Critical Aspects of Technology Transfer to CMOs

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Technology transfer in pharmaceutical manufacturing most often is mentioned as occurring between two organizations and involving discrete product lifecycle stages: e.g., a sponsor and a contract manufacturer and from development to manufacturing. According to the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use: “The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement” (1). Although certain characteristics of technology transfer are preserved during intra- and inter-organization knowledge hand-offs, here I specifically address the latter.

With outsourcing and contract manufacturing well-established in the commercialization strategies of most pharmaceutical and biopharmaceutical companies, technology transfer becomes an enabling asset. It may occur during any stage, scale, or location in a pharmaceutical product’s lifecycle, from discovery to postapproval. The exact nature, detail, depth, and significance of a transfer change depending on circumstances.

Mishandling of technology transfer may be costly to drug sponsors through adding time, costs, delays in achieving process or regulatory milestones, and rework, all the while compromising a company’s reputation. Regardless of how technology transfer hitches arise, they almost always negatively affect a sponsor’s relationship with its contract manufacturing organization (CMO). Thus, parties entering technology transfer arrangements should be cognizant of the five “Cs” (2): commitment, cost and work, compliance, capabilities, and capacity.

Commitment means both parties are aligned regarding deliverables, timelines, and commitment to timely information exchange. Cost and work considerations minimize surprises for both sides. Compliance requires a bilateral understanding of regulatory complexities while maintaining good working relationships with regulatory agencies. Capabilities define the CMO’s expertise and track record. And appropriate capacity precludes surprises related to shutdowns, outages, and unexpectedly long lead times that can affect overall project schedules.

Elements of Technology Transfer
Technology transfer is a multidisciplinary activity involving diverse skills and competencies of participants, including project management, quality assurance/control (QA/QC), technical capabilities, engineering, manufacturing, and validation. Success depends on all involved parties understanding clearly defined objectives for teams and individuals as determined by scope-defining documents related to a validation project plan, contract, and quality. Depending on the stages of origination and destination, information transfer should include the following:

  • Raw materials specifications
  • Process and product specifications
  • Test-method development reports
  • Process development reports and annual product reviews
  • Intermediate and raw product stability at different hold points
  • Executed batch records and standard operating procedures (SOPs)
  • Cleaning procedures and validation methods
  • Formulation and filling specifications
  • Primary and secondary packaging specifications.

Gap Analysis
Gap analysis compares potential or anticipated performance with actual results, thereby helping to align performance and goals for the duration of an outsourcing relationship. The basic idea also can be applied prospectively for assessing suitability of a CMO-based current process needs and contractor capabilities. Generally, gap analyses include the following:

  • Comparing and assessing suitability of existing equipment and facilities, with process requirements and identification of new equipment and facility modification requirements
  • Describing the manufacturing process and flow of personnel and materials at the receiving organization
  • Identifying potential health and safety issues in the project, with possible mitigations
  • Assessing and confirming SOP numbers and types, as well as batch records required for all production and analytical processes
  • Performing a skills assessment to identify training needs
  • Identifying potential good manufacturing practice (GMP) effects on existing projects — or vice versa.

Because analytics drive quality and regulatory considerations, analytical project definition and gap analysis will be part of most technology transfers. That applies particularly to how they affect testing of raw materials, in-process intermediates, released batches, and stability at appropriate stages. A CMO must be made aware of all analytical components and qualifications involved: test status (e.g., fully validated, qualified, or compendial), testing venue, and test method transfer protocols.

For manufacturing-related activities, gap analysis should cover batch records, SOPs and work instructions, operator skills assessment, and definition of required technology transfer batches. Manufacturing process details should include special handling and allowable material composition/quality, equipment requirements, general validation approaches, manufacturing suite classification and viral segregation requirements, support infrastructure (buffer hold/preparation, cleaning and related validation), sterility validation when applicable, control strategy, and potential issues related to process robustness, materials, equipment, or scheduling. All those factors play into project definitions as well.

Gap analysis creates awareness of all components, resources, and identifying factors that have the potential to create delays, additional costs, and/or sources of client displeasure. Analysis might uncover a simple need — e.g., analysis by mass spectroscopy (MS) — that a CMO may not possess and suggest ways to meet that need. Gap analysis most clearly will identify capital equipment mismatches, required facility upgrades, and costs/timelines for meeting “gap” needs. Clients generally are understanding of the existence of such gaps, but they do not relish the thought of CMOs learning as they go.

Quality and regulatory project definitions should account for and document issues related to site changes that come up in every technology transfer project, including the technology transfer protocol itself. Site-change risk assessment includes a transferred process and control strategy with potential historical factors such as cross contamination, change control and deviation history, and process surveillance.

Miguel Montalvo (president of Expert Validation Consulting) has created a comprehensive list of gap analyses within the framework of change control, which is often critical to maintaining progress during an outsourcing project (3). He breaks the components down into general considerations, documents, facilities/equipment/systems, computerized systems, and materials/services.

Potential Pitfalls
The more complex a contract relationship — the greater the number of processes and “products” involved — the greater the opportunity for common pitfalls to arise. With them come delays, cost overruns, and missed expectations.

Parameters: When sponsors (or more likely, contractors) expect an “alliance” or partnership where a more transactional relationship is more appropriate, poorly defined or unrealistic metrics for working relationships and performance commonly follow. Transactional relationships normally involve specific tasks in a much more comprehensive program. Partnerships are more integrated, often encompassing multifactorial support for longer periods or involving proprietary chemical or process-related expertise. Closely related to poorly defined relationships are unclear deliverables (or expectations) and misplaced emphasis on time-to-market or timeliness over quality of results, reporting, or compliance.

Lack of transparency can exist on either side of a sponsor–CMO relationship. On the CMO side, it can include overpromising services or expertise, giving weak feedback, updating infrequently, unilaterally deprioritizing project aspects, and hiding failures. Sponsors in some instances (particularly at overseas CMOs) may withhold “proprietary” information, process robustness information, preferred set points within an operating range, or historical production issues that can lead to unexpected yield issues or batch failures in the transferred process. Across long distances, CMOs might tend to be less than forthcoming regarding nonperformance issues. Vigilance and oversight will prevent some such problems. According to the World Health Organization (WHO), lack of transparency may lead to ineffective technology transfer (4). Therefore, all process issues must be communicated immediately to sponsors as a means of ensuring efficient transfer of knowledge.

Information, operational, and process “silos” arise naturally within companies during drug development. Among the benefits of cloud computing is an ability to maintain need-to-know accessibility to process and information repositories. However, a survey by Dassault Systems found that outsourcing projects often fail because of data that are poorly generated and maintained, mismanaged from the perspectives of security and IP management, and/or not adequately leveraged (5).

Knowledge “islands” are much more difficult to bridge during the hand-off between a sponsor and a contractor who do not share an information repository. Moreover, clients may be aware of conflicts of interest that justify limiting the amount and type of process knowledge they share with a CMO. Neil de Crescenzo (vice president of Oracle Group) notes that knowledge silos prevent leveraging the full value of safety information that can affect the conduct of both clinical trials and manufacturing (6). Regular teleconferences and face-to-face meetings help break down those silos and foster a team approach.

Culture clashes represent another natural disconnect, particularly when sponsors have conducted manufacturing themselves and thus have preexisting notions about how such activities should proceed. Large, established sponsors expecting to outsource as a cost-saving measure also may not understand the infrastructure requirements of significant manufacturing projects. Better established initial objectives make disconnects less likely to occur.

Unforeseen events such as the impact of a major storm are rare and difficult to mitigate. More common are supply chain disruptions and unpredictable events occurring during scale-up or transfer of a process between facilities. CMOs should institute a redundant supply chain for materials, ingredients, and equipment (e.g., chromatography resins used in downstream purification). Scale-up issues can be lessened but not totally eliminated by filling knowledge gaps and eliminating information silos. Sponsors should require written SOPs for overcoming potential adverse events for critical operations.

Managing the Risks
Technology transfer always involves risk. Problems can arise even for processes that transfer faithfully into facilities that possess the required equipment and expertise.

That experience underscores the need to consider engineering runs as an extended commissioning activity taking place before performing final system installation and operational qualification (IQ/OQ). Engineering runs thus can illustrate the need for further equipment modifications or design changes. Within this outsourcing scheme, performing IQ/OQ before completion of engineering runs requires making consequent changes under formal QA change control and equipment requalification, rather than engineering change management.

Technology transfer to contract pharmaceutical manufacturers demands knowledge, transparency, trust, competence, and structured data when appropriate. Many authors have described those familiar qualities, although not perhaps within the exact context of this article. No matter how thorough or transparent is the transfer of knowledge, what separates merely adequate CMOs from the cream of the crop is adaptability and versatility in the face of adverse events and the ability to translate lessons learned to efficient execution of complex projects.

References
1
ICH Q10. Pharmaceutical Quality System. US Fed. Reg. 74(66) 2009: 15990–15991; www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf.

2 DuBois B. The 5 ‘C’s’ for CMO Relationships in Pharmaceutical Supply Chain. 21st Century Supply Chain Blog 3 October 2016; http://blog.kinaxis.com/2016/10/5-cs-cmo-relationships-pharmaceutical-supply-chain.

3 Montalvo M. Gap Analysis Checklist for an Equipment/System/Facility Change Control Program. IVT Network 1 May 2014; www.ivtnetwork.com/article/gap-analysis-checklist-equipmentsystemfacility-change-control-program.

4 Working Document QAS/08.259/Rev2. Guiding Principles on Transfer of Technology. World Health Organization: Geneva, Switzerland, July 2010.

5 WP-5504-1116. Five Reasons the Majority of External Collaborations Fail (and How to Overcome them). Dassault Systèmes/Biovia: Waltham, MA, and San Diego, CA, 2016.

6 TCS, Oracle and DrugLogic Prescribe Safety in a Capsule. Tata Consultancy Services: Mumbai, India, 13 November 2007; www.tata.com/article/inside/LHBBDGiF3hI=/TLYVr3YPkMU=.

Christopher Talpas, PhD, is director of manufacturing sciences at Therapure Biopharma Inc., 2585 Meadowpine Boulevard, Mississauga, ON L5N 8H9, Canada; ctalpas@therapurebio.com; www.therapurebio.com.

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