This document provides guidelines for reserve/retention samples of active pharmaceutical ingredients (APIs) and drug products according to various regulations. It discusses: - Requirements for reserve samples under 21 CFR 211.170 including quantity, packaging, and retention period. - ICH Q7 guidance on reserve/retention samples including storing samples in the same or better packaging than marketed. - Details on developing standard operating procedures for handling, packing, labeling, storing, examining, and destroying reserve/retention samples according to cGMP regulations. - Responses to common questions about reserve/retention sample requirements.

1. Dr. A. Amsavel

2. Guideline for Reserve /Retention Samples
 21 CFR 211.170 Reserve Samples
 21 CFR 211.180 (e) Records and Reports, General
Requirements Reference Documents
 ICH GuidelineQ7 GMP for API: 11.7 Reserve/ Retention
Samples*
 EU Guideline to GMP (Medicinal Products for Human and
Veterinary Use) Annexure-19
 WHO Technical Report Series- 957
* WHO Guideline for API, Eduralex GMP for API, PICs are same

3. 21CFR § 211.170 Reserve samples.
Reserve sample that is representative of each lot in
each shipment of each active ingredient shall be
retained.
ICH Q7: Reserve/Retention Samples (11.7)
The packaging and holding of reserve samples is for
the purpose of potential future evaluation of the
quality of batches of API and not for future stability
testing purposes.

4.  Reference Sample (EU): A sample of a batch of starting
material, packaging material or finished product stored for
the purpose of being analyzed should the need arise during
the shelf life of the batch concerned Critical intermediate or
intermediate when sufficient stability Sufficient size tointermediate when sufficient stability Sufficient size to
permit occasions full analytical at least twice
 Retention Sample (EU): A sample of a fully packaged unit
from a batch of finished product stored for identification
purposes In many instances, reference and retention samples
of finished products are presented identically.
 Ref: EU Guideline to GMP (Medicinal Products for Human and Veterinary Use) Annexure-19

5.  Reserve sample (21 CFR 211.170) :
A sample representative of each lot in each shipment of
each active ingredient or a sample representative of each
lot of drug product At least two times the quantitylot of drug product At least two times the quantity
necessary for all tests required to determine whether the
API or drug product meets its established specifications
Drug products must be stored in the same container-
closure in which it is marketed.

6. Establish SOP for handling of Reserve/Retain Samples
consist the following;
◦ Purpose & Scope
◦ Responsibility
◦ Sample preparation, Quantity, Packing and Labeling,◦ Sample preparation, Quantity, Packing and Labeling,
Storage condition, Sample withdrawal, approval etc
◦ Deviation in the storage conditions if any
◦ Annual Verification
◦ Destruction
◦ Documents & Records

7.  Reserve sample is the representative sample of each Commercial
batch or Lot of APIs. Incase of Drug products- Active ingredients,
primary packaging material & finished products has to kept for
purpose of future reference.
 Collect sample as per SOP, eg. No. of containers to be sampled,
quantitative from each container / bag, how and where samplesquantitative from each container / bag, how and where samples
have to be collected ,
 Define clearly preparation of Representative /composite samples.
 Packing & labeling: Describe how to pack, quantity and Label with
adequate details. Number the packs if multiple packs -1/2 &2/2
Note: define the sampling tool, Container Precaution to be taken and record
in sampling report.

8.  The reserve sample shall be packed and stored in the same
immediate container-closure system in which the drug
product is marketed or in one that has essentially the same
characteristics. (21CFR 211.170)
 ICH Q7-11.72: The reserve sample should be stored in the
same packaging system in which the API is stored or in onesame packaging system in which the API is stored or in one
that is equivalent to or more protective than the marketed
packaging system
Label: Product Name , Batch Number, Manufacturing date
Expiry/ retest date, Quantity, Storage condition, packed by
etc..
 Note: Preferably in 2 packs. Eg 25 gm for analysis (2X25gm)

9.  At least twice the quantity necessary for all tests
required to test for complete specifications, except
for sterility and pyrogen testing (21CFR 211.190)
 Sufficient quantities should be retained to conduct Sufficient quantities should be retained to conduct
at least two full compendial analyses or, when there
is no pharmacopoeial monograph, two full
specification analyses (ICH Q7).

10. 21CFR 211:170
 Reserve sample of API shall be retained for 1 year after the
retest date or 1 year after the expiration date of the last lot of
the drug product containing the API.
Three months after the expiration date of the last lot of the Three months after the expiration date of the last lot of the
Radioactive drug product containing the active ingredient if
the expiration dating period of the drug product is 30 days or
less.
 API in an OTC drug product that is exempted. The reserve
sample shall be retained for 3 years after distribution of the
last lot of the drug product containing the active ingredient.

11.  ICH Q7: 11.7
Appropriately identified reserve samples of each
API batch should be retained for one year after the
expiry date of the batch assigned by the
manufacturer, or for three years after distribution ofmanufacturer, or for three years after distribution of
the batch, whichever is the longer.

12.  Stored in a secure area and under conditions consistent with
specified storage conditions for material or finished product
Storage conditions.
 The storage conditions of API should be equal or better than the
label storage conditions.
 Drug product shall be retained and stored under conditions
consistent with product labeling.
 The storage condition should be monitored for temperature and
if applicable, for humidity.
 In case of deviation from specified storage conditions,
document, investigate and assess impact for each retention
sample

13.  Reserve Sample can be withdrawn for testing in case of
Market Complaint on Quality.
 Such withdrawal of retention samples should be
documented. Eg . Reserve sample log book & Label
 Approval /Authorization from QA Head Approval /Authorization from QA Head
 Record the quantity withdrawn and balance
 Additional Label on the sample pack with details like
date & quantity withdrawn.
 In case Sample is required for testing other than
complaint eg. Query, retesting, reference purpose shall
be justified and documented.

14.  Access to Reserve samples room shall be restricted
 Only authorized personnel must have access
 Quantity withdrawn must be authorized
 Store Controlled Substances & Drugs separate from
other samples to protection against forced entry.
 Monitoring and reconciliation is mandatory ie.
statutory requirement for Controlled Substances

15.  Reserve samples from representative sample lots or
batches selected by acceptable statistical procedures shall
be examined visually at least once a year for evidence of
deterioration unless visual examination would affect the
integrity of the reserve sample (21CFR 211.190)integrity of the reserve sample (21CFR 211.190)
 Any evidence of reserve sample deterioration shall be
investigated in accordance with § 211.192.
◦ Eg. Verification of sample 100% if less than 10 batches or
√ n+1 for more than 20, for huge numbers month wise
plan etc

16.  The results of examination shall be recorded and
maintained with other stability data on the API/drug
product.
 Appearance/Description, Packing Quality, Imprinting, Appearance/Description, Packing Quality, Imprinting,
Overprinting, Intactness of package, delamination,
Peeling/Motting of coated tablets.
 Examination of Reserve samples has to be reviewed
and reported in the Annual Product Review

17.  Control sample & Retention sample shall be destroyed as
per procedure and on the due date
 Prepare the document for destruction and Approval
from QA Head or others as appropriatefrom QA Head or others as appropriate
 Maintain the destruction Record with following details:
◦ Approval for destruction
◦ Quantity destroyed
◦ Due date and Actual date of destruction
◦ How was destroyed and in presence of whom it was destroyed.

18. Why does ICH Q7 permit the use of a packaging system for
reserve/ retention samples that is “more protective than the
marketed packaging system” (ICH Q711.72)?
Unlike stability samples, the purpose of the reserve/retention
sample is not to represent the quality of the batch in the marketsample is not to represent the quality of the batch in the market
place but to allow future evaluation of the quality of the original
API batch (e.g., in evaluation of potential counterfeits).
Therefore, reserve/retention samples may be stored in
packaging (and conditions) that better preserve the original
state of the API. (ref Q7 : Questions and Answers- CDER –FDA- April2018)

19.  Do we need to keep reserve samples of starting materials
intermediates used in API manufacturing?
Q7 does not have an expectation for reserve samples of raw materials
or intermediates, other than intermediates that are being sold. (11.7)
 If the API manufacturer must retain a sample of each batch - and
so must the drug product manufacturer under 21 CFR 211, - canso must the drug product manufacturer under 21 CFR 211, - can
the API manufacturers retained sample satisfy both
requirements?
The purpose of the retained sample for the drug product manufacturer
is to retain a sample of the material as it was received. In most cases it
is unlikely that the API manufacturers sample can satisfy both. On the
other hand, if APIs and drug products are made in the same plant one
retained sample could be enough. (Sec.11.7)

20. Thank YouThank You