Development of the National System of Medicine Reference

Substances in UkraineLeontiev Dmytro

 Deputy director (science)Group Manager “Validation and Reference Substances”

Gryzodoub OleanderDirector

 

Ukrainian Scientific Pharmacopoeial Centre for Quality of Medicines 

(Kharkov )  

+38(057)719-06-01 e-mail ogf@phukr.kharkov.ua+38(067 )954-91-74 leontievd@yahoo.com

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The problem of the Pharmaceutical RS support in

Ukraine

The pharmaceutical RS system accepted in the USSR differed substantially from that one in the countries in which the Good Manufacturing Practice (GMP) has been applied.

The Pharmaceutical RS in Ukraine were absent after the exit from the USSR

Ukraine, in the pharmacy area, works towards harmonization with the European Community (Regulation of the Ministry of Ukraine No. 244, 19.03.1997).

This requires elaboration of the pharmaceutical RS system meeting the GMP requirements and the leading Pharmacopoeias practice.

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The Main Types of the Pharmaceutical RS

RS for the medicines quality testing: Official RS (Pharmacopoeia RS). They are the official

standards to be used in cases of arbitration Working RS. May be used for routine analysis, provided

they are calibrated against the Pharmacopoeia standard

RS for the quality assurance of the test results:

Test Samples for the Program of Proficiency Testing (PPT)

Within-lab RS for the quality assurance of the test results

Samples for the analytical procedures validation (for the “direct” methods – titration, refractometry and so on)

RS for the analytical equipment qualification

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The Main Tasks of the Ukrainian Pharmacopoeia RS System

Creation

Elaboration of the theoretical base of the pharmaceutical reference substance attestation

Elaboration of the requirements for the max acceptable uncertainty for the main pharmaceuticals assays and tests (it determinates the requirements to the Pharmaceutical RS characterization)

Elaboration of the Pharmacopoeia RS characterization procedures

Elaboration of the Pharmacopoeia RS documentation system, quality system, including production, labeling, storage and distribution

Establishment and distribution of the Ukrainian Pharmacopoeia RS

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Elaboration of the Theoretical Base of the Pharmaceutical RS

Attestation

INSIGNIFICANCE PRINCIPLEThe confidence interval (2 )is significant at P% level (i.e.,

insignificant at (100 – Р)% level), as compared to a confidence interval (1), when the summarized confidence interval increases

not more than by Р%, i.e., the following condition is met:  

(1)

For Р=5% (confidence level accepted in analytical chemistry):

(2)

122

21 100

100

P

12 32.0

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Elaboration of criteria for the RS certified value

In accordance with the insignificance principle, the following inequality for the certified value uncertainty (RS) should be met:

(3)MAXRS 32.0

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Assay. Approach for the Substances

The inspecting approach (some of pharmaceutical substances)

The maximal permissible uncertainty of the assay (MAX) is equal to excess of the upper content limit over 100 % (B):

(4)

Hereinafter the relative confidence interval for the confidence of 95 % is meant by the uncertainty

BMAX

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Assay. Approach for the Dosage Forms

The confirming approach (all dosage forms)

For the symmetrical content limits ( В, %) and probability of 95%, taking into account an insignificance principle:

(5)

MAX -MAXIMAL permitted uncertainty of analytical results (assay), %

,32.0 BMAX

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Test “Uniformity of content”

The Test

Stages

Number of

units Criteria

RSD%

Content of active ingredient

I 10 6 %

85-115% (from nominal content)

II 10+20 additiona

l

7.8%

75-125% for one unit from I stage;

85-115% for all another units

•If we have a positive result one time, it doesn't mean that we must obtain a positive result next time for the same analyzed sample

•We can calculate RSDguar for the positive test result for probability ≥0.95 % by use of product rule

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Let р – fraction, for which content must be 85-115% from nominal

Stage  I. The following ratio should be met: р10 0.95; then р 0.995. The probability of 0.995 corresponds to a of student's factor t(99.5%, 9) = 3.69. RSDguar(10) = 15/3.69 = 4.07%.Stage II. The following ratio should be met: р20 0.95; then р 0.9974. The probability of 0.9974 corresponds to a of student's factor t(99.74%, 29) 3.31, RSDguar(30) = 15/3.31 = 4.53%.

The confidence interval for the two-side student's distribution (t95%,9 =2.262, t95%,29 = 2.045):Stage І: 4.07* 2.262 = 9.21%.Stage ІІ: 4.53*2.045 = 9.26% (e.g. the same as for Stage I).

Test “Uniformity of content” 2

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“Uniformity of content” and “Dissolution” Tests

Test “Uniformity of content”

In accordance with the insignificance principle:

MAX = 0.329.2 = 3.0% (6)

Test “Dissolution”. The same criteria

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The objective difficulties of the PHARMACEUTICAL RS SYSTEM CREATION IN UKRAINE

1. Information on the pharmaceutical RS attestation (first of all, the theoretical principles) is a restricted one

2. The approaches of other Pharmacopoeias applied now (e.g., a wide application of the inter-laboratory experiment) can’t be transferred automatically into the conditions of Ukraine

3. There was a lack of the clearly defined criteria to the attestation of the pharmaceutical RS. Only the general recommendations on the RS attestation, that did not take into account the specific character of pharmaceutical RS, were available

4. The attestation procedures, as well as documentation and use of the pharmaceutical RS, differ substantially from those ones accepted for the RS used in other areas

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Elaboration of RS attestation procedures - Assignation of the certified value

Certified value for RS of the Pharmacopoeia of Ukraine must be determined by two methods: by a direct method XAtt (titration, generally) and by subtraction of the obtained content of impurities from 100 %

For the content obtained by the least accurate method (usually, a direct method), the uncertainty of the certified value Att is estimated

For the results obtained, the following ratios should be met:

(7)

(8)

RSAtt RSAtt pImX 100

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Study of the RS uniformity

Problems:

In the former USSR/Ukraine the recommendations on uniformity control were available only for bulk material

The requirements to uniformity must be coordinated with МАХ

The former approaches presumed the separation of variation concerned with the uniformity (by ANOVA). It resulted in unacceptably large minimal number of the samples to be analyzed (up to 90!)

The pharmaceutical RS have to meet the very stringent metrological requirements. Estimation of variation concerned with the uniformity may be impossible in practice (i.e., the variation obtained will be caused not by uniformity, but by the errors of the sample preparation).

So, for the pharmaceutical RS other approaches should be used

    

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The procedure for pharmaceutical RS uniformity study

The uniformity is studied for the packaged RS The maximal permissible non-uniformity is

expressed as a confidence interval for an individual content of the certified substance in RS unit (Unit), which must not exceed RS:

(9)

For the uniformity, only the practical insignificance is estimated. The uniformity characteristic (Unif) includes both the analysis uncertainty and the variation concerned properly with uniformity. When this summary characteristic is acceptable, the requirements to uniformity are met

RSUnit

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RS expiry date establishment

Based on the stability under the storage conditions (preferable way, but expiry date must not exceed ½ from that studied experimentally)

Based on the experimental results of accelerated aging data (there is the risk of incorrect data interpretation)

Proposed approach: Based on a priory information about stability of the RS candidate (pharmaceutical substance typically)

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RS expiry date establishment 2

Decision based on a priory information – the inequality:

(10) - MAX permitted content for the sum of

impurities (%), in compliance with specification for the pharmaceutical substance (RS candidate)

Inequality is completed. Expiry date for RS is equal to expiry date for the attestation material

Inequality is not completed. Expiry date for RS must be established by independent way.

СОMAXiX , MAXiX ,

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Elaboration and Establishment of the Ukrainian Pharmacopoeia RS

System

The following processes, specific for the RS certification have been elaborated and documented :

Choice of the RS candidate Preparation procedures Achievement of required degree of homogeneity Assessment of the stability Procedures guaranteeing RS characterization Realization of measurements traceability Preparation of supporting documents Establishment of the Pharmacopoeia RS Arrangements for ensuring adequate storage facilities Arrangements for the suitable identification, labeling,

packaging and delivery procedures quality monitoring program

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Elaboration and Establishment of the Ukrainian Pharmacopoeia RS

System 2Elaborated and implemented documents are

as follows : Quality manual (1st level) Standards of the Pharmacopoeial Committee (ІІ

level) SOPs (ІІІ level) Other documents – reports, protocols,  logs and

electronic databases, etc. (IV level)

At the time being the RS Department of Pharmacopoeial Center is certified in Ukraine as a measuring laboratory

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Progress of the Ukrainian Pharmacopoeia RS system

functioning

About 500 various Ph RS were certified This is more than WHO RS nomenclature This is about the same as the British

Pharmacopoeia RS nomenclature US pharmacopoeia RS nomenclature is about

2600 Now the Ukrainian Pharmacopoeia RS are

used in most CIS countries by pharmaceutical manufacturers, State Inspections laboratories, and in pre-registration research

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Progress of the Ukrainian Pharmacopoeia RS system functioning

2Priority of RS certification:

For Assay (chemical tests, microbiological and biological ones), for the Identification and another tests

For Impurities control (impurities mainly synthesized by the Ukraine Pharmacopoeial Center)

As herbal markers, produced by the Ukraine Pharmacopoeial Center from herbal raw material

As standardized herbal extracts (this permits the use of one summary extract in substitution of several individual herbal markers)

Instead of RS, specific for former USSR (in a majority, of herbal origin)

System suitability check Other use (turbidity standard, for example, for the turbidity of the

bacterial suspensions visual estimation ) RS for the Quality Assurance of the test results

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Elaboration of Pharmaceutical WRS system (Local RS)

In the USSR, a fundamentally different system of pharmaceutical RS was adopted :

- in the presence of Pharmacopoeia RS it is not permitted the use of any other status RS

- Laboratory certified all the other local RS as primary (mainly based on the titration results)

This required the development of a system of certification of local RS by calibration against the official pharmaceutical RS

The principles developed for the Pharmacopoeia RS certification were applied successfully to the WRS certification

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Elaboration of the Pharmaceutical WRS system

(Local RS) 2The specificity of the WRS certification Certification of WRS is fundamentally different from the

drugs quality control. Requirements to the WRS are 3.2 times as hard as MAX (see insignificance principle).

WRS certification is fundamentally different from the primary RS Certification. Certified value for the SSF is usually set as 100% - Imp. The content of impurities are usually quite low, so the accuracy of their content determination has a little impact on the RS.

In contrast to the FSO, WRS are calibrated against the Pharmacopoeia RS under the conditions used for the analysis of the medicine. The main methods of WRS certification are chromatography and spectrophotometry. It is much more difficult to achieve the necessary uncertainty of WRS for these methods.

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Elaboration of the Pharmaceutical WRS system

(Local RS) 3The procedures for certification of WRS and documentation system have been developed. Special analytical techniques for certification shall be applied as specified below: Volumetric operations performed by gravimetric method (if necessary)Analyze not less than 2 parallel samplesSample weight, dilutions and measurements number are optimized to meet WRSThe systematic monitoring of the results quality are used:

• Check the differences between the analysis results for the two parallel samples (must not exceed the maximum permissible uncertainty)

• Extreme value checking • Check homogeneity of variance for all of the samples.

Check the drift

The system of Local RS, meeting the requirements of GMP, has been implemented in several largest pharmaceutical enterprises in Ukraine

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Elaboration of Test Samples for Program of Proficiency Testing

Execution of PPT programs requires the use of special Test Samples (TS).

TS should be considered as a remedy, which is analyzed by the laboratory.

TS in many respects is similar to the RS - for them it is necessary to assign the certified value, study the uniformity and stability as well.

The new approach is used (based on the insignificancy principle and MAX):

- the uncertainty of certified TS values (TS) should be insignificant compared to MAX:

(11)- the result of the participant (Xi) is satisfactory, if Xi

deviates from the certified values of TS (XAtt), no more than a MAX:

(12)

MAXTS 32.0(%)

MAXAtti XX

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Elaboration of Test Samples for Program of Proficiency Testing 2

Pharmacopoeial Center since 2003 is among the organizers of the Ukrainian PPT Program «Pharma-Test» (testing is conducted annually - in 2012 the 9th round is held).

At the end of 2007 the Pharmacopoeial Center received the status of the official coordinator of PPT Programs.

Laboratory of quality control of medicines of Ukraine, CIS countries, and also the countries of the European community (1164 labs in all) participated in different rounds of PPT.

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Elaboration of Test Samples for Program of Proficiency Testing 3

Test Sample Analytical method, Task

Round 3 – 2004 year (56 participants)

Salicylic acid in alcohol solution Assay, UV-SPh

Lincomycin (substance) Assay, HPLC

Calcium gluconate (tablets) Assay, titration

Round 4 – 2005 year (59 participants)

Glucose (solution) Assay, Refractometry

Glucose (solution) Potentiometric determination of pH

Paracetamol (tablets) Test «Dissolution»

Paracetamol (tablets) Assay UV-SPh, Test “Disintegration”

Round 5 – 2006 year (57 participants)

Cefalexinum monohydricum (substance) Potentiometric determination of pH

Cefalexinum monohydricum (substance) Specific optical rotation, polarimetry

Cefalexinum monohydricum (substance) Specific absorbance, UV-SPh

Cefalexinum monohydricum (substance) Water, semi-micro determination

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Elaboration of Test Samples for Program of Proficiency Testing 3

Round 6 – 2007 year (59 participants)

Sodium acetate trihydrate (substance) Titration in nonaqueous solvent

Sodium acetate trihydrate (substance) Loss on drying

Dexpanthenol (substance) Related substances, TLC

Round 7 – 2008 year (59 participants)

Paracetamol (substance) UV-SPh

Maleic acid (substance) Related substances, TLC

Melting point (3 substances) Open capillary method

Round 8 – 2009 year (67 participants)

Degree of coloration of liquids (2 solutions) Visually

Ceftriaxone sodium (substance) Potentiometric determination of pH

Lincomycin hydrochloride (substance) Lincomycin B, HPLC

Round 9 – 2011 year (about 60 participants)

Fluoroquinolones antibiotic (tablets) Identification, TLC

Cefalexinum monohydrate Water, semi-micro determination

Glycerol (substance) Related substances, GC

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Elaboration of other RS to ensure the quality of the analysis results

The same principles used for the development of other RS:

- RS for validation/verification of test procedures (“direct” methods)

- RS for analytical equipment qualification (pharmaceutical tests)

- RS for in-laboratory quality assurance

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CONCLUSIONS

At the present time, Ukraine is the only country in the CIS, in which all the pharmaceutical RS presented by national

Ukrainian Pharmaceutical RS are widely used in the CIS countries

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Thank you for your attention