Sterile pharmaceutical products processing

In the case of recombinant proteins intended for use in sterile pharmaceutical products, additional process controls on microbiologic aspects of analysis must be established and validated to ensure aseptic conditions throughout the manufacturing process. 

Dry-heat sterilization is generally a less complicated process than steam sterilization it is, however, relatively slow and requires higher temperatures and/or longer exposure times. This is because of the fact that microbial lethality is lower with dry heat than that for steam at the same temperature. There are various temperatures and periods of treatment for dry heat depending on the pharmacopeia. The U.S. Pharmacopeia (USP) states that the dry-heat sterilization process for containers for sterile pharmaceutical products should be at a temperature of 160-170°C for a period of 2-4 hr. The British Pharmacopeia states that items sterilized by dry heat should be kept at a temperature not less than 160°C for at least 1 hr. For the Pharmacopeia Nordica, the recommendation is 30 min at 180°C. Different materials and sterilization equipment used account for the discrepancies between these pharmacopeias, but there is also a lack of sufficient information concerning dry-heat sterilization. ... 

For the production of sterile active pharmaceutical ingredients, section 17 ("Sterile pharmaceutical products") may be applicable to the steps at which the process may have a critical influence on the quality attributes of the finished pharmaceutical product. 

Preparations containing live microbiological organisms should not be made or containers filled in areas used for the processing of other pharmaceutical products however, vaccines of dead organisms or of bacterial extracts may be dispensed into containers, after validated inactivation and validated cleaning procedures, in the same premises as other sterile pharmaceutical products. 

The purpose of open unidirectional airflow benches is to protect products from particulate contaminants by creating a controlled environment. These benches are used, for example, in electronic, biological, pharmaceutical, and food industries. It should be mentioned that within pharmaceutical production, aseptic sterile processes must be carried out in a Class 100 environment (U.S. Federal Standard 209 E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones). To avoid particle contamination in the bench, horizontal or vertical airflow with high-efficiency particulate air (HEPA)-filtered air is used. The air velocity is normally 0.4-0.5 ra s". Some examples of typical arrangements of open unidirectional airflow benches are shown in Fig. 10.51. 

Carbon filters find particular application as prefilters for RO and ion-exchange processes in the production of high purity FW. They are also used in clean-steam boilers and other types of steam generators where the steam is ultimately destined for application in food or beverage production, pharmaceuticals, electronics, surgical instrument sterilization, and similar processes. 

A sterility test is basically a test which assesses whether a sterilized pharmaceutical or medical product is free from contaminating microorganisms, by incubation of either the whole or a part of that product with a nuhient medium. It thus becomes a destructive test and raises the question as to its suitability for testing large, expensive or delicate products or equipment. Furthermore, by its very nature such a test is a statistical process in which part of a batch is randomly sampled and the chance of the batch being passed for use then depends on the sample passing the sterility test. 

In addition to equipment, many processes/procedures undertaken during pharmaceutical manufacture are also subject to periodic validation studies. Validation of biopharmaceutical aseptic hlling procedures is amongst the most critical. The aim is to prove that the aseptic procedures devised are capable of delivering a sterile bnished product, as intended. 

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. 

The purpose of the second edition is to meet the need for a ready-to-use text on the validation of aseptic pharmaceutical production and to provide general information and guidelines. It is a compilation of various theories, sterilization variables, and engineering and microbial studies that can be used independently or in combination to validate equipment and processes. The concepts and methods presented in this edition are not intended to serve as a final rule. Reciprocal methods for achieving this purpose exist and should also be reviewed and consulted, if applicable. 

Application of heat stress to sterilize foods is an old and well-established process but is rather less well developed for pharmaceutical products. Pharmacopoeias of... 

PIC (1989) Guide to Good Manufacturing Practices of Pharmaceutical Products, PIC-Doc PH 5/89 (now PH 1/97 (rev. 2) [7]) Validation of critical processes, significant amendments to manufacturing processes, significant amendments to manufacturing processes, and of all sterilization processes and test methods stipulated. 

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