By MaryAnn Labant
October 23, 2018

Custom Manufacturing Accelerates Time to Market
As the life science industry faces increasing competition—as well as global
regulatory and pricing pressures—outsourcing portions or all of manufacturing
is becoming increasingly prevalent. A custom or contract manufacturing
partner can help eliminate bottlenecks reducing a product’s time to market.
An off-the-shelf product may not exist, or existing products may not ﬁt aprocess workﬂow. Custom manufacturing allows suppliers to not only continue
to produce standard products, but also to add value and manipulate theirdesigns in order to produce a unique product for a speciﬁc customer. Custom
Sponsored Content By Promega
manufacturing should not be confused with original equipment manufacturer(OEM) products. In this scenario, a company rebrands an existing product from another company.
A subset of custom manufacturers, contract manufacturing organizations (CMOs) typically focus more on helping
pharmaceutical companies with comprehensive services from drug development through drug manufacturing. Regardless, if

a custom manufacturer or CMO is used, potential customers evaluate prospective partners in a similar fashion and expect
competitive pricing, regulatory compliance, ﬂexibility on production capability and on-time delivery.
As stated earlier, in custom manufacturing, unique products are developed or packaged to order for a speciﬁc application. It
is not a ‘one size ﬁts all’ operation. Applications run the gamut from simple to complex, whether producing a single
component or the complete, ﬁnal product.
Simple examples include repackaging an existing product in a different size, concentration or company-branded container.
More complex examples include customizing an existing product for a speciﬁc work ﬂow, developing and/or producing aproprietary formulation or product, or developing a new product, including therapeutics, from the ground up based on
supplied speciﬁcations.
Not a One Size Fits All
Genedrive plc provides a compact PCR platform that enables rapid nucleic acidampliﬁcation and detection from plasma, sputum and buccal swabs for rapid
point-of-care diagnosis of infectious diseases, such as tuberculosis and hepatitis
C (HCV), to address large unmet global health challenges. For example, overninety percent of people with HCV are undiagnosed. Pressure exists to identify
these individuals and to immediately start treatment in the hopes of eradicating
the disease globally.
As a company of 40 employees, producing GMP-grade biologics is not part ofgenedrive’s business supply-chain strategy; they decided to turn to industry
experts and to develop custom manufacturing partnerships.

Automation of product ﬁnishing contributes to rapid
turnaround and helps the client meet critical deadlines.
[Promega Corporation]“Early in the HCV assay development we needed to select enzymes, a Taq polymerase and a reverse transcriptase, that had
the required quality and performance to work with blood and plasma, not just puriﬁed nucleic acids. These enzymes need towithstand some severe inhibitors because of the sample composition. Addressing this performance requirement was a toppriority,” explained Gino Miele, Ph.D., R&D director at genedriveplc.com.
“Cost and performance needed to be balanced. Our assays must be affordable in developing countries. This puts extreme
pressure on the price, which is driven by the component costs.”
In another case, Tocagen is developing ﬁrst-in-class broadly applicable product candidates for the treatment of cancer using
their cancer-selective gene therapy platform built on retroviral replicating vectors (RRVs). Their lead product candidate is a
two-part cancer-selective immunotherapy comprising an investigational biologic, Toca 511, and an investigational small
molecule, Toca FC.
Toca 511 is a RRV that selectively infects cancer cells and delivers a gene for cytosine deaminase (CD).
Through this targeted delivery, only infected cancer cells carry the CD gene and produce the enzyme. Toca FC is an orally
administered prodrug, 5-ﬂuorocytosine, which is converted into 5-ﬂuorouracil (5-FU) by CD. 5-FU kills cancer cells andimmune-suppressive myeloid cells resulting in anti-cancer immune activation and subsequent tumor killing.
According to Carlos Ibañez, Ph.D., vice president, product development and manufacturing, Tocagen, tocagen.com, adecade ago, CMOs had minimal experience with manufacture of RRV products; therefore, the company leveraged in-house
expertise to develop a proprietary and scalable production process for its newer generation of gene therapy products. Theythen searched and transferred the process to contract manufacturers that could perform the process and had ambitions tomove from clinical trial supply to global commercial supply.
Partners, Not Simply Suppliers
The scorecard must be balanced; cost is important but equal or greater service levels, quality program adherence, project
management and adaptability must be factored in. In the custom ﬁeld, things change or evolve more commonly than not, andmanufacturers need to be ﬂexible and able to respond.
A custom manufacturer is a partner, not merely a supplier. An experienced manufacturer will set expectations early on interms of capability, meeting timelines, costs and deliverables and provide open interactions between scientists and otherdepartments on both sides of the equation.
Genedrive’s assay reagents are lyophilized, which generates some bespoke enzyme requirements. Enzymes need to beprovided glycerol-free in high concentrations in order to be incorporated into the core formulation and freeze dried.
“At an earlier phase of the business when we began looking for a custom manufacturer that understood our growth path –we wanted a company who made it their business to get down on the ground and to work with us as an active collaborator.
After triaging several enzyme suppliers, we selected a manufacturer who could not only give us the tools, modeling andforecasts that we needed to persuade our management but was poised to grow with us long term,” said Warren Berry,operations director, genedrive.
“Early on our partner made it clear they would work with us to get the right formulation. Currently, one enzyme is provided
ready to use and the other one in a format where we do some downstream manipulation. These formats were acceptable
during assay development; in the future we may elect to have the manufacturer perform the downstream manipulations.
Flexibility was an important component in our decision making; we wanted options to evolve as the assay progressed
through release and commercial scale-up.”
Partners must be aligned on clearly stated goals so that both parties stay the course and expectations are met. For Tocagen,ﬂexibility was also paramount. Their partners required an understanding of both the need for ongoing process adjustments
while meeting clinical supply demands and also the rigor and understanding of generating and following the rigid
requirements for commercial manufacturing that satisfy global regulatory agencies.
“These requirements necessitate a different mind-set and base of knowledge and experience, and we established critical
success factors for the manufacturing partnership: ﬁrst, to understand each other’s needs, capabilities, and vision for success;second, to ensure that all of the necessary resources are available to sustain the partnership long term; and third to facilitateand encourage open, honest and constant communication between all levels of the companies so that everyone was on-board
with the vision,” discussed Dr. Ibañez.
Tocagen wanted to avoid unrealistic expectations on both sides, procedures that were without some form of precedence andlimiting themselves to a process that would be difﬁcult to scale further. A collaborative approach to process optimization,automation, scaling and validation planning was also critically important to them.
“I look at whether a business is shaped to help you achieve your goal, and can become a long-term partner. We needed tohave a relationship in which the provider understood the trajectory of the business and that would take the time and attention
to understand more deeply the journey we were about to embark on. Also that our needs may change rather than this is theproduct and price,” added Mr. Berry.

“As we scale up and implement our launch plans we continually ﬁnd that the ﬂexibility the manufacturer provides to modify
and adapt to meet our business needs is invaluable for a company at our stage of development.”
Long-Term Outlooks
The market may change, expectations and technologies will change;
adaptability is crucial. Setting realistic expectations prior to embarking on acustom manufacturing relationship ensures everyone is on the same page interms of deliverables and timeline.
There must be a spirit of partnership; the relationship is more than a short-term
Automation of product ﬁnishing contributes to rapid
turnaround and helps the client meet critical deadlines.
[Promega Corporation]

project. A decision should not be made on a promise without vetting it
thoroughly inserted Mr. Berry.

Dr. Ibañez advised to decide early if you want the contract manufacturer to own the process or have the ﬂexibility of aportable proprietary process. If the latter is selected, ensure there is internal expertise to develop a process that can becommercially ready. If not, maintain excellent in-house expertise to follow the partners’ course and developing capabilities.
He suggested that a company develop as deep an understanding as possible of the partner’s picture of the relationship andhow it would and should develop, and to talk to several prospects. It can be worth considering different early-stage and laterstage manufacturers. In this case, technology transfer agreements need to be in place up-front, and the phase 1 process must
be compatible with development into phase 3.
Custom processes are unavoidable when developing and manufacturing a novel type of technology such as RRVs. Suchprocesses are also valuable and are expected to form a competitive advantage, both in proprietary know-how and affording
more control of the outcomes.
From many points of view, timely investment in custom processes for a novel type of product should give a rapid pay-off,for example in timely and appropriate product development, internal conﬁdence, regulatory body interactions and productpartnering. However, at the same time, it is important to understand your partner’s position and their desire to use routine
procedures. They must have a sufﬁcient level of conﬁdence in the company and product to appreciate the value of investingtime and resources to learn and validate new processes.

Collaborative Relationships Lead to Unique Solutions
Selecting the best custom manufacturing partner can be a challenge. Key
considerations include depth of scientiﬁc expertise, ongoing technical support,and compliance with regulatory requirements. It is also critical that
manufacturing and logistics capabilities can scale to meet future needs.
Promega offers a range of custom manufacturing services, from simple changes
in dispensed size to uniquely designed products speciﬁcally adapted forindividual client needs. Each client works with a lead scientist and dedicated

The Promega manufacturing facility in Madison, Wis.
maintains certiﬁcation to ISO 9001, ISO 13485, and ISO
18385 standards. [Promega Corporation]custom manufacturing team. Where needed, the team consults with subject
matter experts to ensure that speciﬁcations are captured and the team is delivering the best product that addresses the client’srequirements. Flexibility is a key part of the relationship—products and processes can be adapted to meet the changing
needs of every client.

With more than 450,000 square feet of manufacturing space, including cGMP facilities, Promega has invested in thedevelopment and maintenance of state-of-the-art, high-quality manufacturing facilities. These facilities include
environmentally controlled spaces, separation of pre- and post-ampliﬁcation processes, semi-automated ﬁlling, andautomated packaging of ambient kits with 100% inspection of components and label content. The Promega manufacturing
facility in Madison, Wis. maintains certiﬁcation to ISO 9001 and ISO 13485 standards, as well as ISO 18385, which focuseson minimizing the risks of human DNA contamination in products. Currently, 15 Promega facilities around the world are
certiﬁed to ISO standards.
Built on over 40 years of serving the life sciences industry, Promega’s scientiﬁc expertise encompasses protein engineering,cell biology, bioluminescence, and nucleic acid puriﬁcation and ampliﬁcation. Despite the company’s rapid growth, it
continues to maintain personal relationships with all its custom manufacturing clients. Based on feedback from current
clients, that’s a small detail that can make a big difference when choosing a custom manufacturing partner.