Ranbaxy’s Designs on Quality

In a remarkably short time, Ranbaxy Laboratories has become a force to reckon with in the pharmaceutical industry. Established in 1961, the company operated only in India until the early 1990s, when its founder, Dr. Parvinder Singh, set it on a path toward becoming a global company focused on research and development. Ranbaxy now operates 19 manufacturing facilities in seven countries, including four plants in the U.S.

Ranbaxy’s mission is nothing less than to become one of the world’s top five generic drugmakers, with $5 billion in sales, by 2012. How does such concentrated growth challenge Quality Control and Quality Assessment? We asked Ranbaxy’s Global Quality Chief Ranjit Barshikar to share his insights, thoughts on 21st Century GMPs, ICH and the changing role of pharmaceutical quality operations.

P.M.: When did Ranbaxy first begin to align its quality efforts with its growth plans? R.B.: To help fulfill its mission of becoming a research-based international pharmaceutical company, Ranbaxy began its quality efforts in the early 1990s, through a corporate quality assurance group operating from its R&D center. This has since grown to a 700-person organization. The global quality team reports directly to CEO Dr. Malvinder Singh.P.M.: What are the greatest challenges that your team faces today?R.B.: We strive to integrate our quality organization, seamlessly, with other operational teams within the company. Global growth also brings with it the need to manage cultural diversity and to keep ahead of the different product specifications and packaging requirements in different regions. Conducting technical due diligence is another challenge, but we have a team in place that manages all these issues well, on an ongoing basis.P.M.: How can a corporate quality program be strong, yet flexible enough to accommodate different regulations, cultures and mindsets? R.B.: We believe in having a global outlook, but implementing locally, so we customize our strategy for each country in which we operate. Typically, we first deploy a set of corporate guidelines on cGMPs that are in line with international requirements. Then, after studying and discussing country-specific requirements with local staff, we address them through local standard operating procedures (SOPs).

Our global quality team takes a systematic and methodical approach to minimizing risk, and ensures that reviews are conducted regularly by skilled and highly trained staffers. Our R&D team helps the quality team keep up with frequent changes in pharmacopeial specifications, another challenge.

P.M.: How do you verify that quality standards are being met?R.B.: The quality team performs audits periodically to facilitate and verify cGMP compliance across all manufacturing sites, and to ensure that both corporate guidelines and local regulations are being followed.

Quality systems are in place, and are monitored regularly by cross-functional teams, and our manufacturing facilities and clinical facilities are approved by FDA, MHRA and other global regulatory agencies.

Training is very important. We organize for the QA and QC staff, corporate training and conferences, and we offer a variety of Web-based training courses to help them keep up to date on technical and regulatory requirements, and sharpen their skills. We have very good support from Global HR in training activity.

P.M.: Has Ranbaxy incorporated the spirit of 21^st century cGMPs and “risk management” into its compliance programs?R.B.: We support the risk-based approach and Process Analytical Technology (PAT), both of which should help the industry develop in a way that benefits the consumer and improves product safety. We also support ICH Q9 guidelines. In fact, our company has action plans to adopt these guidelines for the benefit of patients who use our drugs.

Ranbaxy formally incorporated the concept of risk-based compliance a few years ago, during an internal QA staff meeting devoted to “risk mitigation.” Our goal was to generate awareness of risk-based compliance within the quality team, and have each member of the team serve as an ambassador, to communicate the relevant messages to manufacturing, R&D and other departments. Our goal is to continuously identify risks, assess their potential impact and mitigate their effects.

This approach has helped us to build and strengthen a “Quality by Design" culture within Ranbaxy.

P.M.: How are you incorporating PAT into your efforts?R.B.: We’ve formed a global PAT task force whose members come from QA, manufacturing and R&D. We started our PAT efforts off-line, using NIR, and developed testing procedures for both active pharmaceutical ingredients and finished products.

So far, we have successfully implemented over 50 PAT projects, off-line, and this is only the beginning. We’ve discussed the technical and other challenges of in-line monitoring with FDA as well as International Society for Pharmaceutical Engineering ( ISPE), and have plans to install in-line PAT at R&D and manufacturing lines, in phases. We also see to it that our staff participate in various PAT-related conferences as part of their education and training.

P.M.: What role will automation play in QA in the future?R.B.: Its role is vital. We’ve already installed Documentum (EMC Corp., Pleasanton, Calif.) automated document management systems as well as instrument networking systems to enhance productivity and reliability, and plan to move to paperless laboratories, using e-notebooks, in the future.

Our laboratories are already equipped with state-of-the-artinstruments for accuracy and precision measurements.

P.M.: Given the growing drug counterfeiting threat, how is Ranbaxy ensuring the safety of its products and its raw materials?R.B.: There is no single “magic bullet” against the growing number of sophisticated pharmaceutical counterfeiters. Anti-counterfeiting is a global battle that industries and regulators simply must win. Track and trace technologies such as radiofrequency identification (RFID) are important, as is the development of e-pedigrees, but so are security technologies such as color-shifting inks, holograms and chemical markers.

We use RFID technology in the U.S., but we also use bar codes, and we are using Alu-Alu packaging, the machinery for which is costly, and beyond the means of counterfeiters. However, these security measures areexpensive and might increase the price of some medicines. It will be interesting to see how various regions respond. As far as APIs and raw materials are concerned, we test and identify each and every container before it is released for production, to ensure that it meets our quality standards.

P.M.: Dealing with differences between global regulations must be difficult today. What are the biggest differences between the way that the U.S., Japan and Europe handle drug regulation today, and how does that affect quality operations?R.B.: By and large, the regulations are the same for cGMPs in all three regions, but some differences that have an impact on QA strategy and operations are:

• Stability requirements: In the U.S., one can file a product with three months accelerated stability data, whereas in Japan and EU countries, six months of accelerated stability data are required for filing. Stability conditions also differ. In Japan, 40°C+ 1°C is required, where in Europe and the U.S., it is 40°+ 2 °C for generics. These differences call for different SOPs, documentation, monitoring and reviews.



• Sample batches: The number of sample batches required for data submission is another area where global regulations vary. Japan wants data from three batches, the E.U. wants data from two, and the U.S. accepts data from one. Additional batch samples mean additional testing, documentation and checks for QA, and time is a major constraint.



• Product classification: Japan considers each product strength as a different product, requiring different bioequivalence (BE) studies. The U.S. and European regulators accept BE study data from higher strength formulations (assuming that formulation is proportionate) based on pharmacokinetic data.



• Assays and dissolution: are handled differently in different regions, so the same product must be tested for different specifications and requirements. These regional differences require additional time and resources for testing. For example, Japan requires triplicate analysis for assays & dissolution tests where as EU/US requires single analysis.

P.M.: Do you see the harmonization of international pharmaceutical regulations becoming a reality during our lifetimes? Or is it a "holy grail"?R.B.: The International Conference on Harmonization of technical requirements for the registration of pharmaceutical for human use (ICH) was established in 1990 as a joint project involving industry and regulators to help harmonize requirements and improve the efficiency of developing and registering new products in Europe, Japan and the U.S. Helping in these efforts are the Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme (PIC/S).

ICH has already harmonized over 65 procedures including quality, safety, efficacy and multidisciplinary guidelines. Now they are working on new issues such as new technologies and post-approval changes. Critical efforts today center around Pharmacopoeial Interchangeability (Q4B) and GMP Quality Systems. ICH efforts are definitely moving in the right direction, and I believe that harmonization will be a reality.

P.M.: Is ICH moving in the right direction with Q8 and Q9?R.B.: ICH Q9 offers a systematic approach to quality risk management, enabling industry and regulators to focus on what is important for patients. Integration of quality risk management into existing systems and regulatory processes will take time but ICH Q8, Q9 and Q10 together will enable the pharmaceutical community to move towards the desired state for 21^st century quality management. Like 21^st century GMPs, quality-based risk management will become a “best practice” over time.

ICH Q8 provides the opportunity to maximize productivity gains by improving the product and process, using product specifications based on mechanistic understanding of how formulation and process factors impact product performance.

It’s not too much of an exaggeration to say that a “revolution” is now under way, both for industries and regulators. Driving this revolution, globally, are the principles of science and risk-based compliance, process understanding and continuous improvement.

P.M.: Is Ranbaxy implementing operational excellence programs for QA, and what tools is it using?R.B.: We use statistical process control and process capability analysis as a matter of course, in our product performance review. Analyzing product and API quality trend data is a part of this process.

Cross-functional teams achieve operational excellence by working on the product from development through commercialization. They then track performance of the process and the product throughout its life cycle, using a process and analytical method validation approach. We believe that PAT and risk-based compliance will also help us to achieve operational excellence, and plan to introduce Lean-Six Sigma into our quality efforts in the future.

P.M.: Do you envision a shortage of qualified people in the future?R.B.: The war for talent is real and finding the right candidate is never easy. Human resources today are one of the biggest priorities, for every company all over the world. But we believe that “talent attracts talent.” Our Human Resource department is creating innovative HR policies and enhanced visibility.

Ranbaxy has always believed in developing local talent and gives preference to local recruitment in various countries. Our goal is to build a cadre of global executives, groomed from within, fully trained on company processes and operating methods, who can still adapt these practices to their own cultures. To ensure flexibility, we have initiated a global job rotation program for executives in QA.

P.M.: Who will the "quality professional of the future" be?R.B.: The industry is more sophisticated than ever, and faces stringent regulations and heightened customer awareness. Our customers are demanding more, and IT and engineering have advanced. Global competition is increasing, and there is quite a lot of pressure on pricing.

We prefer our quality operations to work in a proactive rather than reactive mode, and we believe that auality must move from product testing to quality by design. In order to operate proactively, QA personnel must have knowledge of plant operations and manufacturing, so professionals who have been exposed to manufacturing, IT and engineering will be the obvious choice.

P.M.: Of the growing number of “centers of excellence” around the world, which do you think will dominate 20 years from now, and what will India's strength be?R.B.: The emerging BRIC (Brazil, Russia, India, China) countries will become increasingly important. Goldman Sachs has estimated that BRIC share of world growth could rise from 20% in 2003 to more than 40% by 2025.

Though the pharmaceutical industry remains one of the most profitable and stable industries, several macro-level issues will direct change, including world demographics, regulatory issues, declining R&D productivity and the General Agreements on Tariffs and Trade (GATT), and Trade-Related Intellectual Property Rights (TRIPS).

Over the next 20 years, the strongest emerging areas for the pharmaceutical industry will be biopharmaceutical and genomics, as well as generic drugs. The global drug market is expected to exceed $900 billion by 2008, and Asia is emerging as a leading market.

India’s specific strengths include a highly competent workforce, a track record of extremely cost-effective chemical synthesis and process development, as well as a solid legal and financial framework. Then, of course, it has a strong foundation in IT.