Sterile parenteral product

Filter media are not repetitive-use items, and although used for more than one lot in production, the media are usually discarded after some predetermined number of uses or time. Therefore, it is impossible to test every filter medium individually, since the challenge test is a destructive test. The nondestructive tests, therefore, require a high degree of correlation with a retention test. When such correlated tests are established and controls maintained, filtration users can depend on filtration to produce a sterile parenteral product. 

Terminally sterilized parenteral products have a level of SA in the range of 0.999999. If we assume that our example solution has 100 organisms per liter, how much could we fdter before the SA dropped below 0.999999 By using Eq. (37)... 

Sterility is defined as the total absence of all viable life forms. Parenteral products and ophthalmic products are expected to be sterile. Parenteral products must be sterile because their route of administration overrides the body s external physical barriers to infection. Ophthalmic products must be sterile because eye damage is often irreparable. No distinction can be made between microorganisms that are known to be specific causative agents of disease and those that are not. 

Although there are many sterilization processes used in association with the manufacture of sterile drug products, the three primary processes are steam sterilization, dry heat sterilization, and sterile filtration. Dry heat sterilization is, in the context of the manufacture of sterile parenteral products, a subset of dry heat depyrogenation (see the following). 

No discussion of maintenance of sterility is complete without addressing multiple-dose ophthalmic presentations. The normal circumstances for sterile parenteral products are that they are unit dose or, if multiple dose, they are penetrated only by sterile transfer devices (syringes, giving sets, etc.) and used on one patient only. This is not the case for ophthalmic ointments and drops unit-dose presentations are quite unusual and generally used only in hospital practice, for example, after eye surgery. 

Water used in manufacture of sterile parenteral products must comply with pharmacopeial limits for endotoxin of no more than 0.25EU/ml (limits in the USP and PhEur for water for injection). In principle water complying with this limit can be produced by... 

Fig. 6 Flow diagram illustrating the various processes in sterile parenterals production.

The objectives of this chapter are to give aspiring formulation scientists a brief yet useful and meaningful overview of conventional parenteral technology as it is applied today and the development of new delivery systems of biopharmaceutical drugs to yield successful, sterile parenteral products for human and veterinary use. 

The performance of pMDIs and DPIs is scrutinized in terms of efficiency and reproducibility of dose delivery, particle size, and distribution under a range of storage conditions, with respect to temperature and humidity, for extended periods of time (up to 2 years).50 Since nebulizer products do not bring the device in contact with the drug until the point of use, a slightly different approach is taken to their approval. Recommended devices and conditions of operation for the delivery of a particular drug must now be stated. The solution formulation is then viewed as a sterile parenteral product and requires concomitant testing. 

This colorless but clear definition of parenteral products has pretty well universal acceptance and is likely almost timeless as well current United Slates FDA thinking is that no new forms of presentation of sterile parenteral products are likely to be approved without strong justification of their being of benefit to the patient. Commercial rntBons are not acceptable. 

Table 1 lists some examples of sterile parenteral products classified as LVPs or SVPs, as a.septically filled or terminally sterilized, and as solutions, suspensions, or solid dosage forms. 

The therapeutic application of sterile parenteral products is almost boundless. Some products can only be administered via the parenteral route others may be administered orally, as suppositories, iniranasally, etc. This begs the... 

Table 1 Some Examples of Sterile Parenteral Products...

Sterile Epinephrine Ophthalmic Solution USP takes us out of the realm of sterile parenteral products into ophthalmics. The manner of presentation of ophthalmics (i.e., as drops or ointments) is likely to be quite familiar. For the most part (but not exclusively) they are in multidose presentations. As such, most formulations include some form of preservative to control proliferation of any microorganisms that may by chance contaminate the product on one or other of the occasions when it is open, or during the time when it is left standing on the bathroom shelf. The inclusion of preservatives in a multidose formulation of an ophthalmic (or parenteral) is not a primary part of the process of achieving sterility. It has quite a separate purpose. 

Terminally sterilized parenteral products are therefore usually manufactured under conditions very similar or even identical to those of aseptic manufacture. 

Specific details of the sterility testing of parenteral products, ophthalmic and other non-injectable preparations, catgut, surgical dressings and dusting powders will be found in the British and European pharmacopoeias. 

In contrast, parenteral suspensions have relatively low solids contents, usually between 0.5 and 5%, with the exception of insoluble forms of penicillin in which concentrations of the antibiotic may exceed 30%. These sterile preparations are designed for intramuscular, intradermal, intralesional, intraarticular, or subcutaneous injection. Syringeability is an important factor to be taken into consideration with injectable dosage forms. The viscosity of a parenteral suspension should be sufficiently low to facilitate injection. Common suspending vehicles include preserved isotonic saline solution or a parenterally acceptable vegetable oil. Ophthalmic and optic suspensions that are instilled into the eye/ear must also be prepared in a sterile manner. The vehicles are essentially isotonic and aqueous in composition. The reader should refer to Chapter 12 for further discussion on parenteral products. 

Like all parenteral products, parenteral emulsions are required to be sterile, isotonic, nonpyrogenic, nontoxic,... 

Large-volume parenterals designed to provide fluid (water), calories (dextrose solutions), electrolytes (saline solutions), or combinations of these materials have been described. Several other specialized LVP and sterile solutions are also used in medicine and will be described here, even though two product classes (peritoneal dialysis and irrigating solutions) are not parenteral products. 

Many dry solid parenteral products, such as the cephalosporins, are prepared by sterile crystallization techniques. Control of the crystallization process to obtain a consistent and uniform crystal form, habit, density, and size distribution is particularly critical for drug substances to be utilized in sterile suspensions. For example, when the crystallization process for sterile ceftazidime pentahydrate was modified to increase the density and reduce the volume of the fill dose, the rate of dissolution increased significantly. 

Five sterilization processes are described in the USP steam, dry-heat, filtration, gas, and ionizing radiation. All are commonly used for parenteral products, except gas and ionizing radiation, which are widely used for devices and surgical materials. To assist in the selection of the sterilization method, certain basic information and data must be gathered. This includes determining... 

Dry heat is widely used to sterilize glassware and equipment parts in manufacturing areas for parenteral products. It has good penetration power and is not as corrosive as steam. However, heat-up time is... 

People are the principal source of contamination in clean room operations. All personnel involved throughout the development and production of a parenteral product must be aware of the factors that influence the overall quality of a product as well as the factors on which they directly impinge. It is of particular importance that production personnel be properly trained so that human error is minimized. They should be made aware of the use of the products with which they are involved and the importance of following all procedures, especially proper aseptic techniques. Procedures must be set up to verify that the product is being manufactured as intended. After manufacture of a batch, production tickets must be carefully checked, sterilization charts examined, and labels verified for correctness and count. 

Process controls include daily testing of water for injection (USP), conformation of fill doses and yields, checking and approving intermediate production tickets, and checking label identity and count. Finished product control includes all the tests necessary to ensure the potency, purity, and identity of the product. Parenteral products require additional tests, which include those for sterility, pyrogens, clarity, and particulate analysis, and for glass-sealed ampoules, leaker testing. 

C. Parenteral Products (Injections, Powders for Injection, Concentrates for Injection, Sterile Implants)... 

Parenteral drug products are required to be sterile. There are principally five different ways to sterilize a product. These are steam, dry heat, radiation, gas. 

According to 211.113 Control of microbiological contamination, pharmaceutical manufacturers need written procedures describing the systems designed to prevent objectionable microorganisms in both nonsterile and sterile drug products. All sterilization processes used to manufacture parenteral drugs need to be validated. 

Category I la. Injections, other parenterals including emulsions, otic, sterile nasal products, and ophthalmic products made with aqueous bases or vehicles... 

The basic principles employed in the preparation of parenteral products do not vary from those widely used in other sterile and non-sterile liquid preparations. However, it is imperative that all calculations are made in an accurate and most precise manner. Therefore, an issue of a parenteral solution scale-up essentially becomes a liquid scale-up task, which requires a high degree of accuracy. A practical yet scientifically sound means of performing this scale-up analysis of liquid parenteral systems is presented below. The approach is based on the scale of agitation method. For singlephase liquid systems, the primary scale-up criterion is equal liquid motion when comparing pilot-size batches to a larger production-size batches. 

Any material introduced into the body, human or animal, parenterally (that is para-enteron or beyond the gut ) must be sterile because the body defenses have been bypassed. This concept is absolute in the sense that one cannot have partially sterile —a product is either sterile or not. Sterility means rendered free of living microorganisms (The Shorter Oxford Dictionary, 1993) or, quoting the United States Pharmacopeia (USP) 28 (2005), completely free of viable microbial contamination. ... 

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