Manufacturing of Cytotoxic

and Non-Cytotoxic Drugs in a

Multiproduct Facility
 Manufacturing of Cytotoxic and Non-Cytotoxic
Drugs in a Multiproduct Facility
drug product, as failures or weaknesses in this
Introduction process can pose risk to the end-user.

When different drug products are produced in The evolution toward a risk-based
shared facilities, the potential for cross-
contamination is always a concern that needs approach for cross-contamination
to be addressed. Drug products provide a
benefit to the intended patient; however, as a FDA awareness of cross-contamination that
cross-contaminant they can pose a risk. This can pose a serious health risk to patients was
is especially true when manufacturing triggered mainly by two cases: (i) In 1998 a
oncology drugs, as many of them are highly- finished drug product, Cholestyramine Resin
potent substances with cytotoxic or genotoxic USP, had to be recalled because of
effects, while others are not. contamination with low levels of intermediates
and degradants from the production of
In the early days of modern cancer therapy, agricultural pesticides (although no pesticides
chemotherapy with cytotoxic small molecules were manufactured in the finishing facility).
was the only treatment option. The The identified root cause was improper
development of targeted therapies based cleaning of storage drums in the bulk
either on small molecules or monoclonal pharmaceutical suppliers’ factory. (ii) In 1992,
antibodies opened ground for rapid evolution a US multi-use bulk pharmaceutical
and a large diversification in the clinical manufacturer, Barr Laboratories, raised an
landscape. Especially in the field of immune- alert. The firm manufactured potent steroid
oncology, monoclonal antibodies products as well as non-steroidal products
accompanied by antibody-drug conjugates using common equipment with cleaning
(ADCs) flourished in the pipelines of an validation procedures that were regarded as
increasing number of pharmaceutical and inadequate (3).
biotech companies. From 2011 to 2016, 68
different agents were approved for over 22 At that time, “visibly clean” as the sole
oncology indications (1). Biomarker-based acceptance criterion was challenged and
split up of indications adds to this complexity made the basis for additional logically
in cancer care, and poses challenges to explainable criteria, such as the 0.001 dose
oncology drug manufacturers. criterion, or the 3 or 10 ppm values (reviewed
in 4). Although these dose-based values were
Recent market reports suggest increasing widely accepted by the industry, none of these
product niches, which may lead to decreasing values made their way into official regulatory
numbers of units per product, making guidance documents. FDA always expected a
dedicated facilities less practical. Outsourcing “scientifically justifiable” basis for the
of drug product manufacturing to a contract establishment of limits and that these limits
manufacturing organization with experience in are safe. By merely looking at dose-based
handling different products in multiproduct limits, the safety aspect is not considered
facilities can be an option. However, the adequately for drugs with a very narrow
experience and expertise of the CMO is crucial therapeutic window – marked by a low
to avoid the risk of cross-contamination of the therapeutic index, which is the ratio of a

2
drug’s toxic dose divided by the effective
dose. This development to science-based
limits found its initial peak in the ISPE Risk-
MaPP Baseline Guide with the definition of the
Acceptable Daily Exposure (ADE) (reviewed in
5). This is a conservative approach to define a
“daily dose of a substance below which no
adverse events are anticipated, by any route,
even if exposure occurs for a lifetime” (6). The
EMA converted this idea into the first official
guideline and established the Permitted Daily Figure 1. Schematic drawing of the process of new
product integration at Baxter’s oncology facility
Exposure (PDE) which is effectively
synonymous with the ADE (7).
The completed risk assessment conducted at
Baxter’s oncology facility is combined with
In practice: product separation at state-of-the-art organizational procedures and
Baxter’s Halle, Germany facility technical standards in accordance with
current industry guidance. The goal is to help
At Baxter’s oncology contract manufacturing ensure the greatest possible reduction of
facility in Halle, Germany, recent different modes of potential cross
developments and guidance documents to contamination – whether it be (i) transfer by
help prevent cross-contamination have been airborne migration of particulates, (ii)
fully adopted. With over 60 years of oncology mechanical transfer from operators or
experience, patient safety and world-class equipment, (iii) residual carry-over due to
manufacturing have always been (and remain) inadequate cleaning, or (iv) mix-up by using
a top priority. wrong products, ingredients or equipment.
Dedicated or single-use equipment is
The risk for cross-contamination is carefully sometimes used to further reduce the low risk
assessed for each new product introduced to of cross-contamination within the risk-based
Baxter’s multiproduct manufacturing approach. Together, this allows the handling
equipment in Halle/Germany (Figure 1). Within of the following at Baxter’s oncology facility:
this risk assessment, both • cytotoxic and non-cytotoxic small
pharmacological/toxicological and physical molecules, including liposomal and
properties of a drug are taken into nanoparticulate formulations
consideration. The former is represented by a • monoclonal antibodies
limit value (e.g. the PDE); with the latter, API • ADCs
and formulation properties are judged to • nucleic acid products, e.g. gene
classify the general cleanability, e.g. the therapeutics
solubility of the API. Based on this risk The risk of cross-contamination at the facility
assessment, each new product is compared in Halle, Germany, is challenged in more than
to the current worst-case product established 30 audits per year by clients as well as thirteen
in the facility: (i) if a new product is not a worst different regulatory authorities. Currently, two
case, it can be securely inserted into the commercially approved non-cytotoxic
existing product matrix; (ii) if a product is a molecules are manufactured on the oncology
new worst case, cleaning validation for the lines, and more than five (5) are in transfer.
equipment at risk must demonstrate
successful depletion of the product after
manufacturing.

3
Summary

With the advent of more product niches and often lowered production quantities, facilities that are
experienced and versatile in handling cytotoxic, highly potent, and non-cytotoxic oncology products
can present a valid option when considering outsourcing. Risks for cross-contamination must be
properly assessed, using state-of-the-art organization procedures, technical standards, and current
industry guidance. Ultimately, patient safety is, as always, the driving force.

Literature:
(1) Global Oncology Trends 2017 QuintilesIMS, May 2017
(2) PDA Course, Technical Reports Trigger Success for Takeda, PDA Letter, May 2016
(3) Validation of cleaning processes, FDA Guide to Inspections (7/93), November 2014
(4) Cleaning Validation for the 21st Century: Acceptance Limits for Active Pharmaceutical Ingredients
(APIs): Part I, Pharmaceutical Engineering, July/August 2011
(5) Cleaning Validation for the 21st Century: Acceptance Limits for Active Pharmaceutical Ingredients
(APIs): Part II, Pharmaceutical Engineering, September/October 2011
(6) ISPE Baseline® Pharmaceutical Engineering Guide, Vol. 7 – Risk-Based Manufacture of Pharmaceutical
Products, International Society for Pharmaceutical Engineering (ISPE), First Edition, September 2010,
www.ispe.org.
(7) Guideline on setting health based exposure limits for use in risk identification in the manufacture of
different medicinal products in shared facilities, European Medicines Agency (EMA), EMA/CHMP/
CVMP/ SWP/169430/2012, November 2014

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