SOP for Handling of Reference Standards, In-House Standards, Primary Standards and Calibration Standards

PURPOSE

To provide instructions for Handling Reference Standards, In-house Reference Standards / Manufacturer’s Standards, Primary Standards, and Calibration Standards.

SCOPE

This SOP applies to the handling and usage of official Reference Standards and the preparation, usage, and handling of In-House Reference Standards, In-House/Manufacturer’s Standards, Primary Standards, and Calibration Standards in the Quality Control Laboratory at Pharmainfo Limited.

RESPONSIBILITY

User Department personnel

• To initiate the Document Change Request and to prepare or revise the SOPs.
• To provide the training as per new or revised SOPs.
• Follow and adhere to all the procedures laid down in the SOPs.

User Department Head/Designee

• To review the new and revised SOPs. (The person who has prepared shall not review/approve the SOP).
• To ensure that the training is provided to all the required personnel.

Quality Head/QA Manager

• To approve the new and revised SOPs.

QA Personnel

• To prepare the master and control copies of the SOPs.
• To Distribute, Retrieve, Archive and Destruct the controlled copies of SOPs.
• To maintain, control and distribute all the SOPs at site.

DEFINITIONS

• Reference Standard: Reference standards are substances of very high purity, having critical characteristics and suitable for the intended purpose and are provided by the official pharmacopeia agencies.
• In-House Reference Standard / Manufacturer’s Standard: These are authentic substances of very high purity with critical parameters, characterized In-house in the event of non-availability of official Pharmacopeial reference standard and are suitable for a specific purpose.
• Primary Standards: These are purified materials, which, after drying under the specified conditions (if specified on the label / in COA), are recommended for use as a standard in the standardization of volumetric solutions/calibration of instruments.
• Calibration Standard: A standard containing known quantities of target analyses (Chemical / Solvent / Reagent), prepared from traceable stock materials of known, certified quality obtained from a reliable source or sources. A calibration standard (Instrument / Device / Tool) with known accuracy and traceability / certified quality obtained from a reliable source or sources, wherever applicable.

PROCEDURE

General instructions to be followed by the Analyst:

• Ensure to practice precautions provided in MSDS / SDS for the material of interest.
• Store the reference standards in their respective storage condition as soon as possible after receipt.
• Check for any specific handling instructions and adhere to them same.
• Minimize the exposure time while handling hygroscopic and light-sensitive materials.
• If standards are removed from refrigerated conditions allow the standard vial/container to attain room temperature before use. Wherever applicable check the attainment of room temperature preferably through an Infrared probe or any suitable device.
• Dry only required a standard quantity on a glass petri dish, wherever applicable.
• Do not dry the standards in their original container.
• Do not put back any excess quantity of the dispensed material into the stock bottles.
• When required to determine the water content of the reference standard, use the minimum quantity of the standard.
• Proportionately smaller quantities of reference standards / in-house reference standards can be used, provided the final concentration is same as per the analytical method.
• When reference standards/impurity standards/working standards are received from the contract giver or from the manufacturer, review the COA and the characterization documents (if available). Enter the details in “Reference Standard, Working Standard and Impurity Standard Entry Register (Received from manufacturer/Contract Giver).
• In this SOP, wherever “Master” is specified, it indicates that Master to be created once.

ALSO READ: SOP for Preparation & Storage of Test Solution

Reference standard source master creation:

• Analyst/Designee QC shall update reference standard source details.

Reference standard pharmacopeia master creation:

• Analyst/Designee QC shall create all Pharmacopeia references (For e.g., BP, Ph. Eur., USP, etc.)

Reference standard / primary standard master creation:

• Analyst/Designee QC shall update available reference standards stock.

Handling of reference standard:

• Analyst/Designee QC shall check the availability of current lots of Reference Standards from authorized distributors or from Pharmacopeia agency, and procure the same.
• Analyst/Designee QC shall procure the standards from the sources authorized.
• Analyst/Designee QC shall verify the details of material with source data (Catalog, website or pharmacopeia) and the correctness of invoice/delivery challan against the received reference standard at the time of receipt;
• If any discrepancy is observed, the supervisor shall inform the manager for necessary action.
• Analyst/Designee QC shall enter the details in reference standard stock register.
• If purity is not available on the container label/catalog/literature supplied along with the container, the analyst shall consider it as 100 %.
• The analyst shall place the reference standard unit along with a desiccant (small silica gel bag) in a stainless-steel container or as per the design of the chamber.
• The analyst shall store the Reference Standards in their original containers protected from heat, light, and moisture and keep them in cold conditions (2°C to 8°C) or as directed in label / MSDS / SDS.

Usage of reference standard:

• The analyst shall enter the usage of reference standards in the reference standard stock register. Check the available stock in case the physical quantity of material is not sufficient enough to retrieve for usage, and destroy the same as per the destruction procedure.

Periodic review of reference standards:

• Analyst/Designee QC shall review the validity status of reference standards lot once in two months by verifying current lot details in official catalogs.
• Analyst/Designee QC shall update the review details of the reference standard periodic review in the reference standard stock register.
• If any existing reference standard lot available in stock is no longer valid, remove the same from use and update the details in the reference standard stock register.
• Once the existing reference standard lot available in stock becomes inactive as it is no longer valid, remove the same from use.
• Analyst/Designee QC shall take necessary actions to procure the new lot at the earliest.
• Stop the use of the reference standard once it is removed from the catalog / expired. Remove it from the regular stock and discard the material as per the destruction procedure available at the location.
• Enter the destruction details in reference standard stock register

Preparation of In – house reference standards:

• When a reference standard is not available from a pharmacopeia source; the analyst shall prepare an In-house reference standard by characterizing a suitable material available in-house or material received from the manufacturer along with COA.
• Review the Manufacturer's COA for compliance to the analytical specification. If any discrepancy is observed, inform the manager for necessary action.
• If the material is available in-house, select the material which is having lowest impurity profile and collect the required amount of sample through the material requisition note.
• Attach a copy of the material requisition note with a working standard analytical report and send one copy to the warehouse/stores.
• Transfer the quantity required for testing (standardization) into a separate container/polyethylene bag.
• Store the remaining portion at a temperature between 2°C to 8°C unless otherwise specified in the respective specification.
• Store the sample withdrawn for testing between 2°C to 8°C unless otherwise specified in the respective specification during testing.
• Perform characterization on at least two parameters and identification by suitable technique (Identification by IR, UV if applicable).
• Also perform material-specific tests like description, LOD/water content, chromatographic purity, etc.
• Prepare a protocol for Evaluation and Characterization of in-house reference standards, and update the same in the register.
• Prepare protocol covering the tests to be performed with acceptance criteria and complete details of the testing procedure.
• Prepare a template as per respective test procedures/pharmacopeia to record the results in the protocol.
• Head QC shall approve the protocol after verifying test procedure/specification reference.
• The analyst shall assign a unique number to the protocol for characterization as 

XXX/IHS/YY/CC/Rn 

where, 

XXX stands for Pharmainfo Ltd.

IHS stands for In-house Reference Standard,

YY stands for the last 2 digits of the year of In-house Reference Standard preparation and (e.g., 24 for the year 2024)

CC stands for a sequential number unique for a particular In-house Reference Standard prepared for that particular year, starting from 01.

Rn stands for revision number of the protocol, starting from 01

ALSO READ: SOP for Preparation of Data Sheets for Working Standard

• Describe chemical substances in the interpretation of characterization.
• Organic Impurities - Chromatographic Impurities / Chromatographic purity / Related substances: Estimate the impurities (%) in the material by a suitable chromatographic procedure.
• Residual Solvents – Organic: Estimate the solvent residues (in %) in the sample by Gas Chromatography or other suitable means. (Refer to manufacturer COA, if available).

• Total organic Impurities (O %) are arrived by adding up Chromatographic impurities and Residual solvents.
• Inorganic Impurities: Determine the Ash content (%) / Residue on Ignition / Sulphate Ash by an appropriate procedure. (Refer to manufacturer COA, if available)
• Estimate the Water content (%) or LOD (%) of the sample by an appropriate procedure.
• Calculate as is basis purity (in %) of the material by the following approach: % Purity (on as is basis) = 100 – (% Organic Impurities + % Inorganic Impurities + % Water/LOD in the sample)
• Calculate from the ‘as is basis Purity’, Purity on Anhydrous basis or Purity on Dried basis by the following formulae:

• The validity of the material on which characterization is performed is two years or as specified in the manufacturer COA or whichever is earlier.
• The analyst shall prepare a summary sheet for In-House reference standard Analytical report
• The analyst shall prepare a container label for the In-House reference standard with the necessary details
• Number the In-House reference standard as: XXX/IHS/YY/BB

Where,

XXX stands for PharmaInfo

IHS stands for In-House reference standard

YY stands for the last 2 digits of the year of In-house Reference Standard preparation (e.g., 24 for year 2024)

BB stands for a sequential number, it will be unique for a particular In-house Reference Standard prepared for that particular year, starting from 01.

• Record the details of usage in In-House Reference Standard Register

Primary standard:

• Procure primary standards along with a certificate of analysis (COA) from the manufacturer.
• Check the COA against the container for Name, Batch No. /Lot No, Manufacturer/Supplier Name, Grade.
• Check for physical integrity, storage condition, and hazardous symbol (if any).
• Paste the Chemical /Reagent label as per the site-specific procedure on Receipt, storage and handling of Laboratory Chemicals.
• Allocate control number for manual routing as follows: XXX/PS/BB/YY/ /CC

Where,

XXX stands for pHARMAiNFO

PS stands for Primary standard

BB stands for unique serial number allotted to the particular standard

YY stands for the last 2 digits of the year of Primary standard preparation (for e.g., 24 for year 2024)

CC stands for serial number of that particular standard prepared during the year, starting from 01

• Enter the details in the register.
• Store the labeled primary standard containers in a desiccator or as per the manufacturer’s recommendation.
• Store in original containers or as per the manufacturer’s recommendation.
• Do not use expired primary standards, discard the primary standards after expiry.

Instruction on the usage of Standard solutions:

• Label and store standard solutions (Reference standard, in-house Reference standard, working standard, impurity standard etc.), which are used for qualitative system suitability parameters at 2°C to 8°C
• The standard solution/system suitability solution (for qualitative purposes only) which is prepared as per standard testing procedure is valid up to 3 months from the date of preparation (unless otherwise specified) or as long as the solution complies with the system suitability acceptance criteria, whichever is earlier.
• Record the observation of standard solution/system suitability solution prepared for qualitative purposes in the observation sheet.
• If a physical characteristic of the stored solution is found not satisfactory, at any point in time discard the same.

Registers/log books

Calibration standards:

• Calibration standards used for inspection, measuring and testing of instruments/equipment to be traceable to national or international standards, wherever applicable.
• If national or international standards are not practically available, the user department can use an independent reproducible standard.
• All standards used for calibration to be stored in an appropriate place.
• Ensure the availability of a valid certificate of analysis/certificate of confirmation for all Calibration Standards.
• Analyst/Designee QC shall maintain a list of all calibration standards available in the laboratory and fill in the relevant details including the validity period
• The list of calibration standards to include all chemicals, reference standards, solutions, devices, tools, etc. used for calibrating instruments/equipment.
• Label each calibration standard/set of calibration standards (For e.g., Weight box) (as applicable)
• Maintain details of Calibration/certification of calibration standards.
• Review the list of calibration standards periodically, to plan recalibration/recertification or procurement of valid calibration standards and update accordingly.
• Clearly mark the standard's expiration or validity date. Do not use expired standards.

Handling of Primary Standards

• Physically, check the COA against the container for Name, Batch No. /Lot No, Manufacturer/Supplier Name, Grade.
• Check for physical integrity, storage condition and hazardous symbol (if any)
• If the received Primary standard found not satisfactory due to physical appearance, bottle damage, incorrect chemicals etc. return the chemical back to stores department.
• Update the received primary standard in the register
• Store the primary standard according to the storage condition

ANNEXURES

Annexure: Receipt & Consumption Register for Standards

ABBREVIATIONS

LOD: Loss On Drying

RS: Reference Standard

QC: Quality Control Department

QA: Quality Assurance Department

PS: Primary Standard

MSDS/ SDS: Material Safety Data Sheet / Safety Data Sheet

IHRS: In-house Reference Standard

HPLC: High-Performance Liquid Chromatography

IR: Infrared spectrophotometer

SOP: Standard Operating Procedure

COA: Certificate of Analysis

UV: Ultra Violet

BP: British Pharmacopoeia

USP: United States Pharmacopoeia

Ph. Eur.: European Pharmacopeia

REVISION HISTORY

Nil

ALSO READ: Qualification of Secondary Reference Standard