Engineering Standards Advance PAT

Transcription

1 Engineering Standards Advance PAT By Manuel Hormaza, CEO and Founder, IBS Caribe We often look at PAT as a limited initiative, usually with a focus on a regulatory mandate and a possible break to speed up approvals. Sometimes we see it as an exercise in multivariate sensor evaluation. Such short term thinking fails to serve companies implementing PAT. A comprehensive and integrated approach is necessary to obtain long term benefits and to reap the revolutionary opportunities that face us. It is better to visualize PAT as a new paradigm, available today due to several converging technologies such as: miniaturization, chemometrics (use of software and mathematical models to manipulate massive amounts chemical or physical data), fiber and laser optics, and CFR Part 11. CFR Part 11 took the first step to enabling PAT, by opening pharma manufacturing IT to the outside world. Not too long before Part 11 was launched, drug manufacturers had to have access to developer s source code in order to use computer-enabled equipment in any process or QC related situation. How fortunate that FDA, under the leadership of CDER s deputy director, Ajaz S. Hussain, has enthusiastically embraced the use of PAT. The Agency s support promises to advance drug manufacturing, and has already spread enthusiasm for PAT, not only in the U.S., but all over the world. Process understanding is the basis of PAT, particularly its physical implementation. Traditionally, in pharmaceutical manufacturing, we have relied on single, mainly chemical variables like potency, ph, and level of impurities to define quality. Process samples are routinely taken to a separate facility for analysis. Out of spec product and problem lots are analyzed post mortem, which has a significant impact on lead times, cost and quality. In contrast, the new PAT paradigm uses multivariate analysis, real-time data, and allows the process to be understood in much greater detail. Process data can compare product, statistically, to referenced or validated lots, and feedback controls can allow the right adjustments to be made when needed. With PAT, problems are solved on the spot and the resulting lead times, quality and costs are significantly improved. Then, once a process is understood, PAT can help manage it. The soft side of implementing PAT is more cultural and collaborative not only with FDA, but also with company associates. Implementing PAT for process understanding requires a new paradigm in operations based on: o Real-time decisions through Lean Manufacturing, SPC, Zero Defects.

2 o Continuously empowered associates - Operators, support personnel and systems staff must understand and decide courses of action that comply with regulations and result in a product whose quality is right the first time. o Business strategies, goals and cost measurements to assure that PAT is conducive to company profitability and lower costs of goods. o Close interaction with researchers for continuous technology transfer and improvement. o Excellent communications with FDA and regulatory agencies to ensure compliance and approvals of changes. Standards will also promote PAT Establishment of standards, especially at the control interfaces, will also enable PAT, and promote its use in the pharmaceutical industry. In the future, these standards promise to allow users to benefit from the plug and play capabilities that have enabled other technologies, including the Internet and cell phones. They will also dictate must have components in sampling lines, sensors, software programs, protocols and peripherals associated with PAT installations.

3 o NeSSI- New Sampling and Sensor Initiative establishes common design and operation criteria of sampling and sensing configurations for both the mechanical side (i.e., substrate flow to analyzers, filters, valves, pumps) and the electronic side (i.e., connections to transducers, actuators, digital storage devices) NeSSI s goal is to reduce cost, improve safety, maintainability, while reducing component size significantly and improving flexibility and interconnectivity. One such standard is ANSI/ISA 76 which allows a complete sampling and sensing system to be mounted on a small manifold (Photo courtesy of Swagelok). COPA- Chemometrics for Online Process Analytics deals with the processing of digital signals and data from sensors, and their interpretation through the use of mathematical modeling, statistics and software to produce reliable information and decisions for process control. Typically, signals originate from multivariate sensors such as images, spectral and thermal sources. Standards provide tools for plug and play capabilities, improving performance and availability, reducing costs, and improving connectivity of sensors to shop floor DCS and MES systems. Both initiatives are sponsored by the Center for Process Analytical Chemistry, (CPAC) a NSF-supported initiative at the University of Washington and several dozens industries. The Good Automated Manufacturing Practices (GAMP) sponsored by ISPE, which has issued the following applicable guides: GAMP4: Good Automated Manufacturing Practices (GAMP) Guide for Validation of Automated Systems in Pharmaceutical Manufacture using the concept of prospective validation and following a life cycle model. The Guide draws together key principles and practices and describes how they can be applied

4 to determine the extent and scope of validation for different types of automated systems. Associated GAMP Guides cover the following o Calibration Management o Validation of Process Control Systems o Legacy Systems o Validation of Laboratory Computerized Systems o A Risk-Based Approach to Compliant Electronic Records and Signatures, published in February 2005, which supplements the existing GAMP 4 Guide for Validation of Automated Systems. o Validation of Process Control Systems. This is the most relevant to PAT, addressing the process control system, and both analog and digital data coming from sensors. It is indeed a fun time when industry and FDA are both seriously engaged in promoting science and technology for the benefit of patients and the competitiveness of our industry. We are fortunate to be part of this peaceful revolution! About the Author Manuel Hormaza, P.E., is CEO and founder of Innovations in Biosciences (IBS), Caribe Inc, which focuses primarily on biopharmaceutical process automation and PAT. IBS Caribe has partnership agreements with Perceptive Controls, Inc., a Michigan-based automation company, and Atlas-Bits, a database and software company that is located in western Puerto Rico in the ViTEC business incubator. Atlas-Bits is managed by Julio Pamias, who also contributed to this article. Manuel Hormaza is a member of IFPAC and co-founder of the Puerto Rico PAT Forum. PAT INITIATIVES IN PUERTO RICO Puerto Rico has an initiative similar to CPAC, although at a much earlier stage of evolution: the pr research and commercialization alliance. Funded by the government, through PRIDCO, the Puerto Rican Industrial Development Company, the alliance involves five local universities, which participate in areas including subsurface sensors, hyperspectral image analysis, and industrial controls. Although its focus of research is broader, the alliance is very interested in PAT and several related projects are now in the proposal stage. Another organization that has spearheaded PAT is the university-industry research consortium (INDUNIV) which is more focused on PAT and pharma projects, jointly with the university of Puerto Rico. Researchers have published extensive works with online NIR use for tablets and mixtures. Currently two researchers receive INDUNIV funds for PAT projects, and some researchers are considering collaborations with CPAC.

5 A BIT OF HISTORY: PAT AND TECH SUPPORT IN PUERTO RICO As you all know, Puerto Rico now boasts substantial infrastructure, needed to support 60 progressive pharmaceutical manufacturing plants producing $26 billion of quality pharmaceutical exports. Local technical support groups are spearheading PAT initiatives at many of these facilities. These groups involve Ph.D. chemists, pharmacists and engineers. Fifteen years ago, it was relatively rare to find such a cadre of professionals working in support of manufacturing. Back then, any non-manufacturing activity was viewed as a cost center not desirable in a tax haven. Eventually, corporate management realized that it is more effective to have local technical support than just corporate technology transfer centers. Thus, many plants started to establish local support groups. As validation requirements increased, industry mergers continued, and product sourcing changed, the practice became commonplace. Consider Upjohn s Lincomycin Streptomyces fermentation, whose ingredients are manufactured in Mexico, Puerto Rico and the U.S. In the past, technical services were supplied exclusively from the U.S., despite the local push to establish independent TSGs to support manufacturing efforts. After a while, a sensible corporate vice president of manufacturing decided to allow a small TSG group in each facility and not only asked them to compete, but to meet annually to share successes and plan, jointly, future development activities. In five years, yields increased by a factor of five, quality problems disappeared standard production costs dropped significantly. Subsequently, local TSGs were respected and considered a necessary support for strategic manufacturing sites. One excellent PAT application example emerged from such collaboration between local and external TSG: A GC-MS was installed for off-gas analysis and dissolved oxygen probes in the cell s media, for respiratory monitoring of cells respiratory quotient (RQ); with the availability of such information as CO 2 generation and dissolved oxygen, the TSG could schedule nutrient shots and adjust other variables, thereby establishing a milestone in improved process understanding. Today, most drug companies in Puerto Rico have local TSGs that not only provide technical support but export new technologies abroad, and improve their parent corporation s competitive advantage. These groups are at the center of many PAT implementation projects on the island, with most following a centralized or regionalized corporate plan and about one third doing their own thing, while keeping corporate goals and developments in mind.