Dr K Anand Kumar, Dy Managing Director, Indian Immunologicals speaks on the aspects that need focus to improve pharma manufacturing standards
India is a leading country engaged in production of cost effective and quality generic drugs. Many countries, in developed and developing world, are dependent on India for their generic drug requirement. One of the main advantages which India currently enjoys is the exceptional cost competitiveness. Same is true in the field of vaccines, Indian manufacturers are able to manufacture quality vaccines at a lower cost. In the last decade, several Indian manufacturers have been prequalified by WHO for supply of vaccines to UNICEF, Pan American Health Organization (PAHO) other international agencies engaged in public health and immunisation.
Growing global demand for quality drugs that are competitively priced has resulted in big opportunity for Indian pharma manufacturers who have manufacturing capability to produce quality products meeting international standards. Large and successful Indian enterprises focus on supplying drug products primarily to the US markets. In the recent past, some Indian manufacturers have suffered setbacks due to issues related to non-conformance to cGMP and data integrity. This has brought focus to practices adapted by Indian manufacturers and resulted in lingering doubt in the mind of international community about quality of Indian drugs. This situation was the result of poor implementation of quality systems in true spirit by some of the companies despite having a robust regulatory guidelines. This has led to increased vigil by USFDA and Indian regulators and situation need to be redeemed at the earliest in order to stay competitive. China, our most fierce competitor is a good example in this regard.
Good manufacturing practices is an essential cornerstone of pharma manufacturing in order to maintain consistent quality of drug products. There are several GMP guidelines national (Schedule M) and international (US FDA, WHO, PIC/s, PDA) covering almost all the aspects of manufacturing right from the facility, raw materials, equipment, manpower, process, quality testing and final product. These guidelines are a live document and are subject to change with time, hence GMP is always termed as current good manufacturing practices (cGMP).
GMP comes at a cost; apart from investment in building a modern facility, maintenance of the facility on a consistent basis requires substantial expenditure, and includes periodical calibration of instruments and validation of equipment and facility.
Most significant of all is manpower which needs to be qualified and regularly trained, not only in core technical skills but also in cGMP and regulatory aspects. Skilled and conscientious manpower is vital in ushering a GMP culture. A sizeable portion of expenditure of all successful enterprises need to be earmarked for acquiring, training and retaining manpower.
There are some aspects to be looked into with an objective to bridge the gap between increasing expectations and present state of affairs.
A significant share of capital is used in construction of the facility. A no-frills manufacturing facility with a simple design and a focus on proper layout for men and material movement as well as process requirement is the basic criteria. We also need to focus on energy efficient construction, which is the need of hour. A large clean room facility requires enormous energy to run and maintain. Let us look at three major components: heating ventilation and air conditioning (HVAC), process and utility equipment and lighting; HVAC consumes approximately 60 per cent of total electricity, lighting accounts for approximately 10 per cent and balance is used by equipment. Hence, it is a must to assess the facility layout design with this perspective, selecting the right clean room grade for a particular activity/ operation, apart from selection of energy efficient equipment.
Worldover, pharma industry has understood the significance of energy efficiency built in the design and operating system. In an increasingly competitive world, to deliver consistent quality and be cost-effective for sustainability of the business, Indian manufacturers cannot ignore this critical aspect of facility design. Moreover, to meet increasingly stringent guidelines and deliver consistently good product quality at a lower production cost, one needs to be mindful of selecting energy efficient technology and practices. A multi-product facility, where some of the support services viz. cleaning and sterilisation, media and solution preparation is common between different products can also reduce installation and operating cost without compromising quality of operation and product/s.
Another critical aspect is water, pharma manufacturers consistently require large quantity of high quality water for manufacturing. Water is a scarce resource and it is the biggest challenge that the industry is going to face in the coming years. Water is used for different purposes in pharma manufacturing operations viz. cleaning and rinsing, media and buffer preparation and formulation apart from running utility services. Quality of water is paramount for all these activities and does have a direct impact on the quality of the product. Design of a water system is a critical aspect as it has high energy need like a WFI generation and distribution system that needs to be maintained at 800 C with continuous recirculation at a flow rate where biofilms are not formed inside the loop over a period of time. Input quality of water is a crucial factor to be considered while designing a water purification system. While modern purification technology can efficiently address organic and chemical impurity, elimination of microbial contamination require greater effort in terms of design and operation. Like electricity, water is required 24×7 and its availability is of great concern, hence design of process, equipment and facility should also be vetted against the quantity of water requirement. In order to reduce consumption of water, manufacturers of biologicals and vaccines are exploring the possibility of single use multi-product facility, where need of water for cleaning during process changeover is obliterated.
Consistent product quality demands a robust manufacturing process which delivers drug substance or drug product batch after batch within the requisite quality specification. Robustness of a process is not only evaluated by quality of the end product but also by the consistency of the process parameters, defined as critical process attributes established during product development and verified during process validation studies. Quality by design (QbD) is a scientific, risk-based approach for product development which helps in complete understanding of critical process parameters and its impact on product quality and performance. From the perspective of a manufacturer engaged in production of biologicals and vaccines for several years, one can simply state that biological manufacturing processes are infinitely more complex than synthetic chemical processes. There are numerous variables in bacterial fermentation and viral culture which need to be continuously monitored and controlled to deliver a good quality antigen. Biological processes are more challenging to control and difficult to reproduce with the same result, batch after batch. Hence, there is a need for exhaustive study of all possible process variables of a manufacturing process during development and the importance of a complete and robust process validation study can’t be understated. It is key to maintain consistent quality. It is mandatory as a part of regulatory compliance to document all out of specification (OOS) results, deviations and changes in the annual product quality review (APQR). This enables the manufacturer to assess, analyse and evaluate the process for its robustness and helps in giving a fillip to consistent quality improvement.
A quality assurance system is the framework under which all manufacturing activities are carried out, right from the receipt of raw materials to dispatch of the finished product. Quality assurance is responsible for overseeing the end-to-end manufacturing process including testing, procurement and dispatch. The role and responsibility of quality assurance is well defined in several guidelines pertaining to pharma products. Validation of process, analytical methods and equipment, audits, in-process quality checks, documentation and batch release is some of the key functions. It is pertinent to point out that documentation is also a very critical component of quality assurance which needs to be clear, correct and reliable. Quality assurance is a most vital element to ensure and assure product quality and its role is ever evolving. Nowadays, pharma companies engaged in research and development (R&D) have a dedicated quality assurance team for supervision which is responsible for evaluating the product and process from a very early stage. This brings efficiency, removes bottlenecks and considerably reduces the time from lab to market. The team engaged in assuring product quality should have varied skills and experience which not only includes sound knowledge of basic science, emerging technology and regulatory guidelines but also possess good analytical abilities and problem solving skills.
With increasing awareness about environment, any responsible pharma manufacturing company needs to assess its products, processes and practices from the perspective of safety to environment which also include people, both operators and customers. In the field of biological manufacturing, processes are evaluated on the basis of risks to operator and environment and classified accordingly, thereby enabling the manufacturer to design and build a safe facility. Manufacturing processes and practices also need to be designed and adapted with the safety of people, product and environment in mind. How we treat our solid and liquid waste in an energy efficient manner is as important as the manufacturing process.
A sustainable business is one which adapts to change in its environment with speed. Indian pharma manufacturers also need to accept, evolve and adapt to global regulatory demands and customer needs. The cornerstone of such change is efficiency.