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article & photos by Joyce Chiu, Perceptive Informatics

On January 26th, on a cold winter evening, nearly 70 ISPE members and guests visited the beautiful Boston Seaport facility of the law firm Foley Hoag to network and listen to three experienced industry practitioners share their experiences on "Biotech Process Scale-up & Technology Transfer," a topic central to the development and manufacture of pharmaceutical drug substances.

The attendees first enjoyed some wonderful appetizers and informal networking.  Many area biotech engineers showed up, with a higher-than-usual number of women and young professionals.  Many also lingered after the formal program ended and continued networking.

What a Process Technology Transfer Needs to Accomplish: Hurdles and Techniques

Jeff S. Socolow, MBA, Sr. Project Manager, Shire Human Genetic Therapies

Jeff opened the evening by providing a general overview of technology transfer - its definition, guiding principles, governance structure, project structure, requirements and pitfalls of the originating and receiving organizations, as well as other considerations.

Process tech transfer is the faithful and compliant transfer of technology, information, documentation and skills from the process owner (the originating organization) to a GMP manufacturing organization (the receiving organization).  A tech transfer has the best chance of success with

• minimal equipment and process changes,
• early partnership with Quality,
• established governance structure,
• extensive planning, and
• team-owned decisions.

A tech transfer consists of five to eight stages and starts with a rigorous facility fit assessment to identify equipment compatibility and gaps at the receiving organization. Included in the assessment are: readiness to establish standards of product quality and productivity, scale (lab or pilot) and considerations for manufacturability.

A tech transfer governance structure consists of an organizational chart where roles and responsibilities are defined; and a gated, stage-based process map with deliverables for each stage, from which a detailed project schedule can be developed.

A breathtaking view from the 13th floor of the Foley Hoag Seaport facility greeted attendees

For the originating organization, having an accurate and locked-down process description (both upstream and downstream) is critical.  Typically the downstream process tends to lag behind the much longer upstream process.  Where external CMOs are involved, sometimes not all the issues can be anticipated; therefore upfront due-diligence and risk assessment and management are all that much more important.

For the receiving organization, assessing their process capability, facility fit and risks; and locking down the bill of materials as early as possible are key.  Some common pitfalls include automation issues, the time it takes to finalize documentation, and training of operators.

The key factors for a successful tech transfer include an approved project scope and plan, effective meeting management, anticipating issues while keeping governance apprised, a detailed and baseline schedule, team ground rules and holding members accountable, standard reporting and collaboration tools, and a well-defined communication strategy.

Technology Transfer: What You Need Before You Start ... and Probably Don't Have

Sheila G. Magill, PhD, BioProcess Technology Consultants

Sheila continued with a definition, kinds of tech transfers, protocols, materials and knowledge.  The definition echoes what Jeff shared - a process transferred from one organization to another, whereby the same results and outcome are achieved.

There are process transfers and analytical method transfers.  In analytical method transfers, it is important to define the critical raw materials, not only going by the vendor's QC methods and release criteria, but also by how they are used in the particular process, that is, their fitness-for-use.

Risk management is an important consideration in tech transfer.  In early clinical stages, it may not be critical, or even desirable, to use cGMP rigor because the process and analytics are still early in their development.  As the process gets closer to late stage and cGMP manufacture, the rigor and compliance to cGMP standards become more important and must be adhered to.

Tech transfers require a clear description of the process or method, deep knowledge about the process in documentation form, materials to enable the transfer, and what constitutes a successful transfer.  These will enable the receiving organization to replicate the results of the originating organization.  In the transfer protocol, there needs to be a clear definition of responsibilities, equipment, materials, activity and personnel. 

In addition, to allow a smooth knowledge transfer, frequent meetings and exchange of information are required, which can consume a lot of time and resources, and the commitment and goodwill of both parties.  These entail the commitment of senior management to provide necessary resources, the need for clear and realistic timetable and a plan.

Tech Transfer from Development to cGMP Manufacture: Challenges & Solutions in Scaling up a New Microbial Process from 5L to 1000L+

Susan Dana Jones, PhD, BioProcess Technology Consultants

Susan concluded the evening by sharing a detailed case study of a microbial process scale-up from 5L to 1000L+.  Because of the large gap in equipment scale and the fact that microbial processes are developed individually, this tech transfer must include detailed assessments of each unit operation, their performance requirements and any variance noted during development.

The audience payed close attention during the evening's presentations.

This SynCo process scale-up has multiple unit operations in both upstream and downstream processes.  The upstream processes at 5L scale include: pre-culture (shake flask), fermentation, cell disruption, batch centrifuge, depth filtration and ultra-filtration.  The downstream processes include cation exchange chromatography, ultrafiltration, gel filtration (fractionation), 0.22 μm filtration and bulk fill.

During process development, tech transfer considerations were included.  Established E.coli fermentation medium, conditions, etc. compatible with the large scale facility were used.  There were no animal-derived media components and no complex feeds or supplements other than pH and dO₂ control.  In addition, knowledge of facility operations at the larger scale influenced process development choices at the 5L scale - a simple fermentation batch operation was used with minimal downstream steps while achieving product quality and purity, as well as half of the fermentation culture was used for downstream processing at scale.

During scale-up, all operating parameters at 5L scale were verified with three batches prior to an engineering batch at scale.  The raw materials intended at scale were used in process development.  Scale-up for chromatography and filtrations steps was linear; fractions in chromatography steps were collected to allow flexible pooling strategy at scale.  In addition, breakthrough studies at small scale can support the choice of filter area at large scale.

With the above strategies in place, the volumes and times between the two scales were established, with good reproducibility at both, while the 1000L scale cell growth, as indicated by optical density, was not as good as at 5L, because of the challenges of effective heat transfer at the large scale.  All of the unit operations showed good to excellent scaleability results, with the exception of centrifugation, because that process is a batch process at 5L and a continuous process at 1000L.

This case study exemplifies some of the best practices used in process development and tech transfer, where the development at the small scale incorporated many careful considerations and minimized risks at the larger scale.