SOP for Raw Material Control (Reference) Sample Storage

In short: A control sample (called a reference sample in EU GMP) is a portion of an approved raw material batch kept so that it can be re-tested if a question arises later. This example SOP shows how a QC department can collect, store, withdraw and destroy such samples. Adapt the quantities, rooms and periods to your own quality system.

This is an illustrative template. Numbers, room names, document numbers and formats marked as an “example in-house criterion” are not regulatory requirements.

1. Objective

To describe how control samples of raw materials are collected, stored, withdrawn and destroyed so that each approved batch can be re-analysed if needed.

2. Scope

This SOP applies to control samples of all raw materials (active substances, excipients and empty capsule shells) held by the Quality Control (QC) department at the manufacturing site. It does not cover finished-product retention samples or packaging materials.

3. Responsibility

• Analyst / Section Head (or designee): collects the control sample at the time of sampling and records it.
• Head QC (or designee): implements this SOP, ensures the retention period is respected and prepares destruction lists.
• QA personnel: monitor and record the temperature and humidity of the control sample room, authorise withdrawal and destruction.

4. Why control samples are kept

EU GMP Annex 19 explains that a reference sample is a sample of a batch of starting material, packaging material or finished product stored so it can be analysed if the need arises during the shelf life of the batch. It serves as a record of the batch and can be assessed in case of, for example, a quality complaint or a query on compliance with the marketing authorisation (Annex 19, sections 2.1 and 2.3). EU GMP Part I Chapter 1 (section 1.9) also expects sufficient reference samples of starting materials and products to be retained for future examination.

US cGMP (21 CFR 211.170(a)) requires a reserve sample of each lot of active ingredient in each shipment, identified and representative, of at least twice the quantity needed for all tests to check specifications (sterility and pyrogen testing excluded).

5. Procedure

5.1 Collection and quantity

1. Take the control sample during routine sampling, as described in your raw material sampling SOP (example: “SOP QC011”).
2. Keep a quantity sufficient for at least two full specification analyses. This matches Annex 19 section 4.1 and 21 CFR 211.170(a); the exact quantity is stated in each material’s specification.
3. Keep control samples only for batches that are approved. A sample from a rejected batch is handled as in section 5.5.

5.2 Packing and labelling

1. Pack the sample in a double-lined polyethylene bag inside a fibre board drum (example in-house practice; choose packing that protects the material as per its storage condition).
2. Divide the sample into two packs of equal quantity and number them 1/2 and 2/2 on the label.
3. Attach the “Control Sample” label (Annexure I) to each pack. The label should show material name, code, batch/lot number, supplier, date of sampling, quantity, storage condition and retain-until date.
4. Place both packs in an outer pack and label it too.

5.3 Storage

1. After analysis and release, move the sample to the control sample room. Keep empty hard gelatin capsule shells in the designated, segregated area of the raw material store.
2. Store the sample at the storage condition stated for the material, for example refrigerated where the label or specification requires it (Annex 19 section 5.2 refers to storage per the marketing authorisation).
3. Arrange samples month-wise in plastic trays (example in-house practice).
4. QA personnel record temperature and relative humidity of the room twice a day (example in-house criterion; limits as per the room monitoring SOP) and review min/max readings.
5. Make an entry in the Control Sample Storage Record (Annexure II).

5.4 Withdrawal

1. Normally take material for re-testing from pack 1/2. Use pack 2/2 only if pack 1/2 holds too little.
2. Record the quantity withdrawn and the balance in the storage record (Annexure II).
3. If a sample must leave the control sample room for any specific purpose, the requesting department raises a requisition (Annexure III) giving the reason and quantity. The QA Head authorises it, and QA personnel remove the quantity and record it in the log book.

5.5 Samples of rejected batches

Keep the control sample of a rejected batch until the related Out-of-Specification (OOS) investigation is closed, then handle it as per section 5.7. See also OOS investigation: complete guide.

5.6 Retention period

Records and samples must be traceable, and the retention period must be defined and checked by an authorised QC designee.

Example in-house criterion: retain each raw material control sample until the longest of (a) the period set by the applicable regulations above, (b) the expiry or retest date of the material itself, and (c) at least 1 year after the expiry date of the last product batch made with that raw material. Batch records, logbooks and related GMP records linked to the sample are kept at least 1 year after the expiry date of the respective product batch (EU GMP Part I Chapter 4, section 4.11; 21 CFR 211.180(a)), or longer if local law or the marketing authorisation requires.

5.7 Destruction

1. An authorised QC designee prepares a monthly list of control samples whose retention period has ended (Annexure IV).
2. A second QC designee checks the list and the QA Head authorises it.
3. Destroy the material through the site’s approved waste-disposal procedure, in line with the material’s safety data sheet and environmental rules. Shred primary and secondary packaging before disposal.
4. QC records the destruction and updates the storage record (Annexure II).

6. Training and distribution

• Trainer: Head, Quality Control. Trainees: QC chemists and section heads.
• Distribution (example): controlled copy 1 to Head QA, controlled copy 2 to Head QC, master copy with QA.

7. Annexures

• Annexure I: Label for control sample
• Annexure II: Control sample storage record
• Annexure III: Requisition form for control sample withdrawal
• Annexure IV: Destruction report of control samples

Frequently asked questions

Is a control sample the same as a retention sample? In EU GMP they differ. A reference sample is kept for analysis; a retention sample is a fully packed unit of finished product kept for identification and visual checks (Annex 19, section 2.1). Raw materials have reference samples only. Many Indian sites call both “control samples”.

How much should be kept? Enough to repeat the full specification testing at least twice (Annex 19, section 4.1; 21 CFR 211.170(a)).

Do solvents, gases and water need a reference sample? Annex 19 section 3.2 excludes solvents, gases and water used in the manufacturing process from the starting material retention requirement.

Can the sample be destroyed before the retention period ends? Only through a documented, QA-authorised decision; otherwise keep it until the period has ended and the list is approved.

Related reading

• Good documentation practice, specifications and retention of documents
• OOS investigation: complete guide

References

• European Commission, EudraLex Volume 4, Annex 19: Reference and Retention Samples (2006 version; revision C(2026) 4135 adopted 23 June 2026, applicable from 24 September 2026). Sections 2.1, 2.3, 3.2, 4.1, 5.2.
• European Commission, EudraLex Volume 4, Part I Chapter 1: Pharmaceutical Quality System (in operation since 31 January 2013), section 1.9.
• European Commission, EudraLex Volume 4, Part I Chapter 4: Documentation, section 4.11.
• US FDA, 21 CFR 211.170 Reserve samples, and 21 CFR 211.180(a), eCFR (current).