The design of a tableting line able to handle potent APIs in a safe
way requires an in depth understanding of the required level of protection.
Here the specifics of the API, the dilution with excipients, the containment
performance of the equipment and the frequency of operation are the key
parameters which are linked by complex interrelations.
Containment
When talking today about solid dosage form
production, often containment immediately becomes one of the issues. Why? The
first reason is that APIs are becoming more and more potent: meanwhile more
than 50% of all NCE (New Chemical Entities) are classified potent (OEL < 10
μg/m³). Secondly, health and safety authorities all around the world are
putting more focus on the protection of operators dealing with these
substances. The third reason is that suppliers of various hardware components
have developed a huge variety of containment solutions, making it difficult to
decide which is best, even for experienced people.
Regulatory situation
“It is the first duty of the
employer to protect (the health) of his employees.” Even though the regulatory
situation differs from country to country, the above statement (taken from the
UK COSHH rules) should be seen as general guidance when handling potent
substances.
Containment risks
During most of the manufacturing
process, the APIs are inside machines or vessels which are more or less ait
tight. The main risk of material escaping into the environment exists whenever
a connection between those pieces of equipment needs to be made or broken, when
a sample needs to be taken, and when the machines need to be cleaned at the end
of a manufacturing campaign. Before the risks for the operators’ health are
discussed we should also spend some thoughts on the risks of cross
contamination. Even in the best designed multi-product facilities cross
contamination will happen. The critical question is how much cross
contamination is acceptable and how it can be ensured that the real levels of
cross contamination are always below the acceptance limit.
Cross contamination
How much cross contamination
can be allowed is mainly dictated by the potency of the products handled. The
most common definition of an acceptable level is: In the maximum daily dose of
product 2 only 1/1000 of the minimal daily dose of the active of product 1
should be found. If we compare now Paracetamol tablets (4000mg max daily dose)
with typical oral contraceptives (containing 0,02 mg as a maximum daily dose)
we see that the acceptable level of cross contamination in case 2 is by a
factor of 200.000 higher than in case 1. Common ways to reduce the level of
cross contamination in multi product facilities include separate production
rooms, air looks and pressure cascades. These are fine for less critical
products but when highly potent substances are handled, strict containment is
the only way to protect both the operators’ health and the other products.
How much containment is required?
In an ideal
world operators would not be exposed to a single molecule of a harmful
substance, but in the real world, this is simply not possible. Three main
factors dictate how much containment is required and, therefore, which method
of containment is best: the nature, especially the potency, of the API handled
is of paramount importance; the type of process to be executed; and lastly the
working regime of the operators.
The product
The
potency of a substance is, in most cases, characterized either by the OEL
(Occupational Exposure Limit) or by the ADI (Acceptable Daily Intake). The ADI
describes the absolute amount of a specific drug substance that an operator can
absorb without any negative effect on health. The OEL describes the maximum
concentration of a drug substance which can be tolerated in the air of the
production room, without any negative effect to the health of the operators.
For established substances, these values are listed in textbooks such as ISBN
07176 2083 2 EH40/2002 OEL 2002 & ISBN 07176 2172 3 EH 40/2002 Supplements
2003. According to those, the OEL for Paracetamol is 10 mg/m³, while the OEL
for Ethinyl estradiol is 35ng/m³. It is important to understand that these
values are based on certain assumptions. Also, the values might change during
the lifecycle of a substance especially after more toxicological data is
generated.
The equipment
Suppliers not specialists in the field often try to promote ’their
containment equipment’ with claims such as “3 µg/m³”, “better than 1µg” or even
worse “OEL 2 µg/m³”. All of these claims are meant to describe the containment
performance of equipment such as extraction booths or containment valves. While
the last claim obviously is wrong (OEL is a product-related number, it only has
the same unit as the containment performance of a piece of equipment), the
problem of the other claims is that the test conditions are not defined. This
makes it extremely difficult to compare figures obtained by using different
test materials, different samplers, different sampler positions or different
analytical procedures.
After designing the first split-valve technology,
GEA Buck®
Valve again took the lead to form (under the umbrella of
ISPE) an expert working group, consisting of experts from
pharma companies, engineering companies and containment equipment suppliers.
This group developed a
guideline in which all of the variants discussed
above are defined.
Based on the understanding of the above GEA Pharma
Systems has the proven ability of creating out of its world class technical
solutions a most appropriate production line.