Innovation in Filter Validation and Technology Transfer
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The presentation discusses innovations in filter validation and microbial retention testing in the pharmaceutical industry, highlighting a Quality by Design (QbD) approach that could eliminate the need for product-specific testing for early-stage products. Key findings emphasize that various process parameters do not impair the microbial retention capabilities of filters, proving their efficiency under challenging conditions. The methodology aims to support Phase 1 manufacturing and improve sterility assurance by utilizing process characterization data.
![#PharmSci360
Slide 15
Process Parameters Evaluated
15
[mAb1] g/L Pressure (psi) Temp (°C) Time (hr)
150 50
4-8 (48 hr)
+
18-23(48 hr)
96
1 50 4-8 (96 hr) 96
150 5
4-8 (48 hr)
+
18-23 (48
hr)
96](https://image.slidesharecdn.com/qbdsterileaapspresentationleahyfinal-210203142216/85/Innovation-in-Filter-Validation-and-Technology-Transfer-15-320.jpg)
![#PharmSci360
Slide 16
Study Challenges
• Viability
• Impact on bacterial viability at low product concentration at
ambient temperature; filtration of low [mAb] only conducted
at low temperature
• Temperature
• Low target temperature (2 °C) caused concentration-
dependent high viscosity and impaired filterability; low
temperature filtration was performed at 4-8 °C
• Process Time
• Lengthy process and contact time require multiple filtration
cycles
• Assay
• Assay filter rinse required due to inhibition of bacterial
viability
16](https://image.slidesharecdn.com/qbdsterileaapspresentationleahyfinal-210203142216/85/Innovation-in-Filter-Validation-and-Technology-Transfer-16-320.jpg)
![#PharmSci360
Slide 17
Experimental Results
17
[mAb1]
g/L
Pressure
(psi)
Temp (°C) Membrane
Volume
(L/m2)
Bacterial
Challenge
(CFU/cm2)
LRV*
150 50
4-8 (48 hr)
+
18-23 (48 hr)
0.2 µm, lot 1 259 8.5 x 107
≥9.1
0.2 µm, lot 2 327 1.1 x 108
≥9.2
0.2 µm, lot 3 333 1.1 x 108
≥9.2
0.45 µm, control 324 1.1 x 108
1.3
1 50 4-8 (96 hr)
0.2 µm, lot 1 319 7.1 x 107
≥9.0
0.2 µm, lot 2 310 6.9 x 107
≥9.0
0.2 µm, lot 3 312 6.9 x 107
≥9.0
0.45 µm, control 298 6.6 x 107
1.4
150 5
4-8 (48 hr)
+
18-23 (48 hr)
0.2 µm, lot 1 330 8.0 x 107
≥9.0
0.2 µm, lot 2 328 7.9 x 107
≥9.0
0.2 µm, lot 3 316 7.6 x 107
≥9.0
0.45 µm, control 341 8.2 x 107
1.6
*LRV (log reduction value)
“≥” indicates complete retention](https://image.slidesharecdn.com/qbdsterileaapspresentationleahyfinal-210203142216/85/Innovation-in-Filter-Validation-and-Technology-Transfer-17-320.jpg)
Innovation in Filter Validation and Technology Transfer
- 1. #PharmSci360 Slide 1 Innovation in Filter Validation and Technology Transfer November 4th, 2019 Annie Leahy Process Solutions, MilliporeSigma, Burlington, MA In collaboration with Pharmaceutical R&D, BioTherapeutics Pharmaceutical Sciences, Pfizer, Andover, MA
- 2. #PharmSci360 Slide 2 Session Description and Objectives Regulatory and manufacturing requirements exist to perform product-specific microbial retention testing on sterilizing filters. The implementation of a Quality by Design approach to microbial retention testing supports a paradigm that would obviate the need for product-specific testing for early stage products that do not have the quantity of material required to easily and efficiently perform such testing. Process and product parameters were varied to determine their effect on microbial retention.
- 3. #PharmSci360 Slide 3 Biography and Contact Information • Annie Leahy is a Technical Consultant Manager in the North America Manufacturing Sciences and Technology (MSAT) group within MilliporeSigma • She leads a highly technical team that ensures successful implementation and ongoing operation of customer applications across the manufacturing process. • Her work focuses on virus and aseptic filtration operations, supporting customers during their manufacturing process to provide best practices and ensure optimal processing conditions. • Annie has over 10 years of experience, which has included developing improved methods for virus spike preparations and mycoplasma retention methods as well as conducting virus and aseptic filtration applications studies at both small and large scale. • She holds a BS in Biology from Dickinson College and an MS in Biotechnology from Northeastern University. annie.leahy@milliporesigma.com
- 4. #PharmSci360 Slide 4 Compatibility Binding Extractables/ Leachables Retention Stability Sterilization Integrity Testing Fit for Use Eight Elements of a Sterile Filter Validation Sterile Filter Master Plan Sterile Filter Master Plan Drug product is not altered by the process Filter meets process needs - Properly sized and constructed to withstand process stress Prove filter is functioning as designed Filter removes all bacteria under process conditions Define impact of any material that migrates from the filter Process does not impact filter Filter does not remove wanted product components Prove critical areas of process are sterile
- 5. #PharmSci360 Slide 5 Sterilizing Filtration • PDA® Technical Report No. 26 5 Sterilizing filtration is the process of removing microorganisms from a fluid stream without adversely affecting product quality. Sterilizing Filtration Validation: Bacterial retention testing is conducted with process feed under process conditions at a challenge level of ≥ 1 x 107 CFU/cm² of effective filtration area. Quantitative retention of the entire challenge ASTM F838: “Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration”
- 6. #PharmSci360 Slide 6 cGMP Manufacturing Regulations Current Good Manufacturing Practices for Finished Pharmaceutical • 21 CFR 211.113(b) ➢Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes. 6
- 7. #PharmSci360 Slide 7 Regulatory Requirements for Ensuring Sterile Product • US: FDA Guidance for Industry CGMP for Phase 1 Investigational Drugs ➢ Product sterility is a critical element of human subject safety ➢ Implement appropriate controls for aseptic processing to ensure a sterile Phase 1 investigational drug • EU: EC Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 13 Investigational Medicinal Products ➢Section 17. For sterile products, the validation of sterilising processes should be of the same standard as for products authorised for marketing. 7
- 8. #PharmSci360 Slide 8 Quality by Design (QbD) An initiative from worldwide regulators, framed in ICH Q8, 2009 • Systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management. • Improve product safety and consistency by linking the manufacturing process design and operation to specific Critical Quality Attributes (CQAs), for instance safety attributes such as sterility and virus safety. • Manufacturing process is examined for steps that can affect specific CQAs. 8
- 9. #PharmSci360 Slide 9 Challenges in Performing Microbial Retention for Phase 1 • Probability of clinical success → approval is 12%1 • During early stages of a project material constraints exist to perform microbial retention testing A bracketed and matrixed approach (following QbD principles) was evaluated to determine the impact of process parameters on microbial retention performance of sterilizing grade membranes 9
- 10. #PharmSci360 Slide 10 • Challenge organism ➢ Brevundimonas diminuta (ATCC® 19146™ strain) ➢ Small (0.3-0.4 x 0.6-1.0 µm), water-borne, motile, “worst-case” organism • Process parameters ➢ Pressure: 30 psi ➢ Temperature: ➢ Time: immediate ➢ Volume (L/m2) ➢ Challenge level: ≥1 x 107 CFU/cm2 ASTM F838 Bacterial Retention Test 10 Saline lactose broth w/ B. diminuta Test Filter (0.22 m, 47 mm) Assay Filter Transfer assay filter to TSA 1 x 107 CFU/cm2 Incubate & Enumerate 100% of test filtrate passes through assay filter Challenge Feed Bacterial Retention Test
- 11. #PharmSci360 Slide 11 Quality by Design Data Matrix • Sterilizing-Grade Filters ➢0.2 µm Millipore Express® SHC hydrophilic polyethersulfone (PES) membrane ➢0.22 µm Millipore Durapore® hydrophilic polyvinylidene fluoride (PVDF) membrane • Data Sources ➢MilliporeSigma published work ➢BioReliance® Validation Services microbial retention studies ➢Pfizer/MilliporeSigma specific testing • Focus on recombinant proteins (primarily mAbs) 11
- 12. #PharmSci360 Slide 12 Retention Validation Data Mining 12 Parameter # of Studies Minimum Maximum Concentration (mg/mL) 31 1 150 Pressure (psi) 51 0.5 50 Temperature (°C) 31 2 30 Volume (L/m2) 20 493 79,710 Time (hr) 34 7 168 pH 13 4.0 8.0 Surfactant (%) 8 0.05 20 Millipore Durapore ® 0.22 µm Membrane ALL RETENTIVE!
- 13. #PharmSci360 Slide 13 Retention Validation Data Mining 13 Parameter # of Studies Minimum Maximum Concentration (mg/mL) 19 1 150 Pressure (psi) 19 5 50 Temperature (°C) 19 2 30 Volume (L/m2) 19 133 10,870 Time (hr) 19 15 168 pH 19 4.9 7.6 Surfactant (mg/mL) 19 0.1 0.4 Millipore Express® SHC 0.5/0.2 µm Membrane ALL RETENTIVE!
- 14. #PharmSci360 Slide 14 • Challenge organism • Brevundimonas diminuta (ATCC® 19146™ strain) • Small (0.3-0.4 x 0.6-1.0 µm), water- borne, motile, “worst-case” organism • Process parameters bracketed to evaluate impact on retention • Pressure • Temperature • Time • Volume (L/m2) • Product Concentration Experimental Overview 14 Bacterial Retention Test Test Filters Microbial assay filters Plate count: 47 mm disc on recovery agar Incubate & Enumerate Pressure Vessel containing Protein B. diminuta 5 or 50 psid REFRIGERATED WATERBATH 0.2µm PES 0.45µm control 0.2µm PES 0.2µm PES
- 15. #PharmSci360 Slide 15 Process Parameters Evaluated 15 [mAb1] g/L Pressure (psi) Temp (°C) Time (hr) 150 50 4-8 (48 hr) + 18-23(48 hr) 96 1 50 4-8 (96 hr) 96 150 5 4-8 (48 hr) + 18-23 (48 hr) 96
- 16. #PharmSci360 Slide 16 Study Challenges • Viability • Impact on bacterial viability at low product concentration at ambient temperature; filtration of low [mAb] only conducted at low temperature • Temperature • Low target temperature (2 °C) caused concentration- dependent high viscosity and impaired filterability; low temperature filtration was performed at 4-8 °C • Process Time • Lengthy process and contact time require multiple filtration cycles • Assay • Assay filter rinse required due to inhibition of bacterial viability 16
- 17. #PharmSci360 Slide 17 Experimental Results 17 [mAb1] g/L Pressure (psi) Temp (°C) Membrane Volume (L/m2) Bacterial Challenge (CFU/cm2) LRV* 150 50 4-8 (48 hr) + 18-23 (48 hr) 0.2 µm, lot 1 259 8.5 x 107 ≥9.1 0.2 µm, lot 2 327 1.1 x 108 ≥9.2 0.2 µm, lot 3 333 1.1 x 108 ≥9.2 0.45 µm, control 324 1.1 x 108 1.3 1 50 4-8 (96 hr) 0.2 µm, lot 1 319 7.1 x 107 ≥9.0 0.2 µm, lot 2 310 6.9 x 107 ≥9.0 0.2 µm, lot 3 312 6.9 x 107 ≥9.0 0.45 µm, control 298 6.6 x 107 1.4 150 5 4-8 (48 hr) + 18-23 (48 hr) 0.2 µm, lot 1 330 8.0 x 107 ≥9.0 0.2 µm, lot 2 328 7.9 x 107 ≥9.0 0.2 µm, lot 3 316 7.6 x 107 ≥9.0 0.45 µm, control 341 8.2 x 107 1.6 *LRV (log reduction value) “≥” indicates complete retention
- 18. #PharmSci360 Slide 18 • All studies demonstrated retention capability to quantitatively retain B. diminuta at a challenge level of ≥ 1 x 107 CFU/cm² of filtration area • Worst case processing conditions did not impact microbial retention • High pressure • High temperature • Extended duration 18 Experimental Results
- 19. #PharmSci360 Slide 19 Conclusions • A bracketed and matrixed approach (using QbD principles) to microbial retention testing supports a paradigm that would obviate the need for product-specific testing for early stage products that have limited quantities of material available to perform such testing • Process characterization matrix approaches can demonstrate a robust process/design space that meets quality attributes (sterility) • Results can be used to support filter validation requirements for Phase 1 manufacturing until product specific testing is performed • Partner with filter vendor to develop a strategy for filter implementation and validation 19
- 20. #PharmSci360 Slide 20 Acknowledgments • Jennifer Juneau • Parag Kolhe • Annie Leahy • Herb Lutz • Kathleen Souza • Danielle DeCesaro • Nhung Nguyen • Stuart Rolfe • Corinne Miller
- 21. #PharmSci360 Slide 21 References • 1Dimasi, Joseph A., et al. “Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs.” Journal of Health Economics, vol. 47, 2016, pp. 20–33. MilliporeSigma, Millipore, Millipore Express, Durapore, BioReliance, 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. © 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.