| Dr BV Sivakumar |
The so-called wonder drug, Thalidomide, of the era of 1960 and its consequences were the first stepping stones leading towards the need of understanding a medicine completely. The Thalidomide incident was the base to scrutinise the quality of new drug substances (Active Pharmaceutical Ingredi ents). It was the onset of conscientious drug approval procedures which paved the way for the publication of numerous guidelines and regulations on the quality of medicines worldwide. Especially the complete focus had turned towards the APIs. APIs is a broad term which encompasses both new drug substances and generic drug substances.
Definition of quality
As per the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), quality is defined as ‘The degree to which a set of inherent properties of a product, system or process fulfils requirements.’ Though the inherent properties of products define the quality, it is always monitored and controlled by a set of specifications with appropriate acceptance criterion. The specifications either exist through pharmacopoeia or can be developed in-house in accordance with process chemistry and within the requirements of ICH.
Defining an effective specification
According to ICH, specification is defined as ‘A list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described.’
The set of specifications of an API always include the inherent properties along with the requirements of its intended formulation. For example, based on the dosage and/or maximum daily dose, the specification for the related substances is established whilst the physical attributes like bulk density, particle size distribution of the API are set based on type of the formulation like oral solid dosage and/ or liquids or based on the formulator requirement.
The quality of an API consists of physico-chemical attributes, physical attributes, chemical attributes, and microbiological attributes. A proficient API specification is based on the sound evaluation of the process chemistry, however, a typical specification of an API embodies tests like description, solubility, tests for identification, loss on drying/ water content, residue on ignition, heavy metals, related substances, assay, chiral purity (as applicable), residual solvents, bulk density, particle size distribution, and microbiological quality. These quality attributes are reciprocally connected with each other in one way or the other.
The reciprocal connection of quality attributes
Description and solubility are inherent physical properties of API but these are not themselves standards or tests for purity even though they may indirectly assist in the preliminary evaluation of the integrity of an article. However, description of a product has its significance when certain APIs are known to change the colour upon storage due to the inherent properties. It is mandatory that the description should be defined accordingly. Such kind of specification help formulators to define the formulation design and to understand the stable nature of the API.
Like description, the drift/change in the trend of the specific solubility pattern and melting range upon storage alerts the manufacturers about polymorphic stability of the API as certain APIs exists in various polymorphic forms and exhibits specific solubility pattern and melting point according to its form.
‘Tests for Identification’ aims to provide confirmation of the identity of the substance in question. This can be achieved by complex instrumentation techniques such as spectrophotometric analysis which includes infra red and nuclear magnetic resonance spectra and chromatographic examinations which include liquid and/or gas chromatography which serve as primary identification. A specific morph of an API has a significant IR spectrum than its other polymorphs or mixture of polymorphs.
Other methods of identification like determination of physical constants such as melting point, freezing point, boiling point, specific optical rotation, angle of rotation, ultraviolet spectrum, specific absorbance, relative density, refractive index and viscosity, as well as chemical reactions such as colour or precipitation reactions serves as secondary identification of the API. It is essential that the task of identification shall not to be confused with the assessment of its purity or the determination of its strength, although ultimately all three aspects are inter-related.
Water content of an API reveals molecular composition such as hydrates. On the other hand, loss on drying just serves as a control and monitoring test and the values are mainly used in calculating the content of assay of the product.
Residue on ignition and heavy metals are indicative of the inorganic impurities and residual heavy metals respectively. These tests deal with the control on physiologically dangerous and harmful impurities which very often creep into the final product through the handling or process. The conventional test for heavy metals indicates the presence and/or absence of 10 heavy metals like arsenic, antimony, bismuth, cadmium, copper, lead, mercury, molybdenum and tin in the API. Higher the content of these inorganic impurities not only affects the quality, it becomes a concern of safety too.
Related substances are structurally related compounds to a drug substance which forms the critical quality attribute of APIs. These related substances may be identified or unidentified degradation products or impurities arising from a manufacturing process or during storage of a material. These impurities can be toxic, may affect the therapeutic activity of the product and is now receiving critical attention from regulatory authorities. Assay, a measurement of the concentration of the actual moiety is in direct relation with the safety, efficacy, strength and purity of an API and formulated dosage. Mass balance of assay and impurities should always be maintained or else should be justified.
One of the major chemical attribute in synthetic API is the chiral property of the product which exists as racemic mixtures and selective isomers. The content and proportion of the unwanted isomers is always considered as contamination in the product which is categorised as API impurities and they impact on the bio-availability and therapeutic activity of the drug in the human body.
Bulk density (BD) and particle size distribution (PSD) are not built-in properties of any API but it can change as to how the material is processed. The BD and the PSD are inter-related attributes. To establish a required BD, the PSD should be defined. BD and PSD are critical parameters in the oral solid dosage formulations as it invariably affects the compression of tablets, capsules and suspensions.
Microbiological attributes also play a significant role and they are not inherent properties but arise during the processing of the product and is ensured by appropriate GMP systems. The total viable aerobic count (TVAC) and total yeast and molds count (TYMC), collectively known as bio-burden, of the API should be limited within the prescribed limits as in the pharmacopoeial chapters.
Challenges in maintaining the quality of APIs
Isolation of selective polymorphs, Synthesis of desired isomers of therapeutic activity, and meeting the advance levels of regulatory compliance are the major challenges in maintaining the quality of APIs.
The case study of Ritonavir launched in 1996 which resulted in unexpected dissolution pattern is the ideal example that demonstrates the importance of the understanding the concept of identifying the typical polymorphs to be manufactured, monitored and controlled appropriately in the process. Each polymorph has a degree of therapeutic activity and is critical for a formulation. Selective polymorphs are isolated by controlled crystallisation process and using specific solvents these are the most critical process parameters in a synthetic API process which requires hours of monitoring and meticulous understanding of the process dynamics.
Only chiral products have isomers and it has got specific isomer/s which has the therapeutic activity. Based on the number of chiral centres in a molecule, the number of isomers exists. However, it is not necessary that all isomers are biologically active. Therefore, it is required to manufacture the desired isomer in a pure form or as a racemic mixture. This is a very crucial challenge for the API manufacturer as it changes the whole composition of the molecule and quality of the product. In a selective isomer synthesis process like optical resolution technique, there are chances of generation of a number of isomers. The synthesis of desired isomer is difficult to control during the manufacturing process as even a small drift in the temperature and solvent addition can lead to the formation of an unwanted isomer which finally impacts the quality.
The biggest regulatory challenge for the API manufacturer is to establish compliance to various pharmacopoeial grades and maintaining a balance between the less regulated markets and regulatory markets through a single process or by a simply modified process as the specifications are often different in USP, BP/EP, JP and IP. Establishing a process which caters compliance to specifications of all market is the toughest quality job in an economically viable way.
Quality by design
Along with the control of the quality parameters in the API, it is important that the quality is built in the API by the process design. The selection of the route of synthesis and thus the selection of the key starting material (KSM) is a building block of the quality in the API. In designing a route of synthesis, the complete knowledge of the raw materials, reagents, solvents and catalysts that are to be applied in the manufacturing process needs to be thoroughly studied for their toxic, carcinogenic, mutagenic and genotoxic properties and ideally, they should be avoided. In case of unavoidable circumstances, the process should be designed to restrain them well below the prescribed levels.
Experience from R&D, manufacturing and knowledge from scientific and technical publications should be reviewed and applied in designing the process to understand the Critical Quality Attributes (CQA) of the API and subsequently the Critical Process Parameters (CPP) which aims at the CQA. The negative experiments during the product development provides meaningful information on the process dynamics and throws light on the selection of specified equipment in terms of its material of construction (MOC), capacity, steerable volumes and other required accessories like distillation columns and their efficiencies, and an idea on selecting the application of basic manufacturing techniques such as crystallisation, isolation by fractional distillation for removing impurities, seeding for crystal formation, kinetic optical resolution and asymmetric synthesis for achieving chiral purity.
GMP to ensure consistent quality
It is a prime responsibility of the management that the culture of implementation of cGMPs shall be brought. The management should emphasise on inculcating the GMP practices as a tradition and not the compulsion. Clear instructions and relevant actions with respect to the quality aspects influence the employees towards their roles and responsibilities in bringing and maintaining the quality of products.
Economically-viable-quality product
The generic API industry countenancing three constant changes. One is the hike in the prices of the raw materials, second is the fall down of API prices and finally, the introduction of new stringent regulations. A process developed early, well optimised and successfully yielding with consistent quality cannot sustain even an year as these three changes occurs often in the API industry. The industry cannot do much for the situation immediately except being innovative on the process which holds a patent and/or focused on the continuous improvement on the process, out sourcing of starting materials/intermediates through appropriate commercial and quality agreements, continuous research on cost reduction, developing strong knowledge on the process chemistry, effective and practical production planning and inventory control, recycling of solvents, recovery of products from the mother liquor as per the regulations and their compliance to quality -could only make a product economically viable and shall become a sustained source of API in the market.
Conclusion
Quality in API is the first requirement of an effective, safe finished dosage formulation. The manufacturing of API involves chemical reactions which are highly complex and every quality attribute is highly interrelated, it is a tricky living to establish, maintain and control the quality in APIs. Nevertheless, the quality of API decides the quality of formulation and formulations demands the requirements on the API. Thus, the quality of API is an integral part of the quality of the formulation or vice versa.