Focus Medicine by the gallon: An industry complying with specific pharmaceutical and industrial legislation

2 Focus Medicine by the gallon: An industry complying with specific pharmaceutical and industrial legislation Jan Strybol, Air Products STRYBOJ@airproducts.com Key Words Medicinal gas, medical device gas, bulk gas, cylinder, therapy, healthcare facility, homecare, compliance, legislation. Abstract Medicinal gases are used in many applications and therapies. Recently several European countries have begun classifying these gases as medicinal products with the result that the full pharmaceutical legislation applies to them. However, medicinal gases differ in many aspects from the other drugs now on the market. authorities have few experts in this area and interpret the Directives differently. This article explains the different aspects of medicinal gases, how the industry complies with the regulations and what challenges and opportunities lie ahead in the market of medical gases. Introduction Which medicines are used daily by thousands of patients at thousands of litres per day in healthcare facilities and in homecare, and although considered as a commodity are truly classified as medicines? They are the medicinal gases. The industrial gases business reached the $49 billion mark in 2005. As part of that, the global medicinal gases market hit the $10 billion mark. Medicinal gases are used in many applications and therapies. Oxygen is not only used extensively in operating theatres and postoperation treatment, but also increasingly in homecare therapy to improve the quality and length of life. Nitrous oxide, xenon and gas mixtures are used in anaesthesia or for analgesia. Other gases such as SF 6 for ophthalmology and CO 2 for endoscopy are classified as medical device gases to 93/42/EEC; the same is true for the cryogenic surgery gases, liquid nitrogen and liquid nitrous oxide. Another large group of medicinal gases are the lung function gases, being mixtures of O 2, CO, He and even CH 4, allowing the diagnosis of deficiencies in the patient s breathing system. All these medicinal gases have to comply with the European and National pharmaceutical regulations, such as the EU Directive 2004/27/EC or the EU Directive on clinical trials 2001/20/EC. This article gives a general overview of some of the main regulations governing medicinal gases and how the gases industry implements them. One Europe 26 authorities In Europe there is indeed one set of regulatory pharmaceutical Directives, which governs the manufacturing and distribution of medicinal gases. However, because these Directives are very general, their interpretation differs from one country to another. Although some European countries still do not require Marketing Authorisations for medical gases (Italy, for example) most other countries do demand it. The need for a manufacturing licence with Good Manufacturing Practice (GMP) compliance is a requirement in every country. Add to this that our gases industry has to comply also with other non-pharmaceutical legislation and finally, the fact that we have a complicated manufacturing and distribution supply chain, and the result is that regulatory affairs of medical gases is a complex environment. Differences of interpretation National regulatory agencies interpret the European Directives and Standards differently. Here are some examples: Bulk medical gases are not well defined: most countries classify them as medicinal products, others though as active pharmaceutical ingredients. In France, the enforcement of GMP results in systems and equipment dedicated solely for medical gases manufacturing and distribution; this is in contradiction with any other European country. Germany allows release by a nominee of the Qualified Person (QP), while Ireland now insists that QP release must be performed at the site of manufacturer. France defines cryogenic liquid nitrogen as medical device-gas, for the treatment of warts, but Spain defines it as medicinal gas product, ie, as drug when in contact with the tissue to be conserved. T O P R A T H E O R G A N I S A T I O N F O R P R O F E S S I O N A L S I N R E G U L A T O R Y A F F A I R S

September Issue 2006 2005 23 11 3 Table 1: Summary of main legislative requirements for medical gases. Pharmaceutical Legislation Marketing Authorisation SmPC and PIL Manufacturing Licence Qualified Persons Medical Gases Industry Compliance For common gases: based on Well Established Use Full compliance. PIL most often not attached to the package. Braille under investigation Additional and specific compliance to Annex 6 of the GMP Every batch is released. High number of small batches per day Quality Assurance ISO 9000 or ISO 13485 Quality Control Packages and closure systems compliance Pharmacovigilance Clinical trials Medical devices and in vitro devices Full compliance to the European Pharmacopoeia monographs Storage tanks, tankers, cylinders with their specific valving; compatible, eg, to oxidants, extreme low temperatures, etc Small central team with multidisciplinary skills, supported by national QPs Through EVWEB Exceptional, due to the high investment cost for one single gas mixture versus business profit Classification of gases based on their intended use: as medicinal product and/or as medical device Other Legislation Pressure Systems Transport Health exposure Environment protection Medical Gases Industry Compliance Compliance to Pressure Equipment and Transportable Pressure Equipment Directives Compliance to the Transport Regulations for Dangerous Goods Compliance to the protection of safety and health regulations for employees and staff who administer the medical gases Compliance to the environmental protection and waste regulations Medical air: is it a drug? Is it a mixture or pure gas? There are still so many open questions and contradictions between countries, which makes it very difficult for us to standardise, control licences through Mutual Recognition and reduce costs through synergies. Pharmaceutical regulatory authorities have few experts on medicinal gases, but since the early nineties, they have been open to cooperate with the industry to improve rules and standards. The medical gases industry not only has to comply with pharmaceutical legislation, but also with many other Regulations and Directives: Transport of Dangerous Goods, Transportable Pressure Equipment and Pressure Equipment Directives, just to name those which have the highest impact on the gases business. The gases industry has come a long way in meeting the requirements of the pharmaceutical legislation: Marketing Authorisation and Manufacturing Licences, QP releasing the batches, recall practices, patient information leaflets, etc. The communication between the industry and the pharmaceutical authorities has increased and improved at National and at European level with the European Medicines Agency (EMEA) and the Pharmaceutical Inspection Convention (PIC). The result is a better understanding and appreciation and a willingness on both sides to move forward. For a long time, the PIC has maintained a Medical Gases Expert Circle. At this moment several of its members are working together with the EMEA in writing a new version of the GMP, more specifically its Annex 6, on medicinal gases. The Medical Gases Industry Association (EIGA) 1 is in contact with the Circle to provide advice and input. Furthermore, we are also actively participating in the Expert Group 9G Medicinal Gases of the European Pharmacopoeia, in writing new monographs for, eg, methane and carbon monoxide. Finally, we participate in the CEN TC215 and ISO 121 Standardisation Committees on Anaesthetic and Respiratory Equipment. Focus continued www.topra.org

4 Medical gases and Regulations Medical gases are peculiar medicines. The manufacture of gases is in fully enclosed production systems, which makes contamination from the atmosphere highly unlikely, but increases the need for documented validation because the inspector cannot see, touch or analyse things that easily. The source of the gases can both be from simply the air around us (which is compressed, purified, liquefied and distilled in its different components), or from natural gas (eg, hydrogen) or as a result of a chemical reaction, for instance to produce nitrous oxide from ammonium nitrate solution decomposition. However, undoubtedly the most conspicuous difference with other medicines such as pills or syrups, is the fact that the package, ie, the cylinder, is recovered and, after a cleaning process, re-used for many other patients over many years. The gas cylinder or bottle, with design pressure up to 300 bar, is made of alloys of steel or aluminium with or without elastomers in the outer layer to make them light weight and thus portable for mobile patients. The closures of these cylinders and the cylinder valves have, thanks to new technology, been changed to integrate all of the following functions: pressure and flow regulation, back contamination prevention and contents gauge. The bulk gases, mainly in cryogenic state (ie, at temperatures typically around 185 C) are produced and transported in tankers (with internal stainless steel vessel) and stored at healthcare facilities in tanks also made from an internal SS lining with an outer carbon steel vessel. The gases industry falls under the chemical branch. Safety of our operators, and of the community in which we work, is well understood and controlled. Risk management principles are embedded in every process. The latest ICH Q9 Quality Risk Management guideline of January 2006 is already well established in the gases industry. Quality of the product and of the services is equally ensured by continuous improvement. Most of the common medicinal gases, such as oxygen, nitrous oxide, as well as air compressed or blended, have been in use for hundreds of years. Still, in order to obtain a Marketing Authorisation, one needs to submit the full five modules of the CTD format. Fortunately, we can base ourselves on the fact that they are well established, hence Modules 4 and 5 can be written based on bibliographic scientific literature and their summaries in Module 2 can be written by experts. (Applications for medicinal gases for animals also exist, but the Authorities have not yet focussed on the requirement for a veterinary product licence). Other gases, such as xenon (Xe) for example, used in anaesthesia, require clinical trials and as such the development of a drug form can take 5 to 10 years before it can be marketed. EIGA, the European Industry Gases Association, has as its mission to provide authorities and standardisation bodies with expert advice on production, transport, storage and applications of medical gases. At country level the national gases associations also have frequent contact with the authorities. All safety critical aspects of the production, storage, distribution and usage of gases are covered within the gases industry by establishing and publishing industry minimum standards. The gases industry mainly uses a quality assurance system based on ISO 9000:2000 or ISO 13485:2003: the latter being specifically for medical devices manufacturers and maintenance. Compliance Even though the manufacturing and certainly the distribution process of medical gases is complex, non-compliance is limited. Compliance is enforced through regular inspections by the regulatory agencies and is supported by a self-inspection programme. Pharmaceutical legislation all has to be complied with day after day, whether it is applied to a batch as small as 100 cylinders or 40 tonnes bulk product in a tanker. The safety, quality and efficacy has to be guaranteed, it must be released by a QP and it must be traceable once released on the market. What are the main challenges of compliance to pharmaceutical legislation? From an industry point of view: The legislative requirements are often not applicable to gases (this can be advantageous, eg, see the explanation above on bibliographic evidence; or disadvantageous, a 5% CO 2 in O 2 product is not the same product as a 6% CO 2 in O 2, although it is used for the same treatment). Different Marketing Authorisations are required and the costs related with this often are not supported by its revenue The authorities interpret and implement legislation differently to the extent that there are even differences between federal states in Germany Medicinal oxygen package with a cylinder integrated valve Peculiarities of medical gases are still not always understood by the pharmaceutical authorities T O P R A T H E O R G A N I S A T I O N F O R P R O F E S S I O N A L S I N R E G U L A T O R Y A F F A I R S

September Issue 2006 5 With regard to the EudraVigilance system: thanks to the fact that, at least for the common medicinal gases, we have close to zero adverse event reactions, we can perform our transmissions with the EMEA using the WEB Trader component of EVWEB. Our industry also assists healthcare facilities with the continuation of compliance to the principles of the pharmaceutical legislation on storage and handling of medicinal gases and training. Compared with Europe, the FDA has other priorities (which have been addressed in Europe): Publication of the cgmp has again been delayed Medical gases cylinder filling plant Requirements are continually changing: the introduction of annual product review, on-going stability testing, Braille on labels, traceability, etc. Traceability is a very complex and expensive requirement because we have to trace the batch of gas product, the cylinder and the cylinder valve in detail to each end customer, meaning not just the healthcare facility, but also the patient at his/her home. Due to the way in which the medicinal gas industry has evolved in the different European countries and the levels to which the regulatory authorities have applied the rules and guidance for GMP, the industry is not as advanced in its implementation as it would like. For example, further improvements are being implemented by the industry on reconciling of labels and label control, validation of our manufacturing and transfilling processes and computer systems (note that most of our air separation plants are run by one man), GMP training, deviation control, protection of cylinders against adverse weather conditions and pharmacovigilance. Medical gases air separation plant with bulk distribution tanker A major concern of the authorities is the prevention of gas mixups (it is possible to connect the wrong gas to the user point). The CGA 2, the equivalent to EIGA in the USA, is finishing a complete training package for healthcare staff explaining, labelling, colour coding and gas connections The USP is planning to establish standards for the labelling and storage of medical gases The integrity of the package and package closure requires validation, eg, the leakage rate of the cylinder valve during the gas product shelf life of up to five years. PROVA Quality is our strength European MAA CTD Preparation Module 2 Summaries Module 3 Consultancy Technical due diligence Full Generic Service Project management Product development Technical transfers MAA preparation Licence Maintenance Part II CTD conversion Technical compliance Variations Renewals General EDMF/CEP CTA WDL/WI Veterinary development/registration Qualified Person Contact: Carole Tidy/Jim Rennie Units 1-4 Craven Court, Stanhope Road, Camberley, Surrey, GU15 3BW, UK E-mail: caroletidy@prova.co.uk jimrennie@prova.co.uk Tel: +44 1276 678870 Fax: +44 1276 686473 Web: www.prova.co.uk Focus continued www.topra.org

6 Outlook The medical gases industry has invested huge sums of money in licences, GMP infrastructure, dedicated medical processes, equipment and people. compliance can always be improved, also legislation is changing and increasingly more demanding. Until recently our industry had little influence on the drafting of legislation, nevertheless we have a good relationship with the authorities. We need to extend this further, invest in regulatory affairs and build on our strength as being one of the safest industry branches in the world. We have to increase our contact with clinicians and technical staff of healthcare facilities concerning regulations, understand their perspective and offering our expertise to assist them with compliance. The fast growing homecare market requires more attention on compliance because we deliver medicinal products, medical devices and services directly to the patient. Medical gases bring great benefits to patients and our company embarks upon clinical trials for new applications even though the regulatory side is complicated and very long, and the price setting is difficult because there is no obvious benchmark. Overall, the medical gases industry believes in the same objective as the authorities, in that we must safeguard public health by means which do not hinder the development of the pharmaceutical industry or trade in medicinal products within the Community. Hospital with dual storage tanks for medicinal liquid oxygen References EIGA: European Industrial Gases Association. www.eiga.org CGA: Compressed Gases Association. www.cganet.com European DG Notice to Applicants Volume 2A procedures for Marketing Authorisation. ENTR/F2/BL D(2002). EMEA s PIM system V2 released into production June 2006 The road to successful multilingual PIM submission is full of challenges. A single day s delay results in deferred revenue and lost market share. Are you ready for simultaneous multilingual PIM submission? With more than 50 offices across 30 countries SDL is ready to help you. We are already solving complex multilingual challenges for life sciences companies such as GlaxoSmithKline. Visit www.sdl.com/lifesciences or call +1 408 743-3508 to find out how SDL s Global Information Management Solutions are meeting multilingual challenges today.