Technologies for the Pharmaceutical Manufacturing Plant of the Future (In Search of the Science of Scale) Berkeley W. Cue BWC Pharma Consulting, LLC July 2009 Disclaimer Whether you agree with what you hear today or not, the contents of this presentation are my views and not those of the ACS GCI Pharmaceutical Roundtable, or any pharmaceutical or technology company (except where acknowledged). Pharmaceutical Product Life Cycle Basic chemical raw materials -> Regulatory starting materials (RSM’s) -> Active Pharmaceutical Ingredient (API)/Drug Substance -> Dosage form/formulation/drug product -> packaged product -> delivery/distribution -> patient use -> drug enters the environment -> environmental fate and effects From David Constable (ex GSK Green Chemistry Advocate) The Pharmaceutical Manufacturing Plant of Today Active Pharmaceutical Dosage Form (DF) or Drug Ingredient (API) or Drug Product Plant Substance Plant • Everything made in batch • Everything made in batch mode mode (2000 – 16000 liter) • Plant operates to 3- • Plant operates to a 3- Sigma standard Sigma standard • High speed tablet and • Some evidence of encapsulation machines process analytical run at high speed less technology than 20% of the time • The last API plant in the • PAT more evident than US was constructed in with API but not extensive 1993 (and decomissioned • Most DF plants are ex US in 2006) Sources of API Raw Materials Now Future http://www.nedlands.wa.gov.au/3/3 http://en.wikipedia.org/wiki/Oil_well 0112/73/street_trees.pm Lignin: A Source of Simple Aromatics http://en.wikipedia.org/wiki/Lignin Since Many Pharmaceuticals Are Aniline Derivatives…….. ?? The known ways of carrying out this transformation are costly, dangerous, inefficient, ugly and definitely not green. An opportunity for innovation. Six Sigma Process Capability SIGMA DPMO COPQ CAPABILITY 6 sigma 3.4 <10% of sales World Class 5 sigma 230 10 to 15% of sales 4 sigma 6200 15 to 20% of sales Industry average 3 sigma 67,000 20 to 30% of sales 2 sigma 310,000 30 to 40% of sales Noncompetitive 1 sigma 700,000 A Waste Prevention Opportunity: Sigma Based • Worldwide Rx expenditures projected to be $750 Billion/yr (IMS 2009) • Assume $1.50/day cost, then 500 billion doses/yr • With pharma sigma values typically 3 => 6.7% defect => >30 billion doses per year are defective and rejected to become waste or reworked • At an average selling price of $1.50/day this represents $$ billions in lost product opportunity • A sigma value of 5 (possibly achievable using green chemistry principles in process design and technology selection) => 0.02% defect => 100 million doses per year defective Process Intensification • In the figure to the left, examples are given for three unit operations that are often used in the chemical industry. Examples of combinations are: – Reaction-separation: Membrane reactor, reactive distillation – Reaction-heat exchange: HEX-reactor – Separation-heat exchange: Dephlegmators or heat integrated distillation – Reaction-separation-heat Source: exchange: Isothermal http://www.ecn.nl/eei/research/ membrane reactor process/index.en.html PAT should enable use of continuous processing in API synthesis What is PAT? Process Analytical Technology is: • a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. • It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. Process Analytical Technology tools: • There are many current and new tools available that enable scientific, risk-managed pharmaceutical development, manufacture, and quality assurance. These tools, when used within a system can provide effective and efficient means for acquiring information to facilitate process understanding, develop risk-mitigation strategies, achieve continuous improvement, and share information and knowledge. In the PAT framework, these tools can be categorized as: – Multivariate data acquisition and analysis tools – Modern process analyzers or process analytical chemistry tools – Process and endpoint monitoring and control tools – Continuous improvement and knowledge management tools An appropriate combination of some, or all, of these tools may be applicable to a single-unit operation, or to an entire manufacturing process and its quality assurance Source: www.fda.org PAT Goals Quality By Design-The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design. Benign By Design- The goal of PAT is to analyze in real time to prevent pollution: Include in-process real-time monitoring and control during syntheses to minimize or eliminate the formation of byproducts Green Chemistry Tie-In to PAT • Gains in quality, safety and/or efficiency will vary depending on the product and are likely to come from: – Reducing production cycle times by using on-, in-, and/or at-line measurements and controls. Energy reduction – Preventing rejects, scrap, and re-processing. Waste reduction – Considering the possibility of real time release. Waste reduction – Increasing automation to improve operator safety and reduce human error. Safety – Facilitating continuous processing to improve efficiency and manage variability • Using small-scale equipment (to eliminate certain scale-up issues) and dedicated manufacturing facilities. Process Intensification • Improving energy and material use and increasing capacity. Energy Uniting QbD and BbD through PAT and Green Chemistry • Quality by Design (QbD) – "QbD is a systematic approach to product and process design and development," • Chi-wan Chen, deputy director of the Office of New Drug Quality Assessment (ONDQA) at FDA's Center for Drug Evaluation and Research • Benign by Design (BbD) – Synonymous with green chemistry: Green chemistry is the utilization of a set of principles that reduces or eliminates the use of hazardous substances in the design, manufacture and application of chemical products. • Paul Anastas and John Warner Current State of Pharmaceutical API Manufacturing • Batch Mode, continuous or semi continuous rare • Early commitment to “locked” process • Early commitment to RSM’s • Industry reluctant to use new technology • Fundamental green chemistry and engineering principles generally less well developed • High degree of uncertainty that precludes risk based (regulatory) decisions or even discussions • Manufacturing difficulties may be due to less R&D experience/”biotech paradigm” • May be inadequate to meet future needs • Process waste is an accepted “cost of doing business” Flow Reactors Flow Reactors: Number Up Instead of Scale Up Commercial Scale Flow Reactors Advantages of Continuous Flow Reactor Chemistry • Increase – Efficiency of chemical processing – Scalability of chemical processing – Quality of chemical processing • Decrease – Cost – Environmental Impact – Process variability Biotransformations Pregabalin (slides compliments of Peter Dunn-Pfizer Global R&D) Pregabalin Launch Process Asymmetric Hydrogenation Route Biotransformation Route Biocatalytical Kinetic Resolution Route Material Flow and Fate Material Utilization Comparison Pregabalin Biotransformation Process-Environmental Benefits Commercial Scale Chromatography Simulated Moving Bed Batch tend to be used in pilot scale facilities Continuous 2-20X more productive than batch, 5-50X less solvent Several drugs made commercially:Insulin, Lexapro, Keppra, Zoloft, Zyrtec single isomer Supercritical Fluid Chromatography Potentially the greenest of all, just starting to be popular in R&D Bioavailability • Bioavailability refers to the extent to and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. • Bioavailability of a drug is largely determined by the properties of the dosage form (which depend partly on its design and manufacture), rather than by the drug's physicochemical properties, which determine absorption potential. Differences in bioavailability among formulations of a given drug can have clinical significance; thus, knowing whether drug formulations are equivalent is essential Source: http://www.merck.com/mmpe/sec20/ch303/ch303c.html Dosage Forms Hot Melt Extrusions Hot Melt Extruder Source:Chokshi and Zia, Iranian J.Pharm. Res., 3, 3-16, 2004 Hot Melt Extrusion Technology http://www.thermo.com/com/cda/newsevents/news_detail/0,,20378,00.html Benefits of HME Processing The benefits of using HME over traditional processing techniques include: • fewer unit operations; • better content uniformity; • an anhydrous process; • a dispersion mechanism for poorly soluble drugs; • a low energy alternative to high-shear granulation; • less processing time compared with conventional wet granulation. http://pharmtech.findpharma.com/pharmtech/Excipients/Hypromellose- Ethylcellulose-and-Polyethylene-Oxide/ArticleStandard/Article/detail/282727 Dosage Forms Spray Dry Dispersions Source: www.bendres.com Spray Dry Dispersion (SDD) Technology SDD- A Scalable Technology SDD Formulations Increase Plasma Concentration (AUC) Batch vs. Continuous Processing For Pharmaceutical Drugs • Vast majority of API manufacture • Limited use of continuous flow uses batch processing processing to date • Batch uses fixed stirred reactors • Continuous uses micro channel • Each scale increase requires flow reactors revalidating critical process • Number up vs. scale up parameters – Critical process parameters do not – Usually the process must be re change optimized at each scale increase • Ideal opportunity for PAT use • Limited use of PAT • Smaller facility footprint • Large facility footprint • Smaller environmental footprint • Large environmental footprint – Lower to no solvent use – 80-90% solvent/water • Cleaning challenge unknown but • Difficult to clean to <10 ppm prior predicted to be easier resident spec – Note: Cleaning solvents not included in MI or E-factor waste calculations Elements of A Greener Approach to Pharmaceutical Product Manufacture • Use raw materials produced from renewable, bio-based building blocks – Cellulose, hemi cellulose and lignin • Manufacture API using micro channel flow reactors instead of batch stirred tank reactors – Number up vs. scale up – PAT monitoring of all critical quality and environmental parameters – Target E</=10, limit solvent use, recover, recycle/reuse whenever possible • API streams are pooled and passed through a purification chromatograph such as SMB or SCF HPLC – Target all PRS’s <0.1% and no PGI’s at LOD/LOQ – PAT monitoring all critical quality and environmental parameters • Purified API eluent is combined with a polymeric excipient(s), selected to maximize bioavailability and delivery rate, and – Processed with hot melt extrusion or spray dried to obtain API/polymer particles – PAT monitoring all critical quality and environmental parameters – Goal is high and reproducible bioavailability/”just for you” concepts • API/polymer particles are tabletted or encapsulated and packaged in biodegradable packaging – Target >5 sigma (now 3 sigma = 7% failure rate) – PAT monitoring all critical quality and environmental parameters • Expiration date is set based on real shelf life and not on some arbitrary 2 year endpoint from a 1 year ICH stability study – May require ongoing stability studies to extend expiry In Closing • How drugs are made in the pharmaceutical Industry will change dramatically over the next couple of decades – Science of Scale – Integrated API and dosage form plants – Extensive use of PAT – Substantial increase in process quality and robustness – Back at the ranch, are you being taught any of the technologies discussed today? – If you want to work in the pharmaceutical industry, why not?