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Regulatory Issues and Challenges Associated with the Development of Performance Specifications for Modified Release Parenteral Products

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Long Acting Injections and Implants

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

Once a parenteral product has been shown to be safe and effective, specifications need to be developed to ensure consistent product performance across batches and throughout the shelf life of that product. This in turn necessitates an appreciation of the physiological variables and critical quality attributes that influence product performance. The assessment of the critical quality attributes and manufacturing processes of new drugs provides the basis for establishing these important quality standards. This chapter provides an overview of the questions and background information that regulators of human or veterinary parenteral dosage forms may consider when establishing the criteria that will ensure repeatable product quality and performance.

The views expressed in this article are those of the author and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.

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References

  1. Swartz MA, Fleury ME (2007) Interstitial flow and its effects in soft tissues. Annu Rev Biomed Eng 9:229–256

    Article  PubMed  CAS  Google Scholar 

  2. Porter CJ, Charman SA (2000) Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci 89:297–310

    Article  PubMed  CAS  Google Scholar 

  3. Wiig H, Gyenge C, Iversen PO, Gullberg D, Tenstad O (2008) The role of the extracellular matrix in tissue distribution of macromolecules in normal and pathological tissues: potential therapeutic consequences. Microcirculation 15:283–296

    Article  PubMed  CAS  Google Scholar 

  4. Wiig H, Tenstad O (2001) Interstitial exclusion of positively and negatively charged IgG in rat skin and muscle. Am J Physiol Heart Circ Physiol 280:H1505–1512

    PubMed  CAS  Google Scholar 

  5. Hvidberg E, Schou J (1959) Subcutaneous absorption of urethane in dehydrated and fasted mice. Nature 184(Suppl 9):646–647

    Article  PubMed  CAS  Google Scholar 

  6. Schriftman H, Kondritzer AA (1957) Absorption of atropine from muscle. Am J Physiol 191:591–594

    PubMed  CAS  Google Scholar 

  7. Hirano K, Ichihashi T, Yamada H (1981) Studies on the absorption of practically water-­insoluble drugs following injection. II. Intramuscular absorption from aqueous suspensions in rats. Chem Pharm Bull (Tokyo) 29:817–827

    Article  CAS  Google Scholar 

  8. Kadir F, Seijsener CBJ, Zuidema J (1992) Influence of the injection volume on the release pattern of intramuscularly administered propranolol to rats. Int J Pharm 81:193–198

    Article  CAS  Google Scholar 

  9. Hirano K, Ichihashi T, Yamada H (1982) Studies on the absorption of practically water-­insoluble drugs following injection V: Subcutaneous absorption in rats from solutions in water immiscible oils. J Pharm Sci 71:495–500

    Article  PubMed  CAS  Google Scholar 

  10. Minto CF, Howe C, Wishart S, Conway AJ, Handelsman DJ (1997) Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and injection volume. J Pharmacol Exp Ther 281:93–102

    PubMed  CAS  Google Scholar 

  11. Tufto I, Rofstad EK (1999) Interstitial fluid pressure and capillary diameter distribution in human melanoma xenografts. Microvasc Res 58:205–214

    Article  PubMed  CAS  Google Scholar 

  12. Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98:335–344

    Article  PubMed  CAS  Google Scholar 

  13. Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK (1994) Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 54:3352–3356

    PubMed  CAS  Google Scholar 

  14. Eikenes L, Bruland OS, Brekken C, Davies Cde L (2004) Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts. Cancer Res 64:4768–4773

    Article  PubMed  CAS  Google Scholar 

  15. Brekken C, Hjelstuen MH, Bruland OS, de Lange DC (2000) Hyaluronidase-induced periodic modulation of the interstitial fluid pressure increases selective antibody uptake in human osteosarcoma xenografts. Anticancer Res 20:3513–3519

    PubMed  CAS  Google Scholar 

  16. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK (2000) Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 60:2497–2503

    PubMed  CAS  Google Scholar 

  17. Yoshikawa H, Satoh Y, Naruse N, Takada K, Muranishi S (1985) Comparison of disappearance from blood and lymphatic delivery of human fibroblast interferon in rat by different administration routes. J Pharmacobiodyn 8:206–210

    Article  PubMed  CAS  Google Scholar 

  18. Luo JP, Hubbard JW, Midha KK (1998) The roles of depot injection sites and proximal lymph nodes in the presystemic absorption of fluphenazine decanoate and fluphenazine: ex vivo experiments in rats. Pharm Res 15:1485–1489

    Article  PubMed  CAS  Google Scholar 

  19. Zuidema J, Kadir F, Titulaer HAC, Oussoren C (1994) Release and absorption rates of intramuscularly and subcutaneously injected pharmaceuticals (II). Int J Pharm 105:189–207

    Article  CAS  Google Scholar 

  20. Charman SA, Segrave AM, Edwards GA, Porter CJ (2000) Systemic availability and lymphatic transport of human growth hormone administered by subcutaneous injection. J Pharm Sci 89:168–177

    Article  PubMed  CAS  Google Scholar 

  21. Wasan KM, Cassidy SM (1998) Role of plasma lipoproteins in modifying the biological activity of hydrophobic drugs. J Pharm Sci 87:411–424

    Article  PubMed  CAS  Google Scholar 

  22. Wasan KM, Ramaswamy M, Ng SP, Wong W, Parrott SC, Ojwang JO, Wallace T, Cossum PA (1998) Differences in the lipoprotein distribution of free and liposome-associated all-trans-retinoic acid in human, dog, and rat plasma are due to variations in lipoprotein lipid and protein content. Antimicrob Agents Chemother 42:1646–1653

    PubMed  CAS  Google Scholar 

  23. Brocks DR, Ramaswamy M, MacInnes AI, Wasan KM (2000) The stereoselective distribution of halofantrine enantiomers within human, dog, and rat plasma lipoproteins. Pharm Res 17:427–431

    Article  PubMed  CAS  Google Scholar 

  24. Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ (2008) Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery. Nat Rev Drug Discov 7:84–99

    Article  PubMed  CAS  Google Scholar 

  25. Wasan KM, Brazeau GA, Keyhani A, Hayman AC, Lopez-Berestein G (1993) Roles of liposome composition and temperature in distribution of amphotericin B in serum lipoproteins. Antimicrob Agents Chemother 37:246–250

    PubMed  CAS  Google Scholar 

  26. Wasan KM, Conklin JS (1997) Enhanced amphotericin B nephrotoxicity in intensive care patients with elevated levels of low-density lipoprotein cholesterol. Clin Infect Dis 24:78–80

    Article  PubMed  CAS  Google Scholar 

  27. Gardier AM, Mathe D, Guedeney X, Barre J, Benvenutti C, Navarro N, Vernillet L, Loisance D, Cachera JP, Jacotot B et al (1993) Effects of plasma lipid levels on blood distribution and pharmacokinetics of cyclosporin A. Ther Drug Monit 15:274–280

    Article  PubMed  CAS  Google Scholar 

  28. Harashima H, Kiwada H (1996) Liposomal targeting and drug delivery: kinetic consideration. Adv Drug Deliv Rev 19:425–444

    Article  CAS  Google Scholar 

  29. Moghimi SM, Hunter AC (2001) Recognition by macrophages and liver cells of opsonized phospholipid vesicles and phospholipid headgroups. Pharm Res 18:1–8

    Article  PubMed  CAS  Google Scholar 

  30. Wasan KM, Lopez-Berestein G (1996) Characteristics of lipid-based formulations that influence their biological behavior in the plasma of patients. Clin Infect Dis 23:1126–1138

    Article  PubMed  CAS  Google Scholar 

  31. Yan X, Scherphof GL, Kamps JA (2005) Liposome opsonization. J Liposome Res 15:109–139

    PubMed  CAS  Google Scholar 

  32. Liu D, Song YK, Liu F (1995) Antibody dependent, complement mediated liver uptake of liposomes containing GM1. Pharm Res 12:1775–1780

    Article  PubMed  CAS  Google Scholar 

  33. Liu D, Hu Q, Song YK (1995) Liposome clearance from blood: different animal species have different mechanisms. Biochim Biophys Acta 1240:277–284

    Article  PubMed  Google Scholar 

  34. Harashima H, Komatsu S, Kojima S, Yanagi C, Morioka Y, Naito M, Kiwada H (1996) Species difference in the disposition of liposomes among mice, rats, and rabbits: allometric relationship and species dependent hepatic uptake mechanism. Pharm Res 13:1049–1054

    Article  PubMed  CAS  Google Scholar 

  35. Brandhonneur N, Chevanne F, Vie V, Frisch B, Primault R, Le Potier MF, Le Corre P (2009) Specific and non-specific phagocytosis of ligand-grafted PLGA microspheres by macrophages. Eur J Pharm Sci 36:474–485

    Article  PubMed  CAS  Google Scholar 

  36. Champion JA, Walker A, Mitragotri S (2008) Role of particle size in phagocytosis of polymeric microspheres. Pharm Res 25:1815–1821

    Article  PubMed  CAS  Google Scholar 

  37. Fogueri LR, Singh S (2009) Smart polymers for controlled delivery of proteins and peptides: a review of patents. Recent Pat Drug Deliv Formul 3:40–48

    Article  PubMed  CAS  Google Scholar 

  38. Kashyap N, Viswanad B, Sharma G, Bhardwaj V, Ramarao P, Ravi Kumar MN (2007) Design and evaluation of biodegradable, biosensitive in situ gelling system for pulsatile delivery of insulin. Biomaterials 28:2051–2060

    Article  PubMed  CAS  Google Scholar 

  39. Wu H, Khan MA (2010) Quality-by-Design (QbD): an integrated process analytical technology (PAT) approach for real-time monitoring and mapping the state of a pharmaceutical coprecipitation process. J Pharm Sci 99:1516–1534

    Article  PubMed  CAS  Google Scholar 

  40. Zidan AS, Rahman Z, Khan MA (2010) Online monitoring of PLGA microparticles formation using Lasentec focused beam reflectance (FBRM) and particle video microscope (PVM). AAPS J 12:254–262

    Article  PubMed  CAS  Google Scholar 

  41. Gunaseelan S, Gunaseelan K, Deshmukh M, Zhang X, Sinko PJ (2010) Surface modifications of nanocarriers for effective intracellular delivery of anti-HIV drugs. Adv Drug Deliv Rev 62:518–531

    Article  PubMed  CAS  Google Scholar 

  42. Gullotti E, Yeo Y (2009) Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm 6:1041–1051

    Article  PubMed  CAS  Google Scholar 

  43. Martinez MN, Rathbone MJ, Burgess D, Huynh M (2010) Breakout session summary from AAPS/CRS joint workshop on critical variables in the in vitro and in vivo performance of parenteral sustained release products. J Control Release 142:2–7

    Article  PubMed  CAS  Google Scholar 

  44. Emami J (2006) In vitro – in vivo correlation: from theory to applications. J Pharm Pharm Sci 9:169–189

    PubMed  CAS  Google Scholar 

  45. Ravivarapu HB, Moyer KL, Dunn RL (2000) Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide. Int J Pharm 194:181–191

    Article  PubMed  CAS  Google Scholar 

  46. Patil SD, Papadimitrakopoulos F, Burgess DJ (2004) Dexamethasone-loaded poly(lactic-co-glycolic) acid microspheres/poly(vinyl alcohol) hydrogel composite coatings for inflammation control. Diabetes Technol Ther 6:887–897

    Article  PubMed  CAS  Google Scholar 

  47. Larsen C, Larsen SW, Jensen H, Yaghmur A, Ostergaard J (2009) Role of in vitro release models in formulation development and quality control of parenteral depots. Expert Opin Drug Deliv 6:1283–1295

    Article  PubMed  CAS  Google Scholar 

  48. Faisant N, Akiki J, Siepmann F, Benoit JP, Siepmann J (2006) Effects of the type of release medium on drug release from PLGA-based microparticles: experiment and theory. Int J Pharm 314:189–197

    Article  PubMed  CAS  Google Scholar 

  49. Siepmann J, Elkharraz K, Siepmann F, Klose D (2005) How Autocatalysis Accelerates Drug Release from PLGA-Based Microparticles: A Quantitative Treatment. Biomacromolecules 6:2312–2319

    Article  PubMed  CAS  Google Scholar 

  50. Fielding RM (2001) Relationship of pharmacokinetically-calculated volumes of distribution to the physiologic distribution of liposomal drugs in tissues: implications for the characterization of liposomal formulations. Pharm Res 18:238–242

    Article  PubMed  CAS  Google Scholar 

  51. Packhaeuser CB, Schnieders J, Oster CG, Kissel T (2004) In situ forming parenteral drug delivery systems: an overview. Eur J Pharm Biopharm 58:445–455

    Article  PubMed  CAS  Google Scholar 

  52. Grayson AC, Voskerician G, Lynn A, Anderson JM, Cima MJ, Langer R (2004) Differential degradation rates in vivo and in vitro of biocompatible poly(lactic acid) and poly(glycolic acid) homo- and co-polymers for a polymeric drug-delivery microchip. J Biomater Sci Polym Ed 15:1281–1304

    Article  PubMed  CAS  Google Scholar 

  53. Anderson JM, Shive MS (1997) Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev 28:5–24

    Article  PubMed  Google Scholar 

  54. Iyer SS, Barr WH, Karnes HT (2006) Profiling in vitro drug release from subcutaneous implants: a review of current status and potential implications on drug product development. Biopharm Drug Dispos 27:157–170

    Article  PubMed  CAS  Google Scholar 

  55. Burgess DJ, Hussain AS, Ingallinera TS, Chen ML (2002) Assuring quality and performance of sustained and controlled release parenterals: workshop report. AAPS PharmSci 4:E7

    Article  PubMed  Google Scholar 

  56. Kempe S, Metz H, Pereira PG, Mader K (2010) Non-invasive in vivo evaluation of in situ forming PLGA implants by benchtop magnetic resonance imaging (BT-MRI) and EPR spectroscopy. Eur J Pharm Biopharm 74:102–108

    Article  PubMed  CAS  Google Scholar 

  57. Markland P, Yang VC (2006) Biodegradable polymers as drug carriers. Encyclopedia of Pharmaceutical Technology: Third Edition: 176–193

    Google Scholar 

  58. Klose D, Siepmann F, Willart JF, Descamps M, Siepmann J (2010) Drug release from PLGA-based microparticles: effects of the “microparticle:bulk fluid” ratio. Int J Pharm 383:123–131

    Article  PubMed  CAS  Google Scholar 

  59. D’Souza SS, DeLuca PP (2005) Development of a dialysis in vitro release method for biodegradable microspheres. AAPS PharmSciTech 6:E323–328

    Article  PubMed  Google Scholar 

  60. Huang X, Brazel CS (2001) On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J Control Release 73:121–136

    Article  PubMed  CAS  Google Scholar 

  61. Ramaswamy M, Wallace TL, Cossum PA, Wasan KM (1999) Species differences in the proportion of plasma lipoprotein lipid carried by high-density lipoproteins influence the distribution of free and liposomal nystatin in human, dog, and rat plasma. Antimicrob Agents Chemother 43:1424–1428

    Article  PubMed  CAS  Google Scholar 

  62. Huong TM, Ishida T, Harashima H, Kiwada H (2001a) Species difference in correlation between in vivo/in vitro liposome-complement interactions. Biol Pharm Bull 24:439–441

    Article  PubMed  CAS  Google Scholar 

  63. Huong TM, Ishida T, Harashima H, Kiwada H (2001b) The complement system enhances the clearance of phosphatidylserine (PS)-liposomes in rat and guinea pig. Int J Pharm 215:197–205

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Lead Scientific Expert for Pharmacokinetics, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD, 20855, USA

    Marilyn N. Martinez

  2. Division of Product Quality Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993-002, USA

    Mansoor A. Khan

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  1. Marilyn N. Martinez
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  2. Mansoor A. Khan
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Correspondence to Marilyn N. Martinez .

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Editors and Affiliations

  1. Cuesta Drive 631, Los Altos, 94024, USA

    Jeremy C. Wright

  2. Browns Road 626, Storrs, 06268, Connecticut, USA

    Diane J. Burgess

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© 2012 Controlled Release Society

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Martinez, M.N., Khan, M.A. (2012). Regulatory Issues and Challenges Associated with the Development of Performance Specifications for Modified Release Parenteral Products. In: Wright, J., Burgess, D. (eds) Long Acting Injections and Implants. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0554-2_24

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