Some Practical Aspects - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 126

combination, there exists an optimum freeze-drying cycle that can be
estimated from measurements of physico-chemical parameters. Any
attempts at corner cutting should be discouraged; they always run a risk
of product quality downgrading. Saving one day in the production cycle
will be a false economy if it results in halving of the product's shelf life.
Inspectors nowadays increasingly ask for cycle justifications, even for
products that have been manufactured and sold without problems for a
number of years. Rational formulation and process development and
transparency in the documentation will result in a process that can
be justified to both the company accountants and the regulatory
authorities.

10.3 Vial Closure and Packaging

In the early stages of product development, vials are typically filled
manually, and stoppers are partially inserted by hand, prior to freeze-
drying. On a production scale, these processes are automated and line
trials must be carried out to ensure that appropriate adjustment can be
made to allow both vials and stoppers to move freely along the lines
without incident and for stoppers to be accurately and reproducibly
inserted prior to loading. The design of reliable and effective stoppering
devices and mechanisms is of the utmost importance and this aspect has
been treated in several monographs. 115
If siliconised stoppers are used, typically a minimum silicone loading
would be sought that would allow movement along the lines whilst not
producing haze in the reconstituted final product. On a small scale,
mismatching of stoppers and vials would typically be of little conse-
quence. After stoppering, vials are quickly removed from the drier and
aluminium overseal crimps are applied by hand. Stopper lifting would
not generally be a problem, since sterility may not be an issue and any
leaks will be quickly dealt with when the overseal is applied. In a large-
scale process, even a small percentage of stopper lifting is a serious issue,
as would also be any breach of sterility. Accordingly, the designs of both
stoppers and vial necks may contain a number of features that are not
immediately obvious but may lead to a potential mismatch.
One such design feature is the ''blowback''. This term refers to part of
the vial neck design with two purposes:

(i) In the vent position, it serves to prevent ''pop-out'' and ''drop-in''.
(ii) In the closed position,

it serves to prevent ''pop-out'' before

sealing.