All medicinal products on the market must be licence. Technical Agreements for third-party analysis
monitored in a continuous programme in order to (which define responsibilities on both sides) must be
demonstrate stability and quality over their entire thoroughly revised under theses premises or must take
market life. Laboratory analysis is a cost factor that still account of it when they are first drawn up. The Qualified
offers room for manoeuvre in many companies, and Person employed by the manufacturing or contracting
with improved study design, the burden of ongoing company must ensure that the tests are carried out in
stability tests can be reduced. In the realisation of more accordance with GMP requirements by means of an audit.
efficient stability testing, however, it is important to be It should be kept in mind that ongoing stability
aware of the potential pitfalls. testing differs from other stability tests in its regulatory
and legal background (see Table 1) (2,3). However, these
BACKGROUND requirements only apply to licensed medicinal products
The revised version of Chapter 1 of the EU GMP which are currently on the market.
Guidelines (1) came into force in 2006; item 1.5 makes
the annual Product Quality Review (PQR) compulsory REQUIREMENTS FOR ONGOING
for all licensed products. This continuous revision of the STABILITY TESTING
consistency and validity of the entire manufacturing The categorical requirements of the GMP Guidelines for
process also includes a stability-monitoring programme ongoing stability testing are that:
as listed under sub-item vii. These ongoing stability tests
are specified in Chapter 6 of the EU GMP Guidelines, ! All medicinal products/formulations have to be
which were updated in the same year. tested, with no exception, in principle, for
Areas of quality control which previously formed only homeopathic products, herbals, and so on
part of R&D are now included in official GMP inspections. ! All finished products and, where appropriate, bulk
This is the case, for example, with the qualification of special products have to be tested (for example, when
equipment for stability testing, such as controlled storage stored or transported for prolonged periods).
cabinets. Standard operating procedures (SOPs) for dealing Excipients and active substances are not taken into
with out-of-specification results, not only for batch release account here
but also during stability testing, and for evaluating out-of- ! Requirements apply in principle to every product
trend results have to be implemented. in every dosage and pack size or (primary)
External laboratories contracted to carry out ongoing packaging type/package
stability testing must be included in the manufacturing ! Tests have to be carried out continuously, usually
one batch a year
Table 1: Summary of the different types of stability testing
(exemplarily for a new registration of a human medicinal product)
! Studies have to be carried out under long-term
Study type R&D study Follow-up (commitment) study On-going study
conditions (for example, 25°C and 60 per cent
Time point Before registration After submission of the dossier After registration and marketing relative humidity) continuously over the period
Aim of the study Setting shelf-life, storage Verify registration data Proof that conditions are of the labelled shelf life
conditions and specifications still valid
Background Registration procedures, Registration procedures, EU-GMP guideline
guidelines for stability testing guidelines for stability Tests following storage under intermediate and accelerated
(for example, ICH) testing (for example, ICH)
Extent Two pilot- or production-scale batches Production-scale, three Continuous; one batch conditions should only be carried out if supplementary
of the finished project. If ‘critical’, batches of the finished product – per year
for example when known as unstable, – each product
information is required at an early stage. In principle, all
three batches – each strength decisions which affect the test protocol, the frequency of
– each package
Competent authority Regulatory agency (for example, Regulatory agency (for example, National GMP surveillance –
testing and the choice of test samples should be product-
BfArM and MHRA) BfArM and MHRA) regulatory agency or health authority
based, targeted and founded on a risk analysis (see Table 2).
Ongoing studies are intended to prove that, over the Table 2: Selection of stability-limiting parameters. Decision should
period of its labelled shelf life and under ‘real life be made on the basis of existing data
Less critical parameters More critical and essential parameters
conditions’, the product remains of the quality defined in
the authorisation/registration documents. Stability Capsules and tablets Organoleptic and physical tests, uniformity of mass and content, Assay and impurities
disintegration and dissolution, microbiological quality
studies done for registration solely provide a ‘snap-shot’.
Liquids (for oral use) Organoleptic tests, uniformity of dosage, density, pH-value, Assay and impurities
Adverse effects such as changes in manufacture and the preservation, microbiological quality
supply chain (even those not on a variation level) should Sterile solutions Organoleptic tests, uniformity of dosage, density, Assay, impurities, sterility
(Ophthalmica, Parenteralia) pH-value, preservation and particles
be identified by ongoing studies. However, this
procedure also implies that the test protocol can be
Table 3: Protocol with reduced frequency of testing for an ongoing study (solid formulation):
adjusted at any time to the current situation. The T = Test, (T) = Test optional, o = designated testing, dossier (2), (3) omitted
stability protocol does not necessarily have to comply Test t0 t3 t6 t9 t12 t18 t24 t36 t48 t60
with the ICH stability testing guidelines. Organoleptic T (T) (T) (T) (T) (T) (T) (T) (T) T
Mass uniformity T o o o o o o o o T
the protocol for the ongoing stability programme may differ Purity T o o o T o T T T T
Microbiological quality T - - - T - o o o T
from that of the initial long-term stability protocol (3),
25ºC/60% rh T (T) (T) (T) T (T) T T T T
giving a reduction in the frequency of testing as an example. 30ºC/65% rh - - o o o - - - - -
If it has been shown that a test parameter is not critical, for 40ºC/75% rh - o o - - - - - - -
Sven Oliver Kruse, PhD, is Managing Director at Diapharm, 3. Note for Guidance on Stability Testing
responsible for the service laboratory Diapharm Analytics GmbH of New Drug Substances and Products
in Oldenburg (Germany). He entered the company in 2001 (CPMP/ICH/2736/99 corr)
and accompanied the transition from a scientific institute to a 4. Note for Guidance on Bracketing and Matrixing
service laboratory. He is also a Qualified Person for the
Designs for Stability Testing of Drug Substances
company. Sven is a member of the Pharmaceutical-Technical
Committee and the working parties ‘Validation’ and ‘PQR/On- and Drug Products (CPMP/ICH/4104/00 adopted
going Stability’ at the German Medicines Manufacturers’ Association (BAH). He 2002 / ICH Q1D)
studied Pharmacy at the University of Münster (Germany) where he received his 5. Sandner and Klöpf, Outsourcing in der
PhD in the field of phytochemistry research and analysis. He is also a member of Pharmaindustrie, Teil 1, Pharm Ind, 68, Nr 7,
the Society of Medicinal Plant Research, the Society of Phytotherapy and the
pp825-828, Teil 2, Pharm Ind, 68, Nr. 8,
German Pharmaceutical Society. Email: sven.kruse@diapharm.com
pp932-936, 2006