In the pharmaceutical industry the basic responsibility of the manufacturer is to provide the drugs which are of the intended quality standard, and are safe and effective. In order to ensure consistency of the quality of drugs, it is necessary that they are produced by strict adherence to the current Good Manufacturing Practices (GMPs). The Indian pharma industry has made remarkable progress in the global market with several achievements to its credit. It prides in being the third largest manufacturer of
the world with an estimated 40 per cent share of generic drugs sold in the US. UK licenses of generics use 40 per cent of APIs from India and has to its credit the highest number of GMP approved facilities by MHRA and FDA outside of the UK and the US. The industry could achieve this growth through its efforts of creating state-of-the-art facilities, comprehensive systems and controls over the period of last 10 years.
the world with an estimated 40 per cent share of generic drugs sold in the US. UK licenses of generics use 40 per cent of APIs from India and has to its credit the highest number of GMP approved facilities by MHRA and FDA outside of the UK and the US. The industry could achieve this growth through its efforts of creating state-of-the-art facilities, comprehensive systems and controls over the period of last 10 years.
Despite these accomplishments, the industry has had occasional unpleasant surprises in the recent past. Serious lapses in GMP compliance were observed by the regulators in some of the leading Indian companies. This has created a lot of adverse publicity and has cast a shadow on the ability of the Indian pharma industry to remain in an ongoing state of GMP compliance.
While the issues are similar to those seen in companies across the world, it is time that the Indian industry approaches this issue with a learning mindset as against a victim mindset and use this opportunity as a catalyst for change to bring in required improvements in the management of quality. This is also important from the point of view of building our abilities to deal with ever increasing pressures of cost and regulatory compliance and to be able to deliver quality medicines keeping the ultimate objective of patient safety in mind.
It is therefore important, at this stage to introspect and re-visit some of the basic issues related to compliance that would help us to create a roadmap for sustaining the excellent growth achieved so far.
Understanding GMPs
Although the Indian pharma industry has been complying with the requirements of GMPs specified in Schedule M of the Drugs and Cosmetics Act, with increasing export opportunities, the leading players of the industry voluntarily raised their standards to comply with the GMP requirements of, what we refer to as regulated market countries such as UK MHRA, EU and US FDA. However, since GMP compliance was a pre-requisite to get access to these markets, an excessive emphasis was seen to been placed on the success in GMP inspections.
This possibly appears to have led to adopting a risk-averse, inspection-oriented approach towards GMPs rather than adopting a quality system-based holistic approach for implementation of GMPs. It is therefore invariably observed that an announcement of an audit by regulatory agencies is often a trigger for reviewing the levels of GMP compliance by many companies, while it is expected that it should be an on- going process.
GMP, as the name suggests, is a practice and practices are followed by tradition. Invariably, the “How” of a practice is known while “Why” is rarely known. Accepting a practice without questioning is considered as compliance hence many traditional practices go unchallenged. Practices also may not be uniform within the company due to diverse backgrounds and cultural differences of the people responsible for implementation. While adherence to GMP should result in consistency of practices, due to lack of uniform understanding and implementation of the GMPs, the good practices are seen to be consistently inconsistent.
It is, therefore, the time to look beyond mere practices and understand the philosophy or the concepts behind the practices. Practices without the support of the philosophy cannot be implemented consistently since the concepts teach us the purpose behind the practice and thus ensure consistent compliance. A well-designed Quality Mangement System (QMS) provides the concepts behind the good practices that is described in some detail in the subsequent part of the article.
Understanding product quality
Another important issue has been the traditional understanding of the product quality that is believed to be determined by testing. It is proved beyond doubt that quality has to be built into the product and testing alone cannot determine it.
However, finished drug products are tested for quality by assessing whether they meet the manufacturer’s proposed and the approved specifications of the regulatory agencies without looking into compliance with the QbD requirements. Besides, over-commitments if made in development and regulatory filing timelines, invariably impact the assessment of the product quality and stability before filing of the product dossier. This will consequently impact the quality during commercial manufacture of the products.
Over-emphasis on GMPs, for the reasons stated above and not on the design of the product has widened the gap of quality parameters between development and scale-up. GMP without product quality is futile; by the same token, a well-designed product can be ruined, if GMP is not followed. Assurance of product quality is built on the solid foundation of product design. In other words, even before manufacture, the safety, efficacy and stability of a product must be unambiguously established and this can only be achieved by adopting a QbD approach. QbD approach lays a solid foundation for achievement of product quality through the life cycle of the product.
It is now mandatory to demonstrate that products are developed by following the principles of QbD. Following the principles of QbD for product design becomes even more important in view of the recent US FDA guideline that has a provision to issue RTR (Refuse-to-Receive) letter if the application is deficient in development aspects.
Adoption of quality systems approach
The industry needs to respond to these challenges with a paradigm shift in its approach towards GMP compliance and product quality and adopt quality system-based and risk- based approach for implementation of GMPs. This calls for creating a formally documented QMS for consistent implementation of cGMPs through out the product lifecycle.
The QMS approach will allow the delivery of products with the quality attributes appropriate to meet the needs of patients, healthcare professionals, regulatory authorities (including compliance with approved regulatory filings) and other internal and external customers.
The regulatory agencies also expect the industry to adopt the QMS approach. The following two guidelines issued by the US FDA and International Conference on Harmonisation (ICH) provide the details.
US FDA announced the Pharmaceutical cGMPs for the 21st Century Initiative with an intent to integrate quality systems and risk management approaches to meet the requirements of the current GMP regulations. The outcome of this initiative was the guidance for industry, “Quality System Approach for Pharmaceutical cGMP Regulations’ issued in September 2006.
The FDA guidance document recommends a risk-based and quality system-based approach to be adopted for CGMP regulation by emphasising management responsibility for quality systems and brings to the fore the key concepts of modern quality systems such as quality by design, quality risk management, change control, CAPA- Corrective And Preventive Actions, quality unit and a six-system model.
The six-system model
Similarly, the ICH Q10 Guideline describes the model for an effective quality management system for the pharma industry, referred to as the Pharmaceutical Quality System (PQS). The PQS recommends enhancing the quality and availability of the medicines, facilitating innovation and continual improvement and strengthening link between pharma development and manufacturing.
It focuses on achievement of the quality of product through the product lifecycle starting from development and includes technology transfer, commercial manufacture and product discontinuation and also lays emphasis on management review of performance and product quality.
PQS - Regulatory expectations
The regulatory deficiencies observed in the recent times are indicative of the lack of adoption of QMS approach by the industry. The focus of inspection has mainly been on how companies react when things go wrong or are changing under pressure. It is expected that the companies investigate the failures with a view to find root cause rather than building arguments for release of the products. The benchmark of investigations performed has not been found to be of required standards, with particular reference to complaints, rejects, deviations and out-of- specification data. Detailed root-cause analysis is invariably not done leading to inadequate CAPAs.
The following statement from Dr Janet Woodcock, Director of FDA, CDER brings out the regulatory expectation: “Pharmaceutical quality management is lacking and we are not anywhere near where we need to be. And it seems as though industry’s objective today is to continue to meet regulatory standards which are minimal expectations, versus adopting a commitment to high-quality medicines.”
Thus, adoption of quality systems approach and risk-based approach by introducing the best - practice PQS appears to be the way forward for demonstrating commitment to manufacture high-quality medicines.
The management’s responsibility
It is often said that “Quality is too important to be left to the Quality Controllers alone.” This statement underlines the importance of the quality function and expects it to be a management function driven by the commitment of the top management.
The PQS (ICH Q10) places the ultimate responsibility for the quality of the products on the senior management. It is the onus of the management to establish a quality policy that depicts the overall intentions and direction of the company and provide leadership to establish and maintain a company-wide commitment to quality.
While every one talks about the need to change towards quality culture, it is not something like manufacturing component which can be changed or replaced and has to be gradually built. An organisation’s culture consists of values, norms and practices of its people and is seen in the behaviour of the people.
The management has to create a quality mindset (quality owned by all), capabilities of the key personnel for active engagement and accountability in the matters of quality and adoption of intelligent systems and processes to establish a best-practice PQS.
An active engagement of the top management helps in effective implementation of the PQS, conducting periodic management review of quality systems, encourages transparency in reporting of deviations and implementation of necessary CAPAs. Thus, it will be seen that the best-practice PQS helps in improving the competitive edge of the company, since each and every individual in the organisation, understands his responsibility for protecting the quality and safety of the products manufactured by the company.
The advantages of the best-practice PQS are seen in favourable quality and compliance trends such as increase in process capability, investigation free lots, compliance risk reduction, internal audit performance and decrease in product complaints and product recalls. It further helps in value creation in terms of reduction in cost of quality by investing in cost of prevention rather than paying dearly for internal and external failures. It thus ensures continuous improvements and protects the firm’s reputation and business.
Globally, there has been a focus on creating a quality culture as evidenced from the title of the ISPE Second Annual Conference topic ‘Re-defining the ‘C’ in CGMP’ as creating, implementing and sustaining a culture of compliance. Implementation of PQS helps in integrating all functions within the organisation that results in creating an exemplary culture of compliance.
Conclusion
Systems and controls do not provide assurance of product quality if a culture of compliance is not maintained.
Quality system and risk-based approach help in creating a quality culture
Focusing on the management aspects of quality rather than adherence to practices and implementation of Good Practices driven through Philosophy of Quality Management will help create and sustain a quality culture within the organisation.
It is time the industry focuses on implementing the best-in-class PQS and re-defines it as the vital Business Management System (BMS).
Source: Express Pharma
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