| Ashish Moghe |
Today, India is considered as the “pharmacy of the world” since it now supplies one third of all the pharmaceutical products sold worldwide. Indian drug manufacturers attribute this success to continuous R&D on products and standardised process infrastructure. India has the largest number of FDA-approved manufacturing plants outside the US. Low costs of production, innovative scientific manpower and increased outsourcing of manufacturing processes to India combined, makes Indian pharma a powerful industry group.
The sector is currently experiencing an annual growth rate of around 16 per cent. This phase of rapid expansion is due to the anticipated loss of patent protection on major blockbuster drugs worth $120 billion, over the next few years, with Indian generic drug manufacturers planning to capture more of this market.
There are approximately 250 large units and about 8,000 small-scale units that form the core of the pharma industry in India. This includes five central public sector units. It is now the third largest in the world in terms of volume and stands 14th in terms of value. According to data published by the Indian Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, total industry turnover between September 2008 and September 2009 was $21.04 billion, of which the export market was worth $8.25 billion. The Indian pharma market has the potential to reach up to $70 billion by 2020.
For the first time in many years, the international pharma industry is finding great opportunities in India. It was once an extremely fragmented market with severe price competition and government price control. Now, the process of consolidation, which has become a generalised phenomenon in the world pharma industry, has started taking place in India.
Risks and issues
Over the past decade, pharma companies have entered a difficult period where shareholders, the market and regulators have created significant pressures for change within the industry. The Indian pharma industry has had to contend with several challenges including the effects of new product patents, drug price control, infrastructure development, regulatory reforms, quality management and conformance to global standards.
The pharma business is a global one and, if manufacturers’ markets include the US and Europe, they must abide by the regulatory requirements set by the US FDA, and the European Medicines Agency (EMEA), as well as national boards such as the Drug Controller General of India (DCGI). In particular, compliance with the regulations dealing with the migration of contaminants from packaging to contents should be a major focus for India.
The migration process
Where glass containers were impervious to chemicals leaching through, the same does not apply to the new generation of drug containers and delivery systems that are made of plastics such as LDPE, HDPE and PP. Plastic containers are very convenient, especially for small units and where squeezing is required. They also offer increased efficiency, reduced breakages and costs. But, it is possible that components from label inks, lacquers, top coats, adhesives, paper or film face stocks, or even the container itself, will leach through and contaminate or react with the medicine inside. The highest potential for migration has been observed with solvent-based inks, UV inks, top coats and lacquers.
Threat to India’s sales
The purpose of packaging is to keep medicines and personal care items fresh, and to protect them from direct contamination. It is important, therefore, for pharma manufacturers in India to be aware of the potential risks in changing from glass to plastic containers. Companies need to consider the threat to consumer safety represented by chemicals migrating from the packaging of all pharma products. Drugs might no longer have the expected effect, or there could be health-related reactions to the presence of unwanted chemicals. Such problems could cause loss of consumer confidence in the particular brand, resulting in reduced market share. By ensuring that all pharma packaging meets industry regulations, manufacturers can be confident in the safety of their products. Although many Indian pharma companies are not aware of the stringent regulations and requirements regarding the migration of chemicals from packaging, others are realising the importance of this issue and are meeting the challenge. Enhanced consumer protection is the main aim of these guidelines, so those who are leading the change will be in a strong position to benefit.
FDA guidelines for drug packaging
The American FD&C Act defines drugs, in part, by their intended use, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals” [FD&C Act, sec. 201(g)(1)]. Any product that is defined by the FDA as “a drug” must conform to Regulation 21 CFR 211.94 – Drug product containers and closures, which states that:
- Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.
- Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.
- Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilised and processed to remove pyrogenic properties to assure that they are suitable for their intended use.(d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilising, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures. This can be interpreted as that the package must not have anything migrate out of it into the product that can in any way alter or affect the safety or efficacy of the drug.
EMEA guidelines for drug packaging
The EMEA, through the Committee for Medicinal Products for Human Use (CHMP) and the Committee For Medicinal Products For Veterinary Use (CVMP), published guidelines in 2005 on plastic packaging intended to be in contact with medicinal products. They indicate the requirement for extraction and interaction studies, as well as the availability of toxicological data for any extractables and leachables detected. Also, the products of the interaction between packaging migrants and the pharma ingredients must be taken into account. These regulations apply to all packaging components: containers, closers, stoppers, over-seals, container inner seals, administration accessories and container labels.
Testing for migration
Extractables: When testing for extractables, the pack is subjected to solvents of varying polarity and at high temperatures, without destroying it. The solvent used for extraction should have the same propensity to extract substances as the active substance/dosage form as appropriate. In the case of medicinal products, the preferred solvent would be the medicinal product or placebo vehicle. The obtained extracts are analysed extensively to gain as complete a picture as possible of all the compounds that might contaminate the drug.
Interaction studies: Interaction studies can include migration studies to monitor the leaching of substances from the plastic material into the formulation/active substance and/or sorption studies to evaluate a possible loss of drug quality due to adsorption or absorption effects. They detect any reactions between the plastic packaging components and product that lead to unacceptable changes in the quality of the product under normal usage conditions.
Migration studies: If the plastic material is composed of layers of different plastic materials, the possibility of migration of components of the external layers into the medicinal product should be evaluated, depending on the nature of the roduct and its intended use. Furthermore, it should be demonstrated that no components of ink or adhesives applied to the outer surface of the container/closure system will migrate into the medicinal product. Migration studies during development are necessary when extraction studies have resulted in one or several extractables. In these situations, it should be demonstrated that in conditions representative of the intended use, substances will not migrate in such quantities as to alter the efficacy and stability of the active substance/medicinal product or to present a toxicological risk. Tests should be performed on at least one batch of the active substance/medicinal product. A leachables study follows a toxicological evaluation. Substances classified as critical are analysed within the pharma product itself, under conditions that reproduce those of the intended use.
Sorption studies: Developmental studies may be necessary to investigate interactions between the packaging material and the formulation due to sorption of the active substance or an excipient to the packaging material, leading to changes in product quality. Sorption studies have to be performed when changes in the stability of the medicinal product are observed, during stability studies, which may be affected by adsorption or absorption of formulation components to the plastic packaging. Migration tests and E&L studies are, to some extent, based on official standard methods and regulations, with numerous techniques needed to get a complete picture. Once all this information is correlated, it can be used to optimise any packaging system with regard to migration properties. Good packaging design provides stability and shelf life to the drug and the delivery systems, and becomes fundamental to the safety convenience and compliance of drugs.
Avery Dennison has the right solutions
Faced with the potential loss of lucrative local and export pharma markets, it is vital that packaging designers and manufacturers in India ensure that any new pharma packaging they develop complies with the relevant standards and regulations. It is just as important to choose a label manufacturer that has the experience and expertise to provide compliant labels. Avery Dennison has dedicated R&D facilities in the US, Europe and Asia, where experienced scientists and technicians work together with customers to develop sophisticated, cutting-edge labelling solutions. As a result, Avery Dennison is able to offer a guaranteed product portfolio of dedicated pharma label materials and adhesives that meet the regulatory and compliance requirements of the highest industry standards.
A sophisticated range
They produce a sophisticated range of lightweight variable information products, as well as removable adhesives and flexible face stocks that are suitable for thermal transfers, direct thermal and laser printing. The portfolio features both film and paper face stocks, which deliver excellent print quality. Understanding the demands of pharma packaging, these products deliver consistent low migration properties and excellent mandrel performance, even with small, thin-walled LDPE containers. Extraction studies, comparing a range of adhesives available on the market, have shown that Avery Dennison S692NP, a clear permanent adhesive, has the lowest risk of migration. One international pharma company tested it during qualification for use on containers of animal eye-drops. The extraction test delivered such excellent results that they decided not to continue testing other adhesives.
Additional support and consultancy services
Avery Dennison offers additional support to customers, providing a consultancy service and helping to produce any documentation that is needed to meet regulations. They have developed their own reliable testing methods and have data sheets and migration analyses available for standard products. The technical representatives at Avery Dennison are also able to work with customers to develop customised solutions for particular applications, such as syringes, saline bags and blood bags that have critical packaging requirements. Apart from low migration characteristics, customers can also choose track and traceability features, plus anti-counterfeiting and anti-tampering devices.With an eye on the future, the change management policy at Avery Dennison requires that any necessary updates in packaging are planned at least an year in advance. This gives packaging manufacturers and brand owners ample lead time to maintain operational stability.
Opportunities for packaging manufacturers
The burgeoning pharma market presents packaging manufacturers in India with huge opportunities for business growth, provided that they meet the stringent regulatory requirements of world markets. With its global experience and expertise, Avery Dennison can be trusted to help manufacturers develop innovative pharma packaging solutions and to obtain regulatory conformance and quality compliance certification for their products.
(The author can be contacted at ashish.moghe@ap.averydennison.com)