The turn of millennium has shown maturing and global expansion of the generic pharma industry. The generic industry has grown twice as fast as the pharmaceutical industry as a whole, with a growth rate of 24% and stands at US$ 50 billion. The generic products can be termed as cheaper surrogates to the expensive branded formulations. The support given by the legislature, increased professional and public acceptance, and improved quality of the generics were the major factors that led to 24% (US data) growth in generics in comparison to 8% in branded formulations. Considering the rate at which this market is growing, it is well poised to capture 51% of the global generic market by the end of this year. At present the top 5 generic companies account for 75% of the US prescription industry. Such escalating growth rate and volumes of generics provides a promising opportunity for investment.
A generic product is therapeutically equivalent to the innovator. For being therapeutically equivalent, the generic product must be pharmaceutically equivalent (i.e. contain the same amount of active substance(s), meet same or comparable standards, have same dosage form and strength, and is intended to be administered by the same route) and bioequivalent (i.e. the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar experimental conditions in an appropriately designed study).
Launching the generic product
As the innovator products approach towards expiry of their patents, several companies compete for generic versions of these products. The number of generic competitors has been observed to rise with the relative increase in brand value. Also the average price decline for a lower-value brand is less than that for a higher value brand, especially the blockbusters. The innovator company can lose a market share of 20% to 70% within the first six months of its patent expiry. In certain cases, like Eli Lilly's Prozac, the loss can be 80% of the market share within the first two months of patent expiry. According to a study, the price of a drug is slashed by 35% when the first generic player enters the market. This price can further fall to nearly 90% with subsequent entries of the second and third generic players. Hence, the time of entry of a generic player is very critical, as it directly affects the profit earned by the company. Thus, 'being the first to gain the most' is a fundamental principle of generic business.
To maintain revenue growth and earn maximum profits in this price-falling market, the generic company must ensure a continuous flow of new products with quality and speed.
Various stages of generic product development include preformulation studies, prototype formulation development, scale-up and bioequivalence study involving a time frame of 8-11 months. Failure at any step would require a complete/partial rework, which would translate into fiscal losses. As the generic sponsor needs to provide an evidence demonstrating that its product is bioequivalent to the reference listed drug (RLD) and bioequivalence is the only reliable measure of product testing, failure at this stage would mount to reworking time of 220 days costing about US$ 2.8 million. This reworking could also delay its entry into the market by as long as 6 months. Product failure at this stage is not merely failure of one quality control test, but it indicates failure of whole product development. It requires carrying out the formulation development exercise from the scratch, complete redesigning and validation of quality control parameters, thus, accompanied with astringent socio-economic repercussions.
In the fast eroding, highly competitive generic market, it is paramount to develop formulation and regulatory strengths, leading to speedy development of cost-effective formulations. A systematic approach aimed at comprehensive development of innovator product provides a robust framework for development of bioequivalent generic products.
Characterisation of innovator product: A strategic approach
The most sensible strategy for a bioequivalent generic product manufacturer is to match qualitative and quantitative composition to the innovator. From a practical perspective, this can significantly increase the chances of developing a bioequivalent product. The qualitative details of the components i.e., active pharmaceutical ingredient (API) and the excipients, present in the drug product can be obtained from standard literature sources like product information brochure, Physician's Desk Reference or website of US FDA (www.fda.gov). However, a much greater confidence for product performance can be obtained by developing a formula, which apart from being qualitatively similar is as far as possible, quantitatively similar to the RLD. This requires a comprehensive characterisation of the innovator product in terms of both the API and excipients. The chances of developing a bioequivalent product thus, can be significantly improved by extending the 'issue of sameness' of generic products, to the 'sameness of formulation', in comparison to the RLD.
The comprehensive characterisation of the innovator product involves: (i) characterisation of the API - particle size, polymorph/solvate/hydrate, (ii) Quantification of excipients - critical excipients and (iii) Identification of manufacturing process.
Solid-state characterisation of API
Solid-state properties of the API, both at the molecular (polymorphs, solvates and amorphous form) and particle level (crystal habit and size) influence the dissolution as well as bioavailability, especially for solubility/dissolution sensitive molecules. These properties can influence the ease of manufacturability of the product (flow, blending behaviour, and compressibility), especially in high-dose formulations where the excipients have a little role to play.
Micronisation, involving increasing the surface area per unit mass, is the foremost strategy to increase the dissolution rate of poorly soluble molecules. Out of the 23 international innovator formulations studied in our lab, 70% of the products had drugs belonging to water insoluble category and micronisation (API particle size range between 1-5 m) was found to be the preferred approach for dissolution rate enhancement (44% cases). Surface-active agents were found to be present in only 17% and a combined approach involving micronisation and surfactants were used in 13% of formulations. The characterisation of particle size distribution of API in the innovator formulation, involves developing analytical tools for identifying the API particles, in the formulation matrix. Experimental protocols involving specialized sample preparation tools and quantification techniques based on judicious combination of optical, polarised light and hot-stage microscopy can be used for this purpose. Identification of API can be based on melting point, birefringence pattern and the difference between the crystal habit of drug and excipients.
The molecular level of the API can be confirmed using complementary techniques like differential scanning calorimetry, X-ray diffraction, and fourier transform infrared spectroscopy. Solid-state characterisation of the innovator formulation can be generated during phase I of the development and can be complemented with in vitro dissolution profiles, thus decreasing the probability of bio-inequivalent formulations.
Quantification of excipients in solid dosage forms
Pharmaceutical dosage forms contain both pharmacologically active compounds and excipients, added to aid the formulation and manufacture of the subsequent dosage form for administration to patients. Indeed, the properties of the final dosage form (i.e. its bioavailability and stability) are, for the most part, highly dependent on the excipients chosen, their concentration and interaction with both the active compound and each other. Few excipients like solubilisers, pH modifiers, stabilisers, preservatives and hydrophobic lubricants though used in small quantities, can significantly influence the stability and dissolution profile of the product and are thus termed as 'critical' excipients. WHO's list of essential medicines contain about 48 drugs belonging to BCS class-II and IV (provisionally classified drugs included). Of the 36 drugs, which are taken orally as solid dosage form, 17 formulations (about 50%) were found to contain critical excipients and of the 18 drugs that may face problems for absorption (higher doses against limited solubility) formulations of 11 drugs (more than 60%) contain solubilisers and wetting agents.
In another review, of top 110 drugs (by US sales in 2003), it was found that 11 drug products have pH adjusting agents and about 22 drugs have solubility related limitations out of which approximately 18 drugs (~82%) have solubilisers in their formulations. These figures clearly suggest that excipients play an influential role in design of dosage forms and generic manufacturers should not ignore their presence.
Generally these excipients exert concentration dependent effects and hence, attempts should be made to keep their concentrations same to that of innovator product. As these are present in small quantities sophisticated separation and quantification techniques like HPLC, HPTLC, size exclusion chromatography, gas chromatography, micellar electrokinetic capillary chromatography, colorimetry, potentiometry, FTIR/ATR-FTIR, and capillary electrophoresis need to be used.
Identification of manufacturing process
Solid dosage forms can be manufactured using wet granulation, dry granulation or direct compression (DC) technique. The choice of the technique is dictated by the stability profile of the API, ratio of API, total tablet weight and physico-technical properties like flow properties and compressibility of the major ingredients. Apart from processability the manufacturing technique can affect the stability and performance of the drug product. Prior identification of the manufacturing process (granulation/direct compression) apart from accelerating process development, aids in selecting the excipient grade.
Success of a generic pharma company is sensitively hinged to the dual concept of 'speed to the market' and 'development cost'. Application of a systematic approach for characterising the innovator formulation, during the pre-formulation phase, can help in fulfilling these objectives. Bioequivalence study is the pivotal component of ANDA development process because of the scientific and cost implications. The concept of 'formulation equivalence' can help in developing cost-effective bio-equivalent generic products, in optimum time.
Phases of generic product development
Note: *R = to be repeated, **PR = partial repeat
- (The authors are with the Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Punjab).