2017 35 32 ChemistryTodayHPAPIfin PDF
2017 35 32 ChemistryTodayHPAPIfin PDF
2017 35 32 ChemistryTodayHPAPIfin PDF
net/publication/321012161
Article in A capillary micro-reactor as a tool to study pressurised reactions The influence of pressure on the stereoselectivity of the Diels-Alder reaction of 2-and 3-Furylmethanol with
maleimides · October 2017
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Abstract The development and transfer of HPAPI manufacturing processes to full production scale presents
particular challenges to a CMO. It is especially important to conduct a full risk analysis including setting
of Occupational Exposure Limits (OELs) for each high potency chemical step. For this we need both reliable toxicity data and a
high level of expertise in toxicology. The risk control strategy defines the equipment and procedures, at both laboratory and plant
scale, in order to run the process safely. We show how this is achieved in practice with the example of a multi-step HPAPI process,
taken from laboratory to routine large scale production. During scale-up and production, the high potency aspects of the process
are continually reviewed in order to improve the safety and efficiency of the process.
Figure 1.
OEB Classification Figure 2. Flow chart for determining OEL/OEB levels.
at Evonik.
The main challenge for the CMO with regard to the hazard
assessment for the process, is the access to the relevant data for
APIs and intermediates which are still in development. If clinical
trials have not yet started, then the drug originator is the only party
having the relevant data and should provide the CMO with all
available data on bioavailability, toxicology and pharmacology.
This information is treated confidentially and only circulated within
a small group of employees. The better the information provided
by the customer, the more rapidly an accurate assessment can
be made by the CMO and the higher the confidence level will
be in the resulting PDE/OEL. As the project progresses through the
On receiving a new customer project request, the high potency clinical stages and the HPAPI receives a market authorisation,
compounds involved have to be assigned an appropriate OEL then more data on the drug is available in the public domain.
for the initial risk assessment in order to allow an initial decision However, the customer’s own data, particularly their own
on procedures and selection of manufacturing facilities. assessments for the derivation of OEL and PDE are typically
The OEL classification of the compound is based initially on preferred as more reliable for determining the Evonik internal
information supplied by the customer as part of the Request For PDE/OEL and the appropriate handling controls.
Proposal (RFP). This may include, among other items, data on The Evonik OELs and OEBs assist in the preparation of the risk
toxicology, pharmacology, bioavailability, clinical trial results, assessment, particularly during the project evaluation period,
and physico-chemical evaluations. Besides the information but for the design of the risk control systems the whole process
provided by the customer, an extensive search for relevant handling sequence, physical properties, routes of potential
literature (e.g. assessment documents from FDA or EMA as well exposure and toxicity need to be looked at in detail. Here the
as scientific publications), is conducted by the toxicologists more than 20 years’ experience of HPAPI handling at Evonik is a
involved, particularly for authorised APIs. The collected internal great help, because of the many best practice solutions shared
and external information is reviewed by an experienced in- among Evonik’s HPAPI expert core team. Normally, the HPAPIs are
house toxicologist, and the most relevant or conservative data manufactured in a multi-product facility, so an additional concern
are selected to determine the point of departure (POD) for the is carry-over of high potency compounds to the production
compound (e.g. a No Observed Adverse Effect Limit – NOAEL, campaign of the subsequent product. The PDE carry-over limits
or the lowest recommended therapeutic dose). This POD are determined in conjunction with the analysis performed
value is then adapted applying different assessment factors, to during the initial OEL/OEB evaluation and are incorporated
extrapolate from effects seen at the POD to an effect-free OEL for into the validation of plant cleaning protocols. ADE and PDE
chronic inhalation exposure in humans. In the case that sufficient values are also determined based on the toxicological
data is not available from the RFP, an exchange and review of and pharmacological data for the product. These limits are
information between toxicologists at Evonik and the customer is calculated according to the relevant guideline from the
initiated to allow a clear assessment to be made. After the OEL European Medicines Agency (9). Suitable trace analytical
and PDE have been established by an Evonik toxicologist, the methods must also be developed for the product, in order to
report is then cross-checked by a second toxicologist to confirm demonstrate the effective cleaning of the plant as part of the
the values determined for the PDE and the OEL, their calculation process validation (10).
CONCLUSIONS REFERENCES
In order to introduce and scale-up a customer HPAPI process 1. Bowman, M., Speciality Chemicals, 30 (July 2013)
to full manufacturing scale, a wide range of disciplines must be 2. Axon, M.W., Farris, J.P., Mason, J., Chemistry Today, 26(2), 57
harnessed to work together for a safe and optimum process (2008)
introduction. This not only requires the introduction of training 3. Belger, T., Chemistry Today, 32(1), 29 (2014)
programs and employment of highly skilled personnel both 4. Harris, R., Chemistry Today, 33(5), 67 (2015)
5. Winkler, G.C., Mirwald, J., Gromek, K., Lovsin Barle, E., Chemistry
in process R&D and in production, but also toxicologists and
Today, 34(4), 32 (2016)
industrial hygiene specialists, as well as safety and hazard
6. Weideman, P., et al, Contract Pharma, 74 (September 2015)
assessment experts. In addition, specialist analysts are required
http://www.contractpharma.com/issues/2015-09-01/view_
features/deriving-health-based-exposure-
limits-in-the-pharmaceutical-industry/11673
7. Dunny, E., O’Connor, I., Bones, J., Drug
Discovery Today, in press (2017), http://dx.doi.
org/10.1016/j. drudis.2017.02.003
8. Haehl, K., Chemistry Today, 31(4),
Supplement, 24 (2013)
9. European Medicines Agency, Guideline on
setting health based exposure limits for use in
risk identification in the manufacture of
different medicinal products in shared
facilities, EMA/CHMP/CVMP/
SWP/169430/2012 (effective 2015)
10. CEFIC Active Pharmaceutical Ingredients
Committee, Guidance on aspects of
cleaning validation in active pharmaceutical
ingredient plants (2014), http://apic.cefic.
org/pub/APIC_Cleaning_Validation_2014.pdf
11. ISPE D/A/CH Affiliate, Containment Manual
(English translation), ISPE Publications (2017)
http://www.ispe.org/publications-guidance-
documents/dach-containment-pharma-manual
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