Saturday, July 9, 2016

Media Fill - Interview Question

Q :What are Interventions in Aseptic manufacturing? and its various types…

Aseptic manufacturing has shown some brilliant improvements scientifically and technically over the past several years, however the pharmaceutical industry is still accepting the aseptic manipulations in the form of human interventions. In this post we are going to know the reason for interventions in aseptic manufacturing and followed by various types with examples.
Def: Interventions are the aseptic manipulations or activities that occur in the critical area (USFDA: Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice)

Q: Why interventions are required in aseptic manufacturing?

Generally, very few operations are often initiated in a click of a button but the majority of the activities involve human interventions to control some of the manual operations like adjusting the machine speed, adjusting fill weights, wiping up the spills, collecting the product samples, clearing the vial jams on the filling lines etc. Each of these processes involve human interventions with the sterilized components and the equipments and thus these shall be simulated as a part of media fill. This is because all interventions prior to or during aseptic manufacturing process poses a greater risk in terms of contamination and hence they shall be controlled and challenged via media fill.

Types of interventions:

There are 03 types of interventions

Inherent interventions:
Also called as routine interventions. These are the interventions that are regularly involved in a manufacturing process like aseptic connections, sterile ingredients addition (stoppers, vials), doors opening and closing etc.

Here is a list of inherent interventions which are needed to be performed in an aseptic operation.

1. Bouncing of vials
2. Clearing of rubber stoppers
3. QA/ Micro sampling
4. Rubber stoppers charging
5. Inprocess fill volume check
6. Door open , closed studies
7. Filling machine assembling
8. Removal of vials without rubber stoppers
9. Clearing of fallen vials on the line
10. Filling needle adjustments to prevent touching the vials
11. Adjustment of filling machine speed
12. Operator Fatigue
13. Shift Change over

Corrective interventions:
Also called as a no routine interventions where few kinds of interventions are not at all routinely involved in an aseptic operation. Interventions like power failure are falls under this category. We need to verify that the maximum possible time for which the entire aseptic area/system is aseptically controlled during the period of power failures.

Similarly, other interventions like increased man power in the aseptic process, fluctuations in area temperature falls under corrective interventions.

Worst case interventions:
This is an optional intervention which can be planned in an aseptic manufacturing process, however care must be taken to avoid contamination of the sterilized components while performing the study. Here is a list of studies which may be performed

a. Hold time of the stoppers, SS items, all other components for 48 hrs after sterilization
b. Manufacturing bulk and filtration bulk hold time
c. Depyrogenated vials before filling hold time

All these interventions that are described above has to be simulated as a part of every media fill to demonstrate that there is no risk involved in terms of contamination while performing such interventions.

Note: The duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions, as well as appropriate consideration of the duration of the actual aseptic processing operation. Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically

Care shall be taken to avoid simulating insignificant interventions in a media fill. For example

Touching the sterile components using non integral gloves
Entering the filling area without disinfecting the hand
There are quite a few number of warning letters issued by the FDA basis the insignificant interventions demonstrated in a media fill.


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