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Preparation of rh-Insulin National Reference standard

National Institute of BiologicalsNoida E-mail: info@nib.gov.in

Meeting of the Manufacturer’sMarch 20, 2009

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WHY the need

╩ There is no National Reference Standard available in our country on rh-Insulin with any metrological trace ability as per ISO guidelines –17511.

╩ The certificate of Analysis also varies from one Manufacturer to another as there are no guidelines and Recommendations laid down for National Reference standard of rh-Insulin incorporated in “ Indian Pharmacopoeia”

╩ International biological standards are the “Primary standards” against which Secondary standards are calibrated. Secondary standards may be -

a) National standard , b) Regional standard, c) Working Reference material .

rh-Insulin Reference Standard

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International conventional reference measurement procedure by International Scientific organization, WHO aInternational conventional reference measurement procedure by International Scientific organization, WHO a

International conventional Calibrator bInternational conventional Calibrator b

Manufacturer’s Working calibrator dManufacturer’s Working calibrator d

Manufacturer’s Product calibrator fManufacturer’s Product calibrator f

Manufacturer’s selected measurement procedure c

Manufacturer’s selected measurement procedure c

Manufacturer’s standing measurement procedure e

Manufacturer’s standing measurement procedure e

METROLOGICAL

TRACEABILITY

International scientific organization: WHO, NIBSC, USP

End User’s routine measurement procedure g

End User’s routine measurement procedure g

Routine Sample h Routine Sample h

RESULT i RESULT i

Manufacturer Or end user

End user

End user

CALIBRATION HIERARCHY & METROLOGICAL TRACEABILITY

MATERIAL CALIBRATION VALUE ASSIGNMENT PROCEDURE IMPLEMENTATION

Source ISO 17511-2003, First edition , 2003-08-15

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Memorandum of Understanding

╩ All the information of API-bulk material supplied during the study will be treated as confidential and proprietary to the manufacturer’s.

╩ A MoU will be developed between

a) NIB ,

b) Industry and

c) IPC

╩ All persons involved herein by signing the agreement confirms that there is no financial or vested commercial interest.

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Collaborators in the StudyCollaborating lab Name Study

Investigator

Pharmacopoeia Indian Pharmacopoeia Commission To Propose

Government

1.National Institute of Biologicals-NCL

2. Office of DCG(I)- NRA

3. CDSCO-zone wise-do-

Industry

rh-Insulin Manufacturer’s:

1. Biocon Bangalore

2. Wockhardt Aurangabad

3. MJ Biopharm Navi Mumbai

4. Cipla Goa

5. Eli-Lily Gurgaon

6. Aventis Mumbai

7. Novo Nordisk Denmark & Bangalore

-do-

Other Standard setting organization

1. European Pharmacopoeia

2. Japanese Pharmacopoeia

3. US Pharmacopoeia

4. WHO

5. NIST-USA

6. REMCO ( Ref material committee of ISO )

To maintain continuous

contacts

Academia To be Proposed To Propose

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Steps in establishing National Reference standard

1. Incorporation of human Insulin National Reference Standard in IP-Monograph for Human Insulin

2. Provide collaborators with set of necessary documents

3. Establish –3.1 Inter laboratory” collaborative study for selecting a

Candidate RS material

3.2 coded material to be distributed maintaining confidentiality

33 Proficiency testing program based on NABL 162 guidelines

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1. Quantitative uses in assays of rh-insulin bulk & formulation, either by:

╔ Biological methods╔ Physiochemical method-HPLC

2. Quantitative uses in Limit tests by Physiochemical method-HPLC

3. Qualitative uses in Identification tests, system suitability tests, chromatographic peak markers

4. Method development , evaluation of method performance

Intended Use

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Goals of Collaborative study

Selection of rh-insulin Candidate material

Obtain API-Bulk material from a major manufacturer of rh-insulin

Detailed rh-insulin testing Protocol to include elements of :╩ Type of tests ╩ No of tests ╩ No of collaborators ╩ Elements of validation ╩ No. of replicates ╩ References to the procedure to be used.╩ Data recording forms for result compilation

Material is Calibrated and Characterized, with regular use of CRM

Statistical control in design and Analysis of Results

Assign Property values and Uncertainties

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Assignment of Property Values

and Their Uncertainties

╔ Investigation of statistical outliers and/or use of robust statistic

╔ Methods used to assign uncertainties to property values

╔ Acquire time-zero information for future continued-suitability for use of rh-insulin Reference standard

╔ 1 Unit of Human insulin =0.0347 mg by definition (28.8 IU/mg).

╔ Value is assigned to rh-insulin bulk in IP.

╔ Need to Work Out : Assignment of Property Value to serve as Standard for Assay of 40 IU and 100 IU Insulin preparations.

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Calibration test as per requirements of IP-2007 & USP

Characterization test on Candidate Reference material as per requirements of IP- 2007 & USP

Calibration test as per requirements of IP-2007 & USP

Characterization test on Candidate Reference material as per requirements of IP- 2007 & USP

Calibration

Potency content

RP-HPLC

Characterization

Identification RP-HPLC Peptide map

Purity % related compounds RP-HPLC

% insulin aggregates SE-HPLC

Characterization

Identification RP-HPLC Peptide map

Purity % related compounds RP-HPLC

% insulin aggregates SE-HPLC

Lead Role of Collaborators

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Work Progress in the study

1. NIB has received rh-insulin working Ref material from Four manufacturer's

2. Material received : i. powder and liquid formii. 4 vials or ampoules from each iii. Certificate information from 3 manufacturer

3. NIB has initiated Calibration using: i. Certified Ref material-NIBSC & USPii. Method –Potency , USP, EP as per Manufacturer CoA iii. Method –Potency -IP not given in Manufacturer’s CoA

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S. No.

Logical order for presentation

Information required Information given by producer

Information given by highest metrological trace ability

1. The identity of the producer body and identification of the reference material

Name and address of certifying body √ √

2. Title of the document √ √

3. Name of the material √ √

4. Reference material code and batch number √ √

5.

A description of the material and its intended use

Description of the material, origin and history No √

6. Intended use No √

7. Instructions on the correct use of the material No √

8. Safety √

9. Level of homogeneity Partial √

10.

The certified values, their Traceability and the period of validity of the certificate

Certified values and their uncertainty intervals at a stated confidence level

Partial √

11. Traceability √ √

12. Values obtained by individual laboratories or methods √ √

13. Uncertified values √ √

14. Date of certification or assignment of property values √ √

15. Stability No √

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Other information

Further information √ √

17. Legal considerations Partial √

18. Signatures and names of certifying officer(s) or officer(s) signing an analysis certificate

√ √ & Leaflet

CERTIFICATE INFORMATION from rh-insulin Reference Material Producers

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Recommending a Strategy

Ideas for Today and Tomorrow

Ideas for Today and Tomorrow

Outcome expected from the meeting g

Outcome Expected from the meeting

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Recommending a Strategy

1 Time Lines Attached schedule to be agreed upon2 Label Text & Leaflet Draft to be reviewed & approved

3 rh-Insulin Candidate material Acceptance from 2-3 manufacturer’sMaterial for supply , filling & packing

4 Testing for Homogeneity Batch of Candidate Ref material a) intermediate checks b) checks in final packed form

5 Authorization of Property value to Reference Standard

By Technical competent body for Reference Standard

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Distribution of designated Ref.Standard

Recommendation of Expert committee

7 Commercial cost of Ref Standard per vial or Ampoule

Cost to be proposed

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