Title: Guideline for Stability Testing for R&D

Manual Number: 045

Prepared by: Date: Supersedes:
Checked by: Date: Date Issued:
Approved by: Date: Review Date:

Manual: 045
Guideline for Stability Testing
for R&D

1
 approved specification, provided that it is stored under the conditions defined on
the container label.

4 Responsibilities

It is the responsibility of R&D to generate stability data to a scientific level that

supports the development, production and worldwide marketing of a drug product.

4.1 R&D Line Management

R&D Line Management, as defined in local procedures, supported by or in

conjunction with other relevant personnel where appropriate, is responsible for:

‡ The principles of a stability program for drug substances, drug products,

comparators and placebo products at all stages of drug development

‡ An awareness of approved and draft stability guidelines

‡ Assessing if reduced stability programs can be applied
‡ Appropriate consultation with Regulatory CMC and subsequently if
necessary with relevant authorities
‡ Ensuring that suitable batches are placed on stability
‡ Documenting and approving stability protocols according to local
procedures
‡ Evaluating stability data against acceptance criteria and reporting data
according to GEL templates and local procedures
‡ Assigning appropriate re-test periods, shelf lives and storage conditions for
drug substances, investigational medicinal products, excipients and
comparators and updating when more data become available
‡ Assigning re-test periods, shelf lives and storage conditions to be
included in the MAA
‡ Ensuring the hand over of stability studies to Operations and agreeing together
the stability protocols for commitment and annual maintenance batches in the
MAA

4.2 R&D QA

QA is responsible for:

‡ Releasing batches of drug substances and drug products for formal (MAA)
stability studies.

‡ It is not necessary for QA to release batches of drug substances and drug

products prior to the start of a stability study, providing there is no undue
delay. A risk assessment for the project is recommended under these
circumstances.

5 Guideline

This section of the Stability Guideline provides recommendations on

stability testing requirements, however provides the flexibility to use alternative

6
 ‡ Stable drug products
‡ Less stable drug products

5.4 Drug product line extensions

Treat drug product line extensions as new drug products and conduct stability
studies according to guidance detailed in 5.2 and 5.3. A reduced stability data
package may be acceptable for the regulatory submission. If the drug substance
manufacturing process is unchanged further stability studies are not necessary.

5.5 Comparators

Comparators used in a clinical trial should be stability tested if modified (e.g.

encapsulated, reformulated or re-packed in packs less protective than the original
pack). As a minimum, one batch is recommended at the long term condition and
optional testing at the accelerated condition to support extrapolation of shelf life.

Consider also placing the unmodified comparator on stability as a reference.

Evaluate testing, at least for appearance. For a comparator product in its original,
or equivalent, package no stability testing is needed.

Stability information on comparators may be found in the literature to support

shelf life decisions. If a modification results in a formulation or pharmaceutical
form that differs significantly from the commercial product, consider collecting
some accelerated stability data in a pre-study.

5.6 Placebo

In some cases, consider testing at least for appearance.

5.7 Holding times and storage of drug product intermediates

Consider providing stability data if the holding times and storage of drug product
intermediates (e.g. bulk solutions or granules) exceeds 30 days. Currently, there
are no guidelines stating maximum allowed holding times of intermediates,
however such stability data are used by Operations post registration to support
products with several discontinuous manufacturing steps.

When the final process is settled it is recommended to manufacture one batch

using the planned maximum holding time for each intermediate. This batch,
representing the longest possible process time should be stability tested at long
term and accelerated conditions.

A shelf life calculated from the last step in the manufacturing process could be
justified when a cumulative hold time stability study of the drug product has been
performed demonstrating appropriate stability (Regulatory approval is needed).

Therefore with suitable cumulative hold time stability data, the date of
manufacture is not the date that the first processing step is performed combining

10
5.14.5 Shelf life for placebo

Placebos formulations from standard excipients should be assigned a default shelf

life according to local procedures. Where placebos have been stability tested at least
for description, extrapolations may be made confirmed by real time data.

5.15 Storage conditions

Information on appropriate storage conditions should be given on labels for

investigational material and for marketing according to available regulatory
guidelines.

14
19