Value 'add'itives

Additives are key ingredients of most medicines. This may be the reason why additives have been inseparable from pharma industry despite having a few drawbacks. Sachin Jagdale provides more details

Active pharmaceutical ingredients (APIs) have always been the heart of a drug. However, pharmaceutical companies have added inactive components to formulations in order to overcome certain challenges of the manufacturing process and make drugs more consumer friendly and economically viable. For instance, a sweet tasting tablet goes down well without really troubling our taste buds. Colourful tablets make pills more interesting for younger patients and also help people differentiate between medications. It may also be that the API needs a binder or a stabiliser.

In fact, medicinal practice has always followed this concept. Our ancestors used ores and minerals like gold, silver leaf, azure etc. Some of them were highly poisonous if used improperly. Considering that ingredients like additives or excipients sometimes amount to two thirds of the weight of a formulation, global pharma industry is well aware of the business potential in this market. Expectedly, the excipients segment has witnessed a boom in the last few decades. The segment is largely fragmented, with a few big players. A major player, Germany's BASF, has recently initiated technical labs in India and China.

"Ensuring that proper additive compatibility tests are performed and also making sure that the supplier of the pharmaceutical additives can provide all regulated related documents i.e. non-BSE/TSE statements will help to maintain the quality of the drugs" - Subodh Priolkar Managing Director-South Asia, Colorcon Asia

"Additives provide protection to solid dosage forms from atmospheric conditions, moisture protection to hygroscopic drugs, targeted delivery in intestine/colon or taste masking for mouth-dissolving tablets and also for bitter drugs" - Suresh Pareek Managing Director Ideal Cure

Added advantage

Until a few decades ago, fillers and binders were the only additives used. Now, as drug delivery systems become more complicated, additives have also evolved to keep pace with technology. Colours, lubricants, fillers, flavours, sweeteners, dispersing agents, and binders are some categories of today's additives segment. The quantity of additives may vary depending on the dosage form, while each additive serves a different function. For example, binders hold ingredients together and prevent them from dispersing so that the digestive track is not afflicted. Lubricants are necessary to remove tablets from machines, whereas printing inks and dyes are required for colour coding. Additives also have an enormous impact on bioavailability of medicines.

Additives make a drug easy to handle and also provide a specific 'look' to a pill. Among hundreds of other uses, additives are important to give an agreeable flavour to the medicine. 'Throat coating' is needed to improve the aesthetics of a tablet by making it easier to swallow. Besides this, 'enteric coating' improves bioavailability and allows sustained release of active ingredients. Today, efforts are on to develop new additives that will replace animal source excipients.

Expanding on the benefits of additives, Suresh Pareek, Managing Director, Ideal Cure, says, "Additives provide protection to solid dosage forms from atmospheric conditions, moisture protection to hygroscopic drugs, targeted delivery in intestine/colon or taste masking for mouth dissolving tablets and also for bitter drugs. Also, additives of our company provide time release mechanism to drugs." Ideal Cure manufactures additives for all of these applications.

Subodh Priolkar, Managing Director, South Asia, Colorcon Asia, another additives manufacturer, opines, "Additives improve manufacture, quality or performance of the drug product. Depending on the requirements, additives can provide taste masking of bitter actives, tailor release the profile, provide protection of the drug from the stomach or vice versa. Our additives perform all these functions."

Need to subtract

The most obvious prerequisite while choosing an additive is that it should be biologically inert and non reactive. However, some of these ‘add-ons’ adversely affect the patient. It is a well known fact that patients respond differently to the same drug, possibly depending on the additive used. Problems also arise when patients change brands or switch from branded to generic drugs. Researchers at the Canadian Cardiovascular Congress 2001 in Halifax, Nova Scotia, proved that patients show pulmonary difficulty along with abnormal drug metabolite concentration ratio after switching from branded drug, cordarone, to its generic form, amiodarone.

While the Food and Drug Administration (FDA) has approved over 733 additives, there are concerns about eight prime drug additives according to the American Academy of Paediatrics (AAP). Anti-asthma drugs contain sulphites that may show reactions like breathing difficulties, chest tightening etc. Sulphites are present in many anti-inflammatory drugs that are used to treat diseases like arthritis.

Similarly, while dyes are the most common ingredients of any medication, dyes like sunset yellow are associated with gastric problems. As erythrosine was suspected to have carcinogenic effects, it was excluded from most oral drugs. Lactose induces diarrhoea and cramping in lactose sensitive individuals, while sweeteners like aspartame and saccharine are known to cause headaches. Some sweeteners are also known to cause hallucinations and dizziness. Children with sulpha allergies are not supposed to take saccharin as it shows short term problems like irritability and insomnia. An ingredient like propylene glycol, which is used to make drugs more soluble, gives rise to respiratory problems. Benzyl alcohol, a preservative, is thought to be the reason of many neonatal deaths and also metabolic complications.

Quality check

"More research should be done to assess long term adverse reactions of additives and replace any relatively unsafe ones with safe and inert substances" - Dr Urmila Thatte Professor and Head Department of Clinical Pharmacology, T N Medical College and B Y L Nair Hospital, Mumbai

Adequate research and quality control can help avoid these pitfalls. According to Dr Urmila Thatte, Professor and Head, Department of Clinical Pharmacology, T N Medical College and B Y L Nair Hospital, Mumbai, "More research should be done to assess long term adverse reactions of additives and replace any relatively unsafe ones with safe and inert substances. There should be no ‘minuses’—excipients should be inert as far as possible—if at all pharmaceutically enhancing the actions of the main medicine."

Although the manufacture of APIs should follow Good Manufacturing Practices (GMPs) imposed by national regulatory authorities, the manufacture of additives is generally not so stringently regulated. There are certain guidelines published by the International Pharmaceutical Excipient Council for GMP manufacture of additives. Incidents of poisoning have shown time and again that it is necessary to develop mandatory GMPs to govern manufacture of additives. It is possible to tackle adverse effects of additives if required precautions are taken. Companies that deal with additives have already taken steps to minimise possible side effects of additives. According to Pareek, "Our manufacturing facilities are WHO GMP certified and we follow cGMP regulations in our plant. We also hold US Drug Master Files (DMF) for most of our products as well as the Australia-based Therapeutic Goods Administration (TGA) approvals for some of our products. All the machines are designed in such a manner so as to do the processing in a closed environment. Operations are carried out ensuring no cross contamination."

Pareek adds, "Various checks are carried out at various stages of manufacturing to ensure consistent and correct quality. Further, the quality assurance department also does tests on various parameters to make sure that the quality is maintained."

According to Priolkar, ensuring that proper additive compatibility tests are performed and also making sure that the additives supplier can provide all regulated related documents will help in maintaining the quality of drugs. For example, it is important to have the 'non-BSE/TSE' statement, which certifies that the product does not have traces of Bovine Spongiform Encephalopathy (BSE) or Transmissible Spongiform Encephalopathy (TSE) statements.

Flavour of the season

If BCC Research, a US-based market research firm, is to be believed, additives made up a $3.5 billion global market in 2006 and the market is growing at an average rate of 3.8 percent per year to $4.3 billion in 2011. There is no escaping the use of additives to provide value added benefits to patients after considering the pros and cons. Just as proteins are basic building blocks of cells, additives are basic building blocks of drugs. The search is on to find safe replacements for harmful additives and this seems to be the only way forward.

sachin.jagdale@expressindia.com