11 th INTERNATIONAL SYMPOSIUM ON PHARMACEUTICAL REFERENCE STANDARDS. Siriphorn Laomanacharoen 21 December 2012

Transcription

1 11 th INTERNATIONAL SYMPOSIUM ON PHARMACEUTICAL REFERENCE STANDARDS Siriphorn Laomanacharoen 21 December 2012

2 11 th INTERNATIONAL SYMPOSIUM ON PHARMACEUTICAL REFERENCE STANDARDS Organised by European Directorate for the Quality of Medicines & HealthCare (EDQM) Location EDQM, Strasbourg, France Date 3 4 September 2012

3 Programme 3 rd September Session 1 Pharmaceutical Reference Standards: Regulatory aspects - Session 2a Pharmaceutical Reference Standards for Biologicals - Session 2b Pharmaceutical Reference Standards: Addressing the challenges in the characterisation of Small Molecules

4 Programme 4 th September Session 3 Pharmaceutical Reference Standards: Material Management/Technology Changes - Closing session

5 Guides from the ISO Committee on Reference Materials (ISO/REMCO) Reference materials

6 Guides from the ISO Committee on Reference Materials (ISO/REMCO) Reference materials

7 Primary Reference Standard Example JLR(C a H b N c O d.hcl.h 2 O) batch: Appearance: white powder Melting point: 160.8C Elucidation of structure - IR spectrum - 1H NMR spectrum - 13C NMR spectrum - Mass spectrum - UV spectrum

8 Primary Reference Standard Example Assay - Water content (KF): 5.47 % (w/w) (n=6, rsd=0.29) (theor. = 5.49) - Chloride content: 5.65 % (w/w) (n=6, rsd=0.18) (theor. = 5.60) - Non aqu.titration:100.1 % (w/w) (n=6, rsd=0.39)

9 Primary Reference Standard Example Assignment of Potency: - Water content: value close to theor. - Chloride content: value close to theor. - Assay (n.a.titr.): % (w/w) - Rel. impurities: 0.1 % (w/w) - Sulphated ash: 0.05 % (w/w) - Solvent content: 0.03 % (w/w) Result: 100-( ) = 99.8% Confirmation by DSC: 99.85% Assigned potency: JLR (C a H b N c O d.hcl.h 2 O) = 99.8 w/w (batch 27349)

10 Establishment of Reference Standards China s Point of View National Institutes for Food and Drug Control (NIFDC) responsible for the characterization of national reference standards. NIFDC could organize local drug testing institutes, drug research institutions and/or drug manufacturers to undertake collaborating study on reference standards.

11 Establishment of Reference Standards China s Point of View

12 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China

13 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Procurement Purity requirements: 1. Assay RS: not less than 99.5 or one batch API with appropriate quality 2. Limit testing RS: not less than 90% TLC or 95% LC, etc 3. System suitability RS: not less than 99.5 or one batch API with appropriate quality 4. Identification RS: One batch API with appropriate quality

14 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Classification 1. Quantitative use Assay standard and limit test standard, value assignment by - Mass balance - Microbial assay or bioassay 2. Qualitative use Identification standard (e.g., IR) System suitability (e.g., HPLC resolution or peak identifier) No purity value assigned on package label

15 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Characterization Structures elucidation of Chemical RS: The first batch UV IR NMR MS Element analysis X- ray Function group analysis

16 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Purity test of Chemical RS: HPLC (DAD) GC TLC CE DSC Compatibility degree method UV, IR, NMR Titration Optical activity Water, residual solvent, loss on drying

17 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Production

18 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Label

19 Compendial Reference Standards Manufacturing National Institutes for Food and Drug Control (NIFDC), China Supply chain The first level NIFDC The second level local drug control institutes

20 Role of WHO International Chemical Reference Substances (ICRS) - primary reference standards established by EDQM under the authority of WHO Expert Committee on Specifications for Pharmaceutical Preparations

21 Role of WHO International Chemical Reference Substances (ICRS) The role of ICRS ICRS are intended for physical and chemical tests and assays as described in The International Pharmacopoeia for establishing official secondary standards The International Pharmacopoeia aims to keep the number of ICRS needed to perform analytical tests at a minimum by different means to facilitate and promote - in particular - effective post-marketing surveillance in low- and middle-income countries to promote the global applicability of the specifications and methods of The International Pharmacopoeia

22 Managing Third Parties for the Preparation and Maintenance of Reference Standards Outsourced Operations Ex. - Prepackaging and labeling of bulk material - Special synthesis of small molecules - IT Support - Disaster recovery storage - Physicochemical characterization tests (where site certification is not required)

23 Managing Third Parties for the Preparation and Maintenance of Reference Standards Outsourced Operations Ex. - Processing and dispensing of routine customer orders - Vial lyophilization - Shipping dock services - Remote distribution centers

24 Managing Third Parties for the Preparation and Maintenance of Reference Standards Problems when Outsourcing Ex. - Instructions are too complex or there is insufficient communication of expectations - Critical raw material requirements not identified - Inconsistent communication model - Quality and Expertise

25 Managing Third Parties for the Preparation and Maintenance of Reference Standards Benefits when Outsourcing Ex. - Avoidance of Capital Spending - Self-Contained Work - Staffing Flexibility and Expense - Vendor Expertise with Minimal Oversight

26 FAQ about USP Reference Materials Why do some USP RS s require a water determination? Many hygroscopic RS s are labeled with the instructions to determine the water content titrimetrically at the time of use. The value is expected to vary from vial to vial; therefore, the water content determined for one vial cannot be used for another vial. In addition, if a vial is used more than once, a water determination must be performed prior to each use. The water value determined should be used to correct the weight of the standard in calculations.

27 FAQ about USP Reference Materials When can one assume that the purity value of an RS is 100.0%? A purity value of 100.0% can be assumed if a USP RS has a quantitative USP compendial application and does not have a purity value provided on the label. If the RS is used only in qualitative USP compendial applications, 100.0% cannot be assumed. USP does not assign purity values to qualitative RS s.

28 FAQ about USP Reference Materials What is the expiry date of a current lot? Current lots are not assigned valid use dates. As long as the lot is listed in the catalog as being the current lot, it is valid and suitable for use. Once the current lot is depleted, it becomes the previous lot and is assigned a valid use date.

29 FAQ about USP Reference Materials Purity Values Changed from Dried Basis to As Is Basis When Possible? For the convenience of our customers, USP is now trying to label a USP RS As Is" whenever possible. It is the preferred option and is selected whenever valid data indicates that the volatiles content is constant over time. The change to "as is" will not affect the USP compendial use of a Reference Standard.

30 FAQ about USP Reference Materials New Reference Standard Label Design - USP will begin to label new lots of RS s as per the new rules set by GHS - May begin to see changes as early as December - Space limitations--some info not required by the new rules may be removed from the label and put onto the USP Certificate to make room for the required information

31 FAQ on CRS of the European Pharmacopoeia For Ph. Eur. assay, %purity value of CRS is provided. For quantitative CRS, purity is 100% unless otherwise indicated. For qualitative CRS, no purity value assigned. Ph. Eur. CRS do not require water/lod determination. Because CRS is established after filling into vial and assigned value is given on an as is basis.

32 FAQ on CRS of the European Pharmacopoeia New labelling information for Ph. Eur. CRS according to GHS will start in 2013 with quantitative RS. Due to space limitation of label, information will be put on the accompanying leaflet. Expiry dates of Ph. Eur. CRS is not provided. Batch validity statement (BVS) for each reference standards (

33 Valid at printing date

34 Date at which a batch becomes no longer valid

35 FAQ on CRS of the European Pharmacopoeia Can I prepare a secondary standard from Ph. Eur. CRS? 2 nd reference standard is established against 1 st standard using an unbroken chain of comparison. The uncertainty associated with the property value of interest of 1 st reference standards shall be known.

36 FAQ on CRS of the European Pharmacopoeia Can I prepare a secondary standard from Ph. Eur. CRS? QUALITATIVE USE: Identification For use in infrared spectrophotometry For use in separation techniques (peak identification) No uncertainty associated with the property «identity» Yes, you can prepare 2 nd standard from Ph. Eur. CRS

37 FAQ on CRS of the European Pharmacopoeia Can I prepare a secondary standard from Ph. Eur. CRS? QUANTITATIVE USE Purity test: For use in separation techniques: a content relative to the signal from 1 st standard is to be established. Assay: the property for which a value is to be assigned for 2 nd standard is similar in magnitude to that of the 1 st standard with which it is compared.

38 FAQ on CRS of the European Pharmacopoeia Can I prepare a secondary standard from Ph. Eur. CRS? You need the uncertainty associated to the property value content. The measurement uncertainty associated to the content value of Ph.Eur. CRS is not stated since it is considered to be negligible in relation to the defined limits of the method-specific assays for which they are used. (ex: content: 97.5 per cent to per cent (dried substance)) (ISO Guide 34, chapter 5.17)

39 FAQ on CRS of the European Pharmacopoeia Can I prepare a secondary standard from Ph. Eur. CRS? No, you cannot prepare 2 nd standard from Ph. Eur. CRS