Technology Transfer Packages for Contract Manufacturing: Iterations During the Development Cycle

• SGL Chemistry Consulting, LLC

Abstract

Throughout the developmtent lifecycle of a drug, API manufacturing processes increase in scale and control, as does the level of required process knowledge. Technology transfer packages that reflect the state of knowledge and capability of a given API manufacturing process serve to set the agenda for the next stage of development. They also enable their recipients to plan, allocate resources and successfully complete the work. This article describes the iterative nature of technical information generation and capture, and its conversion to knowledge during chemical process development and API manufacturing, and the dynamic relationship between technical information obtained and the knowledge base it feeds. Challenges to the timely accumulation and implementation of data and knowledge, based on the current prevailing model of drug development, are also discussed.

Introduction

The virtual model of drug development, in which some or all of the aspects of chemistry, manufacturing and controls (CMC) activities are performed externally at selected vendor companies, is prevalent for a wide range of pharmaceutical companies, from start-ups through larger organizations.¹ Technology transfer is an essential activity in chemistry R&D, production and manufacturing outsourced to contract research organizations (CROs) and contract development and manufacturing organizations (CDMOs). A technology transfer package (TTP) is the key document or set of documents that are the basis for the activity of technology transfer.

TTPs are a means of communicating process information and knowledge to their recipients – the vendors that the sponsors select to perform the work. The most effective TTPs are assembled with a desired outcome in mind, and they depend on pre-existing knowledge. The content for a TTP at a given stage of development comes from the knowledge base in hand at that time. A good TTP and its proper evaluation will lead directly to a high quality proposal and a signed contract. TTPs, along with the requests for proposal (RFPs) that accompany them, are the first step in definition and alignment of goals and deliverables between the sponsor and their selected CDMO. A lack of clarity in communication and misalignment of goals and expectations are often cited as major obstacles to success in technology transfer during drug development.²

TTPs, properly assembled, can assist in the management of both time and risk. Time is a precious commodity in drug development, and risk is inherent and high in the development of new chemical entity (NCE) drugs.^1,3 There are likely to be several iterations of R&D and manufacturing as an NCE drug proceeds through stages of the drug development cycle. Each study performed, lot produced or manufacturing campaign executed makes use of previous knowledge. It is the sponsor’s responsibility to manage the knowledge base for their API – to interpret data, determine remaining gaps, and select phase appropriate content for TTPs. As a process and its knowledge base evolves to suit the needs of a development program, so must the TTP. A TTP provides, at its best, a comprehensive, high resolution snapshot of the state of development of synthetic chemistry or a production or manufacturing process at a given point in time. As discussed in previous articles, depending on the stage of development as well as the resources and investment of the sponsor preparing/providing the TTP, its extent of detail and thoroughness can vary considerably.^1,3,4

Iterations are essential to chemical process R&D and API manufacturing. The incremental and continuous improvement of a given API process has the goal of increasing its capability, in order to meet the supply and regulatory requirements for each successive phase of development. Such requirements include scale, robustness, quality, economy, manufacturability and process operational efficiency. The value and impact of a TTP is maximal when it facilitates the interplay between data, its integration into the knowledge base, and decision making based on what is known.

From the TTP and an RFP, a proposal with a scope of work is generated by a vendor, which determines the work to be done. Completion of this work at the vendor generates yet more data, which needs to be interpreted, digested and rendered into additional knowledge, which expands and deepens the knowledge base of a given API process. The growing knowledge base is then used as a reference to augment the content of the TTP for the subsequent round of work.

Two quotes delineate the issues that confront sponsors in the preparation and use of TTPs in technology transfer. From an interview published in 2010, Grace McNally, from the FDA Office of Compliance of the Center for Drug Evaluation and Research (CDER), stated that “Companies that outsource manufacturing operations need to consider what product and process knowledge is necessary for the contractor to fulfill their responsibilities and how to impart that knowledge during technology transfer…”⁵ And Alan Harris, an expert in technology transfer and management of chemistry outsourcing, describing the current dynamic and variable nature of technology transfer, states that “…the impact of future technology transfer needs to be considered at an early stage of development and regularly reviewed against the changing development and sourcing strategies.”³ Data needs to be rendered into knowledge and decisions need to be made. Judgement needs to be applied by the sponsor company, regarding what content from the knowledge base is provided to their selected CDMOs. There is an increasing lack of predictability of the strategy and practices used for drug development and technology transfer, mostly at the early and middle stages of drug development. The ability to predict and project development needs and to use them to inform earlier stage activities has a profound impact on the content of TTPs provided to the late stage CDMOs that perform process design, optimization, qualification and commercial API manufacturing. Successful technology transfer at this point depends critically on the quality of the late stage TTP.

Synchrony of TTPs With the Development Lifecycle

Traditionally, the activity of technology transfer has pertained to the transfer of the optimized pilot scale process to the commercial manufacturing equipment and site. But as outsourcing is used more and more in the earlier stages, tech transfer may occur several times during the development cycle. Harris, in the book on technology transfer published by the PDA³, cites the phenomenon of “discontinuous development” as having a major impact on its timeliness and efficiency.³ Discontinuous development is the result of fragmentation and interruption of chemistry R&D and manufacturing, caused by:

• Use of outsourcing to develop and manufacture API
• Inadvertent or intentional use of multiple vendors during the development cycle, requiring multiple technology transfers by the time the process has reached later stages
• In-licensing or acquisition of assets at different stages of development
• Variability in the extent of evaluation and input by chemical process R&D and manufacturing experts
• Limited funding or competing priorities at small, entrepreneurial startups
• Placing projects on the “back burner,” until attention is returned to them

Some discontinuous development is unavoidable.¹⁰ It adds the burden of the time and effort required to overcome the inertia of a stalled project, and the need to remind those who resume work on the project of the issues and priorities associated with the work. It is not uncommon to have a new team of personnel assigned to the project, due to the lack of availability or departure of those who did the original work, and this requires an additional introduction to the process and its issues, which extends the lead time to pick up where the process was left. Discontinuous development is one significant reason that multiple TTPs may exist for development of a single drug.

The stages that may involve preparation of TTPs for technology transfer to CDMOs are roughly broken down as shown below:

• Preclinical and Early Clinical Development (Phase I)
• Mid-Stage Development (Phase II)
• Late-Stage Development (Phase III)
• Commercial Launch and Post-Approval

The above stages parallel the overall arc of a development program, in which material is provided for use in the studies relevant to each phase. This article addresses the needs for TTPs at each stage of development, with emphasis on the first three stages.

Preclinical and Early Clinical Development

At the beginning of formal development, around the time a candidate is nominated, the extent of knowledge is very limited, perhaps consisting of the drug candidate’s structure, preliminary synthesis of discovery quantities and target, an initial intended route of administration, a rough timeline for delivery of initial quantities of API, as well as a target IND filing date. Correspondingly, a TTP at this stage may have relatively minimal information, as previously described,¹ limited to a bench-scale synthesis or lab scale-up experimental and rudimentary characterization procedures and data. A TTP serves to indicate capabilities, or lack thereof, relative to what is needed by the sponsor to advance their development program.

At a minimum, the goals of work that is typically done at this point in development are:

• Development and scale-up of an enabling synthesis to supply API for IND-enabling GLP nonclinical studies and Phase I clinical studies
• Creation of specifications for the API to be produced
• Development and qualification of analytical methods
• Assay/purity for the API
• Detection and quantitiation of impurities, per International Conference on Harmonization (ICH) thresholds

Key activities within early development goals include isolation, purification and full characterization of the API, including selection and physicochemical characterization of the final form of the API (salt vs. free base or free acid or co-crystal, crystalline vs. amorphous dispersion, etc.).

In most cases, the API from early scale-up and production is being used in downstream studies, e.g., preformulation, formulation development and exploratory toxicology, as soon as it is available. If adequately planned and coordinated, the results from these downstream studies are available to clarify and refine aspects of phase-appropriate goals, including quantities required and physicochemical attributes related to salt and form selection for regulated preclinical and clinical API supply, e.g., target solubility. Thus, work done during a given stage of development augments what was originally in the TTP.

Evaluation of alternate chemistry or sequencing of synthetic steps, if warranted by difficulties encountered during early chemical development and production, can be performed during the latter part of early development, once there is confidence that the program is likely to proceed beyond Phase I clinical development.

All of the data generated from the activities described above and the knowledge from interpretation and refinement of this data results in an enhanced knowledge base, which is the source of information populating the TTP for mid-stage development.

Mid-Stage Development

The TTP for mid-stage development should leverage a much richer knowledge base than was available at the outset of candidate nomination. Presumably, expediency and theoretical projections regarding supply needs and material attributes have been at least partially if not significantly replaced by more data-based deliverables. The knowledge base informs the goals of improving the capability and performance of the manufacturing process and further defining the attributes of the bulk drug substance in fulfilling the needs of the intended dosage form(s). It is likely that the API process will need to be performed at a larger scale at this point, due to an increased number of studies, related to formulation, nonclinical development and expanded clinical trials with multiple arms. The capacity of the enabling process used to manufacture the Phase I safety and early clinical study supply may be exceeded, with regard to capability, practicality, cost of goods (COGs), etc. There is still at least some flexibility to change the chemistry for early process steps at this point, if necessary, provided that ICH guidelines can be met, regarding any new impurities formed as a result, and that impurities detected and identified from the previous generation process are controlled within the limits qualified by toxicology studies for previous batches. The ability to perform a meaningful comparative analysis of the impurity profile of the previously used synthetic route with those from exploratory potential alternate early process steps depends on having sufficient baseline data in the TTP from early development. Potential genotoxic impurities (PGIs) also need to be more thoroughly evaluated and sufficiently controlled or avoided during this stage.

Mid-stage development typically includes screening experiments for design of experiments (DoE) studies, DoE itself, and early process design and definition. If possible, this information is used to manufacture a demonstration batch or batches to give an indication of process capability and identify additional R&D and optimization to be made prior to manufacture of registration and validation batches in late stage development. The rendering of DoE data into process knowledge that informs demonstration batch manufacture is another example of expansion of the process knowledge base during ongoing work, rather than between discrete stages of development.

The knowledge that is obtained from mid-stage development should, in theory, enable the preparation of a TTP that has content matching what is required for formal traditional technology transfer to a CDMO that has commercial manufacturing facilities. The knowledge base from which this pivotal TTP is prepared also helps to shape the content of a package for an End of Phase II (EOPII) meeting request with regulatory authorities. In preparation for the EOPII meeting, the current state of the API manufacturing process is summarized and a strategic proposal is provided to regulatory agencies for how the transition to late stage development and commercialization will be made, to get buy-in and/ or critical feedback. Based on the feedback, the strategy may need to be altered, which may also require additional remedial R&D and manufacturing work, which in turn can potentially affect the content of both the TTP and the knowledge base.

Late Stage Development - Process Design, Registration and Validation

Content and criteria for the preparation of late stage TTPs have been thoroughly discussed elsewhere.^3,7,8,9 A more abbreviated discussion is provided here.

The goals of successful technology transfer to enter late stage development are:

Creation and formalization of a manufacturing control strategy.

• Demonstration that the process knowledge base is applied to the implementation and qualification of the process.
• Risks and variability inherent to the process are effectively managed.

Metrics indicative of successful technology transfer are:

• Time required to transfer and implement the process in the commercial facility.
• Process performance.
• Manufacturability of API.

In transferring a process to late stage development, there is increased emphasis on certain aspects of the process in the TTP, including:

• Safety and hazard analysis.
• Operational practicality and efficiency.
• Supply Chain/COGs – raw materials, starting materials, reagents, catalysts, processing aids, shipping considerations.
• Waste generation and disposal.
• Equipment.
• A drawback of early process definition is that less flexibility in vendor selection may result from prematurely defined equipment requirements, unless the process is remaining at the same CDMO at which the earlier development work was performed.
• Small companies, in particular, need to maintain maximum flexibility in their API processes for as long as possible during development, since a commercial manufacturer of the API is usually determined after a significant portion of the development work is completed at another organization.
• Consistency in specifications for all critical materials that are process material inputs, whether manufactured in the process (GMP intermediates) or supplied from external sources.

Content for TTPs for late stage development typically includes the following:

• A manufacturing process description, including master batch records (MBRs).
• Definitive safety/occupational exposure limit (OEL) information for API, based on long-term toxicology studies .
• Validated cleaning test methods and verification for all relevant process materials.
• Safety and hazard analysis for all operations.
• A list of potential or actual critical process parameters (CPPs).

Late stage development is a time during which activities are the most compressed, and where the phrase “time is money” is most literally applicable. There are always shortcomings and incongruities that are encountered once a hard look is taken at the state of a given process in comparison with what is necessary to implement it successfully on scale, regardless of how well it has been conceived and executed to this point. The extent of remedial work required prior to formal entry to late stage development is a function of the strategy in the previous stages of development, the inherent difficulty of manufacturing the particular API, and the inclination and resources of the sponsor to mitigate risks identified in the earlier iterations of R&D and manufacturing. There is therefore always some expectation that late stage TTPs that are provided to vendors may not be adequate to transfer the technology into the intended facility, until remedial R&D and manufacturing is done to address the shortcomings of a process.

Challenges and Considerations Related to Preparation of a Late Stage TPP

Late stage development depends critically on a TTP derived from the process knowledge base generated at previous stages. As mentioned earlier, many risks need to be managed in the transition to late-stage development, such as changes to equipment based on scale, supply chain, including shipment, and regulatory factors (selection and justification of regulatory starting materials, process controls and control strategy, etc).

Another significant challenge that has emerged and become prevalent in the last decade or so arises from increased tolerance for risk in exchange for the promise of reduced drug development cycle times. The approach of doing a larger portion of the prerequisite development work “just in time” has been adopted in companies of all sizes. The rationale for this “lean” approach is conservation of capital, and, hypothetically, saving of time. For this reason and those discussed below, the extent and quality of knowledge, and thus of TTPs at the end of mid-stage development, are increasingly variable.

“Just in time” development is characterized by choosing to do studies in reaction to deficiencies as they come up, in an ad hoc fashion, rather than by planning them in advance. Many startups and entrepreneurial companies prefer to do “just in time” development and manufacturing as a strategy or tactic to manage budgets and timelines. It is also done in anticipation of an “exit,” the sale or partnering of the drug candidate asset prior to the need for formal technology transfer. Risk analysis and mitigation is compounded by this “pay me later” strategy, since the risk accrues like a “balloon payment” at the end of a financing agreement – the balance of risk at the end is higher by design, and there is a higher likelihood of “default.” The effect of “just in time” strategies on TTPs and the knowledge base for a given API process is that their content, by definition, will be lacking. Success, if achievable under these circumstances, does mean that less money is spent and that perhaps development is completed in time. However, the likelihood of serious problems and delays is increased.

The potential consequences of either unintended effects of discontinuous development or more intentional “just in time” approaches include incomplete, poorly coordinated transfers of information resulting in duplication of effort, avoidable errors, suboptimal processes, attempts to make up time lost by cutting corners, and inability to provide regulatory agencies with an idea of the late stage (EOPII) development strategy in time to get feedback on its viability, prior to its attempted execution. The net result is that late stage development of many NCE drugs is fraught with issues that might have been better addressed earlier in the effort. The onus is on those assembling TTPs, managing the knowledge base, making decisions and performing technology transfers to execute as judiciously and flawlessly as possible and “get it right the first time,” despite having less time and resources than ever. The proportion of late stage remedial work that will need to be performed prior to formal technology transfer, based on the above issues, is expected to continue to increase, and a new paradigm for development must address this phenomenon in a more strategic way.

Summary

TTPs are snapshots of the state of chemical syntheses or processes created specifically for the transfer of technology to a new vendor or to start a new major development initiative, but they do not exist in a vacuum. As development proceeds, TTP content is culled from a knowledge base that grows as the iterations of R&D and manufacturing occur in the drug development cycle. This article has attempted to emphasize the sequential nature of data and information generation, capture and transfer, and the need to convert it into the knowledge that is necessary for its use at each successive stage of development.

Recently, the ability to create a late-stage TTP with sufficiently robust content, in a timely manner, has become more challenging, due to the ultra-aggressive, stripped down approach to earlier stages of development. The number of hand-offs that a given drug candidate experiences during its development cycle has increased, and these transfers increase susceptibility to disconnection, misalignment, errors and delays. In addition, the intentional deferral of an increasing number of issues until immediately prior to late stage developmental manufacturing has created the need for increased R&D and problem solving at a point where delays and problems can be very costly. Deferral of issues can occur to the point that late stage vendors may decline to provide proposals for late stage work until significant remedial process work is completed. This extends and/or distends mid-stage development. Discontinuous development can compound the situation by undermining continuity, due to uncoupling of sequential stages of R&D and manufacturing. Generation of data, the knowledge base and TTP content benefit from continuity. If current prevailing trends in drug development persist in posing challenges to effective technology transfer, and there is no reason to assume they will not, new strategies will need to be developed to reduce difficulties in negotiating the midstage to late-stage development transition.

References

1. Levy, SG. Effective Outsourcing of Small Molecule Chemistry R&D and API Manufacturing for Emerging Pharmaceutical Companies – A Stepwise Approach to Risk Management, Pharmaceutical Outsourcing, January/February, 2014, posted February 3, 2014 https://www.pharmoutsourcing.com/Featured-Articles/153810-Effective-Outsourcing-of-Small-Molecule-Chemistry-R-D-and-API-Manufacturing-for-Emerging-Pharmaceutical-Companies-A-Stepwise-Approach-to-Risk-Management/
2. Brynjelsen, S, Dagar, S. Managing Technology Transfer: Developing a Complete CMC Package for an In-Licensed Product, Pharmaceutical Technology, 2011 http://www.pharmtech.com/managing-technology-transfer-developing-complete-cmc-packagelicensed-product
3. Harris, A. Chemical Drug Substance Development and Technology Transfer, in Technology and Knowledge Transfer, Keys to Successful Implementation and Management, M. Gibson, S. Schmitt, Editors, PDA / DHI Publishing, River Grove, IL, 2014, pp.97-160
4. Levy, SG. Expediency vs. QbD: Resolving the Conflict in Early and Mid-Stage API Development for Virtual Pharmaceutical Companies, Pharmaceutical Outsourcing, January/February, 2015 https://www.pharmoutsourcing.com/Featured-Articles/171807-Expediency-vs-QbD-Resolving-the-Conflict-in-Early-and-Mid-Stage-API-Development-for-Virtual-Pharmaceutical-Companies/
5. van Arnum, P. A perspective from FDA on ICH Q10 Pharmaceutical Quality System for Contract Manuracturers, Pharmaceutical Technology, 2010 http://www.pharmtech.com/ perspective-fda-ich-q10-pharmaceutical-quality-system-contract-manufacturers
6. Impurities in New Drug Substances Q3A(R2) Current Step 4 Version, October, 2006 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/ Q3A_R2__Guideline.pdf
7. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceutcals to limit potential carcinogenic risk, M7, Current Step 4 version, June,2014 http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf
8. WHO guidelines on transfer of technology in pharmaceutical manufacturing, World Health Organization WHO Technical Report Series, No. 961, 2011 http://apps.who.int/prequal/ info_general/documents/TRS961/TRS961_Annex7.pdf
9. International Society for Pharmaceutical Engineering (ISPE) Good Practice Guide (second edition), May, 2014 http://www.ispe.org/ispe-good-practice-guides/technology-transfer
10. Millili, G. Scale-up & Technology Transfer as a Part of Pharmaceutical Quality Systems, Pharmaceutical Quality System (ICH Q10) Conference, October 4-6, 2011, Arlington, VA http://www.fda.gov/downloads/Drugs/DevelopmentApprovalprocess/Manufacturing/uCM291604.pdf

Stuart G. Levy, PhD is Principal Consultant, SGL Chemistry Consulting, LLC. Stuart’s practice provides expertise in synthetic organic chemistry, chemistry R&D, API manufacturing and other aspects of CMC development to emerging pharmaceutical companies. The expertise provided by SGL Chemistry Consulting is a result of experience gained during employment at small, innovative biotech pharmaceutical companies (SUGEN, EPIX, Elixir) as well as at chemistry CROs/ CDMOs (SERES Laboratories, Ricerca). Stuart is an expert in outsourcing, and has managed outsourced chemistry R&D and API manufacturing for 16 of his 20 years in industry. Stuart obtained his PhD in Chemistry from the University of Illinois at Chicago, and did postdoctoral work in the School of Medicine at the University of California, San Diego.