Meetings & Conferences

International harmonisation

Dr Paul Sugden ((Pharmaceutical Development Services Ltd) reviewed progress with international harmonisation. Because each of the three main regulatory groups (Europe, Japan, United States) for the registration of drugs has significantly different requirements, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) exists to overcome problems with multiple registrations. All three regulatory groups have agreed to accept data complying with ICH guidelines. However, additional guidance covering areas not in ICH guidelines continues to be generated by one or more of the regulatory bodies and there is a continual need to update the ICH guidelines, including the topics related to stability (ICH Q1). The guidelines of most immediate concern, with comments required by August 2002, relate to the evaluation of stability data (ICH Q1E ) and the stability data package for registration in climatic zones III and IV (ICH Q1F). In addition, some European guidelines also required consideration (CPMP/QWP/122/02 and CPMP/QWP/ 2934/99).

The aim of ICH Q1E is to recommend how to use stability data to propose a retest period or shelf life, and how and when limited extrapolation can be used to propose a re-test period or shelf life beyond the observed range of data. Limited extrapolation to extend shelf life beyond the observed storage period would be acceptable. Extrapolation should always take into account the worst-case scenario and assumes the same pattern of change will continue to apply beyond the range of observed data. The need for extrapolation must always be justified. ICH Q1E includes a useful decision tree, indicating when extrapolation of the retest period or shelf-life can be appropriate; however this differs according to whether the product is intended for storage at room temperature or below.

The parent guidelines (ICH Q1A) define the stability data package for the three regulatory regions, all of which are in climatic zones I and II. ICH Q1F extends the utility of Q1A to climatic zones III and IV, especially those relating to storage conditions.

CPMP/QWP/122/02, which extends ICH Q1A to apply to existing drug substances and related drug products in the European Union, was released for consultation in February 2002. The deadline for comments is August 2002. CPMP/QWP/ 2934/99 covers the stability testing of medicines in multidose containers, where repeated opening and closing may pose a risk of microbial contamination or physicochemical degradation. Guidance is given on tests that should be performed and provides study designs to define an in-use shelf life.

Animal-derived products

Dr John Bray (Q-One Biotech Ltd) reviewed the problems in the use of animal products, particular in relation to transmissible spongiform encephalopathies (TSE). The causative agent of TSE remains unknown, although there is a strong correlation with the disease-associated form of prion proteins — that is, abnormal forms of proteins with changed conformation which are protease resistant. Cases of the new variant form of Creuzfeldt-Jakob disease (vCJD) are on the increase even in those countries whose cattle are free of BSE. Biopharmaceuticals are by definition pharmaceutical products which are derived from animal tissues or fluids. Animal-derived products therefore have to be shown to be free of putative TSE agents, either by direct measurement or by introduction of processes shown to destroy or remove the agent.

Validation of processes to remove the agent entail the addition of a model agent such as mouse or hamster-adapted scrapie at the beginning of the process and demonstration of its absence at the end. Analysis is by bioassay as required for registration. However this process is long and expensive and a more economical strategy has been developed using Western Blot analysis as a pre-screen to identify effective steps which can be included in the process, before applying the full-blown bioassay procedure. This approach can significantly reduce the cost of large studies.

Recombinant proteins

Dr Meenu Wadhwa (National Institute for Biological Standards and Control) reviewed the problems in demonstrating the comparability of recombinant proteins used as therapies. Such exercises are required when there has been a change in the manufacturing process, or when a new manufacturer is claiming the product is "similar" to an already marketed product. Comparability is necessary for reasons of quality, safety and efficacy. Relevant guidelines are available from the FDA and from the European Medicines Evaluation Agency (EMEA).

For biopharmaceutical products, the process defines the product and any change, major or minor, has the potential to have a dramatic impact on safety and efficacy.

When the same manufacturer introduces a change in the process, for example by changing manufacture to a different site, detailed studies must be carried out comparing both products and processes. As an illustration, one manufacturer changing the site of production of INF-d1a was able to demonstrate comparability by full characterisation of the products and a full evaluation. Nevertheless the new product was less antigenic.

Where a different manufacturer is making a claim that a product is "similar" to an existing marketed product, the situation is more complicated, especially where no patent protection is offered, such as in products from India, China or Korea. There will be differences in cell banks, processes, equipment and analytical procedures. There will be no access to the original material or its documentation and therefore full preclinical and clinical testing will be necessary.

Herbal medicinal products

Cornelia Höhne (PhytoLab GmbH & Co, Germany) reviewed the regulation and quality requirements for herbal medicinal products, defined as medicinal products containing as active substances exclusively herbal drugs or herbal drug preparations. The particular problems of herbal medicinal products are that they are always complex mixtures, even if they contain only a single active compound. Analysis must always be for multiple components in trace amounts, plant material is not homogeneous, and questions regarding the starting material, such as cultivation and harvesting, are critical. From the analytical point of view, the crucial difference between pure chemical substances and starting material of natural origin lies in the complexity of the latter.

The requirements for documentation for marketing authorisation are no different for herbal medicinal products than for pure chemical products. There are however specific guidelines relating to herbal medicinal products. Specifications for starting material, for example, must include botanical characterisation of the plant part, biological and geographical variation, cultivation, harvesting and drying conditions, and any pre- and post-harvest chemical treatment. Special requirements exist for assays for heavy metals, pesticides and mycotoxins in the product; at present there is no requirement for testing for fall-out products from reactor accidents.

Where the analytical method gives the concentration of active material as a group of compounds, for example as hydroxyanthracene derivatives, this must be justified. Generally, where the active substance is known but not separated from other material in the finished product the analytical method needs to be specific.

Process analytical technology

Dr Rajendra Uppoor (Food and Drug Administration) described the views of the FDA on process analytical technologies (PAT), parametric release, and the manufacture of dosage forms.

PAT represent a paradigm shift away from stage-testing of material during the manufacturing process to continuous monitoring. This leads to improved overall product quality by virtue of decreased product variability, reduced manufacturing and testing time, understanding of causal links between process variables and product performance, and improved safety during the manufacturing processes. For the customer, this means better quality product sooner, and less or no shortages; for the industry, this means increased automation, increased capacity utilisation and efficiency, and reduced scrap, reworking, time to scale-up and time to validate; for the regulatory agencies, this means fewer compliance problems and hopefully faster evaluation.

Successful implementation of PAT will require close co-operation and dialogue between the regulatory authority and the manufacturer — developing a shared vision. The keys to success were to aim for built-in quality, to getting things right first time, asking the right questions and finding answers that matter.

The FDA had a vigorous programme to promote the introduction of PAT, including the need to allay industry fears that this may be an extra burden rather than a positive advantage over traditional quality procedures. From the FDA's perspective the current system provides products of good quality fit for the intended use but there is a low probability of finding a problem that will raise a safety or efficacy concern. Data collected during development of PATs for future regulatory use would be research data; if problems are seen, then this would be the basis for resolution.

Parametric release can be used as an alternative to routine release testing for the drug product in certain cases, when approved by the regulatory authority. Sterility testing for terminally sterilised drug products is one example. For terminally sterilised drug products, the release of each batch is based on satisfactory results from monitoring specific parameters, for example, temperature, pressure, and time during the terminal sterilisation phase of drug product manufacture. PAT may help develop and support parametric release capabilities for non-terminally sterilised drug products.

Clinical trials

The EU clinical trials directive (2001/ 20/EC) will be translated into national legislation by May 2003 and implemented from May 2004. Dr Stephen Robinson (Pfizer Global R&D) described approaches to stability assessment as part of expediting exploratory clinical trials bearing in mind current pressures facing the pharmaceutical industry including the new directive. Pressures on development include the increasing productivity in the discovery phase arising from high-throughput screening, genomics, proteomics and combinatorial chemistry, the high attrition rate at the safety and efficacy testing stages, and new regulations. Specifically, 2001/20/EC does not yet have any detail on data format or requirements for stability studies; however there are indirect references to storage conditions, period of use, and labelling requirements.

To overcome and respond to these pressures, three guiding principles for successful shelf life assignment during the exploratory development phase, bearing in mind that the primary objective is subject safety, can be established. These are to be pragmatic (the procedure must be fit for the purpose), to think holistically (use supportive date intelligently), and to obtain maximum value from data generated.

Some ICH concepts are applicable during Phase I and II trials, but early trial designs and associated formulations demand a more pragmatic and flexible approach.

Sufficient assurance of stability can be gained from purposeful degradation, material assessment and pre-formulation studies to allow initial extrapolation to a practical shelf life (� six months) in order to start clinical trials. This can be confirmed and extended later by formal stability studies.

Holistic assignment of shelf lives is essential to facilitate the rapid evaluation of new chemical entities in Phase I and II trials and new analytical and information technologies can maximise the information from stability data.

Metered dose inhalers

Matthew Bonam (AstraZeneca) discussed developments in specification setting for pressurised metered dose inhalers (pMDIs). The features of pMDIs were first described followed by a review of current guidelines. The FDA has issued a draft document "Guidance for industry — metered dose inhaler and dry powder inhaler drug products, chemistry, manufacturing and controls documentation"; this draft was issued in October 1998 and extends to 62 pages. The EMEA has issued a note for guidance on "Requirements for pharmaceutical documentation for pressurised metered dose inhaler products"; this eight-page document was adopted by the Committee for Proprietary Medicinal Products in February 2002 and will be effective in September 2002.

Factors which will affect dose content uniformity include drug concentration (typically individual cans are within 90 to 110 per cent target), valve metering volume (valve manufacturers will only supply to a specification of mean within 90 to 110 per cent), consistency of can, valve and actuator deposition, suspension stability/sampling, and analytical variability. The FDA has proposed specifications for dose content uniformity which the industry believes are difficult to achieve. Where the same test is required, compared with European requirements, the FDA requirements are often more complex. For example, the FDA specifies particle size distribution by a specific procedure (Andersen) and FDA requirements for foreign particles are more stringent. FDA dose delivery limits are also more stringent; calculations were shown to demonstrate that to meet FDA proposed limits at every time point the RSD for dose content uniformity needs to be better than content uniformity requirements for tablets with no change on storage! The industry's counter proposals, although more reasonable to implement, gave improved levels of protection to both consumer and producer.

Active ingredients

Directives 2001/83/EC and 2001/82/EC apply a requirement for good manufacturing practice to the manufacture of medicinal products but not their starting materials; the source of active specified in a marketing authorisation may be by reference to the drug master file. The proposed amendment extends GMP to starting materials.

Bronwyn Phillips (Medicines Control Agency) explained that these changes were considered necessary, first in the interests of public health to assure the quality of starting materials, secondly in the interests of the single market, thirdly in the interests of obtaining a comprehensive MRA with the US, and finally to give member states the authority to inspect starting materials of animal origin. The proposals are being considered by the European parliament and implementation will be 2004 at the earliest.

There is no automatic obligation for competent authorities to inspect manufacturers of actives or excipients. However, the MCA offers a system of voluntary inspection, whereby inspection is at the request of an active or an excipient manufacturer. The scope of the inspection is defined by the manufacturer, but the basis for actives is the guideline EU GMP Annex 18. A GMP certificate, valid for two years, may be issued. A total of 30 inspections has been carried out to date and the findings included seven critical deficiencies, 36 major deficiencies and 184 other issues. The point was made that although quality control was usually taken very seriously, quality assurance was often under resourced and poorly understood.