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BFS-packaged eye drops for single use

Blow-Fill-Seal, also spelled as Blow/Fill/Seal, in this article abbreviated as BFS, is an automated manufacturing process by which plastic containers, such as bottles or ampoules are, in a continuous operation, blow-formed, filled, and sealed.[1][2] It takes place in a sterile, enclosed area inside a machine, without human intervention, and thus can be used to aseptically manufacture sterile pharmaceutical or non-pharamceutical liquid/semiliquid unit-dosage forms.[3][4] BFS is an advanced aseptic processing technology that is typically used for filling and packaging of certain sterile liquid formulations like liquid ophtalmics, inhalational anesthetics, or lavaging agents, but can also be used for injectables,[1] parenterals,[5] and several other liquid or semiliquid medications,[6] with fill volumes ranging from 0.1...1000 cm³.[7][8][9] Compared against traditional glass ampoules, BFS ampoules are inexpensive, lightweight, and shatterproof.[10] Important BFS system suppliers are Weiler Engineering, Rommelag (Bottelpack),[11] and Brevetti Angela.

History

BFS was developed in the early 1960s[12] at Rommelag.[13] In 1963, Gerhard Hansen applied for a patent on the BFS process.[14] Originally, it was used for packaging of non-sterile products, such as non-sterile medical devices, food, and cosmetics.[10] In the early 1970s, Rommelag's Bottelpack system was first used for packing large volume pharmaceutical solutions.[13] By the late 1980s, BFS had been well-established in the packaging industry, especially for packaging pharmaceutical and healthcare products.[15] During the 1980s and 1990s, BFS came into use for the now common small volume unit-dosage forms.[13] Since the early 2000s, BFS has been emerging as the preferred packaging process for parenteral products.[7]

BFS process

The BFS process functions similarly to conventional extrusion blow molding, and takes place within a BFS machine.[6] First, a plastic polymer resin is heated to >160 °C and compressed to 35 MPa,[12][16] allowing it to be extruded in tubular form,[1] and be taken over by an open two-part[17] mold to form the container. Then, the mold closes which welds the bottom of the container. Simultaneously, the parison above the mold is cut, or the filling needles are placed in the parison head without the parison being cut (rotary BFS type). Next, a filling mandrel with blowing air function is placed in the neck area that seals the container. Sterile compressed air is then introduced through the filling mandrel to inflate and form the container. In the BFS process for smaller ampoules the compressed air system is avoided by using vacuum forming the container instead. After the BFS container has been formed, the desired liquid is filled into the container through the filling mandrel unit. Then, the filling mandrel unit is lifted off, and the head mold hermetically seals the container. Simultaneously, the head contour is formed by vacuum. In the last step, the mold opens and the finished container leaves the mold.[6]

One process cycle takes a few seconds.[12] The process speed and thus process output largely depends upon the BFS container size and the BFS machinery dimensioning. For instance, in the early 2000s, Rommelag's 3012, 305, and 4010 M machines had outputs of approximately 4000, 8000, or 20,000 containers per hour.[11] These machines have been succeeded by the Rommelag 312, 321, 360, 364 and 460 machines with output ranges of up to 35,000 containers per hour.

Sterility requirements

The BFS processes is an aseptic filling process, which produces sterile products and thus needs to be sterile.[18] Aseptic BFS machines must be designed in a way that prevents extraneous contamination.[19] Thus, rotary-type BFS machines are placed in classified areas same as shuttle-type BFS machines (open parison), which have a cleanroom shroud grade-A-compliant provided with sterilised air and kept under overpressure. Automatic SIP programs are used to sterilise the BFS equipment and this avoids human interventions. Due to automatic start up and filling processes BFS machines require no human interaction during the actual BFS process. However, certain adjustments or interventions need to be carried out by personnel. Both particle and microbiological contamination monitoring are required in a BFS machine environment, as well as routine CIP/SIP processes.[20] BFS machines are typically fitted with several different sterilising air filtration systems for the buffer air, support parison air and air shroud grade A air (if needed for shuttle machines, e. g. open parison type ones).[9] Typically, the air is sterilised by filtration systems that have automatic filter integrity testing installed (i. e. automatic water intrusion or particle testing). The air systems are typically integrated into the SIP cycle of the BFS machine. [21]

BFS material

The materials used in BFS packaging are usually polyolefins, mainly polyethylene (LDPE[22][23] or HDPE),[24] and polypropylene (PP).[25][26][27] These materials are robust and inert to ensure sterility and tightness during the product's shelf life.[5] Diffusion tendencies can be reduced by using virgin polymers, but diffusion cannot be prevented entirely. This is due to the nature of polyolefins and their additives, if present.[25] Several polyethylene suppliers have developed special EP or USP grade resin for BFS containers. Permeation into BFS containers and water loss may be an issue with some BFS resin. Therefore, in some applications, secondary packaging methods (laminate pouches) are used.[28]

Advantages

Eye drops sold in blow fill seal packaging

BFS allows many different container designs, a consistent high process quality, a high process output,[7] and is, compared against other packaging processes, inexpensive.[26] In addition to that, BFS containers are lighter than glass containers, and shatterproof, which eases their transport.[10][29] Due to the single-dose nature of BFS containers, they are more convenient to use for patients.[30] BFS technology assures high levels of sterility,[31][32][33] especially compared against conventional filling,[34] which is mainly achieved by the absence of human contact/interventions – a major source of contamination.[35]

References

  1. ^ a b c Niazi, Sarfaraz K. (2020), Handbook of Pharmaceutical Manufacturing Formulations – Volume 6: Sterile Products (3rd ed.), Boca Raton London New York: CRC Press, ISBN 978-1-138-10383-2, p. 33
  2. ^ Steinborn, Leonhard (2005), GMP/ISO Quality Audit Manual for Healthcare Manufacturers and Their Suppliers – Volume 2: Regulations, Standards, and Guidelines (6th ed.), Boca Raton London New York Washington, D.C.: CRC Press, ISBN 0-8493-1847-5, p. 261
  3. ^ Sinclair, C S (1995). "Performance of blow/fill/seal equipment under controlled airborne microbial challenges" (PDF). PDA-Journal of Pharmaceutical Science and Technology. 49: 494–499. Retrieved 24 March 2021.
  4. ^ Bradley, A (July 1991), "Airborne microbial challenges of blow/fill/seal equipment: A case study" (PDF), Journal of Parenteral Science and Technology, 45 (4): 187–194, retrieved 25 March 2021
  5. ^ a b Flickinger, Michael C. (2013), Downstream Industrial Biotechnology – Recovery and Purification, Hoboken: Wiley, ISBN 978-1-118-13124-4, p. 703
  6. ^ a b c Thielen, Michael (2021), Extrusion Blow Molding, Carl Hanser Verlag, ISBN 9781569908419, p. 139
  7. ^ a b c Gibson, Mark (2009), Pharmaceutical Preformulation and Formulation (2nd ed.), Newy York London: informa healthcare, ISBN 978-1-4200-7318-8, p. 339
  8. ^ Spalding, Mark A.; Chatterjee, Ananda M. (2018), Handbook of Industrial Polyethylene and Technology (1st ed.), Beverly: Scrivener Publishing, ISBN 9781119159766, p. 1103
  9. ^ a b Downey, K.; Haerer, M.; Marguillier, S.; Åkerman, P. (2016), The Manufacture of Sterile Pharmaceuticals and Liquid Medical Devices Using Blow-Fill-Seal Technology · Points to Consider (1st ed.), Editio-Cantor-Verlag, p. 64, ISBN 9783871934438
  10. ^ a b c Amin, A.; Chauhan, S.; Dare, M.; Bansal, A. K. (2012), Sorption of antimicrobial agents in blow-fill-seal packs, informa healthcare, doi:10.3109/10837450.2010.516438, ISSN 1083-7450
  11. ^ a b Dean, D. A.; Evans, E. R.; Hall, I. H. (2000), Pharmaceutical Packaging Technology, London New York: Taylor & Francis, ISBN 0-7484-0440-6, p. 438
  12. ^ a b c Swarbrick, James; Boylan, James C. (2001), Encyclopedia of Pharmaceutical Technology – Volume 20, New York · Basel: Marcel Dekker, ISBN 9780824728199, p. 1
  13. ^ a b c Oschmann, R.; Schubert, O. E. (1999), Blow-Fill-Seal Technology, vol. 40, Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH – CRC Press Inc., p. 17, ISBN 978-0849316203
  14. ^ United Kingdom GB1041548A, Gerhard Hansen, "Improvements relating to blow moulding machines", published 1966-09-07 
  15. ^ European Plastics News. (1989). United Kingdom: IPC Press. p. 14
  16. ^ Oschmann, R.; Schubert, O. E. (1999), Blow-Fill-Seal Technology, vol. 40, Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH – CRC Press Inc., p. 21, ISBN 978-0849316203
  17. ^ Rosato, Dominick V.; Rosato, Donald V.; Rosato, Matthew V. (2005), Plastic Product Material and Process Selection Handbook, Elsevier Science & Technology Books, ISBN 9780080514055, p. 302
  18. ^ Oschmann, R.; Schubert, O. E. (1999), Blow-Fill-Seal Technology, vol. 40, Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH – CRC Press Inc., p. 23, ISBN 978-0849316203
  19. ^ Nema, Sandeep; Ludwig, John D. (2010), Pharmaceutical Dosage Forms: Parental Medications – Volume 3: Regulations, Validation and the Future (3rd ed.), New York, London: informa healthcare, p. 7
  20. ^ Swarbrick, James; Boylan, James C. (2001), Encyclopedia of Pharmaceutical Technology – Volume 20, New York · Basel: Marcel Dekker, ISBN 9780824728199, p. 2
  21. ^ Jornitz, Maik W. (2020), Filtration and Purification in the Biopharmaceutical Industry (3rd ed.), Boca Raton London New York: CRC Press, ISBN 978-1-138-05674-9, p. 539
  22. ^ Gad, Shayne Cox (2008), Pharmaceutical Manufacturing Handbook – Production and Processes, Hoboken: Wiley, ISBN 978-0-470-25958-0, p. 103
  23. ^ das Nevas, José; Sarmento, Bruno (2014), Mucosal Delivery of Biopharmaceuticals – Biology, Challenges and Strategies, New York Heidelberg Dordrecht London: Springer, ISBN 978-1-4614-9523-9, p. 444
  24. ^ Vasile, Cornelia; Pascu, Mihaela (2005), Practical Guide to Polyethylene, Shawbury: Rapra Technology Limited, ISBN 1-85957-493-9, p. 124
  25. ^ a b Amin, A.; Sangamwar, A.; Dare, M.; Bansal, A. K. (2012), Interaction of antimicrobial preservatives with blow-fill-seal packs: correlating sorption with solubility parameters, informa healthcare, doi:10.3109/10837450.2011.557733, ISSN 1083-7450
  26. ^ a b Denyer, Stephen P.; Hodges, Norman; Gorman, Sean P.; Gilmore, Brendan F. (2011), Hugo and Russell’s Pharmaceutical Microbiology, Chichester: Wiley-Blackwell, ISBN 9781444330632, p. 387
  27. ^ Oschmann, R.; Schubert, O. E. (1999), Blow-Fill-Seal Technology, vol. 40, Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH – CRC Press Inc., p. 42, ISBN 978-0849316203
  28. ^ Spalding, Mark A.; Chatterjee, Ananda M. (2018), Handbook of Industrial Polyethylene and Technology (1st ed.), Beverly: Scrivener Publishing, ISBN 9781119159766, p. 1104
  29. ^ Oschmann, R.; Schubert, O. E. (1999), Blow-Fill-Seal Technology, vol. 40, Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH – CRC Press Inc., p. 81, ISBN 978-0849316203
  30. ^ Pearlman, Rodney; Wang, Y. John (1996), Formulation, Characterization, and Stability of Protein Drugs – Case Histories; Volume 9 of Pharmaceutical Biotechnology, New York, Boston, Dordrecht, London, Moscow: kluwer Academic Publishers, ISBN 0-306-45332-0, p. 417
  31. ^ Groves, Michael J.; Murty, Ram (1995), Aseptic Pharmaceutical Manufacturing II – Applications for the 1990s, Boca Raton London New York: CRC Press, ISBN 978-0-935184-77-8, p. 364
  32. ^ Swarbrick, James; Boylan, James C. (2001), Encyclopedia of Pharmaceutical Technology – Volume 20, New York · Basel: Marcel Dekker, ISBN 9780824728199, p. 10
  33. ^ Gail, Lothar; Gommel, Udo (2018), Reinraumtechnik (in German) (4th ed.), Berlin: Springer, ISBN 978-3-662-54914-8, p. 602
  34. ^ Sandle, Tim (2016), Pharmaceutical Microbiology – Essentials for Quality Assurance and Quality Control, Cambridge: Woodhead Publishing Limited, ISBN 978-0-08-100022-9, p. 154
  35. ^ Hardee, Gregory E.; Baggot, J. Desmond (1998), Development and Formulation of Veterinary Dosage Forms – Drugs and the Pharmaceutical Sciences (2nd ed.), New York · Basel · Hong Kong: Marcel Dekker, ISBN 0824798783, p. 208
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