DR. REBA CHHABRA HEAD DIAGNOSTIC DIVISION

NATIONAL INSTITUTE OF BIOLOGICALS,NOIDA

(MINISTRY OF HEALTH & FAMILY WELFARE) GOVERNMENT OF INDIA

Regulations of in-vitro

Diagnostic Kits

&

Role of NIB in Testing

Regulations of in-vitro Diagnostic Kits

& Role of NIB in Testing

Administrative

Block Laboratory Block

Library & IT Cell

NIB Campus

About NIB

An Autonomous Institution, Established on January 27, 1992 under the

Administrative Control of MOHFW, Govt. of India, is a premier Scientific

Organization and center of excellence to ensure quality of Biologicals and Vaccines in

the country.

The Institute assures and reviews the quality of number of Biological products

available through domestic manufacturers or imports. This is done in close coordination

with Government of India regulatory authorities as Office of Drug Controller of India,

Indian Pharmacopeia's Commission. Laboratory & Animal facility designed with

technical support of National Institute of Health (NIH), USA to meet the

International Standards.

Total Area of NIB : 74000 Sq. meter (18.2 Acre)

Lab & Animal House Area : 15000 Sq. meter

Laboratory Area : 7000 Sq. meter

Animal Facility : Bioassay – 4500 Sq. meter

Service & Support Area : 3500 Sq. meter

42 BSL-2 Lab and 2 BSL-3 Lab

Laboratories of NIB

Recombinant products: Insulin, EPO, Filgrastim

Blood Products: Albumin, Normal Immunoglobulin

Therapeutic Monoclonal Antibody: Rituximab, Herceptin

Viral vaccines: MMR, Rabies, HPV, JEV, Polio

Bacterial vaccines: BCG, Hib

Enzymes & Hormones: Streptokinase, FSH

Biochemical kits: Glucometer and Reagents

Immunodiagnostic kits: HIV-Ab,HCV-Ab, HBsAg, Syphilis

Blood Grouping Reagents: A,B, AB, RhD

Nucleic Acid Testing: HIV, HCV, HBV

Allergen: Cockroach

In-Vitro Diagnostic Products (IVDs)

• In vitro Diagnostic Products are those substances

that are intended to be used for or use in diagnosis

of disease or disorders in human being or animals.

• IVDs are considered as “Drugs” are defined

under sub-clause(i) of clause(b) of section 3 of

Drugs and Cosmetic Act 1940.

Indian Scenario

Reagents Instruments

Indigenous = ~10 – 15%

Imported

= ~85%

Indigenous = ~40%

Imported

= ~60%

ClassificationIn-vitro Diagnostics Products

IVD products have been classified under the category of “drug”

Fall under the ambit of Drugs & Cosmetics Act 1940 and rules 1945 with some amendments.

IVD-Definition and Regulations in India

Drugs and Cosmetics Act, 1940 and Drugs and Cosmetics Rules, 1945 is the principle drug law in

India regulating Pharmaceuticals along with Medical Devices and Diagnostics.

Ministry of Health & Family Welfare through Drug Controller General of India, is the highest

responsible authority for ensuring safety, well-being and betterment of public health by monitoring

and regulating quality, safety, efficacy of drugs and device through inspection, surveillance and

enforcement means.

NIB was declared as CDL for IVD Gazette Notification No. GSR 249(E) dated 27Aug. 2002.

IVD is defined as per GHTF Doc.# GHTF/SG1/N071:2012 as “a medical device, whether used alone or in

combination, intended by the manufacturer for the in-vitro examination of specimen derived from the human body

solely or principally to provide information for diagnostic, monitoring or compatibility purposes”.

According to CDSCO Guidance Doc.# CDSCO/IVD/GD/RC/01/00, following IVD products have

been classified as “Notified Diagnostic Assay” requiring registration to obtain Import

license/manufacturing license to be sold in India:

• IVD kits intended for HIV, HBsAg and HCV.

Rest all IVD assays are termed as “Non-notified” requiring only Import License to be sold in India.

ClassificationIn-vitro Diagnostics Products

Notified Non-Notified

Classification of IVDs in India

• For detection of HIV

• For detection of HBsAg

• For detection of HCV

• For determining the blood group

Notified Products (Critical)

Classification of IVDs in India

• Malaria, TB, Dengue, Typhoid, Chikunguniya, Syphilis,CancerMarkers, Blood Glucose test strips, glucose reagents, etc.

Non Notified

(Non Critical)

Registration of the company

• Form 40: Application for obtaining the Registration Certificate.

• Form 41 : Registration Certificate

• Registration of the company= $1500 or 92,100 INR

Registration of the product

• Registration of the product: =$1000/product or 61,400 INR/product

• Time required: = 9 months

• Validity : 3 years

Form 9 / Form 10

• Form 9 : Application for obtaining the import license

• Form 10 : Import License

• Validity : 3 years

• Cost involved :

• Fees : 1st product -Rs. 1000.

• Rs. 100 per additional product.

• Time required = within 3 months.

Notified Products

Regulatory Requirements

Test License Requirements

TL:TEST LICENCE

PE:PERFORMANCE EVALUATION

IFU:INSTRUCTION FOR USE

COA:CERTIFICATE OF APPROVAL

Regulatory Requirements - Registration

POA:POWER OF ATTORNEY

SCHEDULE:DI & DII

FSC:FREE SALES CERTIFICATE

CFG:CERTIFICATE TO FOREIGN GOVERNMENT

PMF:PLANT MASTER FILE

DMF:DEVICE MASTER FILE

Legal

Documents

Regulatory

Documents

Technical

Documents

1.Form-40

2.POA

3.DI

4.DII

5.Whole sale license (form

20B, 21 B)

1.Plant Registration

Certificate(PRC).

2.Manufacturing & Marketing

Licence.

3. Free Sale Certificate from the

country of origin.

4. Free Sale Certificate from

anyone of the GHTF countries.

5. CE Declaration of Conformity.

6. CE Design Certificate.

7. CE full quality Assurance.

8.Copy of ISO/EN-13485

Certification.

9.List of countries where the

device is being sold.

1.Plant master file ( PMF).

2.Device Master File

( DMF).

3.Post Market Surveillance

files ( PMS).

Documents required

for Registration-Summarization

Regulatory Approval Process Flow Chart in India

(In-Vitro Diagnostics)

To

Obtain Evaluation reports

RenewalNEW

PRODUCT LAUNCH

Requesting documents from Global Regulatory Authority

Non-Critical Care IVD/Non-Notified

NCD kits for disease of National Importance (e.g.-Dengue, Malaria, Tuberculosis, Syphilis, thyroid, blood glucose,

Cancer etc.)

Critical Care IVD/Notified

Application for Test License in Form-11

(small quantity duly justified)

Import IVD kits

under Test License

for performance

evaluation

For NCD, evaluation done at any National or NABL Accredited

Lab

For CD, evaluation to be done at NIB or any govt. institution

of repute

To be continued

Regulatory Approval Process Flow Chart in India (In-Vitro Diagnostics)

Application for Import License of product in Form-10 (NCD)

Follow-up with CDSCO to resolve, if clarification sought on any point.

If no query, Import License approved within 8-10 weeks.

Application for Registration of Manufacturing Site along with product manufactured from the site in Form-40

(CD)

Follow-up with CDSCO to resolve, if clarification sought on any point.

If no query raised, Registration Certificate approved within 6-7 months.

Application for Import License of the product in Form-10

Registration Cert. and Import License can be applied together to CDSCO.

Total Time for approval: 8-9 months.

Requirements for Import of

IVDs in India

Notified IVDs

Registration Certificate in form-41.

Then Import Licence in Form-10.

Non-Notified IVDs

Only Import Licence in Form-10.

Important Clauses in D&C Act Relevant to IVD

Rule 21(d): Requirement of Free-Sale Certificate from the country of origin to register a product,

Rule 24: i. Requirement of valid Wholesale/Retail sale/stock/distribution license by the applicant in India.

ii. Requirement of duly filled and signed Undertaking by Manufacturer in Form-9.

iii. Vide Amendment effective from Jan 2005, registration of Non- notified diagnostic kits not required to obtain Import License.

Rule 24A: Requirement of Power of Attorney (PoA) from Manufacturer in favor of Authorized Indian Agent duly attested by Indian Embassy of the said country to register a Manufacturing premise and the product manufactured from it.

Rule 25: Different Products from same Legal manufacturer manufactured at different manufacturing site need to be registered separately.

Rule 26(iii): Sampling of every batch or random, if determined by port authority for testing at CDL.

Rule 26(vi): Retail-invoice record of sale to be kept.

Rule 27: Requirement of submission of duly filled Schedule- D(I) and D(II) to obtain RC.(w.e.f 2003 information in Annexure-B need to be submitted specially for diagnostic kits.)

Rule 27A/28A: 3 years validity of RC/Import License.

Rule 31: Requirement of minimum shelf-life of 60% of any product at the time landing in India.

Rule 38: Statement to accompany imported drugs.

Rule 65: Condition to fulfilled to get a premise registered for storage, distribution or sale of product.

Rule 109(A): Labelling of Medical Devices.

Role of NIB

in IVD Testing / Evaluation

• IVD testing in India is currently restricted to “Notified IVD”

products.

• IVD testing in India currently occurs under the following

scenario:

3 Lots of any New Notified IVD assay for launch in Indian

market need to be evaluated as per regulatory requirement cited

in D&C Act and rules, 1945 to register the same for sale in

India.

Testing of on-market Notified IVD assays, done as part of

random sampling of imported lots by ADC Officials stationed

at all listed Ports of Entry in India.

STATUS - Immunodiagnostic Kit Lab Immuno Diagnostic Kit Laboratory is notified as Central Drugs Laboratory (CDL) by

Government of India vide Gazette No. G.F.R 601 E, dated 27th August 2002 for in-vitro

diagnostic devices for HIV, HCV, and HBsAg.

For Syphilis Rapid and ELISA kits the laboratory has been certified as per CDSCO

letter No. 29/Misc/4/2013-DC (52) dated 14th February, 2014.

The lab has a Quality Management System in place and is NABL Accredited in

accordance with the standard ISO/IEC 17025: 2005 in the field of Immunodiagnostic

kits vide certificate no. T-2011 dated 05.12.2013 for Biological Testing.

The Laboratory has been conducting Quality evaluations of indigenously

manufactured and imported kits (Rapid, ELISA, CLIA, ELFA, Confirmatory, Ag/Ab

& Combo kits) for HIV, HCV, HBV and Syphilis which were forwarded by Central

Drugs Standard Control Organization (CDSCO).

Successful Participation in National Serology Reference Laboratory, Australia EQAS

for HIV, HCV, HBV and Syphilis Serology since 2009.

Ongoing Supply of Performance panel of HIV, HCV and HBsAg to indigenous kit

Manufacturers since Feb 2010.

This ensures quality evaluation of diagnostic kits for safeguarding public health in

the country.

STAKEHOLDERS

IMPORTED

S.No. Name of Manufacturer & Country S.No. Name of Manufacturer & Country

1 Alere Medical Co.ltd; Japan 17 Guangzhou Wondfo Biotech Co.Ltd; China

2 Acon Biotech Co. Ltd.; China 18 Immunetics Inc; USA

3 Abbott Healthcare Pvt Ltd; Germany 19IND Diagnostic Inc; Canada

4 Artron Laboratories Inc.; Canada 20 InTec Products Inc.PR; China

5 Biokit, S.A; Barcelona 21 Inverness Medical Japan Co.,Ltd; Japan

6 Bio-Rad Laboratories; France 22 LG Life Sciences; Korea

7 bioMerieux SA; France 23 MedMira Laboratories Inc; Canada

8 Bioland Co.,Ltd; Korea 24 Mp Biomedicals Asia Pacific Pte.Ltd.; Singapore

9 BioLytical Laboratories; Canada 25Novartis Vaccines and Diagnostics Inc.; California

10 Beijing Kinghawk Pharmaceuticals Co.,

Ltd.; China

26New Market Biomedical ltd; UK

11 Beijing Wantai Biological Pharmacy

Enterprise Co. Ltd; China

27NewScen Coast Bio-Pharmaceutical Co.Ltd.P.R.; China

12 Biotest AG; Germany 28 Orgenics Ltd.; Israel

13 CTK Biotech Inc.; USA 29 Ortho Clinical Diagnostics.; USA

14 Dia Sorin;UK 30 Roche Diagnostics GmbH; Germany

15 Green Cross Medical Sciences Corp.;

Korea

31 Siemens Healthcare Diagnostics Products GmbH;

Germany

16 General Biologicals Corp.; Taiwan 32 Zhongshan Bio-Tech Co.Ltd.; China

INDIGENOUS

S.No. Name of Manufacturer & Location

1 Avantor Performance Materials (I) Ltd; Dehradun

2 Transasia Bio Medicals Ltd; Daman

3 SD Bio Standard Diagnostic Pvt Ltd; Gurgaon

4 Bhat Bio-tech India Pvt Ltd; Bangalore

5 Cosmos Advanced Diagnostics LLP; New Delhi

6 Cadila Pharmaceuticals Ltd;Gujarat

7 J.Mitra & Co.Pvt.Ltd;New Delhi

8 Lab Care Diagnostics (India) Pvt.Ltd; Gujarat

9 Meril Diagnostics Pvt Ltd.Vapi; Gujarat

10 Nectar Lifesciences Limited; Chandigarh

11 Reliable Pro-detect Biomedicals Pvt Ltd; Shimla (H.P)

12 RFCL Limited; Dehradun

13 Qualpro Diagnostics; Goa

14 Span Diagnostics Ltd; Surat

15 Yuvraj Biobiz Incubator India Pvt Ltd; Chennai

Key Features ofImmunodiagnostic Kit Laboratory

Highly experienced and trained staff .

Coded Samples used to remove bias.

Panel characterization using ELISA/CLIA/ELFA and confirmation by

Confirmatory/ Supplementary Assays.

Supply Performance Panels for HIV-Ab, HCV-Ab and HBsAg to indigenous

manufacturers.

Online Sample Tracking System in place for Products submitted for testing

since 2012.

Maintain FIFO system.

Turn-around time (TAT): 30 working days

National Reference Laboratory by National AIDS Control Organization

(NACO) for HIV testing, for the states of Uttar Pradesh and Uttarakhand.

RAPID

HCV Antibody

HIV 1&/ 2 Antibody

HBV (HBsAg & other markers)

Syphilis

ELISA/ELFA/CLIA

HIV 1&/ 2 Antibody

HIV Ag-Ab

HCV Antibody

HBV (HBsAg & other markers)

Syphilis

CONFIRMATORY

HCV Antibody (Western Blot and

Line Immuno assay)

HIV 1&/ 2 Antibody (Western Blot and

Line Immuno assay)

HBsAg (Neutralization)

Type of Kits Referred by CDSCO for Quality Control Evaluation

Sample Receipt & Report Dispatch Unit (SRRDU)

• An independent unit since 2008,it acts as a interface between

industry and NIB.

• Main entry point of all samples to the institute for testing and

ensuring timely dispatch of all test reports.

• Archive unit attached with it for documentation and record

keeping.

Detailed information : refer nib website-www.nib.gov.in

IVD Testing/Evaluation and Role of NIBTesting Requirements:

Documents:

Copy of Import license/Test License (Imported product) for new product evaluation.

DCG(I)/ADC(I) Letter (for regular batch testing)

Certificate of Analysis from the manufacturer/NCL.

Batch release certificate from National Testing Lab/National control Authority of country of origin.

Name of three countries where the product is being marketed

Batch Non-Withdrawal Certificate of submitted batches from any market by Manufacturer.

Manufacturing and QC protocols of the product

Qty. Required for submission and Testing Fee