Ongoing Stability Testing: Requirements, …

1 Ingredients, Formulations & FinishingAll medicinal products on the market must bemonitored in a continuous programme in order todemonstrate Stability and quality over their entiremarket life. Laboratory analysis is a cost factor that stilloffers room for manoeuvre in many companies, andwith improved study design, the burden of ongoingstability tests can be reduced. In the realisation of moreefficient Stability testing , however, it is important to beaware of the potential revised version of Chapter 1 of the EU GMPG uidelines (1) came into force in 2006; item makesthe annual product Quality Review (PQR) compulsoryfor all licensed products.

2 This continuous revision of theconsistency and validity of the entire manufacturingprocess also includes a Stability -monitoring programmeas listed under sub-item vii. These Ongoing Stability testsare specified in Chapter 6 of the EU GMP Guidelines,which were updated in the same of quality control which previously formed onlypart of R&D are now included in official GMP is the case, for example, with the qualification of specialequipment for Stability testing , such as controlled storagecabinets. Standard operating procedures (SOPs) for dealingwith out-of-specification results, not only for batch releasebut also during Stability testing , and for evaluating out-of-trend results have to be laboratories contracted to carry out ongoingstability testing must be included in the manufacturinglicence.

3 Technical Agreements for third-party analysis(which define responsibilities on both sides) must bethoroughly revised under theses premises or must takeaccount of it when they are first drawn up. The QualifiedPerson employed by the manufacturing or contractingcompany must ensure that the tests are carried out inaccordance with GMP requirements by means of an should be kept in mind that Ongoing stabilitytesting differs from other Stability tests in its regulatoryand legal background (see Table 1) (2,3). However, theserequirements only apply to licensed medicinal productswhich are currently on the FOR Ongoing Stability TESTINGThe categorical requirements of the GMP Guidelines forongoing Stability testing are that: All medicinal products/formulations have to betested, with no exception, in principle, forhomeopathic products, herbals, and so on All finished products and, where appropriate, bulkproducts have to be tested (for example, whenstored or transported for prolonged periods).

4 Excipients and active substances are not taken intoaccount here requirements apply in principle to every productin every dosage and pack size or (primary)packaging type/package Tests have to be carried out continuously, usuallyone batch a year Studies have to be carried out under long-termconditions (for example, 25 C and 60 per centrelative humidity) continuously over the period of the labelled shelf lifeTests following storage under intermediate and acceleratedconditions should only be carried out if supplementaryinformation is required at an early stage. In principle, alldecisions which affect the test protocol, the frequency oftesting and the choice of test samples should be product -based, targeted and founded on a risk analysis (see Table 2).

5 EU GMP Guidelines require Ongoing Stability testing for the market-life of all medicinal products but with sensible and skilled planning of thetest protocol, it is possible for expenditure, and hence production costs, to be kept to a in Pharmaceutical TechnologyBy Sven Oliver Kruse at Diapharm AnalyticsGmbHOngoing Stability testing : Requirements, Solutions and Potential PitfallsStudy typeR&D studyFollow-up (commitment) studyOn-going studyTime pointBefore registrationAfter submission of the dossierAfter registration and marketingAim of the studySetting shelf-life, storage Verify registration dataProof that conditions areconditions and specificationsstill validBackgroundRegistration procedures, Registration procedures,EU-GMP guidelineguidelines for Stability testing guidelines for Stability (for example, ICH) testing (for example, ICH)

6 ExtentTwo pilot- or production-scale batches Production-scale, threeContinuous; one batch of the finished project. If critical , batches of the finished product per yearfor example when known as unstable, each productthree batches each strength each packageCompetent authorityRegulatory agency (for example,Regulatory agency (for example,National GMP surveillance BfArM and MHRA)BfArM and MHRA)regulatory agency or health authorityTable 1:Summary of the different types of Stability testing (exemplarily for a new registration of a human medicinal product )IPT 28 2009 12/3/09 13.

7 56 Page 78 Ongoing studies are intended to prove that, over theperiod of its labelled shelf life and under real lifeconditions , the product remains of the quality defined inthe authorisation/registration documents. Stabilitystudies done for registration solely provide a snap-shot .Adverse effects such as changes in manufacture and thesupply chain (even those not on a variation level) shouldbe identified by Ongoing studies. However, thisprocedure also implies that the test protocol can beadjusted at any time to the current situation.

8 Thestability protocol does not necessarily have to complywith the ICH Stability testing SAVINGS REALISATION AND PITFALLSItem of the EU GMP Guidelines specifically states thatthe protocol for the Ongoing Stability programme may differfrom that of the initial long-term Stability protocol (3),giving a reduction in the frequency of testing as an it has been shown that a test parameter is not critical, forexample during the course of commitment (follow-up)studies or later in Ongoing studies that have already beenperformed, the frequency of testing may be given example shows that, overall, there is a possiblereduction in the required frequency of testing of about50 per cent or even more (see Table 3).

9 It should benoted that at the end of the shelf life, all the testparameters should be checked again (in this case t60), inorder to prove Stability over the entire storage the product is manufactured in different strengths(same API with similar matrix) and pack sizes, the bracketing recommendations can be applied (4). If thereare more than two sizes for any parameter, this provides foronly the extremes to be tested (see Table 4). This exampleshows the requirements in the guidance. Assuming anidentical bulk product , then if the exemplary productabove is packed in blister packs of 10 tablets, each withidentical primary packaging material, the effect ofsecondary packaging for example, different secondarypackaging for different foreign markets does not have tobe taken into account.

10 testing of only one pack size wouldtherefore be sufficient. The same applies to multi-dosecontainers, where only the most sensitive size of containerwould have to be tested on a worst case scenario the latter (ideal) example, the number of tests couldbe reduced from nine to two, with corresponding cost-savings. However, consideration of the individual case isalways important. It may be necessary, for example, for thefirst batches to be tested in accordance with the full protocolin order to provide sufficient data for trend combination of Ongoing studies with follow-up(commitment) studies is often discussed.