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ABSTRACT then filled with drug solution and sealed in ration of all ophthalmic dosage forms is
Ophthalmic preparations are sterile one operation. Blow-fill-seal-technology that they are sterile.
liquid, semi-solid, or solid preparations has a theoretically lower risk of microbial
intended for application to the conjunc- contamination compared with convention- This paper considers the key elements
tiva, the conjunctival sac, or the eyelids. al aseptic filling. Quality control of these relating to the manufacture of ophthalmic
Sterility is a key issue in manufacture and products includes traditional tests such as products from the perspective of microbi-
use of ophthalmic products. Preservative identification, potency, purity, impurities, al contamination control. Its focus is upon
selection is a critical activity in product sterility, and particulate matter and per- the aseptic dispensing of the products and
design. Other important aspects requiring formance tests such as dissolution or drug environmental and technological require-
assessment in the manufacture of ophthal- release. Physical or chemical instability will ments including blow-fill-seal filling and
mic products include sterility, tonicity, pH, be demonstrated by noticeable changes in container sealing systems.
buffering, drug toxicity, solubility, stabili- the dosage form such as changes in color,
ty, viscosity, aseptic filling, packaging and consistency, agglomerates, grittiness, emul- PRESERVATIVE SELECTION
storage. Microbial content or bioburden sion breakdown, crystal growth, shrinking The first contamination-related consid-
of the raw materials, in-process intermedi- due to evaporation of water, or evidence eration is with the selection of the preserva-
ates, and drug substance or active product of microbial growth. The finished product tive and its efficacy. An ideal preservative is
ingredient are potential sources of con- must also be subject to the sterility test and a rapidly effective and topically non-irritat-
tamination and require incoming testing endotoxin tests. ing. It may be a single antimicrobial agent
of ingredients. Most ophthalmic products or a mixture of such agents. Preservatives
are sterilized by aseptic filtration through INTRODUCTION are designed to prevent the growth or to
a 0.22-μm filter. Preservatives in the oph- Ophthalmic preparations (eye prepara- destroy microorganisms accidentally intro-
thalmic solution will, to varying degrees, tions) are sterile liquid, semi-solid, or solid duced into the product when the container
bind or be adsorbed onto many common preparations that may contain one or more is opened during use. Preservatives are a
membrane filter materials. Most commer- active pharmaceutical ingredients. Oph- necessary additive.
cial liquid ophthalmic products are pack- thalmic products are intended for appli-
aged in plastic containers fitted with noz- cation to the conjunctiva, the conjunctival There are several critical considerations
zles for drop wise administration. Plastic sac, or the eyelids. The course of treatment in selecting a preservative for inclusion in
containers are generally sterilized by gam- may extend during several days. Although the dosage form. These include preserva-
ma irradiation or ethylene oxide. Facilities eye preparations contain a preservative, tive stability, chemical compatibility with
used to prepare ophthalmic preparations there is a probability of microbial contam- the other components of the formulation,
are required to operate within a controlled ination after the package sterility seal has compatibility with packaging materials,
environment using HEPA filtration to min- been broken during the period of use. and concentration. Preservative agents
imize contact of airborne contamination must to be effective throughout the entire
with critical sites such as open product These forms of medication must be ad- shelf life of the product (1). Common pre-
prior to application of closures, injection ministered directly to the eye because many servatives used with ophthalmics include
ports, and vial septa. Aseptic filling oph- of the ingredients such as peptides, pro- benzalkonium chloride (BAK), parabens,
thalmic medications is typically achieved teins, and chemotherapeutic agents would potassium sorbate, chlorhexidine acetate,
through the use of blow-fill-seal (BFS) be inactivated in the gastrointestinal tract chloroscresol, and polyhexamine gluconate
technology in which product containers are if they were taken orally. The issue of over- (2). A preservative will only provide pro-
formed from plastic granules on-line and riding importance in relation to the prepa- tection from microbial growth for a short
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Tim Sandle
time period. For this reason, pharmacists principles and methods (8) Process Controls
usually recommend disposal of most types • ISPE Baseline Guide to Sterile Manu- The microbial content or bioburden of
of eye drops 28 days after the product is facturing Facilities (9). the raw materials, in-process intermedi-
opened. ates, and drug substance or active product
In addition, the European Pharmaco- ingredient is important. These materials
REGULATORY AND COMPEN- peia describes “Methods of Preparation of are potential sources of contamination. In-
DIAL REQUIREMENTS FOR Sterile Products” in Chapter 5.1.1. coming testing of these ingredients are an
OPHTHALMIC PREPARATIONS important part of overall microbiological
The European Pharmacopeia does MANUFACTURE control and cleanliness of the manufactur-
not include any specific chapters on the There are a number of important aspects ing process.
manufacture of ophthalmic preparations, that require assessment in the manufacture
although the monograph on eye prepa- of ophthalmic products. These include the Throughout manufacturing, certain
rations includes a short section on produc- following (10, 11): procedures should be monitored by car-
tion (01/2008:1163). However, guidance • Sterility rying out appropriate in-process controls
is provided in the United States Pharma- • Tonicity during the actual manufacturing process.
copeia in the form of USP general chapter • pH and buffering These should be designed to guarantee the
Ophthalmic Ointments <771>. This chap- • Inherent toxicity of the drug effectiveness of each stage of production.
ter addresses some of the parameters and • Need for a preservative In-process controls during production of
characteristics relating to the preparation • Solubility ophthalmic preparations should include
of ophthalmics, such as added substances, • Stability in an appropriate vehicle monitoring environmental conditions
containers, metal particles and leakage (3). • Viscosity such as particulate and microbial contam-
In the future, the performance tests (dis- • Aseptic filling ination; bioburden testing, assessment of
solution and drug release) for ophthalmic • Packaging and storage of the finished pyrogens, pH, and clarity of solution. Bac-
preparations will included in a new general product. terial endotoxin contamination presents a
chapter titled Ophthalmic Preparations— serious theoretical risk. Use of the Limulus
Performance Tests <1771>. This is intend- Water for Injection (WFI) should be amoebocyte lysate (LAL) test is advanta-
ed for issue in 2015. used in the manufacture of aqueous oph- geous as an analytical tool. The integrity of
thalmic drops. The above topics are dis- the container including absence of leakage,
In addition, there are a number of guide- cussed below. etc., is an important consideration. Appro-
lines available in relation to aseptic filling, priate limits should be set for the particle
the usual method of preparation of oph- Processing size of the active ingredients.
thalmic dosage forms. Aseptic processing The preparation of aqueous ophthal-
is highly regulated and there is considerable mic drops requires careful consideration Sterile Filtration
guidance in the US Code of Federal Regu- of several physico-chemical factors. These When an ophthalmic preparation is
lations (CFR 21, such as CFR 21 Sub-part C include the need for isotonicity, a certain compounded from a non-sterile ingredient,
(211.42)), FDA documents, and in the EU buffering capacity, the desired pH, the ad- the final product must be sterilized. Steril-
GMP “Rules and Guidance for Pharmaceu- dition of antimicrobial agents and/or an- ization by autoclaving in the final container
tical Manufacturers and Distributors” (4). tioxidants, the use of viscosity-increasing (terminal sterilization) may be possible for
Nonetheless, regulatory guidance is limited agents, and the choice of appropriate pack- some products if product stability is not
to the basic principles expected of pharma- aging. Ophthalmic drops are considered adversely affected and appropriate quality
ceutical manufacture. There are aspects isotonic when the tonicity is equal to that control procedures are followed. In most
which are open to interpretation or that be- of a 0.9% solution of sodium chloride. The cases, however, product stability concerns
come part of current Good Manufacturing eye can usually tolerate solutions equiva- necessitate aseptic filling of product.
Practice (cGMP). lent to 0.5-1.8% of sodium chloride. The
pH of ophthalmic drops should be equiva- Prior to the aseptic filling of the oph-
With aseptic filling, the principal sourc- lent to that of tear fluid, which is pH 7.4. To thalmic preparations, the bulk solutions
es of guidance are: achieve this, buffer may need to be added must be sterilized. Filtration of the prepa-
• FDA Guidance for Industry 2004 on to the preparation. The decision to add a ration through a 0.22-μm filter into a sterile
Drug Products Produced by Aseptic buffering agent should be based on stability final container is the most commonly used
Processing (5) considerations. The pH selected should be method. Such filters can remove most bac-
• USP <1116> Microbiological Control the optimum for both stability of the active teria and fungi, but not all viruses or myco-
and Monitoring of Aseptic Processing pharmaceutical ingredient and physiologi- plasmas. Fibre-shedding characteristics of
Environments (6) cal tolerance. If a buffer system is used, it filters should be minimal. The integrity of
• ISO 13408 Aseptic Processing of must not cause precipitation or deteriora- the sterilised filter should be verified before
Healthcare Products (7) tion of the active ingredient. The influence use and should be confirmed immediately
on the lachrymal flow should also be con- after use by an appropriate method such as
• ISO 14698-1. Cleanrooms and associ-
sidered. a bubble point, diffusive flow, or pressure
ated controlled environments–Biocon-
hold test.
tamination Control’: Part 1: ‘General
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Tim Sandle
units are purpose-built machines in which, ingredients or preservatives are absorbed test is justified, other supporting analytical
in one continuous operation, containers by the plastic, which affects product content procedures should be used to achieve over-
are formed from a thermoplastic granulate, and stability (21). Hence it is important to all specificity.
filled with the pharmaceutical preparation, understand the interaction of ophthalmic
and then sealed by a single automatic ma- antimicrobial preservatives with BFS pack- The preservative used in any ophthalmic
chine (14). Blow-fill-seal-technology has a aging in the event that adsorption levels are product must be evaluated. While it is not
theoretically lower risk of microbial con- high. Adsorption is a concern for both ac- necessary to perform testing on a batch-by-
tamination compared with conventional tive drug and preservatives (22). A further batch basis, the preservative used in each
aseptic filling. BFS is an automated process potential disadvantage is that the operation product must be assessed as part of prod-
where containers are formed, filled and can suffer many process interruptions aris- uct development. The test must be repeat-
sealed in a continuous operation without ing from burnt containers (23). ed should any changes to the formulation
human intervention. This is performed in of either the preservative or the product
an aseptic enclosed area inside the BFS ma- PRODUCT STERILITY occur. In addition, the test should be re-
chine. Aside from the demonstrable efficacy of run at regular intervals. Preservatives must
the product, sterility is the most import- meet the requirements of Antimicrobial Ef-
The BFS process begins with a pharma- ant issue given the route of administration fectiveness Testing.
ceutical-grade plastic resin being is ver- of ophthalmic (24). The manufacture of
tically heat-extruded through a circular sterile products, like ophthalmics, is not The compendial Antimicrobial Effec-
throat to form a hanging tube called the straightforward and microbial contami- tiveness Test (AET) is essentially a sus-
parison. This extruded tube is then en- nation control needs to play an essential pension test designed to demonstrate the
closed within a two-part mould, and the role. There are severe risks for patients if extent of microbial kill. The AET test com-
tube is cut above the mould. The mould sterile products become contaminated. prises a controlled inoculum of the chal-
is transferred to the filling zone or sterile Risks to patients with ophthalmic products lenge organisms is placed in suspension
filling space where filling needles mandrels include serious infection, blindness, and with the preservative sample to be tested,
are lowered and used to inflate the plastic even death. Ocular infections and loss of and the number of survivors determined
to form the container within the mould. vision caused by contamination of extem- at different time points. Key aspects of
Following the formation of the container, poraneously prepared ophthalmic prod- the test are with developing a method for
the mandrel is used to fill the container ucts have been reported (25). Enhancing neutralisation of the preservative. Residu-
with liquid. After filling, the mandrels are the probability of sterility is gained through al preservative in the recovery agar could
retracted and a secondary top mould seals environmental controls during manufac- artificially depress the recovery of viable
the container. All activities take place in- ture – building quality into the process. cells. It is thus important to neutralize this
side a sterile shrouded chamber inside the Sole reliance must not be placed on the residual activity to get accurate counts of
machine. The product is then discharged end-product sterility test. Final product survivors (26).
to a non-sterile area for labelling, packag- sterility testing has several weaknesses in-
ing and distribution (15, 16). cluding low statistical certainty of detecting A further quality control test of impor-
contamination. tance is measurement of pH (27). The pH
Microbial contamination of containers and buffering capacity of an ophthalmic
during BFS manufacturing is normally very MONITORING AND CONTROL preparation are important for preservation
low (17). However, there are a number of There are a number of quality attributes since the stability of most commonly used
variables that can influence the possibili- that must be considered for the manu- ophthalmic drugs is largely controlled by
ty of a container becoming contaminated facture and release of ophthalmic prod- the pH of their environment.
(18). These include the effects on the rate ucts. Procedures and acceptance criteria
of vial contamination of systematic chang- for testing ophthalmic preparations are Each vial of finished product must be
es in the process variables, rate of provision divided into two categories. Traditional subject to visual inspection. The inspection
of ballooning air, delay in the application quality control tests assess general quality should focus on cracks or abrasions to the
of mould vacuum, and duration of transfer attributes such as identification, potency, vials and evidence of any particulate matter
of the open vial. A relationship has been purity, impurities, sterility, and particulate in solution products. Suspension dosage
established between the level of airborne matter. Performance tests assess in vitro forms containing dispersed solid particles
microorganisms in the machine operating product performance such as dissolution are obviously not tested for solution clarity.
environment and the extent of product or drug release of the active drug sub- The packaging system should be closed or
contamination (19). stance from the drug product. Both quality sealed to prevent contamination or loss of
and performance tests assure the identity, contents. Evidence of physical or chemical
One advantage with blow-fill-seal prod- strength, quality, purity and efficacy of the instability will be demonstrated by notice-
ucts is that they are less fragile and lighter drug product. able changes in the dosage form. For exam-
to transport than glass containers. Another ple, change in color, change in consistency
advantage of the process is that the equip- A specific and stability-indicating test such as excessive “bleeding” (separation of
ment is amenable to cleaning and sanitisa- should be used to determine the potency excessive amounts of liquid), formation of
tion using automated steam-in-place sys- strength (content) of the drug product. In agglomerates or grittiness, emulsion break-
tems (20). However, sometimes the active cases when the use of a non-specific assay down, crystal growth, shrinking due to
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