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DEVELOPMENT AND IMPLEMENTATION OF A LARGE-SCALE HPAPI

MANUFACTURING PROCESS

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 PHARMACEUTICAL
Industry perspective
CHEMISTRY: APIS, HPAPIS
IAN GRAYSON1*, JOCHEN BECKER1, TIM POHLMANN1,
KAI BLUMBACH1, KENNY MCCLEARY2, MATTHEW VAN HOOSIER2
*Corresponding author
1. Evonik Nutrition & Care GmbH, Hanau-Wolfgang, Germany
2. Evonik Corporation, Indiana, USA

Development and implementation of a

large-scale HPAPI manufacturing process
KEYWORDS: HPAPI, OEL, containment, scale-up, industrial hygiene, risk control, custom manufacturing.

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.

INTRODUCTION the containment challenges for HPAPI manufacture (7).

Highly Potent Active Pharmaceutical Ingredients (HPAPIs) today
constitute a significant and increasing proportion of new drugs.
It has been estimated that more than 25% of all new drugs in
development, including antibody-drug conjugates (ADCs) are
HPAPIs (1). A large number of pharmaceutical companies and
contract manufacturing organisations (CMOs) have invested
in manufacturing facilities for HPAPIs over the last ten years.
Although some are well established, late entrants to the field
still have to gain experience in large scale manufacturing and
handling of HPAPIs. The manufacture of HPAPIs, especially at
large scale, requires particular attention to safe handling and
containment systems, to prevent exposure of the workforce,
release of a HPAPI or pharmaceutically active intermediate,
and cross-contamination with other products manufactured
in the facility or on the site. The systems and methods chosen
to achieve this by different manufacturers and recommended
by consultants in the field have been presented previously in
Chemistry Today (2-5).
The containment system requirements for any particular process
depend on the hazard assessment of the toxicity of the drug
substance or intermediate, the Occupational Exposure Limit
(OEL), the risk assessment and risk control strategy. In addition,
permitted daily exposure limits (PDE – European usage) or
acceptable daily exposure limits (ADE – USA usage) need to
be established in order to select equipment of appropriate
cleanability and to set cleaning limits (5,6). In this paper, the
term PDE is used. In order to facilitate the individual risk control
strategy, or in the case that data is insufficient to derive an
OEL (e.g. in case of intermediates or raw materials), Evonik
Health Care uses a system of five Occupational Exposure
Bands (OEBs) with associated global containment guidelines
for all its pharmaceutical manufacturing sites, both for drug
substances and formulated drug products as well as for isolated
intermediates. The differences in Occupational Exposure Banding
between manufacturers were recently compared in a review on
For a CMO to be a reliable partner in the manufacture of
HPAPIs, it is important to have a complete systems approach
in place for the customer, including not just physical
containment, but also skilled and experienced personnel for
hazard and risk assessment, effective project management,
training of employees working on the HPAPI project, and
analytical and cleaning protocols, among other criteria. We
have previously presented the factors which are important for
a pharmaceutical customer in choosing the right CMO for an
HPAPI project (8). In this article, we describe the steps taken to
determine the OEB for a new HPAPI process, the qualification
of the equipment, the handling of the project, and the clean-
down protocols, with the aid of a typical project which was
scaled up from laboratory to full manufacturing scale.
DETERMINATION OF OEB/OEL FOR HPAPI PROCESSES
For the manufacture of highly potent compounds, it is
important to have comprehensive procedures and policies
in place to cover all aspects of classification and handling of
HPAPIs. To this end, Evonik has implemented a policy on potent
compound handling, which covers the following key areas:
• Toxicological assessment of compounds with
pharmacological and/or toxicological activity and
setting of OEL and PDE values. In case data are not
sufficient to derive an OEL, assignment of an default OEB
range, based on a basic hazard review, applying for
example in silico predictions of mutagenicity using FDA-
accepted software tools available in-house.
• Industrial hygiene risk assessments prior to handling
potent compounds and an ongoing program to monitor
performance.
• Guidelines for facility design and exposure control
approaches to establish the safe handling of potent
compounds and their pharmaceutical dosage forms at

20 Chimica Oggi - Chemistry Today - vol. 35(5) September/October 2017

 laboratory, pilot plant and production scales of operation.
• Training and communication programs to ensure that
employees are familiar with / aware of the hazards
presented by potent compounds in the workplace and
that they have competent knowledge of the controls
used to prevent exposure.
• An effective project management system to ensure that
potent compounds are managed appropriately
throughout the project and the product life cycle,
including project evaluation, R&D work, analytical, pilot
and large scale manufacturing as well as waste disposal.
The FDA and consultants advising in the field of HPAPI
manufacture have defined a highly potent active ingredient or
intermediate, as one which has an OEL of ≤10 μg/m3 air as an
8 hour time-weighted average. Based on the OEL, the potent
compound is placed into an OEB, which guides the handling
and control strategy for the material, as well as the substance-
and process-specific risk assessment. The OEBs used at Evonik
are shown in Figure 1, and compounds assigned to an OEL <10
μg/m3 (OEBs 3, 4 and 5) are all considered as highly potent.
Figure 1.
OEB Classification
at Evonik.
On receiving a new customer project request, the high potency
compounds involved have to be assigned an appropriate OEL
for the initial risk assessment in order to allow an initial decision
on procedures and selection of manufacturing facilities.
The OEL classification of the compound is based initially on
information supplied by the customer as part of the Request For
Proposal (RFP). This may include, among other items, data on
toxicology, pharmacology, bioavailability, clinical trial results,
and physico-chemical evaluations. Besides the information
provided by the customer, an extensive search for relevant
literature (e.g. assessment documents from FDA or EMA as well
as scientific publications), is conducted by the toxicologists
involved, particularly for authorised APIs. The collected internal
and external information is reviewed by an experienced in-
house toxicologist, and the most relevant or conservative data
are selected to determine the point of departure (POD) for the
compound (e.g. a No Observed Adverse Effect Limit – NOAEL,
or the lowest recommended therapeutic dose). This POD
value is then adapted applying different assessment factors, to
extrapolate from effects seen at the POD to an effect-free OEL for
chronic inhalation exposure in humans. In the case that sufficient
data is not available from the RFP, an exchange and review of
information between toxicologists at Evonik and the customer is
initiated to allow a clear assessment to be made. After the OEL
and PDE have been established by an Evonik toxicologist, the
report is then cross-checked by a second toxicologist to confirm
the values determined for the PDE and the OEL, their calculation
Chimica Oggi - Chemistry Today - vol. 35(5) September/October 2017
and their justification. In the case that sufficient data is not
available from the customer to determine an OEL, the compound
is assigned to a default OEB, which at Evonik is OEB 3 for an API, if
there are no indications of particular toxicological properties such
as mutagenicity. The internal workflow for the determination of
the OEL and setting of the correct OEB is shown in Figure 2.
Figure 2. Flow chart for determining OEL/OEB levels.
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
clinical stages and the HPAPI receives a market authorisation,
then more data on the drug is available in the public domain.
However, the customer’s own data, particularly their own
assessments for the derivation of OEL and PDE are typically
preferred as more reliable for determining the Evonik internal
PDE/OEL and the appropriate handling controls.
The Evonik OELs and OEBs assist in the preparation of the risk
assessment, particularly during the project evaluation period,
but for the design of the risk control systems the whole process
handling sequence, physical properties, routes of potential
exposure and toxicity need to be looked at in detail. Here the
more than 20 years’ experience of HPAPI handling at Evonik is a
great help, because of the many best practice solutions shared
among Evonik’s HPAPI expert core team. Normally, the HPAPIs are
manufactured in a multi-product facility, so an additional concern
is carry-over of high potency compounds to the production
campaign of the subsequent product. The PDE carry-over limits
are determined in conjunction with the analysis performed
during the initial OEL/OEB evaluation and are incorporated
into the validation of plant cleaning protocols. ADE and PDE
values are also determined based on the toxicological
and pharmacological data for the product. These limits are
calculated according to the relevant guideline from the
European Medicines Agency (9). Suitable trace analytical
methods must also be developed for the product, in order to
demonstrate the effective cleaning of the plant as part of the
process validation (10).
21
SCALE-UP AND COMMERCIAL OPERATION OF A CUSTOMER
HPAPI PROJECT
The following case study is a typical business example of
a CMO process to an HPAPI. The customer supplied Evonik
with a multi-stage process to a heterocyclic compound,
which was the active pharmaceutical ingredient (API).
As the process was convergent rather than linear in nature,
only the final two stages were judged to be highly potent,
as it was only at these steps that the final API skeleton was
assembled. The supplied process was considered to be
a good technical fit for the proposed HPAPI production
unit at the Evonik Tippecanoe site (Lafayette, Indiana),
with additional process development work carried out at
our HPAPI lab in Hanau, Germany. The customer supplied
toxicological data (animal studies) to Evonik. Based on
this information, the Evonik toxicologists had sufficient
information to calculate a quantitative OEL value that was
within in the range 0.1 – 1 μg/m3. The product was therefore
assigned to Evonik OEB 4.
The isolator in the HPAPI lab was qualified by using
naproxen sodium as a model drug, and containment
down to an OEL of 5 ng/m3 was demonstrated. (11) The
laboratory equipment was therefore suitable for the
supplied process. In preparation for the laboratory work,
analytical methods and reference samples were received
from the customer, and the methods were reproduced
in our laboratories. The analytical development required
for HPAPIs should not be underestimated, as there was a
very large number of in-process controls to be transferred
and reproduced, covering a wide range of techniques:
GC, HPLC, NMR, water content by Karl Fischer, and
residual solvents by headspace GC. Over a period of a
few weeks, all stages were reproduced in the HPAPI lab,
and a multi-gram final product sample was prepared
for the customer. The customer’s analysis of the sample
corresponded to that of Evonik, so the project was then
cleared for transfer to production scale. The total time from
initial project evaluation to customer analysis of the HPAPI
lab sample and preparation for scale-up was less than
4 months. Throughout the process development period
there were regular tele-conferences with the customer to
discuss progress; this close collaboration with the customer
contributed greatly to the speed with which the process
was developed and transferred to production.
Following acceptance of the laboratory sample by the
customer, the process was transferred to the Tippecanoe
HPAPI bulk operations production unit (Figure 3), and
a demonstration campaign was run in the 2 m3 train.
A containment strategy was developed, based on the
defined OELs and the known capabilities of the plant
equipment. After a successful conclusion to this initial campaign,
and after further discussions with the customer, the process
was then scaled up to the 8 m3 train. The experiences
from the initial 2 m3 campaign, including the dispensing
of raw materials, and the cleaning of surfaces, were
reviewed after the campaign, and revised procedures
were implemented for the scale up to the 8 m3 train.
Routine production has continued at this scale, with
several campaigns run to date. There is a process in
place for providing continuous review and improvement
of procedures and practices with each subsequent
production campaign.
22
Figure 3. HPAPI Manufacture at Laboratory and Production Scale.
Early phase development HPAPIs often come with incomplete
data sets, which are not sufficient to determine the initial OEL.
In such cases, conservative default OEB ranges are used, in
order to ensure personnel protection. The control strategy
focuses on qualified containment equipment and additional
layers of protection. As the project progresses through the
clinical phases, the focus shifts to optimisation of the highly
potent aspects of the production, in order to reduce the
exposure risk and to increase the economic effectiveness of
the process. In the case of the process described here, the
production train used was qualified to manufacture an HPAPI
down to an OEL level of 0.1 μg/m3. The customer provided a
well-defined set of data, which facilitated a rapid assessment
of the hazards and a speedy transfer to production.
Although the process was robust, scale-up challenges were
encountered during equipment clean-down, as the HPAPI
was being manufactured in a multi-product facility. This
meant that the PDE limits of residual product were set at
a very low level, and there was a high solvent use in order
to reach the required level of cleanliness. Also, equipment
may need to be opened and inspected after cleaning
operations, with an additional risk of exposure to high potency
materials. Analytical methods were developed to measure
levels of HPAPI down to the ppb level (10) In addition, the
handling and decontamination of the waste generated by
the cleaning process had to be addressed. The Tippecanoe
production facility is equipped for high temperature
incineration of both liquid and solid waste, and is therefore
able to dispose of the high potency waste streams cost
effectively on site. Secondary issues such as cleaning
assumed a higher importance than the chemical process
itself as the HPAPI was scaled up to the 8 m3 train.
At the full production scale, additional containment measures
had to be considered. There was an increased focus on the
cleaning protocol; however the larger scale plant had a greater
cleanability because of its clean-in-place design, and the
availability of more “hard” barrier containment systems in place,
compared with the “soft” containment technologies used on
the smaller scale plant. For example, the small scale plant made
more use of glove bags, rather than the fixed containment
equipment such as rigid glove boxes on the full scale plant.
Process optimisation also focused on the wider supply
chain challenges. These included the dispensing of raw
materials the handling and storage of the highly potent
intermediates and finished product. On scale-up, the
robustness of the process allowed for the reduction of
in-process checks by up to 50%, which reduced the
complexity of the process and also reduced the handling
of highly potent materials. These changes, as well as all other
process improvements, were only introduced after detailed
Chimica Oggi - Chemistry Today - vol. 35(5) September/October 2017
 discussions with the customer. With an established large-
scale production and repeat campaigns, the production
team began to look at optimisation of the highly potent
aspects of the process, to improve the cost efficiency.
Concurrently, additional industrial hygiene data and
workplace monitoring were generated in order to review
the use of additional personal protective equipment by
operators. A better understanding of the toxicology profile of
the HPAPI and intermediates was achieved, so that potential
adjustments in PDE residue limits on clean-down could be
introduced. These all led to a streamlining of the production
process, which was particularly important for the customer,
as the drug product was fast-tracked for commercialisation.
to implement the in-process, intermediate and final HPAPI
analyses, and also to develop trace analytical methods to
support the cleaning protocol for the HPAPI plant. The operation
of the process has to be designed according to the risk control
strategy, and this strategy should be reviewed at each scale-up.
In all these areas, close contact and dialogue with the customer
is essential. All significant changes need to be discussed and
agreed with the customer before implementation. It goes
without saying that for the introduction and operation of a CMO
production process, and particularly for an HPAPI process, a
close relationship and mutual trust in the exchanging of sensitive
technical and toxicological data between the customer and
the CMO is essential for success of the project.

CONCLUSIONS REFERENCES

In order to introduce and scale-up a customer HPAPI process 1. Bowman, M., Speciality Chemicals, 30 (July 2013)
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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
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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
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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

About the author

The API manufacturing
Themanufacturing
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Ian Grayson has many
years of experience in
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