Nov 2015" with attachments and Training Attendance) for revised SOP and SOP training details.

d) Failure to record events that are necessary to reconstruct studies. Specifically, volumes of subject plasma samples and internal standard solutions during subject sample analysis for studies on sample batch processing forms.

CRBio Response: Current sample batch processing form captures the details of solutions used, sample retrieval time, processing start time, end time, auto sampler load time and number of samples. Extraction steps checklist captures details involved in sample analysis as per respective method SOP. Project data checkup form contains the details of calibration curve, quality control samples and their acceptance criteria, batch acceptance and samples identified under repeat analysis but all the above forms failed to capture specific volumes of subject plasma samples and internal standard solutions.

!1-'J~~ervation from the Inspector on 15 Oct 2015, we have started documenting the ac ~ tions in comments column of extraction steps checklist.

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Refer Annexure IX (Extraction steps checklist from study# - ).

However in all the future studies we will ensure that volumes of subject plasma samples and internal standard solutions are documented in the extraction steps checklist to reconstruct studies as per the revised SOP.


SOP No- , "Project Sample Analysis" effective from 02 Nov 2015 is revised to incorporate the required details in the extraction steps checklist and to define the procedure for documenting the details in the extraction steps checklist that are necessary to reconstruct studies specifically, volumes of subject plasma samples and internal standard solutions. Training is imparted to all the applicable study personnel.

Section 6.9 of the revised SOP No. - , "Preparation of Method SOP" effective from 02 Nov 2015 defines the following procedure to capture all the necessary details in the "Extraction steps check list":

The analyst shall document the actual details such as but not limited to (the below mentioned points depends on the extraction method):

• Aliquotion volume of the sample. • Volume of addition of diluent/ internal standard dilution.

• Time taken for vortexing and Instrument/Equipment ID (as applicable).

• Addition of extraction solvent.

• Time taken for centrifugation and Instrument/Equipment ID (time, temperature and RPM as applicable).

• Extraction on the solid phase extraction manifold and Instrument/Equipment ID (as applicable).

• Addition of reconstitution solution.

• Evaporation and Instrument/Equipment (Time, Temperature).

• Any other additional details shall be captured in the "Remarks".

Refer Annexure-X (SOP No- "Preparation of Method SOP" effective from 02 Nov 2015 with attachments and Training Attendance) for revised SOP and SOP training details.


nical Research and Biosciences


2. Observation: Failure to identify the root-cause of high internal standard (IS) variability observed during bioanalytical runs. Specifically ,the IS signals of subject samples in following runs are consistently different from those of calibrator and QC samples in the same run, suggesting that the QC samples did not represent subject samples to demonstrate accuracy: Study# (Subject#)

CRBio Response: In all the studies conducted, we prefer to use only deuteriarated Internal Standard so the variability in the IS area can be reduced. However, for some of the molecules the internal standard variation is still observed.

SOP No- which was effective at the time of studies execution, specifies that the samples

in which !STD response varies by more than ±50% (50 to 150) of mean ISTD response of the accepted CC and QC samples are categorized as identified repeats for internal standard variation. Refer Annexure XI: (SOP No . ._"Repeat Analysis")

and in Study #

the sample runs were accepted as per the SOP -Repeat Analysis. Internal standard area of all accepted samples were within ±50% (50 to 150) of mean !STD response of the accepted CC and QC samples.

Incurred sample reanalysis results in the said studies indicates that the variability in internal standard response did not impact the concentrations of the subjects as 87 .8% of the samples (96. 7% of samples in Study# 1- and 78.9% in study# - ) had met the acceptance criteria.

For all the future studies through investigation will be performed as applicable to identify the root

cause of high internal standard (IS) variability during bioanalytical run and necessary steps will be taken as per the new SOP.


SOP to handle high internal standard (IS) variability during bioanalytical run is prepared and is effective from 02 Nov 2015.

For all the future studies, internal standard trend across the batch will be monitored and average IS

area of accepted known samples (CCs and QCs) will be compared against the average of accepted unkno . es by plotting in MS excel. If the percentage difference is within 20%, the batch

.,.,,i.,,lfl~ ~~~~~se the batch shall be investigated for root cause considering several factors like

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solvents, matrix effect etc. and necessary steps will be taken as per the respective SOP. Training is imparted to all the applicable study personnel on the implemented SOP.

Refer Annexure XII:( SOP No.~ "Investigation of high internal standard variability in subject samples" effective from 02 Nov 2015 with attachments and Training Attendance) for SOP and SOP training details.

List of attached Annexures to this document:

Annexure-I: Bioanalytical project report: BAR

Annexure-II: Subjectl audit trail in study#

Annexure-Ill: Method Validation Report MVR No.

Annexure-IV: Training attendance on good documentation practice.

Annexure-V: SOP No. ~"Project Sample Analysis" and training attendance.

Annexure-VI: Subject. audit trail in stud~

Annexure-VII: Project Data Checkup Form and Authorization for Repeat Analysis Form.

Annexure-VIII: Deep Freezer Log book.

Annexure-IX: Extraction steps checklist from study# - .

Annexure-X: SOP No. - "Preparation of Method SOP" and training attendance.

Annexure-XI: SOP No. - ''Repeat Analysis".

Annexure-XII: SOP No. - "Investigation of high internal standard variability in subject

sarnples"and training attendance.

umar Head -Operations RA Chem Pharma Ltd, Clinical Research and Biosciences Division.

RA CHEM PHARMA LTD Clinical Research and Biosciences

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