Parametric release

Annex 16 Certification by a Qualified person and Batch Release Annex 17 Parametric Release... 

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. 

The Ph Eur mentions the possibility of parametric release for certain terminal sterilization processes (saturated steam, dry heat and irradiation) where sterilization parameters can be accurately monitored and recorded and controlled. Much of the information in the two draft documents relates to parametric release of sterile products, but the possibility of parametric... 

Acceptance of parametric release will be on a pro-duct-by-product basis and will involve specific inspections attended by both inspectors and assessors from the regulatory agency concerned. 

Currently the main application of interest for parametric release is to replace the sterility test as a control method in appropriate cases (given the limited value of that test to predict sterility assurance due to statistical considerations, although it is also pointed out that a sterility test provides a final opportunity to identify a major failure, although other means should provide a more reliable way of detecting such failures). The concept is applicable to well-founded methods of sterilization where the product stability is known and development data have identified the critical process parameters. The measured parameters should be such as to ensure that correct processing of the batch provides sufficient assurance that the sterility assurance level intended has been achieved. 

The draft guidelines give considerable information on how an applicant can submit relevant data to request parametric release. However, since this is unlikely to be accepted until considerable manufacturing experience of the product concerned has been gained, it is probable that this will be submitted as a later variation application rather than in an initial marketing authorization application. 

CPMP/QWP/2431/98 Concept paper on the development of a CPMP note for guidance on parametric release (November 1998) CPMP/QWP/3015/98 draft Note for guidance on parametric release (released for comment April 2000)... 

If PAT is to make a stronger contribution to the production of biofuels and of other non-health bioproducts, one area that needs to move forward is the acceptance by standards monographs (e.g., ASTM) of some PAT monitoring tools (e.g., parametric release of biodiesel with NIR). For instance, accepted and proven techniques for release of many solid dosage forms and other medicines are still not accepted in the biofuels area. 

Parametric release testing was defined by the European Organization for Quality [38] as an operational alternative to routine release testing where samples are taken from every finished batch for testing in accordance with the release specifications. This approach has been used successfully in Europe and the United States for a validated terminal sterilization. The European Pharmaco-... 

Committee for Proprietary Medicinal Products. EMEA Draft Guidance on Parametric Release—C. Int. Pharm. Regulatory Monitor, Lanham, MD (May 2000). 

The quality control of the final product must be carried out before release of the batch (except for the sterility and the endotoxin tests for extremely short-lived radionuclides). Consequently, all procedures must not only be very fast but also very accurate, and in all cases it is very important to have a properly established quality assurance system that might permit parametric release of the produced batches. The quality control assays that must be carried out in the radiopharmaceutical includ the following ... 

Injectable products, ophthalmic products, and inhalation solutions Pharmaceutical ingredients Purified water Manufacturing environment Products As above Loop and taps daily Every shift in critical aseptic processing areas Every batch with the exception of terminally sterilized products approved for parametric release... 

All injectable and ophthalmic products with the exception of terminally sterilized product subject to parametric release should undergo Sterility Testing at release. 

Clearly reproducibility, regular monitoring and documentation are required. However, parametric release would imply abandoning the sterility test, an option that many manufacturers have not yet adopted, possibly because of the fear of litigation based on the premise that any sterile product would, if tested, have passed the test for sterility. 

In well-understood and well-characterized sterilization processes (e.g. heat and irradiation), where physical measurements may be accurately made, sterility can be assured by ensuring that the manufacturing process as a whole conforms to the established protocols for the first three of the above headings. In this case the process has satisfied the required parameters thereby permitting parametric release (i.e. release based upon process data) of the product without recourse to a sterility test (see Chapter 19). 

Sterility. This is a critical test for parenteral products. Where data generated during development and validation justify parametric release, this approach may be proposed for terminally sterilized products. 

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