Finishing of Sterile Products

The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance bears a particularly great importance, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test. 

In the manufacture of sterile products, it is not sufficient that the finished product should meet the requirements of the quality control. The method of manufacture is of particular importance. Low bioburden of starting materials should be assured, and during the manufacture, the manufacturing area, personnel equipment and intermediate products should be controlled by microbiological tests. 

Sterilization of the finished drug delivery formulation is an important consideration often overlooked in the early design of lactide/glycolide delivery systems. Aseptic processing and terminal sterilization are the two major routes of affording an acceptably sterile product. Both of these methods are suitable for products based on lactide/glycolide polymers if proper care is exercised in processing or selection of the treatment procedures. 

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. 

For nonpharmacopeial materials a full specification should be included in the application. This should include appropriate tests and requirements for physical characteristics, identification, relevant purity tests, and performance-related tests. Characteristics likely to influence bioavailability of the finished product should be controlled. Routine tests and specifications should be described. Methods should be validated. The material should be fully characterized, with full data on the chemistry concerned and including consideration of the safety of the excipient. Any relevant European Directive requirements or other international specifications should be met, but additional requirements might apply depending on the intended use of the product—e.g., for materials to be used in sterile products. 

The sterilization processes described in the Ph Eur are preferred, especially terminal sterilization in the final container alternative processes have to be justified. All sterilization processes will need to be described and appropriate in-process controls and limits included. Where Ph Eur prescriptions are followed, there should be a statement to this effect in the application. Most of this information should be discussed in the development pharmaceutics section. Reference is made to the specific guidelines on ethylene oxide sterilization and irradiation sterilization, which are discussed further below. The possibility of parametric release for terminal processes such as saturated steam and irradiation is mentioned (see below). For all sterile products there should be a sterility requirement included in the finished product specification regardless of the outcome of validation studies. 

Samples of drug product are sampled for sterility testing per manufacturing site SOP, Collection of Finished Product Samples, included as (provide reference attachment number). 

Sterilization by filtration is a major unit operation used in aseptic processes. Aseptic processes require the presterilization of all components of the drag product and its container. Then all of the components are brought together in a controlled aseptic environment to create the finished sterile product sealed within its container/closure system. The level of sterility attained by an aseptic procedure is a cumulative function of all the process steps involved in making the product. Therefore, the final level of sterility assurance for such a product cannot be greater than the step providing the lowest probability of sterility. Each step in the aseptic process must be validated to known levels of sterility assurance [43],... 

The nature of the primary contaminating product—The nature of the primary potentially contaminating product refers to how the product is administered to the patient. Is the product a finished pharmaceutical dosage form or is it a precursor or chemical intermediate that will be used as a starting material by other companies to manufacture finished products Are the products sterile or nonsterile What is the route of administration of the product (e.g., oral, topical, intravenous, ophthalmic) The answers to these questions will dictate the actual calculations to be used to determine acceptable limits. 

How the product will be used by the patient or the customer—Here again our industry is so diverse that we must indicate that the limits calculated should take into account the nature of the customer. Is the customer another company that uses the product, which may be a chemical, to make another intermediate, or is the customer the patient who actually takes the product in the form of a finished pharmaceutical dosage form Is the product a sterile product and do we need to consider bacteria as a potential contaminant or is the product a nonsterile product in which bacterial contamination may be a lesser issue If the product is a finished pharmaceutical dosage form, will it be used intravenously, orally, ophthalmically, topically, rectally, vaginally, or by other means ... 

Packaging is vital in maintaining the state of a sterile product up to the moment that the packaging is opened for withdrawal or use of the product. The regulator-ies expect manufacturers to test finished packages to confirm package strength,... 

Product behavior for a sterile product in manufacturing is also influenced by the conditions imparted due to requirements for aseptic processing. Materials prepared under laboratory conditions in a development environment are typically processed differently than in a manufacturing environment. For example, the level of cleanliness and bioburden are different. Product attributes, such as the nucleation and crystal growth of ice, would occur at different temperatures and rates. This has an influence on product behavior during processing and finished product attributes, as discussed earlier. 

Although bacterial endotoxins are of microbiological origin, they are not lost with loss of viability. Of the sterilization processes commonly used in the manufacture of sterile parenteral dosage forms (see above), only dry heat is capable of destroying bacterial endotoxins in a reasonable time frame. There is therefore no practical way of removing bacterial endotoxins from finished drug products thus, they must be controlled at source. 

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