What is technology transfer in pharmaceutical manufacturing, and what should a tech transfer protocol cover?

1What technology transfer is.

ICH Q10 names technology transfer as one stage of the product lifecycle, between pharmaceutical development and commercial manufacturing. Its goal is “to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realisation”, and that knowledge becomes the basis for the manufacturing process, the control strategy, the process validation approach and continual improvement.¹

WHO sets out the practice in its guideline on technology transfer, Annex 4 of Technical Report Series No. 1044 (2022), which replaced the 2011 version. It defines technology transfer as “a logical procedure that controls the transfer of any product or process, including product or process knowledge, together with its documentation and professional expertise”. A transfer runs from a sending unit (SU) to a receiving unit (RU).²

The guideline covers transfers from research and development to production and between production sites, for new and marketed products, and its principles may also be applied to investigational products. It is written for pharmaceutical products, but says the same principles can be applied to vaccines, biotherapeutics and cell and gene therapy products. The rigour of a transfer should be “commensurate with the respective product life cycle phase”.² A transfer succeeds when there is “documented evidence that the RU can routinely reproduce the transferred product, process or procedure against a predefined set of specifications”.²

2What has to be in place before the protocol.

WHO puts due diligence and a gap analysis first, through visits to both units. The gap analysis identifies the critical elements available at the SU but missing at the RU, and covers personnel, premises, equipment and instruments, utilities, cleaning, quality control, documentation, computerised systems, qualification, validation, and health, safety and environmental matters including waste. WHO recommends that both units’ quality units take part.²

The parties sign formal written agreements that set each one’s responsibilities before, during and after the transfer, covering, for example, data management, data integrity, documentation and validation. The SU and RU jointly verify that completed protocols and reports are available for installation and operational qualification of the RU’s manufacturing, packaging and analytical equipment, for qualification of its manufacturing and packaging rooms, and for cleaning validation. The guideline leaves intellectual property, legal, financial and commercial terms out of its scope, but calls them prerequisites to define and control before the transfer starts.²

3What the transfer protocol should cover.

WHO calls the controlling document a master plan or technology transfer protocol: “a document that describes the intended sequential phases and activities of the transfer”. Section 7.1 lists what it should include.²

The transfer strategy and acceptance criteria are set “a priori” in the protocol, with regard to the clinical or commercial stage and the regulatory requirements of the countries concerned.²

The protocol rests on what the SU hands over. That includes the product’s composition, method of manufacture, in-process controls, specifications and packaging; a description of the manufacturing steps with process maps and master batch records, hold times and the order of material addition; analytical procedures; the control strategy and any design space; validation reports, annual product quality reviews and stability data; and a list of equipment with makes and models. The units compare equipment side by side by working principle, capacity, make and model, and where batch sizes differ, assess the impact as part of the risk assessment.²

4How analytical methods and cleaning transfer.

Analytical procedures should be in place at the receiving laboratory before it tests process validation samples. WHO lists confirmation testing, comparability testing, co-validation between laboratories and paper-based knowledge transfer as approaches, chosen on a risk basis, and asks for a separate analytical transfer protocol with the experimental design, acceptance criteria and a procedure for deviations.²

In the EU, Chapter 6 of the GMP guide, in operation since 1 October 2014, sets this out at 6.37 to 6.41. The transferring site checks the method against the marketing authorisation and reviews its original validation against current ICH requirements, with a documented gap analysis to find any supplementary validation. The protocol identifies the tests and methods, extra training, standards and samples, transport and storage conditions, and acceptance criteria based on the current validation. Deviations are investigated before the transfer closes, and the report documents “the comparative outcome of the process”.³

Cleaning procedures and their validation are normally site specific. The SU provides information on cleanability, solubility, toxicological assessment including health-based exposure limits, its existing procedures, and its residue limits with their rationale; the RU designs its own cleaning from that.²

5How the transfer is executed and closed.

WHO divides a project into four phases: initiation, planning, transfer execution, and review and close-out. During execution the RU determines critical steps, including hold times, end points and sampling, writes its own training plan and SOPs, and generates site-specific stability data if required.² ICH Q10 expects the change management system to provide “management and documentation of adjustments made to the process during technology transfer activities”.¹

The RU produces validation batches to show it can make the product to its specifications, or as part of process performance qualification.² FDA’s 2011 process validation guidance describes process qualification as evaluating whether the process “is capable of reproducible commercial manufacturing”.⁴

The transfer report summarises the scope, the critical parameters as obtained at the SU and the RU, and the conclusions, and records changes, deviations and investigations. A responsible person authorises it, and it states whether the team has completed the transfer. Close-out also checks that stability studies are under way, post-marketing commitments are monitored and new suppliers are in the quality system.²

6When a site transfer is also a regulatory change.

For an approved NDA, 21 CFR 314.70 requires the applicant to notify FDA of each change to a condition established in the application. A change to the production process, equipment or facilities with a substantial potential to have an adverse effect on identity, strength, quality, purity or potency needs a prior approval supplement; one with a moderate potential needs a supplement at least 30 days before distribution; one with a minimal potential goes in the annual report. The applicant must assess the effects of a manufacturing change before distributing product made with it.⁵

FDA’s SUPAC-IR guidance of November 1995 classifies site changes for immediate-release solid oral products that keep the same equipment, procedures and controls into three levels: from a move within one facility, reported in the annual report, to a move to a different campus, filed as a changes-being-effected supplement with stability data and a multi-point dissolution profile comparison. New manufacturing locations should have a satisfactory CGMP inspection.⁶

7How it runs in Seal.

Where the receiving site uses Seal, it starts from a permitted copy of the configured process as a separate draft, which keeps the steps, fields, calculations and references and none of the sign-offs. Each difference from the source, such as a longer hold, a larger working volume or another method revision, becomes owned work with its own evidence and approval, as the technology transfer blueprint sets out. Copying the process does not approve equipment equivalence, validation or site readiness.

Neil, Seal’s AI agent, compares the sending process with the receiving site’s equipment and plan and drafts a transfer gap assessment whose findings link to their sources; the transfer team evaluates comparability and approves trial readiness. The MSAT blueprint follows the transfer through engineering batches, method transfer, training, qualification and validation, showing which knowledge was accepted, adapted, rejected or is still provisional.