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Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives

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Ophthalmic Product Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 37))

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Abstract

All ophthalmic products must meet regulatory standards for microbiological quality and safety for their intended use. This chapter outlines holistic control strategies for sterility, endotoxin, and preservative efficacy to achieve ophthalmic product safety. While finished product testing for sterility or pyrogens confirms the microbiological quality of the products, there are certain challenges in developing a sensitive microbiological test that assures product quality. Product matrices/composition may interfere with the test. Additionally, testing only a small portion of the batch poses a statistical challenge to the confirmation of product quality of the entire batch. Therefore, stringent microbiological control cannot solely rely on end-product testing. The risk of microbial and/or pyrogenic contamination can be minimized only when proper microbiological control strategies, employed throughout the manufacturing process, are combined with finished product testing. While proper manufacturing process control provides assurance to the finished product microbiological quality, preservatives in a formulation are added to provide adequate protection from microbial contamination or proliferation that may arise during the use of the product. Preservative concentration must be safe to the patient but must robustly meet the requirements for preservative effectiveness of killing microorganisms for ophthalmic products.

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Abbreviations

AAMI:

Association for the Advancement of Medical Instrumentation

AC:

Anterior chamber

ANSI:

American National Standards Institute

Anti-VEGF:

Anti-vascular endothelial growth factor

APET:

Antimicrobial preservative efficacy test

BAK:

Benzalkonium chloride

BET:

Bacterial endotoxins test

BFS:

Blow-fill-seal

CCIT:

Container closure integrity test

CDRH:

Center for Devices and Radiological Health

CE:

Conformité Européenne

CFR:

Code of Federal Regulations

CFU:

Colony-forming unit

CMC:

Critical micelle concentration

D values:

Decimal reduction times

DPBS:

Dulbecco’s phosphate-buffered saline

E. coli :

Escherichia coli

EMA:

European Medicines Agency

EP:

European Pharmacopoeia

EU:

Endotoxin unit

FDA:

Food and Drug Administration

HEPA:

High-efficiency particulate air

h:

Hour

ICH:

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

ISO:

International Organization for Standardization

IVT:

Intravitreal

JP:

Japanese Pharmacopoeia

kg:

Kilogram

LAL:

Limulus amebocyte lysate

LER:

Low endotoxin recovery

MAT:

Monocyte activation test

MIC:

Minimum inhibitory concentrations

mL:

Milliliter

μm:

Micrometer

NMT:

Not more than

OSD:

Ophthalmic squeeze dispenser

OVD:

Ophthalmic viscosurgical device

PDA:

Parenteral Drug Association

Post-IVT IOI:

Post-intravitreal intraocular inflammation

PS:

Polysorbate

PTP:

Proactive TASS Program

Q&A:

Questions and answers

RABS:

Restricted access barrier system

rFC:

Recombinant factor C

RPT:

Rabbit Pyrogen Test

SOC:

Stabilized oxychloro complex

TASS:

Toxic anterior segment syndrome

TGA:

Australian government Department of Health Therapeutic Goods Administration

US:

United States

USP:

United States Pharmacopeia

WFI:

Water for injection

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Authors and Affiliations

  1. Abbvie, Irvine, CA, USA

    Ayako Hasegawa, Melissa Gulmezian-Sefer, Ying Cheng & Ramakrishnan Srikumar

Authors
  1. Ayako Hasegawa
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  2. Melissa Gulmezian-Sefer
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  3. Ying Cheng
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  4. Ramakrishnan Srikumar
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Corresponding author

Correspondence to Ayako Hasegawa .

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Editors and Affiliations

  1. Chief Operating Officer, Tarsus Pharmaceuticals Inc, Irvine, CA, USA

    Seshadri Neervannan

  2. Professor of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Uday B. Kompella

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Hasegawa, A., Gulmezian-Sefer, M., Cheng, Y., Srikumar, R. (2021). Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives. In: Neervannan, S., Kompella, U.B. (eds) Ophthalmic Product Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 37. Springer, Cham. https://doi.org/10.1007/978-3-030-76367-1_9

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