Stability Testing - Design and Interpretation for International Registration, February, 2000 This was IBC's 6th Annual conference on Stability Testing. The first international guideline on stability testing was adopted at ICH2 in Orlando, in October 1993. This Q1A ICH guideline has served as the 'core' guideline for international stability testing and all of the subsequent ICH, national and regional guidelines on stability-covering line extensions, biotechnology products, photostability, generics etc. The conference documentation includes topics such as: bracketing and matrixing designs, requirements for Climatic Zones III and IV and analysis and interpretation of the stability data. Please find 2 Executive Summaries from papers presented at IBC Life Sciences, Stability Testing Conference. Please click on one of the below options to view the Executive Summary written from that presentation. Marketing Authorisation Variation Applications - Stability Data Requirements Carrying out Stability Testing of Clinical Trial Materials For further information and details of the comprehensive documentation available from this event, please visit: www.ibc-lifesci.com/ly1191 1. Marketing Authorisation Variation Applications - Stability Data Requirements [top] A significant number of different changes to the Chemistry and Pharmacy (Part II) part of a Marketing Authorisation dossier have a possible impact on stability. There is consequently a need to generate stability data in support of these changes and clarification is required of the extent of any required data. Variation applications are generally submitted to reflect the availability of new data (shelf life extensions) or to introduce changes (quality improvements, marketing driven or commercial). The main areas where there are stability considerations concern shelf life extensions and changes to the active ingredient(s), product and use of the product. The significance of any change is related in some way to the dosage form. Variation applications are different to new Marketing Authorisation applications in that there is an already defined baseline. The quality standards, which must be met, have been defined in the finished product specification in terms of validated test methods and limits. In addition, comparable data should be available in most instances where data has been acquired prior to and after grant of the Marketing Authorisation. The way variation applications are handled have changed significantly during the last few years following the introduction during March 1995 of the Commission Regulations (541/95 and 542/95) on the handling of variations to mutual recognition and centralised Marketing Authorisations. The Regulations, which were amended during mid 1998,were immediately binding, no change in national law was consequently required and they have provided the basis for the effective handling of changes. The MCA has applied the system to all variation applications since 1 June 1995 and the amended regulation since 1 September 1998. The Regulations identify 34 categories of defined minor changes (Type I) in Annex I of the Regulation along with 7 sub categories. Each category has specified conditions, which must be met. Annex II detail changes which cannot be achieved by variation and consequently require a new Marketing Authorisation. All other changes can be handled as Type II variations. The Regulations also detail time scales for the handling of each type of variation, Type I (30 days) and Type II (90 days) and specify the time allowed for responses to be received if further information is required. The Type I list contains clear definitions and conditions and also consideration should be given to any specific exclusions based upon product type. The information in the Annex is not sufficient to be stand alone in terms of supporting data requirements and a separate guideline " Dossier requirement for Type I variations", was developed during November 1995 to support the Type I list. This guideline details the supporting information required for each specific category. The guideline was recently updated (November 1999) to reflect the amendments to the Regulations. This has resulted in the inclusion of more information about stability data requirements, which is welcomed since the previous document was lacking in this respect. Special note should be made of products where the manufacturing process is an intrinsic part of the product quality. The majority of Type I categories concern changes in Chemistry and Pharmacy and a significant number of these have potential stability implications. Interpretation of the guideline indicates that as far as Type I changes are concerned they fall into three categories. No stability data requirement stipulated, on-going commitment given to monitor stability and finally data is always required. Examples of each type will be discussed during the presentation to highlight the current situation and they will be identified by their Type I category number. Currently where reference is made in the guideline to stability data, it is stated that stability studies will be carried out in accordance with the relevant stability guidelines. This is referring to the other stability guidelines that are in place regarding conditions to be used etc. As far as Type II changes are concerned a guideline has been compiled and came into effect during October 1998. The changes included in it are the most complex and the way the document has been put together is that stability data requirements are proposed for three commonly encountered situations - manufacturing process of the active ingredient, formulation of the product and immediate packaging of the product. In addition, an attempt has been made to differentiate between the requirements based upon the stability of the active and nature of the product. Generally, batch data is required at real and accelerated conditions on a minimum of two batches (pilot scale) stored for 6 months. There are exceptions to this and in the introduction to the document it is stated that less data can be presented if it can be justified. The test conditions to be used are referred as being the same as those specified in the main stability guideline - " Stability of new drug substances and products". It should be noted that all Type II variation applications must be supported by an Expert report, which should critically discuss and justify the data presented in support of a particular change. The majority of variation applications we currently receive and are supported by stability data (approximately 1500) fall into the Type I category. The main changes concern shelf life and storage precautions. Generally most applications we receive are of good quality but there are some common deficiencies. Very few applications are ultimately refused (1-2%). In summary the processing of variation applications has changed considerably during the last few years. You need to familiarise yourselves with the system and the data requirements. Consideration should be given to the content of the agreed guidelines. It is acknowledged that it is very difficult to give extensive guidance for the most complex changes because of the variety of changes that can be requested and the different characteristics of different active ingredients and dosage forms. Ultimately it is the responsibility of the Marketing Authorisation holder to consider if a change has a potential affect on quality characteristics and consequently stability and to design appropriate stability studies, based upon their existing knowledge and experience of the active(s) and product, to support the change. Dr. W. Keith L. Pugh Team Leader, Variations MCA 2. Carrying out Stability Testing of Clinical Trial Materials [top] Although the seven-year-old ICH initiative to harmonise regulatory requirements has achieved a great deal, this has mainly focussed on the final NDA dossier or equivalent in other countries. During early clinical investigations, some international differences still exist in the stability data required to perform first studies in Man with an NCE, and the stage at which this is required; for example, no CTX is required in the UK for early Phase I studies. These differences are scientifically, relatively minor compared to NDA requirements, and the overall aim to ensure safety in volunteer / patient studies would appear to be satisfied. ICH has provided a standard mechanism for evaluating and comparing stability data in dosage forms undergoing clinical investigations. Nevertheless, it is still of primary importance to be aware of the likely causes of instability in all dosage form types, ahead of formal stability test programmes, and to take steps to avoid them during initial formulation design activities leading to clinical batches. Clearly, researchers tend to produce more stability data on their NCE products than on comparators used in the same clinical investigations and yet strategically important comparative efficacy and marketing support data is generated during such studies. Additionally, potential variables at this early stage, such as improvements in NCE (drug substance) quality and alterations made to comparators in order to achieve blinding, can contribute to this risk area. Overall, scientific groups and regulatory bodies should jointly act globally to generate constructive guidelines for reference at the IND, CTX etc. stage of NCE development. D Jordan BPharm., PhD., MRPharmS Quintiles Scotland Limited Heriot-Watt University, Edinburgh