Reference and Retention Samples – Regulatory Perspective

Every pharmaceutical manufacturer sometimes goes berserk about ever changing regulations and multiple interpretations of the same guideline by various GMP experts. One of the grey areas is storage of reference and retention samples. This becomes an area of big concern for the pharmaceutical manufacturer handling number of Stock Keeping Units (SKUs). Following questions keep confusing a manufacturer about reference and retention samples are:

1. What’s the difference between Reference and Retention Samples?
2. Why the samples need to be stored?
3. Who to store what?
4. How much quantity to store?
5. For how long they are to be stored?
6. Under what conditions reserve and/or retention samples to be stored?

This is important to know that very regulatory agency viz. USFDA, EU, WHO, TGA, PIC/s etc. have more or less uniformity in requirements when it comes to storage of reference and retention samples.

This article will try to answer all the above questions and many more. So, let’s get started:

1. What’s the difference between Reference and Retention Samples?

 Reference Sample: Reference sample is a sample stored for the purpose of future analysis which consists of Active Pharmaceutical Ingredients (APIs), other critical starting material (if any), packaging material and finished product. This may be required for the assessment of the finished product manufactured in case any issue crops up during the shelf life of the batch concerned. It is highly recommended that the firm shall also consider storing reference samples from critical processing stages providing critical quality attributes or intermediates that are transported outside of the manufacturer’s control should be kept. However, due consideration shall be given to the stability of such intermediates.

 Retention sample: Retention sample is a sample of marketable pack which is a completely packaged unit from a batch of finished product. The major reason for its storage is for identification purposes in case any issue crops up during the shelf life of the batch concerned.

This is to be noted that for finished products, in many cases the reference and retention samples will be stored identically, i.e. as fully packaged units. In such cases, reference and retention samples may be considered as substitutable.

Both the reference and retention samples shall be as far as possible be a true representative of the batch of starting material, intermediate product or finished product from which they are taken.

 

2. Why the samples need to be stored?

The reason for storage of reference and retention samples are:

1. For carrying out analysis of the sample in case of any market complaint or defect or failure.
2. For identification of the sample in case of any complaints of counterfeit or spurious product in the market.
3. Any query pertaining to labeling/ packaging or other conditions of marketing authorization
4. For investigation in case of any adverse event observed
5. As a part of compliance to the regulatory requirements.
6. For carrying out investigation in case of any type of failure.

3. Who to store what?

Manufacturer: Reference sample from a batch of starting material, and/or intermediate product and Retention sample of each batch of the imported finished product

Importer: Retention sample of each batch of the imported finished product

Packaging (if different from manufacturer): Reference samples of each batch of primary and printed packaging materials. Retention sample of each batch of the imported finished product.

4. How much quantity to store?

 As a thumb rule, the reserve and retention sample shall at least be double the quantity necessary to perform all the tests required to determine whether the API (in case of reference sample) and finished product (for retention sample) meets their established specifications (Pharmacopoeial and/or In-house), except for sterility and pyrogen testing.

It is important to note that higher quantities can be stored as per firm In-house requirements. Above all, law of land or national regulations shall be followed in case of any discrepancy.

 

5. For how long they are to be stored?

The reference as well as retention samples of each batch of finished product shall be stored for at least one year post expiry of the product

The samples of APIs shall be retained for at least two year after the release of the finished product. In Indian context, as the shelf life of formulation shall not exceed the shelf life of API used, hence, reference samples shall be stored up to its shelf life. Packaging materials shall be retained up to the shelf life of the concerned finished product.

6. Under what conditions reserve and/or retention samples to be stored?

The retention samples shall be stored in their marketable pack as the same is drawn from the finished goods. Retention samples shall be stored under the same temperature and RH conditions as mentioned on the pack or as per the marketing authorization granted.

The reference sample shall be stored in its finished primary packaging or in packaging composed of the same material as the primary container in which the product is marketed. Reference samples shall be stored under the same temperature and RH conditions as mentioned on the pack.

Important Considerations:

1. Samples kept for stability studies shall not be considered as retention samples.
2. Traceability record of all the samples shall be thoroughly maintained.
3. Duplication of retention samples of finished products packed in multiple packs for various markets may not be required in special circumstances viz. where very small quantities of a batch are packaged for different markets or in the case of very expensive medicinal products.

References:

1. Section 211.170 of 21 CFR of USFDA
2. PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PI009-14)
3. WHO Technical Report Series no. 986, Annexure 2
4. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use; Volume 4, Reference and Retention samples, Annexure 19
5. Schedule M of Drugs and Cosmetics Act