Ingredients, Formulations & Finishing Manufacturers of pharmaceutical products and the suppliers who provide them with excipients are facing an uncertain future with the formal introduction of Good Manufacturing Practice (GMP) requirements in the European Union. However, there is still considerable debate about the form these will take and also the opportunity for stakeholders to have their say. The European Commission says it has a clear mandate to draw up legislation, at least for some high- risk excipients (see inset box), in the interest of public health. This stems from a series of cases in which excipients have been involved in major public health problems, as well as from other concerns including the possibility of transmissible spongiform encephalopathy (TSE) contamination in animal-derived excipients. DRUG CONTAMINATION INCIDENTS An incident in Panama in 2006 saw 21 people die after taking a government-made cough syrup formulated with diethylene glycol that had been mislabelled as glycerine, a widely used excipient. Another 38 people were affected by side effects including disorientation and kidney failure. Earlier this year, several countries – including Panama – issued a major recall of toothpaste made in China because it contained diethylene glycol that had again been mislabelled as glycerine. While no deaths were reported in this case, previous contamination episodes involving medicines have been far more serious. In 1996, glycerine contaminated with diethylene glycol killed 88 people in Haiti, while in 1990- 1992 paracetamol syrup contaminated with diethylene glycol from propylene glycol led to 236 deaths in India and Bangladesh. In 1990, 47 people died in Nigeria after taking cough syrup contaminated with solvents. The complex supply chain in the Panama case – which saw the glycerine/diethylene glycol pass from a supplier in China not registered to supply pharmaceutical-grade products, through the hands of several companies and traders before being bought by the Panamanian government – illustrates the view that, in most cases, problems with excipients have occurred because of a failure in good distribution practice (GDP) rather than GMP. EXCIPIENT-SPECIFIC GMP The European Commission’s aim is to develop a set of agreed guidelines, incorporating both GMP and GDP, which get away from the current non-harmonised approach to regulating excipients. The Commission has already completed a major overhaul of pharmaceutical legislation and brought in new GMP standards for active pharmaceutical ingredients (API) as part of Directive 2004/27/EC. Critically, this reform effort has made the extension of GMP requirements to at least some excipients inevitable, as Directive 2004/27/EC states that: “... this point (GMP for starting materials) shall also be applicable to certain excipients, the list of which as well as the specific conditions of application shall be established by a Directive adopted by the Commission.” The parameters of such a Directive are clear and designed to safeguard supply chains in Europe regardless of the source of ingredients. It will apply to both total and partial manufacture or import of starting materials, and the various processes of dividing up, packaging or presentation of the starting materials prior to incorporation into a medicinal product. This will include re-packaging or re-labelling, such as might be carried out by a distributor, according to the Commission. A draft Directive – entitled “Specific Conditions on the Application of Principles and Guidelines of GMP for Certain Excipients” – was drawn up in December 2006. The main topics covered by the Draft can be seen in Table 2. On the face of it, the public health problems seen in recent years put the need for some form of GMP for excipients beyond doubt. But – as ever – the devil is in the detail, and the debate at the moment is all about setting GMP requirements that are appropriate to excipients, and do not simply mirror those developed for active pharmaceutical ingredients. European Excipient Regulation: Implications for Manufacturers and Suppliers GMP standards for excipients now look to be on the cards in Europe; the question is – how far will they go? By Kevin McGlue at Colorcon and IPEC Europe Kevin McGlue is Director, Global Quality Assurance, at Colorcon Ltd, and a member of the board of IPEC Europe, as well as chair of the IPEC Europe GMP Committee. A chemist by training, he has worked for Colorcon in various capacities since 1987, and was appointed to his current post, with overall responsibility for all QA activities worldwide, in February 2006. He is a member of the IPEC team responsible for the production of the new joint IPEC/PQG Excipient GMP guide. 74 Innovations in Pharmaceutical Technology At the moment, the identity of the actual list of excipients that look set to come under the EC’s regulatory oversight is currently under discussion, but a shortlist of candidate groups has been established based on the probability and severity of adverse events that could occur (see Table 1). Excipients making the list are those known to have a history of problems, such as glycerine, or those which have a high-risk route of administration, have an important function in the medicinal product, are used in high quantities or in products that patients take over a long period, or are biologically derived. Other considerations include, for example, whether the excipient is made in multipurpose or multiprocess plant, which could increase the risk of contamination. IPT 23 2007 30/8/07 10:09 Page 74
Transcript
Ingredients, Formulations & Finishing
Manufacturers of pharmaceutical products and thesuppliers who provide them with excipients are facingan uncertain future with the formal introduction ofGood Manufacturing Practice (GMP) requirements inthe European Union. However, there is stillconsiderable debate about the form these will take andalso the opportunity for stakeholders to have their say.
The European Commission says it has a clearmandate to draw up legislation, at least for some high-risk excipients (see inset box), in the interest of publichealth. This stems from a series of cases in whichexcipients have been involved in major public healthproblems, as well as from other concerns including thepossibility of transmissible spongiform encephalopathy(TSE) contamination in animal-derived excipients.
DRUG CONTAMINATION INCIDENTSAn incident in Panama in 2006 saw 21 people die aftertaking a government-made cough syrup formulated withdiethylene glycol that had been mislabelled as glycerine, awidely used excipient. Another 38 people were affected byside effects including disorientation and kidney failure.Earlier this year, several countries – including Panama –issued a major recall of toothpaste made in China because itcontained diethylene glycol that had again been mislabelledas glycerine. While no deaths were reported in this case,previous contamination episodes involving medicines havebeen far more serious. In 1996, glycerine contaminated withdiethylene glycol killed 88 people in Haiti, while in 1990-1992 paracetamol syrup contaminated with diethyleneglycol from propylene glycol led to 236 deaths in India andBangladesh. In 1990, 47 people died in Nigeria after takingcough syrup contaminated with solvents.
The complex supply chain in the Panama case – whichsaw the glycerine/diethylene glycol pass from a supplier inChina not registered to supply pharmaceutical-gradeproducts, through the hands of several companies andtraders before being bought by the Panamaniangovernment – illustrates the view that, in most cases,
problems with excipients have occurred because of a failurein good distribution practice (GDP) rather than GMP.
EXCIPIENT-SPECIFIC GMPThe European Commission’s aim is to develop a set ofagreed guidelines, incorporating both GMP and GDP,which get away from the current non-harmonisedapproach to regulating excipients. The Commission hasalready completed a major overhaul of pharmaceuticallegislation and brought in new GMP standards for activepharmaceutical ingredients (API) as part of Directive2004/27/EC.
Critically, this reform effort has made the extension ofGMP requirements to at least some excipients inevitable, asDirective 2004/27/EC states that: “... this point (GMP forstarting materials) shall also be applicable to certain excipients,the list of which as well as the specific conditions of applicationshall be established by a Directive adopted by the Commission.”
The parameters of such a Directive are clear anddesigned to safeguard supply chains in Europe regardlessof the source of ingredients. It will apply to both total andpartial manufacture or import of starting materials, andthe various processes of dividing up, packaging orpresentation of the starting materials prior toincorporation into a medicinal product. This will includere-packaging or re-labelling, such as might be carried outby a distributor, according to the Commission.
A draft Directive – entitled “Specific Conditions on theApplication of Principles and Guidelines of GMP forCertain Excipients” – was drawn up in December 2006.The main topics covered by the Draft can be seen inTable 2.
On the face of it, the public health problems seen inrecent years put the need for some form of GMP forexcipients beyond doubt. But – as ever – the devil is inthe detail, and the debate at the moment is all aboutsetting GMP requirements that are appropriate toexcipients, and do not simply mirror those developed foractive pharmaceutical ingredients.
European Excipient Regulation: Implications for Manufacturers and SuppliersGMP standards for excipients now look to be on the cards in Europe; the question is – how far will they go?
By Kevin McGlue at Colorcon and IPEC Europe
Kevin McGlue is Director, Global Quality Assurance, at Colorcon Ltd, and a member of the board of IPEC Europe, as wellas chair of the IPEC Europe GMP Committee. A chemist by training, he has worked for Colorcon in various capacities since1987, and was appointed to his current post, with overall responsibility for all QA activities worldwide, in February 2006.He is a member of the IPEC team responsible for the production of the new joint IPEC/PQG Excipient GMP guide.
74 Innovations in Pharmaceutical Technology
At the moment, the identityof the actual list of excipientsthat look set to come underthe EC’s regulatory oversightis currently under discussion,but a shortlist of candidategroups has been establishedbased on the probability andseverity of adverse eventsthat could occur (see Table 1).
Excipients making the listare those known to have ahistory of problems, such as glycerine, or those whichhave a high-risk route ofadministration, have animportant function in themedicinal product, are usedin high quantities or inproducts that patients takeover a long period, or arebiologically derived. Otherconsiderations include, for example, whether the excipient is made in multipurpose ormultiprocess plant, which could increase therisk of contamination.
IPT 23 2007 30/8/07 10:09 Page 74
THE EXCIPIENT INDUSTRYA key barrier to developing effective legislation has beenthe disparate nature of the excipient market and the lackof a defined excipient industry, with players in the sectorspanning commodity food ingredient manufacturersthrough to companies that specialise in functionalingredients for pharmaceuticals. Overall, there are morethan 1,200 excipients in use in medicinal products – notincluding colours and flavours – but only about 300-400have monographs in recognised pharmacopoeia.
This range of excipients, from simple sugars tocomplex polymers, means that ‘pharmaceutical’ GMPstandards – that is, those enshrined in Eudralex Vol IVPart 2 for active pharmaceutical ingredients – areunlikely to be appropriate for all but a handful ofexcipients. Meanwhile, other standards such as ISO 9001– widely used in other industries such as food – do notgo far enough.
For example, Part 2 calls for full ‘three batch’ validationprogrammes as is standard in the pharmaceutical world,but it is unlikely that a manufacturer of a simple ‘foodingredient’ with minimal pharmaceutical use would dothis. In reality, for such excipients it should be sufficient to
demonstrate consistency, for exampleusing capability studies. Likewise, Part 2also demands full ongoing stabilityprogrammes for active pharmaceuticalingredients, while for excipients itshould be possible to refer to historicaldata, given that the shelf-life of manycommon excipients is well defined.
So for manufacturers of ingredientsand medicines alike, there is uncertaintyabout the GMP standards, which may be required in the forthcoming ECDirective, and questions remain abouthow those standards will be monitoredand enforced in practice.
Added to this is the fear that if theregulations are too strict or require majoradministrative, operational and/or capitalexpenditure, some suppliers may chooseto exit the market for pharmaceuticalexcipients altogether. This is particularlya concern in the case of companies for which sales of products to the
Excipients prepared from materials derived from transmissiblespongiform encephalopathy (TSE) relevant animal species(excluding lactose)
Excipients derived from human/animal material with a potentialfor viral contamination risk
Excipients claimed to be sterile (or sold as sterile) and usedwithout further sterilisation
Excipients with the claim “endotoxin or pyrogen controlled”
Propylene glycol
Glycerine
1. Scope
2. Definitions
3. Quality management systems
4. Personnel
5. Buildings, facilities and equipment
6. Documentation and records
7. Material management
8. Production and process controls
9. Packaging and identification labelling of excipients
10. Storage and distribution
11. Quality control
12. Complaints and excipient retrieval
13. Contract manufacturers
14. Obligations of the holder of the manufacturing/import authorisation of the medicinal product
Table 1: Excipient categories under discussion
Table 2: Draft specific conditions on theapplication of principles and guidelines
of GMP for certain excipients
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IPT 23 2007 30/8/07 10:09 Page 75
pharmaceutical industry may represent only a small part oftheir overall business.
MANUFACTURING IMPLICATIONSSo what are the consequences for pharmaceutical companiesif one or more of their excipient suppliers decides theycannot or don’t want to meet the new requirements, andchoose to exit the market? One option of course is to find anew supplier, although this could require additional stabilityand/or bioequivalence studies to assure that the clinicalperformance of the affected product is not compromised. Ifanother supplier proves hard to locate, then a company may be forced to reformulate with a new excipient, whichcould involve new clinical studies. In extreme cases,pharmaceutical manufacturers may decide that the onlyoption is to withdraw a product – and this in turn couldhave healthcare consequences.
The adoption of GMP for excipients is likely to have amajor impact on pharmaceutical manufacturers in terms ofthe quality assurance process; as they will have responsibilityfor ensuring that listed excipients are up to code, theyshould ideally inspect suppliers’ manufacturing sites andprocesses. This could mean that companies have to inspectan increasingly large number of suppliers, and indeed thatsuppliers themselves face multiple inspections that couldprove impossible to cope with.
Other potential assurance problems could arise ifpharmaceutical companies are denied access to an audit, orindeed if the supply chain is complex and involves suppliersoutside the EU. Pharmaceutical products manufacturedoutside the EU or under contract also raise assurance issuesas manufacturers will not be able to test for compliance, andyet the Qualified Person (QP) signing off for sale mustensure that any listed excipients contained in them weremanufactured in accordance with EU excipient GMP. Asystem will therefore need to be developed so thatpharmaceutical companies can ensure that only excipientsmade to EU GMP guidelines have been used – perhaps bywriting this into contracts. Consideration also needs to begiven to how manufacturing changes made by supplierscould affect compliance with EU excipient GMP.
COMMISSION CONSULTINGMindful of the possible consequences of the proposedlegislation, the Commission has kicked off a consultationeffort that will try to gauge the impact of the legislation inits draft form, and identify what quality systems arealready being used by companies, as well as those areaswhere modifications need to be made. In a first step,replies have been collected to two questionnaires: one for excipient manufactures (which can also be completed by distributors) and a second for excipient usersand distributors.
The consultation process at the EC could lead to severalpossible outcomes. One is that it results in the formationof formal legislation, including GMP principles asoutlined in draft guidelines issued in December. TheCommission could also opt for a more hands-offapproach, for example by adopting detailed guidelinessimilar to those in the GMP Guide for PharmaceuticalExcipients drawn up by the International PharmaceuticalExcipients Council (IPEC) and Pharmaceutical QualityGroup (PQG) in 2006; the Guide aims to provideharmonised guidance for excipients, set at an appropriatelevel, and takes into account the existing standards thatmanufacturers have been using.
Alternatively, it could opt for risk-managementprinciples and tools, such as those laid out in theInternational Conference on Harmonization (ICH Q9)framework, and allow the industry to self-regulate byapplying its own GMP principles based on an assessmentof risks to the patient.
The hope is that, for some manufacturers, the EC’sdeliberations could simply be a formalisation of the qualitystandards they are already applying in practice, as somecompanies have already adopted GMP systems inaccordance with the IPEC/PQG guide.
DEVELOPMENTS OUTSIDE THE EUThe current concerns about health risks posed byfraudulent, contaminated or poor excipients are beingmirrored by regulators elsewhere, notably the US andChina. In the US, for example, the FDA recentlypublished non-binding guidance that asks for the testing of every received container of glycerine for diethylglycol as part of an effort to draw attention to thepossible risks to public health from contaminated ormislabelled excipients.
Meanwhile, China has tabled its own legislation onGMP for excipients and – perhaps stung by the negativepublicity about the products tainted from use of Chineseingredients and allegations of weak enforcement ofregulations – announced in June 2007 that it plans to goeven further, implementing a series of new controls onfood and drug imports and exports, as well as randomtesting of medicines for quality.
In Europe it is encouraging that the Commission hasembarked on such an inclusive consultation procedure,and the hope is that it will be successful in formulatinglegislation which strikes the right balance betweenavoiding risks to public health from quality-impairedproducts, and avoiding excessive regulation that could affect the ability of suppliers to fulfil the needs ofthe market.
