SOP for Management of Reference Standards and Reference Solutions

In short: This is an illustrative SOP for how a Quality Control laboratory receives, stores, uses, verifies and disposes of reference standards (pharmacopoeial, secondary/working and impurity standards) and the solutions prepared from them. Adapt the numbers and annexures to your own quality system; the storage and validity values shown are examples, not regulatory requirements.

This is an example SOP template. It must be adapted, reviewed and approved under your own site quality system before use.

1. Objective

To define a procedure for the receipt, handling, storage, qualification, use and disposal of reference standards and reference solutions used in the Quality Control laboratory.

2. Scope

This SOP applies to all reference standards (including impurity standards and working standards) and reference solutions used for testing in the Quality Control department.

3. Responsibility

Role	Responsibility
Analyst or designee	Follows this SOP, records every use and preparation.
Head of Quality Control or designee	Implements the SOP, approves qualification of working standards, initiates procurement.
Quality Assurance	Reviews and approves the SOP and periodically checks the records.

4. Definitions

Term	Meaning (as commonly used)
Primary (pharmacopoeial) reference standard	A highly characterised, high-purity material from an officially recognised source, for example a USP, Ph. Eur. (EDQM), BP or WHO (ICRS) standard.
Secondary / working standard	A material of established quality and purity, shown by comparison with a primary standard, used for routine analysis.
Impurity standard	A characterised material of a known impurity or degradant, used for identification or quantification.
Reference solution	A solution prepared from a reference standard for use in a test.

5. Procedure

5.1 Receipt and identification

On receipt, check the product name, lot or batch number, quantity, container integrity, supplier certificate or certificate of analysis (CoA), and safety data sheet (SDS) where available.
Confirm the lot is the current valid lot (or a previous lot still within its valid use date) per the supplier catalogue.
Assign a unique reference number, for example USPRS/A1/1, where the first part shows the source (here USP), A1 is a serial code for the product, and the last number is the version.
Sign and date the original container. Enter the details in the reference standard register (Annexure I): item, reference number, lot number, date of receipt, quantity, storage and usage directions, valid-until or retest date.
Maintain an index (list) of all reference standards (Annexure II).
Where a standard is not available from any pharmacopoeia, obtain one from the manufacturer with a CoA and qualify it as a secondary/working standard (section 5.3).

5.2 Storage

Store each standard as directed on its label, CoA or SDS. Where no condition is stated, the site may define a default (for example 2 to 8 °C, protected from light and moisture).
Where the site practice is to keep vials in a sealed bag with silica gel, change the silica gel at a defined interval and record it (the original SOP used six months).
Allow a refrigerated standard to reach room temperature, in its closed container, before opening, to avoid moisture uptake.
Segregate impurity standards and keep them under the supplier storage conditions.

5.3 Qualification of working (secondary) standards

Qualify each batch of working standard against a primary standard before first use, under a written protocol. This is consistent with ICH Q7 11.19, which requires the suitability of each secondary batch to be determined before first use by comparison with a primary standard.
The protocol should cover identification, assay or purity (and water or loss on drying) compared with the primary standard, acceptance criteria, and the assigned potency on the as-is or dried basis.
Record the traceability to the primary standard (source, lot, reference number) on the qualification report and the CoA.
Assign a retest date and requalify periodically as per a written protocol (ICH Q7 11.19). If results are doubtful or disputed, repeat the test with the primary standard (WHO TRS 943 Annex 3, Part B).
If no primary standard from an officially recognised source exists, an in-house primary standard has to be established with testing that fully shows identity and purity, and the testing is documented (ICH Q7 11.18). This is normally beyond routine QC and needs QA approval.

5.4 Use of reference standards

Check the valid lot or retest date every time before use. Do not use an expired standard.
Verify the status of pharmacopoeial lots against the supplier catalogue at a defined frequency (the original SOPs said every two or three months, or whenever a new catalogue is received). Record the check (Annexure VII).
Use the potency or content stated on the label or CoA, on the basis stated there. If the label and catalogue give no value, the original SOP assumed 100%.
Where drying is directed, dry only the quantity needed. Never dry the original container and never return dried or weighed material to it.
Use the minimum quantity needed, particularly for impurity standards.
Record each use in the usage log (Annexure I): date, analyst, product/test, quantity taken, balance, instrument or analysis reference.
When a new lot is received, introduce it by recording a new version number and withdraw the old lot once its valid use date has passed or the new lot is in use, as per the SOP and catalogue.

5.5 Reference solutions

Prepare reference solutions only when required, using the minimum quantity of standard.
Allot a number such as RSSoln/A01/01 (solution, serial code, version) and record: name of the standard and its reference number and lot, test, weight, dilution, solvent, preparation date, valid-until date, and the analyst.
Label each container (Annexure III) with the name, number, concentration, preparation date, valid-until date, storage condition and preparer’s initials, and enter it in the solution index (Annexure IV) and the preparation record (Annexure V).
Store in tightly closed containers, protected from light, at the validated or defined condition (the originals used 2 to 8 °C). Allow solutions to reach room temperature before use.
Assign a validity based on solution stability data or the method. The original SOP used six months for stock solutions; the shorter of this and the demonstrated stability should apply.
Before use, inspect for colour, clarity and particles. Discard the solution if any change is seen.
After the first analysis, attach the initial data (for example chromatograms) to the usage log (Annexure VI). After each later use, compare the response with the initial data. Discard the solution if there is a significant change, for example new degradation peaks.
Discard a reference solution if the lot of the standard used to prepare it changes, and prepare a fresh solution with a revised version number (for example RSSoln/A01/02).

5.6 Disposal

Discard expired, consumed or compromised standards and solutions as chemical waste per the site waste SOP.
Record the disposal date, quantity and authorising person in the usage log and update the register and index.

6. Training

Trainer: Head of Quality Control. Trainees: Quality Control chemists and sectional heads.

7. Distribution

Controlled copy 1: Head of Quality Assurance
Controlled copy 2: Head of Quality Control
Original: Quality Assurance

8. Annexures

No.	Title
I	Reference standard register and usage log
II	List (index) of reference standards
III	Reference solution label
IV	Reference solution index
V	Reference solution preparation record
VI	Reference solution usage log
VII	Verification of reference standard status

9. Abbreviations

CoA: Certificate of Analysis. SDS: Safety Data Sheet. RS: Reference Standard. CRS: Chemical Reference Substance. BP: British Pharmacopoeia. Ph. Eur.: European Pharmacopoeia.

10. Checking lot validity

Check the current status of a pharmacopoeial standard from the issuing body’s own catalogue: the USP catalogue is on usp.org and the European Pharmacopoeia catalogue is on edqm.eu. Use the catalogue search on those sites for the product and lot.

11. Revision history

Version	Date	Change
Example	-	Fill in under your document control system.

Frequently asked questions

Is a working standard a replacement for a pharmacopoeial standard? No. A working standard is a secondary standard whose suitability is shown by comparison with a primary standard before first use and re-checked periodically (ICH Q7 11.19).

Do I have to test a pharmacopoeial standard before using it? ICH Q7 11.17 says primary standards from an officially recognised source are normally used without testing when stored as the supplier recommends. Follow the label and certificate.

Who decides how long a reference solution is valid? Your laboratory, on the basis of solution stability data, with the date applied on the label (ICH Q7 11.16). The six-month figure in older SOPs is not a regulatory number.

What records do regulators expect? For finished pharmaceuticals, 21 CFR 211.194(c) requires complete records of testing and standardisation of laboratory reference standards, reagents and standard solutions.

References

United States Pharmacopeia (USP), General Chapter <11> USP Reference Standards, current USP-NF (a proposal based on the version official 1 Nov 2020 adds digital reference standards).
World Health Organization, Annex 3: WHO general guidelines for the establishment, maintenance and distribution of chemical reference substances, WHO Technical Report Series No. 943, 2007 (a revision was circulated for comment in 2025 as working document QAS/25.972; check WHO for the adopted version).
ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Section 11.1 (11.16 to 11.19), Step 4 (November 2000).
US FDA, 21 CFR 211.194(c), Laboratory records (Current Good Manufacturing Practice for Finished Pharmaceuticals).