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•Parenteral products are radically different from other dosage forms in terms of standards of purity and safety.
•Apart from complying with standards of potency and stability, parenterals have to meet exacting standards of microbial (sterility and pyrogens), physical (particulate matter), and chemical (isotonicity, buffering capacity, etc.) parameters.
Various layers of protection in a typical Parenteral manufacturing process.
Terminal Sterilization• In 1991 USFDA proposed that all sterile products
should be terminally sterilized, unless data were available to prove its adverse effects on product stability . This was primarily due to the fact that all product recalls during 1981 to 1991 involved aseptically processed products .
• Certain drug classes, such as biologics, multidose ophthalmic products, and dispersed systems, are exempt from this.
• The most commonly used technique for terminal sterilization is autoclaving, which makes use of saturated steam.
• Compendial cycles for autoclaving in USP/EP/BP prescribe a 15-minute exposure at 121°C.
The most heat resistant microorganism actually contaminating the formulation—or Bacillus stearothermophillus because of its high heat resistance—is used as a standard microbe for development of autoclaving cycles.
New Techniques of Terminal Sterilization:There is a strong need to develop terminal sterilization techniques that can help in achieving acceptable Sterility assurance level without causing damage to the product.
• PurePulse® Technologies USA has developed a technique called Pure Bright sterilization.
• It uses broad-spectrum pulsed light (BSPL) to effectively inactivate bacterial organisms and spores in static and flowing solutions, as well as on dry surfaces.
• BSPL generated from xenon lamps contain visible, infrared, and UV wavelengths in ratios similar to sunlight.
• The major difference from sunlight is that the UV wavelengths are removed due to filtration by Earth’s atmosphere.
• Rapid intense pulses of BSPL are used for inactivation of pathogens.
ASEPTIC PROCESSING• Aseptic processing involves filling of pre-
sterilized formulations into cleaned and pre-sterilized primary packaging components.
• In absence of any post-filling sterilization step, the SAL of finished product is a direct function of SAL of individual components.
• Many aseptically manufactured presentations, especially multi dose products, contain preservatives that serve a dual purpose of
(a) providing antimicrobial activity and(b) preventing proliferation of any microbe
that might contaminate the product during repeated use.• Sterility assurance levels for aseptic processing
is determined by performing media fill trials
Sources of Contamination and Control Strategy During Aseptic Manufacture
Contributing parameter
Control strategy
Environmental air Passing air supply through High Efficiency Particle Air (HEPA) filters.Laminar air flow (90 feet/min) is used to “sweep away” particles and microbes from the sensitive areas.Environmental air Pressure differentials to protect areas of critical operations.
Contributing parameter
Control strategy
Manufacturingequipment
• For fixed equipment Vacuum cleaner equipped with HEPA filtered exhaust.
• Wet wiping with disinfectant solution for Manufacturing equipment.
• For demountable equipments cleaning and autoclaving should be performed.
Contributing parameter
Control strategy
Formulation andprimary packagingcomponents
• Powders for injection are supplied as sterile by bulk drug manufacturers.
• Liquid products are filtered through sterile 0.22 μm membrane filters.
• Glass vials are cleaned and dry heat sterilized Rubber stoppers are cleaned and sterilized by autoclaving.
Contributing parameter
Control strategy
Personnel • Medical examination to screen personnel working in aseptic area.
• Entry of personnel to aseptic area should be through changing rooms.
• Containment of personnel microbial flora by protective clothing.
• Localized barriers between personnel and areas of filling operations, by means of laminar airflow or by using isolator barriers.
Contributing parameter
Control strategy
Water anddrainage
Purification of water by distillation or reverse osmosis.
Storage of WFI at temperatures >80°C and in vessels fitted with continuous circulation loop.
Efficient drainage at the manufacturing shop floor to prevent accumulation of water.
Blow-Fill-Seal Technology (BFS)BFS technology involves a fully automated
process in which the primary container for the formulation is (a)formed from a thermoplastic.(b)Aseptically filled with filtered solution(c)sealed, in a single operation in a controlled
environment.
• BFS uses an automated process requiring minimal human intervention once the machine settings have been set.
• The formed plastic container is filled with sterile product and instantly sealed, thus avoiding contamination.
• A hermetically sealed bottle formed during the process helps avoid the use of sealing devices like rubber closures and seals.
Formation of blow-fill-seal pack.
• Various thermoplastics like polyethylene (PE), polypropylene (PP), various copolymers and polyalomers are commercially available.
• PP offers distinct advantages by allowing exposure to 121°C for autoclaving. Bottles produced on the BFS machine can be individual or strip-dose formats, in sizes from 0.1 ml to 2000 ml, and outputs as high as 30,000 units/hour can be achieved.
• BFS technology has offered a cost-effective means of Microbial contamination control introducing high-quality aseptically processed products with additional advantage of reduced breakage, reduced hazard of accidental injury, and reduced pack volume over glass containers.
RECENT ISSUES IN STERILIZATION BY FILTRATION
• Sterilization by filtration has traditionally involved use of 0.2/0.22 μm rated filters and Pseudomonas diminuta (now called Brevundimonas diminuta) as the standard challenge organism.
• USFDA defines minimum qualifying area of 107/cm2
of filter area.
• Stressful conditions may affect the changes in the morphology of the microbes.
• In this study,40% reduction in size of Burkholderia pickettii was observed.
• These developments are causing a shift from 0.2/0.22 rated filters to 0.1micron filters.
STERILE PREFILLED SYRINGES (PFS)
• PFS have become a popular packaging system for parenteral products due to their advantages of ease of administration, dosing accuracy, and increased assurance of sterility. PFS consists of a barrel, a plunger rod with rubber fitting, and a luer-lock tip/stainless steel needle.
• The manufacturing process for PFS may involve (a) filling of formulation in previously cleaned and sterilized PFS or (b) cleaning, sterilization, de-pyrogenation of non sterile syringes, followed by filling .
• The filling is carried out in Class 100 area, and other operations can be carried out in Class 10,000/100,000 area.
• Terminal sterilization of PFS by autoclaving poses a unique challenge due to the possibility of rubber plunger migration during the process. This “pop-off” of rubber plunger can be prevented by using autoclaves with a counter-pressure feature.
PROCESS VALIDATION, HAZARD ANALYSIS AND CRITICAL CONTROL POINTS (HACCP)
HACCP involves seven principles: (a)analyzing each step for hazard.(b)Identifying all critical control points
(CCP).(c)verifying the limit for each CCP.(d) verifying monitoring and testing of
limits.(e)verifying corrective actions.(f)verifying operational procedures for CCPs,
and(g)verifying that records of each CCP are
documented in the batch record.
Critical Control Points in a Typical Parenteral Product Manufacturing
Test OrganismThe selection of a biological indicator appropriate for use with a particular sterilization process requires the consideration of a number of factors.
First is identification of the appropriate test organism. The test organisms indicated in Table 1 are generally recognized to exhibit greater resistance to the indicated sterilization processes than typical bioburden.
An example of different biological indicator formats, including spore suspensions, inoculated carriers, paper strip biological indicators, and self-contained biological indicators.
Suspensions and Inoculated Carriers : Aliquots of the test organism are either inoculated directly onto product or onto suitable carriers that are then placed in those locations of the product considered to be the most difficult to sterilize. Following sterilization processing the number of surviving test organisms is determined by either direct transfer to growth medium (fraction-negative analysis) or removal of the test organisms from the product or carrier for direct enumeration.Paper Strip Biological Indicators : This type of biological indicator, consisting of a paper strip carrier inoculated with a suspension of test organisms and packaged in a glassine or Tyvek outer envelope has seen little change since its commercialization during the 1960s.
Self-Contained Biological Indicators : Self-contained biological indicators are widely used in many applications, as they do not require the user to aseptically transfer the inoculated carrier to growth medium.Self-contained biological indicators incorporate both the test organisms and the growth medium within the same unit and are typically of two distinct types.The simplest form of self-contained biological indicators consist of a hermetically sealed glass ampule or vial containing spores of Geobacillus stearothermophilus suspended in growth medium with a pH indicator dye. Following sterilization processing the ampule is incubated and growth of the test organisms detected as a change in the color of the growth medium.
WATER MICROBIOLOGY
PRE TREATMENTS OF WATER
• The principal purification units of distillation, reverse osmosis, ion-exchange, and electrodeionization can purify at least some small quantity of water of any degree of contamination even without pretreatment.
• The question is how much before the particular purification unit is fouled or possibly irreparably damaged.
• Chlorine will rapidly and irreversibly degrade polyamide RO membranes. Chloride ions will cause the corrosion of stainless steels.
Chlorination• As a first step, raw waters are commonly
chlorinated to kill pathogenic microbes. Chlorine concentrations of 1 ppm effect a 97% kill of E. coli in 0.6 minutes at 5–25°C, and 0.5 ppm amounts have the same effect in 7 minues at 5°C. Salmonella and Cholera are killed by 3 ppm.
• When chlorine contacts water it reacts to form hypochlorous acid. HOCl dissociates to yield hydrogen ions, H+ (or hydronium ions, H3O+), and hypochlorous ions, OCl−. The sum of the hypochlorous acid and the hypochlorite ions is called the “free available chlorine.” Hypochlorous acid is about 100 times stronger in its oxidizing potential than is the hypochlorite ion.
chlorine partakes oxidatively in a free radical chain reaction with TOC present in the water to form the carcinogenic trihalomethanes (THM).
REMOVAL OF THMThe trihalomethanes found in feed waters consist of mixtures of chlorine and bromine atoms substituent on the single carbons created by the free radical chain scission reaction of chlorine on longer carbon-to-carbon TOC chains.
Monobromo, dichloromethane Br-CH-Cl2; monochloro, dibromomethane Cl-CH-Br2; bromoform HC-Br3; and chloroform HC-Cl3 constitute the trihalomethanes.
The THMs, except for chloroform, are destroyed to an 85% extent by 185 nm UV.
They are removed by reaction with anion exchange resin in hydroxyl form; chloroform only to the extent of 50%. They are adsorbed by activated carbon in proportion to the surface area of the carbon and increasingly with bromine content; chloroform CHCl3 10%, bromoform CHBr3 50%.
Deep Beds and Multimedia Filtration
• Multimedia bed design is versatile, but there is no ready way to match its available constructions to the TSS, to the total suspended solids contents of given waters.
• Particles too small in size to be retained even by the (bottom) most finely ground, densest medium bed may be present, as also colloidal particles.
• Coagulation and flocculation techniques are then invoked to agglomerate the ultrafine particles to sizes that can be removed by the deep beds.
Cross sections of representative filter particle gradations.
Diagram (a) represents a single medium bed such as a rapid sand filter.The bottom half of a filter of this type does little or no work.Diagram (b) represents an ideal filter uniformly graded from coarse to fine from top to bottom. Diagram (c) represents a dual media bed, with coarse coal above fine sand, which approaches the goal of the ideal filter.
Softening and Solubility Product
Water softening is usually accomplished by way of sodium-form ion-exchange wherein the ion-exchange resin in the softening unit removes the hardness-causing elements from the feed waters by exchanging them for the sodium ions it releases.
This fore-stalls subsequent mineral fouling of the RO by membrane-blocking deposits of alkaline earth salts of limited solubilities, such as the sulfates, carbonates, and fluorides of calcium, barium, or strontium.
The solubility product of a salt is the maximum product of its cation and anion concentration expressed in moles per liter that can exist in equilibrium with its undissolved phase at any one temperature.
