Eye drops and other ophthalmic preparations are used by millions of individuals all over the world; in order to keep them safe and guarantee effectiveness, maintaining sterility is vital to proper ophthalmic manufacturing.
According to the American Society of Health-System Pharmacists (ASHP) Pharmacy-Prepared Ophthalmic Products guidelines, the following should be considered when preparing eye drops in the pharmacy/hospital setting2:
Adhere to aseptic techniques and sterilisation procedures to ensure that eye drops are sterile (free from microbial contamination).
Ask a colleague to double check your calculations of the amount of each ingredient that will be used in preparing the eye drops; this will minimise error.
All ingredients should be mixed in sterile, empty containers. When using more than one container for compounding a sterile preparation, each container should be labelled.
Compounding should be performed in a certified laminar airflow hood or, for a cytotoxic or hazardous product, inside a biological safety cabinet.
The compounded eye drops should be clearly labelled according to the hospital or pharmacy policy for prescription labelling.
The label should contain information about the concentrations of active ingredients and preservatives and information about storage conditions, handling requirements, and expiration dates.
The storage instructions on the label should be clear. For example, room temperature means 15–25 °C, refrigerator means 2–8 °C, and freezer means below 0°C.
Eyedrops processing is quite literally a sight for sore eyes. There is no shortage of eye care products, from eyewashes to anesthetics to antibiotics. But formulating eyedrops is a complex affair with multiple safety checkpoints. Technological advances bring a pair of fresh eyes to manufacturing, ensuring higher-quality products for specialized applications.
Ophthalmic products must be manufactured in a sterile, pyrogen-free environment and packaged to ensure good shelf life. The goal is to deliver enough API to be absorbed at the eye surface, but not so much that it spills.
The purified water is pumped through airtight and aseptic pipes to the formulation tanks. Raw ingredients that have passed inspection on delivery are subject to an air shower to clean away unwanted particles and then stored temporarily. Then, the ingredients are precisely weighed and charged to the formulation tanks in a specific order. Although formulation is computer-controlled, operators still manage the overall process and keep a vigilant eye on the system to ensure quality.
Eye drops are made from the following main ingredients:
A. Active pharmaceutical ingredient (API): Can be in powder or concentrated solution form
b.Solvent: Can be sterile water or buffer solution
c.Preservative: An antimicrobial agent to prevent contamination.
The manufacturing process for eye drops includes:
Water purification: A crucial step in the process
Formulation: Using purified water and raw ingredients to produce the solution
Filling: Bottling the product
Inspection: Thorough checks for perfect products
Packaging and storage: Preparing the product for travel to help patients.
Ophthalmic manufacturing; that is, the manufacturing of any preparations or applications intended to be used directly on the conjunctiva or conjunctival sac or on the eyelids; requires careful oversight and accountability. The mucous membranes of the eye are susceptible to infection and disease if foreign elements are introduced via ophthalmic preparations, and because the eye is connected directly to the central nervous system, infections present serious concerns for the health of the subject.
Damage to the eye up to and including long-term loss of sight, or even more serious complications, can occur if ophthalmic manufacturing does not follow cGMP and other guidelines and doesn’t have the proper oversight to ensure sterility and accountability throughout the process.
While the most commonly-known ophthalmic products on the market are probably eye drops, ophthalmic manufacturing produces a range of preparations and products intended for use on and around the eyes, including liquid, semi-solid, and solid formulations. What all ophthalmic products have in common is the need for sterility and safety that ensures they are ready for use on or near the eye when the end-user is ready to deploy them.
Ophthalmic manufacturing safety begins with good manufacturing practices.
Cross-contamination is a particular concern in ophthalmic manufacturing, especially in facilities which also manufacture other chemical or pharmacological products.
This is one reason why it is vital for ophthalmic manufacturing facilities to follow cGMP guidelines in every step of the process, from the filtration of water through filling and into packaging and storing of the final ophthalmic solution.
Most eye drops are emulsions, solutions, or suspensions in liquid, which means that most of the ophthalmic manufacturing process begins with water for injection (WFI).
Some CMOs create their own WFI on-site by filtering water n a sterile environment, while others obtain sterile, filtered water from another source.
Beginning as far back as securing the WFI, sterility is vital throughout every step of the manufacturing process, assuming that the end product cannot be sterilized via routine methods.
Appropriate in-process controls throughout the chain of manufacturing can help guarantee effectiveness, sterility, and traceability of the end product. These include the monitoring of environmental conditions, as well as checking for pyrogens, pH, and the clarity of the solution.
When it comes to eye drops, the container and applicator, if appropriate, is part of the end product, and needs to be manufactured, handled, and inspected with the same rigor used on the preparation itself.
Contamination from the container is just as serious as contamination within the process of formulating the preparation, and can result in eye drops that are diluted, contaminated, or less effective.
An often-overlooked aspect of ophthalmic manufacturing is ensuring that the packaging is adequate to protect the product not only from potential contamination, but also from light, moisture, or damage due to handling in the CMO, at the warehouse, and on store shelves or wherever the product is ultimately headed.
Most eye drops are designed to be used, a few drops at a time, over a course of days, weeks, or even longer, until the bottle is depleted.
This means that ophthalmic manufacturers have a duty to ensure that the product is not only stable and effective when it leaves their facility, but that it will remain stable and effective throughout its intended shelf life.
At its most basic, this means including information like the expiration date, period of use, and date of manufacture on the label, along with all other FDA-required data.
The label should also include batch or lot numbers, as well as directions for how to store and apply the product so that it retains its effectiveness for the duration of its intended use and shelf life.
This also means ensuring that the proper steps are being followed throughout the manufacturing process to guarantee the stability and effectiveness of the product, not to mention the traceability of all of its ingredients.
Any deviation in the manufacturing process can potentially affect the product, not only at the point of manufacture but also during its later shelf life.
All processes should follow cGMP and any other relevant guidelines, and should remain consistent throughout.
Eye drops and other ophthalmic preparations should be monitored for contamination, separation, agglomeration, discoloration, emulsion breakdown, crystal growth, or any other unexpected changes both during the manufacturing process and after.
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Built-up area of approx. 100,000 sq. ft with separate areas for production, stores & non-process blocks.
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Highly skilled and experienced technical staff
Immaculate environmental monitoring, calibration, and validation program
c-GMP compliant with latest manufacturing equipment Dedicated & modular laboratories with the latest sophisticated instruments as per GLP norms Automated access control system and fully equipped cameras Separate entry and exit for man, material, and service personnel for both process blocks In-house water & sewerage treatment plant.
In general, eye drops are prepared in one of two ways:
Dissolving the active pharmaceutical ingredient/preservative (in powder form) in a suitable vehicle (either sterile water or a buffer solution).
Diluting a concentrated solution of the active pharmaceutical ingredient using sterile water or buffer solution.
There are several important elements that should be considered when preparing eye drops.
1.Sterilisation
Eye drops must be sterilised to ensure they are free of microbial contamination. The method of sterilisation depends on the stability of the drug at high temperature.
The options are:
Autoclaving. Autoclaving is used to sterilise pharmaceutical products (solutions, suspensions, powder) which are stable at high temperature.
Eye drops in the final packaging (filled and sealed eye drop bottles) are usually sterilised at the end of the production process (terminal sterilisation) using autoclaving (saturated steam at 121–132°C) for 15 minutes to kill microorganisms.
Filter sterilisation. If the drug is not stable at high temperatures, eye drops in solution form can be sterilised by filtration through a 0.22 μm filter into a sterile final container. This method is called filter sterilisation and it should be conducted under aseptic conditions using a laminar flow cabinet. Filter sterilisation is not suitable for use with eye drops in suspension form, as the 0.22 μm filter will remove the finely dispersed drug particles and make the eye drops ineffective.
2.Inherent toxicity of the drug
The pharmacist should check the drug-specific data safety document (the drug safety data sheet) to get information about the toxicity of the drug. The pharmacist should adhere to the established guidelines for handling each drug.3
3.Removal of particulates
All compounded eye drop solutions should be filtered using a 5 μm filter to remove any visible particulate matter.2 This can be done using glass sintered filters or polypropylene fibre filters under minimal pressure. This pressure can be generated using either a hand-held or foot suction pump.
4.pH
The pH of eye drops is important for drug solubility and for the stability of some drugs.3 For optimal ocular comfort, it should be similar to the pH of natural tears (pH 7.4). However, sometimes it is not feasible to prepare eye drops with pH 7.4 due to drug stability or solubility issues. The acceptable pH range for eye drops is in the range of 6.5–7.8 to ensure patient comfort. A more acidic or alkaline pH can induce tearing, discomfort and pain.4,5 A suitable buffer can be used to control and maintain the pH of the eye drops during storage, such as citrate or acetate buffer.
5.Tonicity
Tonicity is defined as the ability of water to enter or exit through a membrane (e.g. cell membrane), via osmosis. The tonicity of the eye drops depends on the concentration of dissolved solutes (e.g. buffer salts and the active pharmaceutical ingredient). Ideally, the tonicity of eye drops should be similar to natural tears, which have a tonicity equal to 0.9% saline. In general, a range of 0.5–2% saline tonicity is well tolerated by most patients. Hypertonic solution (higher than the tonicity of 0.9% saline) can cause tearing. This increase in tear flow reduces the concentration of the drug in the eye, leading to reduction of drug efficacy.3,6 Hypotonic solutions (lower than tonicity of 0.9% saline) do not cause tearing, but might cause ocular discomfort.
6.Preservatives
The addition of preservatives to multi-dose eye drops is crucial to prevent secondary contamination during storage and application.7 Several studies have reported severe ocular infections related to preservative-free ophthalmic preparations prepared in local pharmacy settings.7,8
Selection of suitable and safe preservatives is important.7 Eye drops that are intended for long-term use, e.g. for chronic eye conditions, should ideally be preservative free. These medications are not suitable for local production as they require highly specialised production facilities and special packaging, e.g., single-use packaging that avoids contamination during use. Note: some drugs, such as chlorhexidine, do not require the addition of preservative when prepared in the form of eye drops, because the drug itself acts as a preservative.
7.Stability
The drug should be stable in the selected solvent (e.g., buffer solution or sterile water). The stability of eye drops prepared within hospitals or pharmacies should be assessed according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines to determine the optimum storage conditions and drug shelf life.9 The shelf life (expiration date) should be determined based on the documented stability data and the potential for microbial contamination.
8.The chemical stability of the active pharmaceutical ingredient(s), preservatives, other excipients (non-active pharmaceutical ingredients), and packaging should be considered when assessing the overall stability of the final ophthalmic product.
Packaging and storage of the final product
The final container/packaging should be suitable for ophthalmic use and should not compromise the stability and efficacy of the topical preparation.2
Many compounded ophthalmic eye drops can be packaged in either sterile plastic bottles with integrated dropper tips (a standard eye drop container) or in glass bottles with separate droppers. The stability of some eye drops might be affected by the type of eye drops container used; for example, cyclosporine is absorbed by polyvinyl chloride, a polymer used in some plastic dropper bottles.