ISPE Tampa Conference22-25 February 2010 Tampa, Florida USA Potent Product Process and Facility Design S.C. Singhai y Laboratories Ltd. Dr. Reddy’s 23-02-2010 Safe Harbor Statement This presentation includes forward-looking statements, as d fi d in defined i the th U.S. U S Private P i t Securities S iti Litigation Liti ti R f Reform A t off Act 1995. We have based these forward-looking statements on our current expectations and projections about future events. Such statements involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. Such factors include, but are not limited to, changes in local and global economic conditions, our ability to successfully implement p our strategy, gy, the market acceptance p of and demand for our products, our growth and expansion, technological change and our exposure to market risks. By this nature, these expectations and projections are only estimates and could be materially different from actual results in the future. 2 1 ISPE Tampa Conference 22-25 February 2010 Tampa, Florida USA 3 Our Businesses •Near- Medium Term Value Creation •Medium-Long Term Value Creation (Proprietary Products) 4 2 Approved by USFDA (2).India The Indian Express •Asia-Pacific Asia Pacific HRM Congress 2007 •Best Employers in India 2007 Award Global HR Excellence Award for Innovative HR Hewitt Associates & The Economic Times Practices 6 3 . MCC (South Africa). Florida USA Infrastructure Bandwidth API Facilities Six FDA-Inspected plants in India One FDA-Inspected plant in Mexico One FDA-Inspected plant in Mirfield. ANVISA (Brazil). TPP (Canada) One FDA-Inspected plant in USA Biologics Facility One in India. UK More than 2.3 million liters reaction volume Finished Dosage Six in India. TGA (Australia). multiple regulatory agency approvals Custom Two Technology Development Centers (TDC) in India and Pharmaceutical One in Cambridge Cambridge. ISPE Tampa Conference 22-25 February 2010 Tampa. UK Services Discovery Research Hyderabad. India Center 5 Achievements •NDTV Profit Business Leadership Awards 2007 •Dun & Bradstreet American Express Business Leader in the Pharmaceutical Sector Corporate Awards 2007 •Best Corporate Social Responsibility Initiative •Pharma Excellence Awards 2006-07 for 2007 sustained Growth BSE . With ISO 14001 and ISO 9001 Units certifications. MHRA (UK). 7 Agenda : What is Potent ? Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 8 4 . ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA The views expressed here are personal and does not represent the organization. ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA What is Potent ? • History y dates back to 19th Century y • A pharmacologically active ingredient in dose of 1 mg or below • Needs special containment during processing • Has OEL of at or below 10µg/m3 of air • A novel compound of unknown potency and toxicity 9 Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 10 5 . 12 6 .6 billion in 2006 – IMS Health. Bn 6 Global sales of oncology drugs were $ 34. Florida USA Relevance “Potent” Drugs in the Pharma Industry 14 Pipeline have increased from 5% in Growth Forecast 1980 to 20% in 2010 12 High-Potency APIs are estimated to 10 have an annual growth of 12%. most sponsors will assume highest level of containment in absence of data Technologies to catch pace to handle specific issues involved in processing. 0 2004 2006 2008 2010 2012 2014 Year 11 Relevance Investing in Potent compound manufacturing remains risky Large capital investment required for manufacturing High investment required prior to approval – low chances of commercial success & cannot predict the “winners”. 4 Th There are 300-400 300 400 highly hi hl potent t t compounds currently in production for 2 clinical evaluation or commercial manufacture. Duration of commercial success > 6 years Containment requirement not confirmed until very late in development – It’s a Late-Stage Decision In early clinical. Currently around 5-10% of products on $ 8 the market contain HP-APIs. ISPE Tampa Conference 22-25 February 2010 Tampa. ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 13 Process Design Considerations • Product category g y • Dosage Form: Parental / Topical / OSD • Scale • Toxicological effect • Route of Ingestion • C t i Containment t risk i k • Environmental impact • Regulations/Standards/Guidelines 14 7 . Powder Spread • Activity Duration : Occasional of Shift based • Product Exposure : Open or Close • Process : Continuous or Batch • Design the process with less manipulation steps • Explore PAT Application • Less validation / routine samples • Sampling Issues 15 Process Design Considerations • Assessing occupational exposure to workers during actual operations involving the API. raking. • Avoid Such Interventions (manual—scrap down. • Practical Dust control concept • Closed Material Handling • Cleaning Validation • Target Shirt Sleeve Operation 16 8 . perform cleaning). Medium. • Potency : Low. determine process end points. changing contaminated or blocked parts such as mill screens. Florida USA Process Design Considerations: • Design the Containment Solution based on. extract samples. High. OEL / OEB • Dosage Form: Parental / Topical / OSD • Product Diffusion Capability : Aerosol generation. ISPE Tampa Conference 22-25 February 2010 Tampa. 40 hours/week. Florida USA OEL? Airborne concentrations which will not result in adverse effects in workers (8 hr/day. OEB 4 or 5). Time Weighted Averages.A Late Stage Decision of development 17 Containment Classification: 18 9 . ISPE Tampa Conference 22-25 February 2010 Tampa. TWAs) • Up to 50% of product OELs are at ≤10µg/m3 (i.e. • Containment requirement . • Blend will have different OEL than active alone. 03 0 10 5 0 -1 Years Back 19 Risk Evaluation: Product & Process Attribute Low Risk High Risk Process Wet Dry y Particle Size Coarse Fine Nature of Powder Bulky Fluffy / Micronized Operation Closed / Contained Open Activity Static Turbulent Process Area / cabinet . ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Changing OEL Levels 120 100 OEL (µg / m3) 80 60 40 20 10 1 0. pressure Low High Material handling Closed Open Experience Relevant None Process Steps One step / integrated Multiple steps Sampling None More Cleaning WIP / CIP Open Waste handling Closed and 100% Localized and Partial 20 10 . • The PPEs are uncomfortable and lead to cross contamination 22 11 . • Earlier the approach was separate rooms with –ve pressure and double air locks with PPEs to prevent cross contamination • Recently the drive is towards shirt sleeve operations because. Florida USA Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 21 Facility Design • Established global shortage of high containment manufacturing facilities facilities. ISPE Tampa Conference 22-25 February 2010 Tampa. operations. ISPE Tampa Conference 22-25 February 2010 Tampa. Environmental En i onmental Safety • Protection of Environment from Product exposure 23 Facility Design Considerations : • Key Factors: • Product(s) to be Manufactured • Dedicated or Segregated facilities / equipment Vs. Multiple-Product-Multi-Use Facilities • Operational Flows – Personnel. Florida USA Facility Design Philosophy : The facility shall be designed to achieve the Operator Product Safety following objectives: Safety • Protection of Personnel from Product exposure. • Protect the Product from cross contamination contamination. Isolator Technologies • HVAC Requirements • Ergonomics and safety 24 12 . Equipment • Minimize contamination & cross contamination • Clean room Vs. Material. No MAL or PAL (-ve Pressure) • PAL & MAL Single Chamber In-and-Out (-ve Pressure) • PAL & MAL Double Chamber In-and-Out (-ve Pressure with Bubble and Sink Airlocks) • Process: • Open Process : -ve Pressure with Airlocks • Engineering Controls : LEV. Other ß-Lactams : Campaign as per EU-GMP. Isolator Barrier System for Category 3 & 4. Down-flow Booth. EU-GMP. Some Hormones & : Campaign HPAPIs Note: Campaign is associated with appropriate cleaning validation.FDA GMP. WHO-GMP & PIC/S GMP P i illi D Penicillin Drugs S t d facility : Segregated f ilit Cephalosporin : Segregated facility as per J-GMP. Campaign. 25 Facility Design Considerations • Facility: • Single Door to Corridor. WHO-GMP. ISPE Tampa Conference 22-25 February 2010 Tampa. J-GMP. Florida USA Current Regulatory Guidance on Facility Requirements As per FDA. ICH-API GMP. • Closed Integrated Process 26 13 . PIC/S GMP. • Use of Push–Push Or • Restricted Personnel Safe Change Filters Movement • CIP / WIP Systems • Restricted Material Movement. 27 Containment Measures Product Personnel Protection Environmental Protection Protection • Independent Modules. • Properly designed • Properly designed HVAC • Close handling Systems Gowning procedure. contamination & Disposal • Properly designed Systems for solid & HVAC System Liquid waste. • Isolators and cRABS PTS/ DCS) • Use of Exit showers/ • Appropriate De– • Split valves/ RTP Mistifiers. 28 14 . Mist/water showers are preferred. Florida USA Facility Design Considerations • Recirculation of production area air into non-production areas not permitted • Exhaust Air to be HEPA filtered and not to be re-circulated • Redundant HEPA Filters required in Certain Cases Eg: Parenterals • Closed material handling and transfer • Gravitational transfer design preferred • Integrated g equipment q p or p processors p preferred • Split butterfly valves (SBVs) / Alpha-Beta ports for transfers. System (Isolators/ cRABS / • Use of Space Suits. ISPE Tampa Conference 22-25 February 2010 Tampa. • No Air showers. ceiling etc. Liquid. areas excluding equipment. criteria: • Specialized design of HVAC • Proper Spill Kit / misting System. then remove for secondary cleaning. • Proper cleaning and • Concentration of Product : • Proper P pressure cascade d d i drainage system t with ith High / Low. ISPE Tampa Conference 22-25 February 2010 Tampa. equipment to handle air • Product Nature : Solid / • Proper sealing of processing borne contamination. • Use of safe change/push- • Method of De. push filters / scrubbers • PPEs 29 Stage Wise Potent Material Handling At Warehouse Dispensing & Sifting • HPAPI dispensed & Sifted in Isolator.e wall. • Emergency Equipment selection Includes following. cleaning • Washings collected into catch pot for further treatment and disposal. rooms i . • Each container is dispensed completely in required lot sizes. decontamination shower.toxification. • Use of bubble/sink air lock decontamination facility. • Sifted material is collected into bin using SBV. • Wet Inside Isolator (WIP). Florida USA Type of containment Primary Secondary Emergency Containment Containment Containment Means non-exposure of Secondary containment Emergency containment potent product from revolves around processing provisions equipment. • Operation type : Open / Closed. 30 15 . • Use U PAT for f End E d point i t (Torque. WIP. • Wash-Out / Secondary cleaning using PPE. Milling & Blending • Transfer of material using SBV. 32 16 . • Collection of product into an integrated bin • Mechanically Clean. • Exhaust Air equipped with dry Scrubber and BIBO Filters. ISPE Tampa Conference 22-25 February 2010 Tampa. Drying. 31 Stage Wise Potent Material Handling Compression / Capsule Filling • Charging of blend using SBV. • Wash-In-Place / Clean-In-Place for the equipment. (T L Loss On Drying & Blend Uniformity). • Granulation & Drying and dry milling in Single Pot Processor • Discharge into Bin Blender via SBV and Blend. sampling systems and collection in Running sleeve • Discharge into a Integrated De-duster & Metal Detector. Florida USA Stage Wise Potent Material Handling Granulation. Vacuum. from bin blender • Chamber with –ve Pressure • Auto rejection. Florida USA Stage Wise Potent Material Handling Coating / Packaging • Charging of tablets using SBV. prepare coating solution in a contained manner • In-process tests in Isolator • Clean-In-Place for equipment • Packaging in –ve pressure 33 Stage Wise Potent Material Handling – OSD PFD 34 17 . ISPE Tampa Conference 22-25 February 2010 Tampa. from bin • Use contained automatic coater • In case of API is in coating solution. • Clean-In-Place/Wash-In-Place 35 Specifics For Parenterals Manufacturing Filling • +ve ve Pressure Integrated Isolator Line (Grade A or better) • Liquid Path Transfer Port for Connecting Filling Vessel. • External surface decontamination of vials prior to unloading. • VHP Decontamination for Machine and Transfer Isolators. Weight. • -ve pressure Isolator (Grade C) • Aseptic Filtration using S2S connection.∆P. 36 18 . li • Minimum Manufacturing Steps and Checks In Isolators. Filtration • Di Dispensing i as shown h earlier. Viable & Non-viable particles • Leak tightness for Isolators and Gloves prior to each run. • Peristaltic Pump is a preferred for filling • Online Monitoring For . ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Specifics For Parenterals Manufacturing Compounding. • Alpha Beta Docking Connections for Filtration and Compounding Vessel with load cells / level transmitter. ISPE Tampa Conference 22-25 February 2010 Tampa.000 containment manufacturing room • Negative pressure. • Single-pass / Re-circulatory HVAC with HEPA-HEPA • Safe-change EU 13 HEPA filters • Pressure cascade with audio visual alarms • Combination of Bubble / Sink designs • HEPA In Return Air Path 38 19 . • Si l system Simpler t d designs i • Easy to clean. Smooth surfaces and contours • Ergonomics • Backup in case of primary containment failure • Easy to maintain • Design to handle process upsets • Minimizing of Material Build-Up & Exposure Potential Using Barriers and Air Purging • Dynamic Inflatable Gaskets 37 Points to Consider – HVAC Design • Class 100. Florida USA Equipment Selection Considerations • Closed operations. ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Waste Water Treatment Localized Treatment Vs. 39 Types of Isolators Positive Pressure Filling Line 40 Courtesy: Getinge 20 . Centralized Treatment Threat: Risk with treated compound Separate sewage system for highly potent molecule effluents 100% collection of potentially contaminated water Pipe-in-Pipe design consideration for effluent transport. ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Barrier Isolation Benefits • Minimises Exposure p to Operator p • Lowest Cross Contamination • Smaller contact surface area • Minimal energy requirements • Material Handling without exposure • Id l ffor Aseptic Ideal A ti P Processing i • Localized Inert gas environment is possible 41 Contamination & Containment 42 21 . • Manufacturing Process • Analytical Process • Cleaning Process • Effluent treatment Process • Containment Process/IH Study 44 22 . Florida USA Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 43 Validation Requirements Validate.. ISPE Tampa Conference 22-25 February 2010 Tampa. 100 cm².e. Florida USA Cleaning Validation • Risk with product residues • Determine “worst case” API based on toxicological data (LD 50.. limit determination based on OELs) cm • New techniques: Ion Trap Mobility Analysis 45 Industrial Hygiene Study – Key Features • Highly Recommended for OEB 4 & 5 • Operator’s Exposure Evaluation • Surrogate Material Selection • Validated Method of Analysis .LOD & LOQ • All Processes To Be Evaluated • Sampling Plan • Sampling Techniques • Sample Handling • Results Evaluation & Action Plan 46 23 . ISPE Tampa Conference 22-25 February 2010 Tampa. daily dose and solubility) • Challenge “worst case” positions with “worst case” API • Verification by sampling (rinse and swab i. Exposures. Florida USA Training & Communication • Understanding of Hazards. ISPE Tampa Conference 22-25 February 2010 Tampa. Controls & Safe Work Practices (SOPs) • Make MSDS & Maintain Chemical Inventory • Labeling & Posters • Effective training through all hierarchical levels • Notify Employees about Industrial Hygiene Exposure Study Results • Coaching about Risk Control Plans and Verification of Implementation 47 Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 48 24 . • In the event of a failure... ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Containment Systems – Common Reasons For Failure • Design: • Incorrect equipment selection • Inadequate design • System cannot achieve the goals set • Understanding the relationship between OEL’s and performance • Operation: • Operability –must be a workable system • Ergonomic aspects correctly addressed • Failure to understand your process • False beliefs: • Increased containment levels -increase cost • Higher containment levels cause loss of efficiency 49 Containment Systems – Common Reasons For Failure . no-one will know what to do. • Without training. • No-one will know or understand what they are doing or why. • Operator p involvement: • Good operators make bad processes work - they can also make a good process fail! • They know more about the process than anyone else. 50 25 . low ACH • Minimization of disposables • Hugely reduced carbon footprint 52 26 . Florida USA Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 51 Future Facilities … • Trend towards • Shirt & Sleeve Design • Closed integrated process equipment • Minimal process steps and transfers • Minimal MAL’s and PAL’s • Application of PAT for reducing / eliminating interventions and sampling • HVAC for people Recirculation. ISPE Tampa Conference 22-25 February 2010 Tampa. is not true • Development p & manufacture of highly g yp potent compounds p requires. • Significant planning • Proper equipment and facility design • Extensive employee training • Implementation of the necessary procedures • Don’t Generalize. • Engineering allows us to reduce exposure – It doesn doesn’tt guarantee it • Any containment system is only as good as its weakest link. ISPE Tampa Conference 22-25 February 2010 Tampa. • 90% of workplace accidents have human errors as a cause 54 27 . Florida USA Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 53 Summary • “One Size fits all”. be Specific. DrDr. Julian Wilkins. VP – PharmaConsult US • Technology Department Department. ISPE Tampa Conference 22-25 February 2010 Tampa. Florida USA Acknowledgement: • Mr. Reddy’s Reddy s Laboratories • ISPE 55 Outline : What is Potent Relevance Process Design Considerations Facility & Equipment Design Validation Requirements Containment Systems Common Reasons For Failure Future Facilities Summary Q&A 56 28 . ISPE Tampa Conference 22-25 February 2010 Tampa. Reddy’s Laboratories Limited. Vice President Technology Transfer and Facility Projects Dr. Hyderabad – 500 072. Florida USA Q&A Question and Answer 57 Thank You S. Singhai.com 29 .C. India +91 40 44642369 +91-40-44642369 +91-98490 49800 singhaisc@drreddys.