rules and regulations, it is the pharmaceutical manufacturer who is responsible ...
cipients» where the excipient plays a critical part in assuring end patient safety.
WHY GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL EXCIPIENTS NEED A SPECIAL APPROACH The fact that medicinal products have to be manufactured according to GMP is now well established. Under current GMP rules and regulations, it is the pharmaceutical manufacturer who is responsible for overall operations i.e. including the quality of components: the active ingredient(s), the excipients and the packaging materials. Pharmaceutical manufacturers have to qualify their suppl iers as part of their overall quality systems. In the absence of official rules of guidance, manufacturers use in conjunction with testing, direct audits, questionnaires, or third party audits to construct their case. Recently, the ICH has produced the Q7A guideline describing the GMP standards for active pharmaceutical ingredients (APIs). This guidance is now being transposed into local and regional rules. In the European Union, GMP guidance may also be made applicable to «certain excipients» where the excipient plays a critical part in assuring end patient safety. Unlike APIs, excipients do not have a universally accepted standard defining the GMP standards required in their manufacture. In the majority of cases, application of ICH Q7A, or medicinal product GMPs, are wholly inappropriate, not least because excipients are, in the large majority of cases, not made specifically f or pharmaceutical use. Most pharmaceutical excipient manufacture is usually less than 10%, and often less than 5%, of the total production of that particular material. Table 1 highlights some differences in this regard.
Table 1: Differences Between Excipients and Actives Active Ingredient Manufacturing plans dedicated to pharmacy High value, small volume Limited source of products More regulated Clear rules imposed GMP practices Process/batch system More experts in regulatory affairs in pharmaceutical world
Excipient Multiple usage away from pharmaceutical industry High volume, low value Multiple sources Less regulated, voluntary systems Customer-oriented food/cosmetics/general market Quality management culture Continuous process, bulk process No specific expertise in pharmaceutical market
Excipients are used in the vast majority of medicines and are used in many different applications as illustrated in Table 2. listing the «top» excipients according to frequency of use in solid oral dosage forms (source: USA FDA inactive ingredient data, 1996). This pattern is probably mirrored within Europe.
Table 2: Frequently used excipients Excipient Magnesium stearate Lactose Microcrystalline cellulose Stearic acid Silicon dioxide Carboxymethyl starch Croscarmellose sodium Gelatin Sucrose Talc Acacia
No of medicinal products > 2500 > 2000 > 1500 > 1000 > 1000 > 500 > 500 > 500 > 500 > 500 > 250
Other uses Cosmetics, food Food Food Food, cosmetics (soap) Tooth paste, abrasives Cosmetics, food Food Food, photo Food Cosmetics, food Food, cosmetics
Calcium phosphate Crospovidone
> 250 > 250
Glycerin HPMC Povidone Titanium dioxide
> > > >
250 250 250 250
Food, tooth paste, abrasives Food production (filtration of beverages) Cosmetics, food Cosmetics, food Food additive Cosmetics, food, paint
For these reasons, it is very important to consider the econo mics of such materials when setting out to establish appropriate levels of GMP. In most cases, these items are produced in bulk and are low margin products. Any high costs to meet potentially overstated GMP needs will almost certainly result in the manufacturer not being interested in servicing the needs of the pharmaceutical market which only represents a small proportion of total output. The key word is therefore ‘appropriate’; the fact that these are already food grade materials should provide a suitable basis for the development of other simple safeguards in general GMP guidance to enable Industry to regard the materials as totally suitable for pharmaceut ical production. So it is crucial that any GMP standards for the manufacture of excipients reflect the nature of the manufacturing process, the infrastructure of the Industry and to some extent acknow ledges that excipients can be used in many different end use applications. These expectations have several implications, including that the principles of GMPs used by excipient manufacturers should be compatible with the quality systems and GMPs used by pharmaceutical manufacturers. One such example of a key GMP principle is the need for traceability throughout excipient manufacture to enable all parties in the supply chain manufacturers to investigate defects in medicines that may have been caused by the excipient. An important consideration is when the pr imary use of an excipient is in food, where the rules and regulations for food manufacturing should be acceptable for most pharmaceutical purposes. For example, when the pharmaceutical use of a material is in an oral dosage form, the excipient should be fit for use providing it meets any supplementary specified requirements in a pharmacopoeia monograph. In cases where special pharmaceutical grades (purity, functionality) are needed, additional steps and quality measures are necessary. Sometimes, the food grade can be used as a starting material and sometimes, a special process for the whole manufacturing is needed. International Pharmaceutical Excipients Councils and the Pharmaceutical Quality Group (UK) have long recognised the need to define special quality system GMP requir ements for excipient manufacture and have published their interpretations independently. They have now agreed to co-develop a joint guide which will benefit from wider international alignment. It is intended that this collaborative guide will provide a baseline standard of GMP for excipients and possibly with annexes for special pharmaceutical industry requirements, such as those needed for excipients used to manufacture sterile products. It is our belief that this publication will help excipient manufacturers to design their quality systems to meet their pharmaceutical customer’s requirements, yet avoid the risk of cost escalation that could result from unnecessary and inappropriately high levels of GMP being demanded. International Pharmaceutical Excipients Council Americas International Pharmaceutical Excipients Council Europe Pharmaceutical Quality Group (UK)
