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Sterile filtration of complex injectables by Partha Banerjee


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Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.

As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.

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Sterile filtration of complex injectables by Partha Banerjee

  1. 1. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Sterile filtration of complex injectables Partha Banerjee
  2. 2. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada 2
  3. 3. Agenda 1 2 3 Background Considerations for Sterile filtration of liposomes Liposome sterilization methodology 4 5 Regulatory Guidelines Essential parameters- our observations 6 Sterile filtration of viscous formulations 3 7 Sterile filtration of oils, emulsions and ointments
  4. 4. Background 4
  5. 5. • As per the US Food and Drug Administration (FDA), complex parenteral products are those formulations which contain either complex ingredients or API, complex formulation, i.e., delivery carrier, complex route of administration, complex dosage form, or complex drug device combination . • The manufacturing of the complex injectable products is different and a great level of observation of quality and care is required during their manufacturing, packaging, distribution, and storage. • Complex injectables have gained increasing attention due to their widespread use in life-threatening and chronic diseases treatments. The category includes diabetes, oncology, and hormonal therapy to name but a few. • Pic Source – iStock. Sterile Filtration of Complex Injectables | 20 October 2020 Complex injectables – Background 5
  6. 6. Complex injectables – what are they? Complex drug products have become so prevalent that the FDA has defined them with the following categories: • Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of [active pharmaceutical ingredients]); complex formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally acting drugs, complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels); or complex dosage forms (e.g., implantables, transdermals, metered dose inhalers, extended-release injectables • Complex drug-device combination products (e.g., auto-injectors) • Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement. Complex processing challenges include, among others, aseptic manufacturing, the inclusion of highly potent compounds, milling/particle engineering, spray drying, extrusion, and microfluidization. 6 Ref: Synthetic peptide drug products that refer to listed drugs of rDNA origin, Draft guidance, October 2017. Sterile Filtration of Complex Injectables | 20 October 2020
  7. 7. Solubilization & Bioavailability Enhancement Techniques Drug-Eluting Systems The Four Categories of Complex Drug Products In considering the above, complex drug products encompass a wide range of technologies and dosage forms. However, we’ve found that these complex products generally revolve around four conversations or categories: Sterile complex injectables Highly Potent APIs and/or Controlled Substances 7 Sterile Filtration of Complex Injectables | 20 October 2020
  8. 8. • The FDA requires certain types of drug products to be provided as a sterile dosage forms to avoid the possibility of microbial degradation or infection occurring because of their use. • This includes several types of drug products, including injectables (small or large volume parenteral products), ophthalmic drugs, otic dosage forms, and implantable products.  Sterility of finished dosage forms can be assured via different processes Terminal Sterilization Aseptic Manufacturing Sterile Filtration Sterile Complex Injectables 8 Sterile Filtration of Complex Injectables | 20 October 2020
  9. 9. • Filtration is used for clarification purpose (clarification filtration) and/or to sterilize solution using sterilizing grade filter membranes (0.2 µ or smaller pore size filters). • Filtration of parenteral products ensures removal of particulate matter and can be used either for clarification or for sterilization purposes. • As it’s a critical operation we classify filtration as per • Criticality and point of use. • Usage. Sterile Filtration of Complex Injectables | 20 October 2020 Sterile filtration – Notable points 9
  10. 10. 10 Filter in final fill – top 3 segmentations - Utility filters  Where process fluids come from facility-wide systems, are not tailored to a specific process and do not have contact with the drug substance or potential drug substance.  Part of a No-Impact System - Where the equipment of system has no impact, direct or indirect, on product quality (ISPE Commissioning & Qualification Baseline Guide (2001))  Filter does not affect product quality (e.g. distribution gas filter, water prefilter) Critical • Where process fluids “are in direct contact with sterile final product or critical surfaces of the associated equipment.” (PDA TR40) • Part of Direct Impact System - equipment or system that will have focused and immediate impact on product quality (ISPE Commissioning & Qualification Baseline Guide (2001)) • Filter directly affects product quality (e.g. sterile hold vessel vent filter, sterile liquid filter) Moderately Critical • Where process fluids “will not be in direct contact with exposed sterile product or surfaces.” (PDA TR40) • Part of an Indirect Impact System - equipment or system expected to have incidental or secondary impact on product quality (ISPE Commissioning & Qualification Baseline Guide (2001)) • Filter indirectly affects product quality (e.g. vent filter in grade D, bioburden reduction filter) Sterile Filtration of Complex Injectables | 20 October 2020
  11. 11. 11 Filtration Portfolio – classified as per usage Particulate Control Sterility Assurance (LRV: 107 CFU/cm2) Bioburden Control (LRV: 106 CFU/cm2) Milligard® PolysepTM II LifegardTM Durapore® (0.22 um) Millipore Express® SHR Millipore Express® SHF Durapore® (0.45 um) Milligard® PES (0.2 um) Milligard® PES (0.45) Milligard ® PES (0.8 um) Millipore Express® PHF Sterile Filtration of Complex Injectables | 20 October 2020
  12. 12. In this presentation we will be discussion the sterile filtration and filter validation approach of Liposomes, nano emulsions and viscous fluids. 12 Sterile Filtration of Complex Injectables | 20 October 2020
  13. 13. Considerations for Sterile filtration of liposomes 13
  14. 14. Liposomes Characterization  Size: small, intermediate, or large  Number of lipid bilayers, composition, and mechanism of drug delivery Small unilamellar vesicles (SUV) − comprise a single lipid bilayer. Diameter ~25 to 75 nm. Large unilamellar vesicles (LUV) − comprise of a single lipid bilayer. Diameter >75 nm. Multilamellar vesicles (MLVs) comprise − Contain many concentric lipid bilayers. Diameter ~ 1-5 μm. 14 Sterile Filtration of Complex Injectables | 20 October 2020
  15. 15. Preparation Methods for Liposomes Three common approaches Preparation of globules Size reduction Purification The liposome preparation method affects purification! 15 Sterile Filtration of Complex Injectables | 20 October 2020
  16. 16. PDI – Poly dispersity index  PDI is basically a representation of distribution of size populations within a given sample  Degree of non uniformity of size distribution particles  Indicates a monodisperse system.  PDI is a very essential parameter and its analysis helps to understand the size distribution of globule based formulations. 16 Sterile Filtration of Complex Injectables | 20 October 2020
  17. 17. Z Average Value • The z-average is an intensity-based overall average size based on a specific fit to the raw correlation function data. Basically the particle size. Zeta Potential • The zeta potential of a particle is the overall charge that the particle acquires in a particular medium. Knowledge of the zeta potential of a liposome preparation can help to predict the fate of the liposomes in vivo. • Measurement of the zeta potential of samples is done using the technique of laser Doppler velocimetry 17 Sterile Filtration of Complex Injectables | 20 October 2020
  18. 18. Liposome sterilization methods 18
  19. 19. Liposome Sterilization Methods: Advantages vs disadvantages Ref: Liposomes as sterile preparations and limitations of sterilisation techniques in liposomal manufacturing ;April 2013; Asian Journal of Pharmaceutical Sciences 8(2):88-95 19
  20. 20. Liposome Sterilization Heat sterilization • Not generally accepted o Lipid/active not heat stable o Leakage o Safety issues Gamma Irradiation • Not generally used • Degradation of lipid and cholesterol • Safety issues not assessed • Cryo-radiation also not effective Sterile filtration 20 Sterile Filtration of Complex Injectables | 20 October 2020
  21. 21. Liposome Sterilization by Filtration – the riddle  Widely used  Limited by vesicle size and size distribution  Very little published information  Challenges: − allow particles (vesicles) of up to 300 nm to pass through − retain bacteria that can be as small as 200 nm (width) Lipid Globule B. Diminuta 21 Sterile Filtration of Complex Injectables | 20 October 2020
  22. 22. Regulatory guidelines 22
  23. 23. Section 3 – Discussion on Liposome drug products – Guidance for Industry Description of Manufacturing Process and Process Controls We recommend including a detailed process flow diagram and a description of unit operations with ranges for the process parameters and process controls. These ranges should be supported by pharmaceutical development studies. The process and mechanism of liposomal drug loading, as well as the removal of free (un-incorporated) drug from the liposome formulation via purification should be described in detail. The manufacturing process should be validated to demonstrate manufacturing process consistency and reproducibility before commercial distribution. Liposome drug products are sensitive to changes in the manufacturing conditions, including changes in scale (size of the batches). Appropriate process controls should be established during product development. Prior knowledge can be leveraged and risk assessment techniques can be used to identify manufacturing process parameters that potentially affect finished product quality. Some examples of manufacturing process parameters that may affect liposome drug performance are shear force, pressure, pH, temperature, batch-size-related hold times, lyophilization parameters, etc. You should provide adequate justification for the selection of the operating ranges for different batch sizes. The physical and chemical complexity of liposome drug products present unique challenges to the sterilizing filtration process. For example, components of liposomes could interact with the filter matrix and clog it. Therefore, validated product-specific purification and sterilization methods should demonstrate the ability of the microbial sterilizing filters to function correctly, without compromising the integrity and structure of liposomes. 23 Sterile Filtration of Complex Injectables | 20 October 2020 Ref: US Department of Health and Human Services, Food and Drug Administration, CDER: April 2018
  24. 24. Regulatory Comments - Sterilizing Filtration of Liposomes “Bulk holding times have been minimized or eliminated to control potential microbial contamination. In response to a concern raised with respect to microbial contamination, a pre-sterilized bioburden limit was adopted by the applicant above which batches will be rejected.” EMEA Scientific Discussion Documents “The particle size distribution is measured as an important part of the in-process controls.” “…..followed by two 0.22 micron sterile filtration steps, aseptic filling, and lyophilisation.” 24 Sterile Filtration of Complex Injectables | 20 October 2020
  25. 25. Or – Can we follow draft guidance? 25 Sterile Filtration of Complex Injectables | 20 October 2020 Ref: US Department of Health and Human Services, Food and Drug Administration, CDER: April 2018
  26. 26. We accept the potential challenges….Sterile filtration 26 • The sterility of such liposome solutions is typically ensured using 0.2μm rated sterilizing grade membranes, but due to the high viscosity and low surface tension of these formulations, they can cause pre-mature blocking and increased risk of bacterial penetration through a 0.2μm sterilizing grade membrane. • The low surface tension of liposome solutions affects the contact angle with membrane and reduces bubble point leading to bacterial penetration through the membrane. • This poses a great challenge to select an appropriate sterilizing grade membrane for a given process and for filter manufacturers to develop a sterilizing grade membrane that specifically addresses these needs. Sterile Filtration of Complex Injectables | 20 October 2020
  27. 27. Can I consider Aseptic Manufacturing? Raw materials (including organic and aqueous solvents, the natural sources of lipid components as well as other additives such as buffers) are sterilised after passing 200 nm filters. The equipment can be autoclaved and sterilised. Liposomes are prepared and then assembled into their containers via aseptic filling Sources of contamination : environmental air, operating personnel and the water for drainage) should be critically controlled by performing the filling process on work stations in clean rooms. Risk of contamination during aseptic processing remains Especially if the initial raw materials are not sterilised adequately. Limitations with natural sources of lipid components Can only be subjected to filtration due to possible physicochemical degradation. Contaminants In the raw materials or introduced during manufacturing cannot be removed from the final product during aseptic manufacturing is performed. Terminal sterilization - active process of removing Aseptic filling, and aseptic manufacturing - passive process of avoiding contamination 27 Sterile Filtration of Complex Injectables | 20 October 2020
  28. 28. A typical Single use template for fill finish operations - 28 Sterile Filtration of Complex Injectables | 20 October 2020
  29. 29. Essential parameters- our observations 29
  30. 30. 30 The Target 30 Sterile Filtration of Complex Injectables | 20 October 2020 Yes No
  31. 31. Considering Particle size – Effect of Operating Parameters 31 Increased stirring rate - • could improve droplet dispersion • prevent droplet coalescence • results in smaller apparent particle size Optimum dispersion conditions - • The dispersion condition of the droplets changes according to its concentration in the poor solvent. • Therefore, the effects of feed rate of good solvent and poor solvent ratio is important • It controls the droplets concentration in poor solvent, on the particle size of nanospheres. 31
  32. 32. Considering elevated temperature of feed- • At elevated temperature lipid membrane passes from tightly ordered gel state (stable) to a liquid crystal phase (metastable or unstable) • Freedom of movement of the individual molecule is higher. • This is due to the fatty acid chain adopting a new conformation other than the all trans state chain configuration, such as a gauche confirmation state (chain tilt phenomena) 32 Sterile Filtration of Complex Injectables | 20 October 2020
  33. 33. Considerations for Sterile filtration of oils, emulsions and ointments. 33
  34. 34. Sterile Filtration of Oils, Emulsions and ointments. • Most pharmaceutical fluids are water based. But several hydrophobic APIs (Active Pharmaceutical Ingredients) are often dissolved in an oily base, such as vitamins etc. • Many of these components are heat sensitive and therefore sterile filtration is the most preferred way. Examples of oily substances which are filtered are soy bean oil, castor oil, sesame oil, paraffin (liquid and solid at ambient temperature), silicon oils etc. • Examples for Emulsions used in the pharmaceutical industry are adjuvant solutions for vaccines or Liposomes which are capable to solubilise hydrophobic APIs in a water environment. Other examples include narcotics which is administered in soy bean oil in water emulsion with egg lecithin. Many emulsions are non-Newtonian therefore flow over pressure curve is not linear. • Some ointments can be heated up to more than 100°C but there are chances that the bacteria spores can even survive. For that reason the preparation of oily pharmaceuticals got in the focus of the regulatory bodies. By sterile filtration bacteria spores can be eliminated reliably. 34 Sterile Filtration of Complex Injectables | 20 October 2020
  35. 35. High flow rates Drying of the filtration equipment Sterile Filtration of Complex Injectables | 20 October 2020 Top points to consider while handling these formulation - Product specific integrity testing Filter validation aspects - 35
  36. 36. Optimizing the filtration train – • Flow rate estimation prior to a filterability trial roughly can help. For this Darcy's Law utilised. Provided we are working with a non Newtonian liquid. Very essential when we develop the formulation. • This equation describes the flow of a fluid through a porous medium: Where Q is the flux or discharge per unit area, e.g., m /s. Permeability of the medium, k (Sqm ) cross sectional area A (Sqm), and the pressure drop (delta P), all divided by the dynamic viscosity, μ and the length the pressure drop is taking place over. • There are certain requirements for the sterilizing grade filtration of oils. Express range of filters are the most suitable for filtration of oil containing liquids. So Polyethersulfone and Polyamide have good chemical compatibility. Optimizing robust prefilters like Milligard PES (of varied pore sizes) can really aid up the over process economics. • Other important considerations include single use application in the process. 36 Sterile Filtration of Complex Injectables | 20 October 2020
  37. 37. Filter validation aspects - • Considering Validation aspects for sterile filtration applications a bacteria challenge test. (BCT) has to be performed. Prior to this test in a Viability study it has to be demonstrated. • Due to the high viscosity at ambient temperature of different oily substances the filtration is performed at 60 to 80°C. At this temperature there is no viability of the test bacteria given and we may need to perform a two stage study. • Unclear composition of different oils avoids a direct detection in the contact solution specifically during extraction and analysis. • After filtration the oily liquid can not be removed by water flushing from the membrane. For integrity testing Product specific Integrity Test values can be established for direct IT measurement after filtration. 37 Sterile Filtration of Complex Injectables | 20 October 2020
  38. 38. Considerations for Sterile filtration of viscous formulations 38
  39. 39. Sterile Filtration of Viscous formulations - • Viscosity enhancers are key ingredients in many lens care solutions and ophthalmic prescriptive drug products. • These additives are commonly cellulose based compounds but hyaluronic acid is becoming increasingly popular in new formulations. • Solutions containing viscosity enhancers can present difficulties during sterile filtration due to batch to batch variability. • Even with careful optimisation of the mixing process, premature filter blockage is still common resulting in frequent filter changeouts mid-batch, product loss and increased processing time. • And they pose challenges for sterile filtration. 39 Sterile Filtration of Complex Injectables | 20 October 2020
  40. 40. • Multiple filter changeouts during batch processing: Premature filter clogging is evident even after careful optimization of manufacturing process (eg Mixing) and filtration train. • Product loss – • The influence of raw materials and process parameters – Which may include granularity of these cellulose based viscosity enhancers, Mixing techniques. • Batch to batch variation. • The temperature of the solution is also a very important factor during the filtration process, increasing the temperature can promote gelation of the solution that will lead to premature clogging of a filter. • What about binding of preservatives or essential API of the formulation to filter matrix – when flow rate is less, contact time is on the higher sides. • The filterability of solutions can change significantly depending on the time between mixing and filtration. • Sterile Filter validation. Top points to consider while handling these formulation - 40 Sterile Filtration of Complex Injectables | 20 October 2020
  41. 41. Optimizing the filtration train - • Volume maximization study followed by a recheck during pilot scale runs – • Advantages of composite asymmetric filter geometry • Usage of a proper safety factor To allow for process variability due to feed, process and membrane device in a robust process, a safety factor is typically included to define a required filtration surface area. The required area for a process will be the minimum surface area for an average performance times the safety factor. The actual variability of a process needs to be defined on a case-by-case basis. In absence of a detailed characterization study, one could use the following typical economically rationalized safety factors for various unit operations as described in Herb Lutz, Journal of Membrane Science 341 (2009) p268–278. Exact safety factors can be defined through experimentation. In case of anticipated large variations (high relative standard deviation. RSD), safety factors more than recommended safety factor can be included in defining the required surface area. In case specific information is available around low anticipated variability, a smaller safety factor can be used. 41 41 Sterile Filtration of Complex Injectables | 20 October 2020
  42. 42. 42 Sterile Filtration of Complex Injectables | 20 October 2020 THINK DIFFERENT
  43. 43. Approach 1 – Imitate process - 43 Complex Injectables Sterile Filtration of Complex Injectables | 20 October 2020
  44. 44. Approach 2 – Pre-screening study (Filter validation) Conducting the pre-validation screening study is not mandatory. But, if there is passage, it might be easier to determine the mitigation plan prior to the retention validation instead of a retention test failure investigation. Assess – Process duration, Actual temperature, Actual pressure, Actual scale down volume Important consideration – Stable parameters. Calculate – Scale down volume, achieved per Square surface area of the filter Important consideration – Process contact time Pre–screening to be conducted with one filtration line only. Important consideration – Pressure based study and no recirculation mode. Inoculation 44 Sterile Filtration of Complex Injectables | 20 October 2020
  45. 45. Approach 3 – Considering Standard vs High Area filtration devices. Sterile Filtration of Complex Injectables | 20 October 202045
  46. 46. Approach 4 – Selecting a well defined prefilter – Like Milligard® PES 46 Benefits: Fast flow and high throughput Validated bioburden reduction (1.2/0.2 μm nominal and 1.2/0.45 μm pore sizes only) Predictable scalability from small to production scale devices High thermal stability: compatible with steam-in place and autoclave sterilization methods Caustic stable Gamma stable and available in single use assemblies Sterile Filtration of Complex Injectables | 20 October 2020
  47. 47. Points to consider in terms of  Filterability  Filter validation. 47 Sterile Filtration of Complex Injectables | 20 October 2020
  48. 48. Filterability Process considerations: Keep vesicle size and size distribution small Incorporate active in bilayer when feasible Select process temperature in relation to Tc and lipid composition Pre-wet filters with vehicle/buffer Increase differential pressure gradually May need to exceed certain differential pressure to initiate flow Filter considerations: Evaluate filterability early in process development Evaluate different filter media types, hydrophilic PES generally works the best Use pre-filtration to optimize filterability 48 Sterile Filtration of Complex Injectables | 20 October 2020
  49. 49. Filter validation - Bacterial Retention study Evaluate sterilization approach early in process development Choose synthetic lipids when possible Keep vesicle size and size distribution small Evaluate different media pore size ratings and types Consider “new technology” – Like stacked disc formats (Millipak® range of filters with Durapore membrane, high area device, AMPP (aseptic multi purpose port) Hydrophilic PES generally works the best
  50. 50. And we stand unique - 50 M LabTM / Validation lab. support Liquid filters - Durapore® Liquid filters – Millipore Express ® Gas filtration - Aervent® Next Gen technology Documentation • Trusted name brand >40 yrs. • Extreme strength • Durable for reuse • Low protein - preservative binding • High thermal and gamma stability • Fast flow • Broad chemical compatibility • Excellent wettability after autoclaving • High thermal and gamma stability • From-buffer/media/protein intermediates to viscous/complex molecules – wide application. • Meant for critical applications • Sterility assurance • Liquid bacterial retention • Virus aerosol retention testing • High air or gas flow rate • Oxidation resistance for a long service life • Greater hydrophobicity • Stacked disc membranes – for higher flow/low hold up. • AMPP – Aseptic multipurpose port – protects product from contamination, maintains sterility • High area device - Unique shape, taller pleats and narrower core – double membrane area. • Composite asymmetric membranes – no its not 2 separate layers.  Facilitating qualification processes  Supporting risk assessment, management and mitigation  Expediting approval preparation and extending compliance • Want a pilot scale demo run. • What IT troubleshooting – real time view • Visualize scale up scenario. • Project status. • Sample recon – if difficult to ship • Ready to audit labs.
  51. 51. 51 Product Support Services - Uniqueness continues - Process Reviews  Filter review  Compliance review  Integrity testing review Steam in Place review Training • Filtration • Integrity testing - Introductory & Advanced Troubleshooting. • IT testing - Compliance • Filter validation • SIP & Sterilization • Microbiological analysis • Sterility Testing Sterile Filtration of Complex Injectables | 20 October 2020
  52. 52. Partha Banerjee The vibrant M, Millipore, M Lab, Aervent, Durapore, Milligard, Polysep, Lifegard, and Millipore Express are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.