REFERENCE STANDARDS and TESTING STANDARDS

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REFERENCE STANDARDS TESTING STANDARDS & WORKING STANDARDS

Definations::

1. Reference STANDARDS : Substances of high purity with critical characteristics suitable for specific purposes. They are supplied by official pharmacopoeial commissions. Usually these are counterparts of international standards. Standard, generally having the highest metrological quality available at a given location or in a given organization, from which measurements made there are derived. standard is normally used to calibrate other standards. Definations :

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USP's official Reference Standards Highly characterized specimens of drug substances, excipients , impurities, degradation products, dietary supplements, compendial reagents, and performance calibrators. They are specified for use in conducting official USP–NF tests and assays. USP'S reference standards are used in more than 130 countries around the world. Certified Reference Materials (CRMs) USP also offers CRMs, which represent the next generation of exceptional quality USP Reference Standards. They have undergone additional metrologically based testing and statistical analysis to meet both USP‘s criteria and guidelines established by the International Organization for Standardization (ISO).

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2.TEST STANDARDS: Materials of high purity, which are characterized and judged for suitability of standards to be compared with when evaluating non- pharmacopoeial working standards. 3.WORKING STANDARDS Laboratory working standards may be prepared for routine analysis provided. they are standardized at regular intervals with reference to official reference standards. Official reference substances are to be used in case of doubt or dispute.

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. Reference Substances Test Standards (From pharmacopoeia) (In-house developed) Working standards

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Reference STANDARDS : International chemical reference substances are established on the advice of the WHO Export Committee on specifications for pharmaceutical preparations supplied by WHO collaborating Centre. For Chemical Reference Substances, Stockholm, Sweden. BPCRS (British Pharmacopoeia Chemical Reference standards) Supplied by Medicines Control Agency Laboratory, Stanmore, England CRS/EPCRS (European Pharmacopoeia Chemicals reference substances) supplied by European Pharmacopoeia Commission Secretariat, Strasbourg, France.

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USP Reference Standards are established and released under the authority of UPSC Board of trustees upon recommendation of the USP Reference Standard Committee which passes on the selection and suitability of each lot. Other reference substances issued by UPSC: Formal USP and NF reference standards not official but in demand FCC reference standards specified in current edition of the Foods Chemicals Codex Authentic Substances (AS) – purified samples of chemicals including substances of abuse USP reference standard committee collaborates closely with WHO in order to minimize the differences in the actual units of potency and in some cases in the preparation of a reference standard.

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IPRS – Indian Pharmacopoeia Reference Substances, abbreviated to RS are issued under the direction of the Ministry of Health & Family Welfare, Government of India by Central Drug Laboratory (CDL), 3 kyed street, Calcutta –16. CDL also issues CDLRS where IPRS are not provided. IFPRESS – Indian Foundation For Pharmaceutical Reference Standards - A-21 MIDC, Street-3, Andheri (E) – Mumbai 400 093, is authorized by CDL & government authorities to issue CRS-IP Certified Reference Substance IP RS were introduced in USP X for biological assays. RS are now required for numerous other procedures as well. measurements relative to a reference standard to attain accurate and reproducible results.

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WHY DO WE NEED REFERNCE STANDARDS? Analytical Need : Analytical necessity and GLP/GMP requirement. This transforms quality from opinion to fact. Enhancement of Quality Assurance : Reference standard usage is a benchmark and generally accepted practice in international commerce. Avoids complications and ambiguity in expression. Legal Need : Endorses the regularity compliance. Affords protection against possible product quality liability.

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Role of analytical laboratory Receive from authorized source and allocate unique number for proper identification. Maintain proof of receipt. Appropriately label the container in which the standard is stored. Store at specified storage condition (generally between 2 to 8 o C unless otherwise specified) generally in original container. Avoid humid storage condition. Assume potency to be 100 % unless otherwise specified. Do not dry the material in the original container. Dry the material only where required and as per the directives.

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Determine water content using minimum quantity with diluted Karl Fisher reagent. Maintain usage log. Replace old lots/batches with current lots/batches as listed in pharmacopoeial forum or official catalogues

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WORKING STANDARDS Standard that is used routinely to calibrate or check material measures, measuring instruments or reference materials. A working standard is usually calibrated against a reference standard. Selection /preparation of batches Testing/approval / documentation Containerization Storage Handling/usage Validity

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SELECTION / PREPARATION OF BATCHES Any commercial/ R& D batch with low level of impurities and assay close to 100 % can be selected. Re-purification of commercial batch in the laboratory may be required to achieve impurity levels suitable for working standard. e.g. Guanine (impurity) free Acyclovir USP working standard. Quality of batch selected for working standard is related to the application. e.g. working standards of impurities, which are used only for identification by retention time, can be of lower purity. But, working standards of impurities, which are used for qunatitation , must be of higher purity.

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TESTING / APPROVAL / DOCUMENTATION Prepare testing protocol for each working standard based on the utility of the same. e.g. A current commercial batch, which has already been approved and meets the purity/assay requirement need not be tested again it is used only for identification by IR/UV. Comparison of IR/UV spectrum of the sample with the reference substance is sufficient to certify the sample as working standard. A current commercial batch, which has already been approved need to be tested again for assay against the reference substance if it is intended for assay test.

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Establish the identity of the working standard in comparison with reference substance, even if it is not used for any identification test.e.g.IR,UV,TLC , HPLC, GC Determine LOD/water content of the working standard if the standard is intended for any quantitative measurements. This is to understand whether any correction is required for weighing during routine analysis. Review / approve protocol & test data. closure system

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CONTAINERIZATION Policy on quantity packed in individual containers to be available Single use containers Quantity sufficient for fixed number of analysis Quantity sufficient for fixed period of time (week, month etc.) Select type of containers depending on the above policy. Consider the following Glass containers Light resistant Appropriate size Closure system for prevention of contamination and misuse.

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Cleaning of containers – consider the following: Initial cleaning prior to use Cleaning for re-use Drying for removal of water/solvent Prevention of water condensation during cooling Cleaning /drying of

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STORAGE Store at the same temperature at which corresponding reference substance is stored Place the glass containers inside small SS containers with cotton cushioning to prevent breakage and also pace some silica gel pouches to absorb the possible condensation of moisture. Change silica bags frequently. Ensure all storage facilities are connected to uninterrupted power supply Ensure all storage facilities are connected with appropriate temperature and alarm systems. Ensure continuous monitoring and recording of temperature of storage facilities Ensure all standards are kept back in their respective storage facilities immediately after usage and not at the end of the day.

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HANDLING / USAGE Handle the same way in which reference substances are handled After approval of the containers from different storage conditions, allow the containers to equilibrate to room temperature before weighing Ensure minimum exposure of material to atmospheric conditions Take necessary precautions while weighing light sensitive /hygroscopic materials. Do not insert any dispensing equipment into the container as this may contaminate the standard. Always dispense the material on to a dispensing equipment (weighing paper, spatula etc.) by gentle tapping

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Do not put the excess material back into the container Follow appropriate safety measures while handling potent materials Assume potency to be 100 % unless otherwise specified. Do not dry the material in the original container. Maintain usage log indicating quantity used, analytical reference, signature of the user with date.

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VALIDITY Assign validity based on the following factors: Characteristics of the material such as: Stability Thermal Stability Hygroscopicity Light sensitivity Container and closure system Frequency of usage Analytical method in which it is used Cost of preparation and standardization

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Tests to be performed for standardizing (preparing) working standards: Description : Note down the description & physical appearance Identification : IR, Melting point, UV absorption maxima, Retention time using official reference standard USP RS/ BPCRS/EPCRS/RS of current lot Loss on drying or water content by KF perform in triplicate Purity : by TLC /GC/HPLC/ spectrophotometric method

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Assay : Perform in triplicate using proper STP. Use relevant pharmacopoeial reference standard in assay by HPLC or UV method. Results should not differ by more than o.5 (absolute value from average assay) Calculate potency i.e. Assay on as is basis of working standard. Potency = A (100-B) 100 A. Average assay on dried/ anhydrous basis B. Average LOD / water content by KF