Process chemistry AS PER PCI SYLLABUS FOR M.PHARM
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pharmaceutical process chemistry is process WHERE FROM THE RESEARCH TO FINISH PRODUCT INCLUDING THE PRODUCT DEVELOPMENT AT LABORATORY LEVEL THAN PILOT PLANT WHERE THE PRODUCT IS MANUFACTURED IN 10X THAN FINAL AT 100X THAT IS SCALE UP PLANT.
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Process chemistry AS PER PCI SYLLABUS FOR M.PHARM
- 1. Pharmaceutical Process Chemistry SHIKHA D. POPALI HARSHPAL SINGH WAHI GURUNANAK COLLEGE OF PHARMACY
- 2. INTRODUCTION 2 “Drug” –a compound that interacts with a biological molecule, triggering a physiological effect. Drugs (active pharmaceutical ingredients) can be classified into 4 groups depending on their origin; 1) Natural products 2) Fermentation products 3) Semi-synthetics –substances produced by partial synthesis 4) Completely synthetic products
- 3. Background Average cost of developing a drug was $500 million in 1999 and takes 12-25 years usually. The chances of a candidate drug that is identified becoming approved is approximately 1 in 10,000. (For every 10,000 trial compounds, 20 reach trials on animals, 10 reach clinical trials on humans and 1 gets FDA approval) Discovery stage (research labs) involves preparation of potential drug compound on 10 mg to 10 g scale. Toxicology tests are carried out on this material. If these are successful, greater quantities of the compound will be required for clinical trials. At this stage, development work begins. -Immediate goal – to produce clinical trial material. -Longer term goal– to develop a commercially viable scaled-up validated process. 3
- 4. Terminology Development–covers all work between research and production (e.g. analytical, chemical, formulation) and continues when production begins. Scale-up– process of going from laboratory preparation to whatever scale of manufacture is required to satisfy the market demand (usually 1,000 to 50,000 L range) Technology Transfer -Transfer between manufacturing sites -Transfer within a manufacturing site (Partnerships for collaborative R & D) 4
- 5. Process chemistry 5 Process chemistry involves development of practical, safe and cost effective processes for the synthesis of compounds selected to progress from research/discovery to a larger scale. Within the pharmaceutical industry synthetic routes developed within medicinal chemistry often have to be completely redesigned by process chemists, and this is in part due to their differing requirements. The differences between medicinal and process chemistry and the multitude of factors that need to be taken into consideration when scaling up a chemical process.
- 6. Medicinal chemistry Vs For medicinal chemists diversity and flexibility of a route is important. They synthesise a wide range of analogues of a lead compound on a small scale (20 mg) for testing in order to increase activity, reduce side effects and to produce an API that may be easily and efficiently administered to the patient. For this the compound must have the right properties in terms of activity, toxicity, solubility, pharmacokinetics and pharmacodynamics. 6 In contrast, process chemistry involves development of practical, safe and cost effective processes for the synthesis of compounds on a larger scale (kg to several tonnes) that have been selected to progress from medicinal chemistry. They generally therefore work on a single target molecule and define the best route to that target. Process chemistry
- 7. Process chemistry 7 The key stages in process chemistry for the development of an active pharmaceutical ingredient
- 8. Process chemistry 8 The key stages in process chemistry for the development of an active pharmaceutical ingredient
- 9. Process chemistry 9 The key stages in process chemistry for the development of an active pharmaceutical ingredient
- 10. DOE in Process Parameters 10 With the most recent ICH and FDA guidances endorsing a new paradigm of process validation based more on process understanding and control of parameters and less on product testing. After using process knowledgeto relate the attributes to each process unit operation, the inputs and outputs of each unit operation are defined to determine process parameters and in- process controls.
- 11. DOE in Process Parameters 11 ICH Q8(R2)provides thefollowingdefinitionsusing thetermcritical: • Critical process parameter (CPP).A processparameterwhosevariabilityhasanimpactona criticalquality attributeand,therefore,shouldbemonitoredorcontrolledtoensurethe processproducesthe desired quality. • Critical qualityattribute (CQA).A physical,chemical, biological,or microbiological propertyor characteristicthatshouldbewithin anappropriatelimit, range,or distributiontoensurethedesired product quality. The definition for CPP states that a parameter is considered critical when its variability has an impact on a CQA. The amount of impact is not defined, which leads to the question, does even a small impact to a CQA mean that the parameter is critical?
- 12. DOE in Process Parameters 12 It is not difficult to imagine the example of an extreme shift of a process parameter having a minor impact on a CQA, whether measurable or not. Extreme temperatures can destroy many pharmaceutical products; however, if a process inherently cannot produce such temperatures, is temperature still considered to be critical and, therefore, required to be monitored and controlled?
- 13. DOE in Process Parameters 13 When these definitions are strictly interpreted, then one of two extremes would be: • Every quality attribute is critical (they all ensure product quality); every parameter is critical (product cannot be made without controlling them) • No parameter is critical because if they are controlled, all quality attributes will pass specifications. Reality lies somewhere between these extremes. Logic and common sense dictate that additional criteria must be necessary to aid in determining criticality. There is great value in understanding not only if a parameter/attribute is critical (i.e., has an impact), but also how much impact the parameter/attribute has.
- 14. Process chemistry 14 The key stages in process chemistry for the development of an active pharmaceutical ingredient
- 15. Process chemistry 15 The key stages in process chemistry for the development of an active pharmaceutical ingredient
- 16. Process chemistry 16 The key stages in process chemistry for the development of an active pharmaceutical ingredient
- 17. Term synthesis means in Greek “put together”. Synthetic chemistry is the “art” of building-up complex molecular structures of compounds putting together smaller, easily accessible compounds. 17Synthetic Strategy
- 18. Synthetic Strategy 18 The construction of a complex organic structure, defined target molecule, requires first of all the identification of the smaller fragments that can be used to build-up the final target. In the case of oligomers such as peptides, oligosaccharides or oligonucleotides, the choice is obvious: the constituent monomers are the building blocks, and the synthesis requires the junction of those monomers by condensation. Two functional groups, one for each monomer, are involved in the reaction
- 19. What is Development? Broad range- between research and production- and overlaps with both In API (Active Pharmaceutical Ingredient) manufacture, begins when active substance is identified and activity demonstrated and more active substance is required. Once a process that works on plant scale is produced and is validated, development work still continues to improve cost, efficiency, quality and environmental impact and to deal with changing circumstances (vendors, equipment, new regulations (FDA21 CFR part11, Risk-Based Approach etc)) 19
- 20. Development Stages 1) Chemical Development Begins when activity of potential API is demonstrated and more active substance is required (for clinical trials). Process research; –New synthetic routes (literature survey) –Some initial optimisation –Yield improvements –Possibly scale-up to large lab equipment/ kilo lab (up to about 20 L) 20
- 21. Development Stages cont’d 2) Process Development -Optimization (change conditions and parameters) -Minor change of route / intermediate -Cheaper / more efficient reagents (new to market) -Environmentally-friendly reagents and effluent considerations -Yield / concentration improvement -Statistical methods (e.g. Experimental Design; want maximum amount of unbiased information about factors affecting a process from as few observations as possible. Caution -“Facts are stubborn things. Statistics are more pliable”) 21
- 22. Development Stages cont’d Process Development cont’d -SCALE-UP (Kilo Lab, Pilot plant trials) -Transfer to Manufacturing Parallel synthesis reactor block -for optimization of condition 22
- 23. Development Stages cont’d 3) Process Support Further optimisation (continuous improvement) Fine-tuning of yield and throughput Cost reduction Troubleshooting (reworks, reprocessing, deviations) New vendor approval (use tests) Waste minimisation (recycling) 23
- 24. Chemical Development Selection of Synthetic Route GET THE BEST ROUTE FROM THE BEGINNING -Difficult to change later Route should be short, efficient, robust and give a high yield prior to scale-up Discovery route often not the best. Expedient not optimal. (raw materials may not be available in bulk, process may not be efficient and may be safety hazards on large scale) Compare like with like during selection (Same level of optimisation and same scale. Are products of same purity obtained? What is the cost comparison?) Main constraint is TIME 24
- 25. Chemical Development Selection of Synthetic Route cont’d Shortest route usually best (less effluent, shorter lead time, short plant occupation, less analytical work) A convergent synthesis will be cheaper than a divergent (linear) one with the same number of steps Literature not always correct and perseverance with a reaction is required Better to try routes with high chance of success but those which offer significant benefits should be attempted even if little precedent 25
- 26. Chemical Development In Convergent Synthesis, sections of the target molecule are prepared and joined together to form the target molecule. A better yield than a linear synthesis with the same number of steps will be obtained. The advantage is significant if the subroutes converge close to the end of the synthesis. (page 489, “Medicinal Chemistry, An Introduction”, G. Thomas). 26
- 27. Process Development Optimisation of Synthetic Route –Once Selected Work up very important Can steps easily be combined (telescoping)? Need excellent process control and understanding of process limits (“stress” the reaction –higher temperature, longer reaction time, less efficient mixing). “Critical” steps / parameters (Quality) Good analytical methods (standards) Isolate and characterise by-products A very innocuous process change can often have a significant influence 27
- 28. Costing of Processes Must be a standard costing procedure Should be dated and updated Assumptions should be stated May be several factors leading to variation –scale, plant configuration etc. Compare like with like and be conservative Carried out by independent person Want to be able to see which factors increase cost significantly and why 28
- 29. Scale up process Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to production scale. 29
- 30. Why Scale-up? Scale up is basically needed for: Market growth Introduction of new processes Reduction in making expensive errors in design and operation Concentrate on addressing areas of doubts and uncertainty Economic feasibility 30
- 31. Scale-up Product and process development for scaling up is typically move in small steps. For instance, the development is initially from lab scale to bench scale then move to pilot scale and finally to commercialization scale. By performing scale up step by step, the risk with large investments could be lessen. 31 Several Steps
- 32. Application of the SELECT criteria to scale up Safety Environmental Legal Economic Control Throughput 32
- 33. Application of the SELECT criteria Safety Safety is the number one criteria for research and development. It describes safety risks including thermal and reactive hazards, and toxicity, which become increasingly important as processes are scaled up. 33
- 34. Application of the SELECT criteriaEnvironmental The pharmaceutical industry follows the environmental ideals of preventing, minimising and rendering harmless any reagents used and wastes generated from processes. Different metrics are utilised within the industry to track and minimise environmental impact. Steps taken to improve environmental credentials for a process are considered 34
- 35. Application of the SELECT criteriaLegal It describes legal considerations including regulation of substances by governments, environmental legislation and patent law. 35
- 36. Application of the SELECT criteria Economic It discusses economic considerations. 36
- 37. Application of the SELECT criteriaControl Quality control is essential for commercial production of an API (active pharmaceutical ingredient). Selectivity, stability, purification, registration and validation of processes, product specifications and genotoxic impurities all need to be considered to ensure quality is suitable for market. 37
- 38. Application of the SELECT criteriaThroughput Making sure that we can produce enough within a given time, where chemical yields plays an important role, trying to work as concentrated as possible; if you have one very diluted step in the middle of synthesis this can really be a bottleneck. If you have to perform that several steps before the API this might be real bottleneck and not allow you to make a sufficient volume. What's quite often used is a telescoping of reactions, meaning you work in the same solvent for a number of consecutive steps which is really improving throughput because -you don't need to isolate intermediates, -don't need to filter or centrifugate them, -you don't need to dry them as -you don't need to bring them again or dissolve them again for the next step So, that's one way to really improve throughput.. 38
- 39. Summary: Application of the SELECT criteria 39 Criteria Sub-criteria Examples of Potential Issues Safety Process safety Explosions Exposure to harmful substances Carcinogens, sensitisers Environmental Wasted resources Quantity & variety of solvents Substances harmful to the environment Aquatic toxins, ozone depleters Legal Infringement of Intellectual Property Competitor patenting key intermediate Regulation of reagents and intermediates Economic Meeting Cost of Good (profit margin) Long synthesis or expensive starting materials Investment costs (equipment) Control Control of quality Meeting specifications/ GMP Control of physical/chemical parameters Throughput Time scale of manufacture Long synthetic route Availability of starting materials Rare natural products
- 40. OBJECT IVE 40 Stages of Scale up process
- 41. 41 Stages of Scale up process
- 42. Planning for Scale up Decide on process Decide on batch size (not too large an increase) Order raw materials (allow for 10% lower yield) Carry out safety tests (Exotherms, HAZOP –hazard and operability studies) Discuss the process and plant requirements with production manager/engineer (materials of construction). Existing multipurpose plant usually. Prepare safety data sheets and discuss handling of hazardous reagents or intermediates Ensure analytical procedures, equipment and staff are available 42
- 43. Planning for Scale up cont’d Write out detailed procedure (assume nothing); Cleaning check and preparative work Charging and weighing Temperature and time limits Sampling (in-process checks) Transfers Work-up and isolation Drying and effluent disposal/treatment Make allowance for delays / problems (rework procedures, identify suitable “hold points”) 43
- 44. Planning for Scale up cont’d Leave space in procedure to record data and observations Highlight safety procedures and steps to take if spillage occurs Provide training 44
- 45. Planning for Scale up cont’d Significant Differences Between Lab and Plant Heat transfer Agitation (frothing) Mass transfer (affects kinetics) Visibility –of reactions, separations, for cleanliness checks Separation (stirring, not shaking) Time (slower additon rates and heating/cooling times, longer work up) Hazards (Toxic, Exotherm and Electrostatic) Off-gas treatment Safe and efficient sampling techniques needed (Process Analytical Technology -Real time reaction monitoring; FT-IR, Particle size, etc.) 45
- 46. Planning for Scale up cont’d Process Development Taking Account of Differences Between Lab and Plant Equipment Use safety data already produced to help characterise reaction Study effect of scale-dependent factors (mixing, mass transfer and heat transfer) at lab scale Plan a logical set of experiments in time-frame available Mimic plant conditions; slower addition of reagents, slower rate of heat increase and decrease and mixing, lab system should be baffled if reactors are (no vortex) Obtain mass and heat transfer data for reactor type, agitator type and solvents to be used. Use simulation software to predict effects of mass and heat transfer and mixing changes on scale-up. 46
- 47. Essential steps 47 Laboratory Mock-UPS (Source: Euzen et al., 1993)
- 48. Production Capacity Table below shows the general production capacity of each scaling up step in the process industries. 48 Scaling factor Typical production capacity Bench/ Laboratory 0.001 – 0.1 kg/h Pilot Plant 10 – 100 kg/h Demonstration Plant 100 – 1000 kg/h Commercial Plant > 1000 kg/h
- 50. The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA) Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO) The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. 50 Validation of Large scale Process
- 51. Validation of Large scale Process Traditional vs new paradigm Post approval changes/chan ge controls/risk analysis Development- Basic Process validation- 3 batches Pilot batch manufacturing Enhanced- Development and process qualification Control Strategy ICH Q8, QbD Continuous and extensive monitoring of CQAs and CPPs for each production batch ICH Q9 and Q10 51
- 52. 52 Pre-validation phase Protocol Preparation Information from product development studies (identification of critical attributes) Information from primary/ clinical manufacturing (scale up information) Process risk assessment information (identification of critical steps) Validation phase Protocol execution Includes demonstration of content uniformity of the clinical batch Process validation phases Post valdn phase: Review of process, deviations, failures, need for improvement, scale up etc…
- 53. FDA, January 2011 WHO, Revised Annex 7 of WHO GMP guide (draft for comment) European Medicines Agency (EMA), February 2014 Continuous process verification (CPV) Continuous process verification (CPV) Alternative approaches: -Traditional approach -Continuous process verification -Hybrid approach Process design and Initial validation (process qualification- PPQ) are initial phases of CPV Process design and initial validation (initial process verification) are initial phases of CPV CPV protocol to be supported by extensive dev. information and lab or pilot scale data. Executed on each production batch No mention of number of batches for initial process performance qualification / validation (rather must be justified based on overall product and process understanding) Mentions data on at least three pilot or production batches collected as part of process design Number of batches specified for traditional approach - minimum of three production batches unless other wise justified 53 Latest guidelines
- 54. Prospective validation Concurrent validation Retrospective validation Protocol reviewed and accepted, Product PQD; OR Protocol executed before submission or PQ Protocol reviewed and accepted, Product PQD Protocol does not need to be submitted Execute and finalize process validation on the first three production batches Execute and finalize process validation on the first three production batches Prepare product quality review report on already manufactured production batches Commercial batches to be released only after satisfactorily conclusion of process validation on three batches Each validation batch can be validated and released. Applicable for low demand products (such as NTDs, orphan drugs or other seasonal products) Applicable for submissions meeting criteria for established products as described in Annex 4, TRS 970 54 Types of process validation and dossier requirements
- 55. Design Qualification( DQ) verification process to meet particular requirement relating to the quality of Pharmaceutical and manufacturing process. 55 Process validation- Role of assessment Design qualificat ion Operatio nal qualificati on Performa nce qualificati on Process validatio n GMP Dossier Performance qualification (PQ) (process qualification)- process of testing to ensure that the individual and combined systems function to meet agreed performance criteria on a consistent basis and to check how the result of testing is recorded. The purpose is to ensure that the criteria specified can be achieved on a reliable basis over a period of time. Operational Qualification (OQ) process of testing to ensure individual and combined systems function to meet agreed performance criteria and to check how the result of testing is recorded. The purpose is to ensure that all the dynamic attributes comply with the original design. DQ plan covers user requirement, user specification, Technical specification and DQ report. Process Validation :- Owners are responsible for Validating Their Processes (personnel, equipment, methods, SOPs) to ensure compliance to cGMP/GLP regulations.
- 56. Case study; Process Development for Labetalol Production BACKGROUND Labetalol –antihypertensive, 30,000 Kg p.a. produced by Schering-Plough. Labetalol Manufacturing Process Mono-pot reaction in jacketed, glass-lined 10,000 L reactor. Addition of liquid reagents and jacket temperature computer controlled. Solid reagents charged manually via handwhole. Phase separation using sight-glass. Solid product from second step isolated by centrifugation. Product tested to determine if recrystallisation necessary. When required purity achieved, product is dried 56
- 57. Labetalol Process –Step 1 Solvent system modified to isopropanol / ethyl acetate containing hydrogen bromide from methanol / ethyl acetate to reduce formation of third impurity. Original process used chloroform. Concentration was increased threefold increasing throughput and reducing solvent waste. 57 Main Impurities
- 58. Labetalol Process – Step 2 Process Development Large excess of dibenzylamine used to ensure reaction driven to completion (cheap reagent and easily washed out) Propylene oxide added as it reacts with HBr side-product as it’s produced. Presence of HBr would neutralise dibenzylamine and no reaction to give product would occur. Propylene bromohydrin side-product easily washed out. Use gentle reflux to ensure propylene oxide doesn’t escape 58 +
- 59. Summary Stages of development are Chemical Development, Process Development and Process Support Development essential before scale-up and validation –get process right first Time constraints a major factor Have process in control (“critical” parameters) Consider differences between lab and plant scale. Try to mimic plant conditions in lab to anticipate effects when scale up. Prepare process description carefully for scale-up Development always on-going 59
Editor's Notes
- Will cover syntheticaspects of pharmaceutical production processes. Average cost of developing a drug was $500 million in 1999 and takes 12-25 years usually. The chances of a candidate drug that is identified becoming approved is approximately 1 in 10,000. (For every 10,000 trial compounds, 20 reach trials on animals, 10 reach clinical trials on humans and 1 gets FDA approval) Discovery stage (researchlabs) involves preparation of potential drug compound on 10 mg to 10 g scale. Toxicology tests are carried out on this material. If these are successful, greater quantities of the compound will be required for clinical trials. At this stage, development work begins. -Immediate goal–to produce clinical trial material. -Longer term goal–to develop a commercially viable scaled-up validated process.
- Synthetic Strategy The construction of a complex organic structure, defined target molecule, requires first of all the identification of the smaller fragments that can be used to build-up the final target. In the case of oligomers such as peptides, oligosaccharides or oligonucleotides, the choice is obvious: the constituent monomers are the building blocks, and the synthesis requires the junction of those monomers by condensation. Two functional groups, one for each monomer, are involved in the reaction
- Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to roduction scale. The primary objective of the text is to provide insight into the practical aspects of process scale-up. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) for which “scale-up” simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) in which an increase of the scale is counterproductive and “scale-down” is required to improve the quality of the product.
- Scale is answer the question How to scale up from small scale to large scale? Product and process development for scaling up is typically move in small steps. • For instance, the development is initially from lab scale to bench scale then move to pilot scale and finally to commercialization scale. • By performing scale up step by step, the risk with large investments could be lessen.
- So the first criterion is Safety. No coincidence that this is really the number one criteria because we cannot afford to develop a process which on large scales is failing and that there is, for example, an explosion, where potentially people can die and that also there can be a complete destruction of the commercial supply chain, where also it could mean that patients do no longer have access to the medicine at a certain moment. There are at least two types of, or two categories of hazards. The first one is thermal and reactive hazards, has to do with the property of the reaction itself, to avoid that there is a thermal runaway we have the reaction mixture is getting to a temperature above which it is no longer stable. Second, on the large scale if there is a reaction where gas is evolving. It's completely different than on lab scale. If you are doing, for example, a BOC de-protection on small-scale, you do not worry about the fact that you are generating iso-butene, but on large scale we are talking about potentially significant volumes of iso-butene during the BOC de-protection. That's just one example, but at de-methylation with HBr where you are generating methyl bromide, you might not consider that in a lab environment but on large scale it's an important attention point. Certainly potential explosives, to be careful when handling these on large scale. Some of the reagents we are using are really corrosive, so on the long term we have to make sure that we can run, we can keep our equipment in a decent state. So we have to select the right equipment and protect it as much as possible. And also pyrophoric material, pyrophoric reagents, need special attention; for example, for storage, but also for dosing, for neutralization after the reaction . The second category are the toxic hazards, where the general principle is that first of all we try to avoid them. Avoid them by not using them, by using other reagents which are less toxic. If there is no real alternative, we try to reduce them; reduce the amount and after that we try to control that. On the one hand by containment and by engineering the process and the equipment, such that it's in a closed environment. And it's really needing also to protect the workers who has to handle these reagents on a large scale. And there's a difference between acute and chronic toxicity as you are aware of, for some of them you will observe it immediately that there's something wrong, for others you only see the effect after a long time. General principle is: If you can't scale it safely, don't scale it at all. A little bit of foam in the lab can be funny, not a problem, but some foaming on large scale, uncontrolled, and it can be, potentially, very toxic what's coming out of the reactor here. I'm sure you agree with me that you don't want to to see that..
- So the first criterion is Safety. No coincidence that this is really the number one criteria because we cannot afford to develop a process which on large scales is failing and that there is, for example, an explosion, where potentially people can die and that also there can be a complete destruction of the commercial supply chain, where also it could mean that patients do no longer have access to the medicine at a certain moment. There are at least two types of, or two categories of hazards. The first one is thermal and reactive hazards, has to do with the property of the reaction itself, to avoid that there is a thermal runaway we have the reaction mixture is getting to a temperature above which it is no longer stable. Second, on the large scale if there is a reaction where gas is evolving. It's completely different than on lab scale. If you are doing, for example, a BOC de-protection on small-scale, you do not worry about the fact that you are generating iso-butene, but on large scale we are talking about potentially significant volumes of iso-butene during the BOC de-protection. That's just one example, but at de-methylation with HBr where you are generating methyl bromide, you might not consider that in a lab environment but on large scale it's an important attention point. Certainly potential explosives, to be careful when handling these on large scale. Some of the reagents we are using are really corrosive, so on the long term we have to make sure that we can run, we can keep our equipment in a decent state. So we have to select the right equipment and protect it as much as possible. And also pyrophoric material, pyrophoric reagents, need special attention; for example, for storage, but also for dosing, for neutralization after the reaction . The second category are the toxic hazards, where the general principle is that first of all we try to avoid them. Avoid them by not using them, by using other reagents which are less toxic. If there is no real alternative, we try to reduce them; reduce the amount and after that we try to control that. On the one hand by containment and by engineering the process and the equipment, such that it's in a closed environment. And it's really needing also to protect the workers who has to handle these reagents on a large scale. And there's a difference between acute and chronic toxicity as you are aware of, for some of them you will observe it immediately that there's something wrong, for others you only see the effect after a long time. General principle is: If you can't scale it safely, don't scale it at all. A little bit of foam in the lab can be funny, not a problem, but some foaming on large scale, uncontrolled, and it can be, potentially, very toxic what's coming out of the reactor here. I'm sure you agree with me that you don't want to to see that..
- So the first criterion is Safety. No coincidence that this is really the number one criteria because we cannot afford to develop a process which on large scales is failing and that there is, for example, an explosion, where potentially people can die and that also there can be a complete destruction of the commercial supply chain, where also it could mean that patients do no longer have access to the medicine at a certain moment. There are at least two types of, or two categories of hazards. The first one is thermal and reactive hazards, has to do with the property of the reaction itself, to avoid that there is a thermal runaway we have the reaction mixture is getting to a temperature above which it is no longer stable. Second, on the large scale if there is a reaction where gas is evolving. It's completely different than on lab scale. If you are doing, for example, a BOC de-protection on small-scale, you do not worry about the fact that you are generating iso-butene, but on large scale we are talking about potentially significant volumes of iso-butene during the BOC de-protection. That's just one example, but at de-methylation with HBr where you are generating methyl bromide, you might not consider that in a lab environment but on large scale it's an important attention point. Certainly potential explosives, to be careful when handling these on large scale. Some of the reagents we are using are really corrosive, so on the long term we have to make sure that we can run, we can keep our equipment in a decent state. So we have to select the right equipment and protect it as much as possible. And also pyrophoric material, pyrophoric reagents, need special attention; for example, for storage, but also for dosing, for neutralization after the reaction . The second category are the toxic hazards, where the general principle is that first of all we try to avoid them. Avoid them by not using them, by using other reagents which are less toxic. If there is no real alternative, we try to reduce them; reduce the amount and after that we try to control that. On the one hand by containment and by engineering the process and the equipment, such that it's in a closed environment. And it's really needing also to protect the workers who has to handle these reagents on a large scale. And there's a difference between acute and chronic toxicity as you are aware of, for some of them you will observe it immediately that there's something wrong, for others you only see the effect after a long time. General principle is: If you can't scale it safely, don't scale it at all. A little bit of foam in the lab can be funny, not a problem, but some foaming on large scale, uncontrolled, and it can be, potentially, very toxic what's coming out of the reactor here. I'm sure you agree with me that you don't want to to see that..
- So the first criterion is Safety. No coincidence that this is really the number one criteria because we cannot afford to develop a process which on large scales is failing and that there is, for example, an explosion, where potentially people can die and that also there can be a complete destruction of the commercial supply chain, where also it could mean that patients do no longer have access to the medicine at a certain moment. There are at least two types of, or two categories of hazards. The first one is thermal and reactive hazards, has to do with the property of the reaction itself, to avoid that there is a thermal runaway we have the reaction mixture is getting to a temperature above which it is no longer stable. Second, on the large scale if there is a reaction where gas is evolving. It's completely different than on lab scale. If you are doing, for example, a BOC de-protection on small-scale, you do not worry about the fact that you are generating iso-butene, but on large scale we are talking about potentially significant volumes of iso-butene during the BOC de-protection. That's just one example, but at de-methylation with HBr where you are generating methyl bromide, you might not consider that in a lab environment but on large scale it's an important attention point. Certainly potential explosives, to be careful when handling these on large scale. Some of the reagents we are using are really corrosive, so on the long term we have to make sure that we can run, we can keep our equipment in a decent state. So we have to select the right equipment and protect it as much as possible. And also pyrophoric material, pyrophoric reagents, need special attention; for example, for storage, but also for dosing, for neutralization after the reaction . The second category are the toxic hazards, where the general principle is that first of all we try to avoid them. Avoid them by not using them, by using other reagents which are less toxic. If there is no real alternative, we try to reduce them; reduce the amount and after that we try to control that. On the one hand by containment and by engineering the process and the equipment, such that it's in a closed environment. And it's really needing also to protect the workers who has to handle these reagents on a large scale. And there's a difference between acute and chronic toxicity as you are aware of, for some of them you will observe it immediately that there's something wrong, for others you only see the effect after a long time. General principle is: If you can't scale it safely, don't scale it at all. A little bit of foam in the lab can be funny, not a problem, but some foaming on large scale, uncontrolled, and it can be, potentially, very toxic what's coming out of the reactor here. I'm sure you agree with me that you don't want to to see that..
- So the first criterion is Safety. No coincidence that this is really the number one criteria because we cannot afford to develop a process which on large scales is failing and that there is, for example, an explosion, where potentially people can die and that also there can be a complete destruction of the commercial supply chain, where also it could mean that patients do no longer have access to the medicine at a certain moment. There are at least two types of, or two categories of hazards. The first one is thermal and reactive hazards, has to do with the property of the reaction itself, to avoid that there is a thermal runaway we have the reaction mixture is getting to a temperature above which it is no longer stable. Second, on the large scale if there is a reaction where gas is evolving. It's completely different than on lab scale. If you are doing, for example, a BOC de-protection on small-scale, you do not worry about the fact that you are generating iso-butene, but on large scale we are talking about potentially significant volumes of iso-butene during the BOC de-protection. That's just one example, but at de-methylation with HBr where you are generating methyl bromide, you might not consider that in a lab environment but on large scale it's an important attention point. Certainly potential explosives, to be careful when handling these on large scale. Some of the reagents we are using are really corrosive, so on the long term we have to make sure that we can run, we can keep our equipment in a decent state. So we have to select the right equipment and protect it as much as possible. And also pyrophoric material, pyrophoric reagents, need special attention; for example, for storage, but also for dosing, for neutralization after the reaction . The second category are the toxic hazards, where the general principle is that first of all we try to avoid them. Avoid them by not using them, by using other reagents which are less toxic. If there is no real alternative, we try to reduce them; reduce the amount and after that we try to control that. On the one hand by containment and by engineering the process and the equipment, such that it's in a closed environment. And it's really needing also to protect the workers who has to handle these reagents on a large scale. And there's a difference between acute and chronic toxicity as you are aware of, for some of them you will observe it immediately that there's something wrong, for others you only see the effect after a long time. General principle is: If you can't scale it safely, don't scale it at all. A little bit of foam in the lab can be funny, not a problem, but some foaming on large scale, uncontrolled, and it can be, potentially, very toxic what's coming out of the reactor here. I'm sure you agree with me that you don't want to to see that..
- Finally, the last criteria which is important is the Throughput. Making sure that we can produce enough within a given time, where chemical yields plays an important role, trying to work as concentrated as possible; if you have one very diluted step in the middle of synthesis this can really be a bottleneck. So, for example, certain types of chemistry like metathesis, ring-closing metathesis, which is in most cases run at very diluted conditions. If you have to perform that several steps before the API this might be real bottleneck and not allow you to make a sufficient volume. What's quite often used is a telescoping of reactions, meaning you work in the same solvent for a number of consecutive steps which is really improving throughput because you don't need to isolate intermediates, don't need to filter or centrifugate them, you don't need to dry them as you don't need to bring them again or dissolve them again for the next step so that's one way to really improve throughput..
- Finally, the last criteria which is important is the Throughput. Making sure that we can produce enough within a given time, where chemical yields plays an important role, trying to work as concentrated as possible; if you have one very diluted step in the middle of synthesis this can really be a bottleneck. So, for example, certain types of chemistry like metathesis, ring-closing metathesis, which is in most cases run at very diluted conditions. If you have to perform that several steps before the API this might be real bottleneck and not allow you to make a sufficient volume. What's quite often used is a telescoping of reactions, meaning you work in the same solvent for a number of consecutive steps which is really improving throughput because you don't need to isolate intermediates, don't need to filter or centrifugate them, you don't need to dry them as you don't need to bring them again or dissolve them again for the next step so that's one way to really improve throughput..
- Bench scale and lab scale systems are important early-stage tools for assessing and scaling new technology. Application are a precursor to larger pilot and demonstration scale plants. Researchers can then plot reaction yield and selectivity under a variety of operating conditions( Temp. Pressure Change solvent and volume.) Reactor volumes in bench and lab scale systems are typically less than 1000ml. The most common operating configurations at the bench or lab scale are batch for continuous stirred tank reactor (CSTR), or autoclave etc. Pilot plants Scale provide the first window into continuous processing and often incorporate unreacted feed or product recycle. They are the workhorse of the process development world. Catalyst performance tests are carried out to determine, or confirm, yield and selectivity data, and the lifetime of the catalyst is measured under a variety of operating conditions. Reactor size at the pilot plant scale typically ranges from 1 and 100 litres. Demonstration Scale differ from pilot plants in that the equipment and process flowsheet much more closely resemble commercial scale operations. Extended operating runs permit catalyst lifetime studies over a longer period of time, while significant quantities of final product can be generated for market testing. Developers need to go to through the demonstration scale to prove to the market and investors that their technology meets its performance expectations, such as product yield and properties, and catalyst life, and is ready for commercialization.
- Bench scale and lab scale systems are important early-stage tools for assessing and scaling new technology. Application are a precursor to larger pilot and demonstration scale plants. Researchers can then plot reaction yield and selectivity under a variety of operating conditions( Temp. Pressure Change solvent and volume.) Reactor volumes in bench and lab scale systems are typically less than 1000ml. The most common operating configurations at the bench or lab scale are batch for continuous stirred tank reactor (CSTR), or autoclave etc. Pilot plants Scale provide the first window into continuous processing and often incorporate unreacted feed or product recycle. They are the workhorse of the process development world. Catalyst performance tests are carried out to determine, or confirm, yield and selectivity data, and the lifetime of the catalyst is measured under a variety of operating conditions. Reactor size at the pilot plant scale typically ranges from 1 and 100 litres. Demonstration Scale differ from pilot plants in that the equipment and process flowsheet much more closely resemble commercial scale operations. Extended operating runs permit catalyst lifetime studies over a longer period of time, while significant quantities of final product can be generated for market testing. Developers need to go to through the demonstration scale to prove to the market and investors that their technology meets its performance expectations, such as product yield and properties, and catalyst life, and is ready for commercialization.
- Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to roduction scale. The primary objective of the text is to provide insight into the practical aspects of process scale-up. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) for which “scale-up” simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) in which an increase of the scale is counterproductive and “scale-down” is required to improve the quality of the product.
- Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to roduction scale. The primary objective of the text is to provide insight into the practical aspects of process scale-up. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) for which “scale-up” simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) in which an increase of the scale is counterproductive and “scale-down” is required to improve the quality of the product.
- Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to roduction scale. The primary objective of the text is to provide insight into the practical aspects of process scale-up. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) for which “scale-up” simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) in which an increase of the scale is counterproductive and “scale-down” is required to improve the quality of the product.
- Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to roduction scale. The primary objective of the text is to provide insight into the practical aspects of process scale-up. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) for which “scale-up” simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) in which an increase of the scale is counterproductive and “scale-down” is required to improve the quality of the product.
- Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally important for the pharmaceutical industry—the procedures of transferring the results of R&D obtained on laboratory scale to the pilot plant and finally to roduction scale. The primary objective of the text is to provide insight into the practical aspects of process scale-up. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) for which “scale-up” simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) in which an increase of the scale is counterproductive and “scale-down” is required to improve the quality of the product.
- The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA) Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO) The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.(EMA)
- The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA) Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO) The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.(EMA)
- Design Qualification( DQ) is a verification process on the design to meet particular requirement relating to the quality of Pharmaceutical and manufacturing process. DQ plan covers user requirement, user specification, Technical specification and DQ report. Operational Qualification (OQ) is the process of testing to ensure that the individual and combined systems function to meet agreed performance criteria and to check how the result of testing is recorded. The purpose is to ensure that all the dynamic attributes comply with the original design. Performance qualification (PQ), also called process qualification, is the process of testing to ensure that the individual and combined systems function to meet agreed performance criteria on a consistent basis and to check how the result of testing is recorded. The purpose is to ensure that the criteria specified can be achieved on a reliable basis over a period of time. Process Validation :- Owners are responsible for Validating Their Processes (personnel, equipment, methods, SOPs) to ensure compliance to cGMP/GLP regulations.
- Solvent system modified to isopropanol / ethyl acetate containing hydrogen bromide from methanol / ethyl acetate to reduce formation of third impurity. Original process used chloroform. Concentration was increased threefold increasing throughput and reducing solvent waste.
- Labetalol Process –Step 2, Process Development Large excess of dibenzylamine used to ensure reaction driven to completion (cheap reagent and easily washed out) Propylene oxide added as it reacts with HBr side-product as it’s produced. Presence of HBr would neutralise dibenzylamine and no reaction to give product would occur. Propylene bromohydrin side-product easily washed out. Use gentle reflux to ensure propylene oxide doesn’t escape