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Pharmaceutical Manufacturing and Packing Sourcer

Fit for Purpose

Simplification in pharmaceutical formulation can encompass several definitions, but it certainly doesn’t equate with ‘doing less’ – rather, it often requires considerably more advanced processes than the industry is used to

The pharmaceutical industry is facing unprecedented pressure to reduce costs, streamline processes and drive increased productivity. All phases of the discovery and development cycle are affected, including development of the dosage form and the processes applied in the manufacturing of formulated products. As part of this transformation, we are seeing an increased focus on tailoring drug formulation and manufacturing strategies to provide dosage forms that enable key clinical questions to be more efficiently and effectively answered at each phase of clinical development, including first-in-man (FIM), recommended dose and completion of Phase 1, proof of concept, Phase 2b, and so on.

Approaches to drug formulation and manufacture have evolved over the years, with a major trend being the desire to get to FIM with a formulation quite similar to the final commercialisable form. Unfortunately, this approach can result in delays of the FIM trial for candidates – even those with a low risk of failure due to safety and tolerability. This approach can also waste time and resources when a significant attrition is relatively easy to forecast, as may be the case of a new chemical entity with a new scaffold, or one that operates via an unprecedented mechanism of action. Indeed, numerous challenges can be encountered, including:

  • Later dosing in humans
  • Set-up of market-like formulations and processes at the very beginning of development
  • The need for a larger amount of API to execute pharmaceutical development activities with a material that should be representative of the scaled-up active ingredient
  • Time and resources dedicated to all molecules at the same level with no rationalisation of investment for those needing more extensive formulation development, such as improvements to bioavailability, prior to dosing into humans

Such a differential development approach challenges all disciplines – including toxicology, DMPK, chemistry and pharmaceutical development, and clinical sciences – to design the minimum regulatory package for FIM studies suitable for supporting the clinical trial investigation, with the maximum return in terms of clinical endpoints, pharmacokinetic data, and clear ‘go/no go’ decisions. Given this framework, striving for simple formulation and manufacturing approaches is essential. Unfortunately, the process of simplification can have significant drawbacks due to the need to identify early in the process what can be skipped or eliminated and what must remain.

This concept of ‘simplification’ in dosage form development is a relatively new trend, with varying definitions. We can define simplification of the formulation development process as designing the most straightforward approach to dose an active molecule into humans with a dosage form that requires a limited number of additional ‘ingredients’, a limited number of operational units, and still is effective in releasing the active drug into the body. A common mistake in the industry is to equate ‘simplification’ with a process that is ‘simplistic’ or requires ‘doing less’.

The risk here is that the formulation is merely a galenic exercise; and while it may be an excellent galenic exercise, it may be completely disconnected with the drug’s final use in vivo. In this case, ‘doing less’ equates with doing something of little use and provides little insight about the relationship between in vivo performance and the dosage form attributes.

Simplified, but not Simple

The process of simplification demands a clear understanding of the biopharmaceutical profile of the API, the final dosage form and an assessment of the risk associated ultimately with the progression of the simple formulation with the target commercial dosage form.

Striving for a simple formulation and manufacturing is a must, as it saves time and resources (key drivers in the early stages of development), and reduces the complexity of the overall process. At a very basic level, this approach allows companies to accept gaps during early development with the knowledge that those gaps can be addressed at a later stage of development.

With this approach, the delivery system or dosage form can be qualified, highlighting weaknesses and scientific knowledge gaps to determine what must be addressed at this stage and what can be addressed in a further phase (having the mitigation plan already ready anyway). For example, solid state stability/ polymorphic profiling may not be fully qualified in early stages when this attribute is not critical for the in vivo performance.

Simplified systems for early phases means:

  • Utilising the most efficient route for delivery of the product to answer key clinical questions
  • Getting clear yes/no answers to the key questions with minimal risk of inadequate performance
  • Use of minimal resources to manufacture (cost, time and effort)
  • Minimal evaluation effort (first intents have value in this respect)
  • Consideration of patient benefit and full development/ commercial efficiency

Examples of what can be skipped while using a simplification approach are resolution of long term stability issue (with the caveat of always knowing/understanding the source); addition of the excipient required to support industrial batch production requirements; and development of imaging.

The main drivers we can single out that are responsible for this focus on simplification include several factors.

A desire to reduce the investment in drug candidates prior to demonstration of their clinical efficacy is essential, as is the need to apply first intent strategies to speed up the development of APIs with the most manageable physiochemical profile to focus greater efforts on to the development of ‘troublesome’ molecules. The management should also need to reduce the time-to-market for new chemical entities (NCEs) and in particular for molecules with unprecedented mechanisms and/ or potential blockbusters, and should desire to increase the sustainability profile for emerging markets, both in terms of cost containment and increased manufacturability opportunities.

Answering Questions at Each Phase

A set of critical objectives must be achieved at each stage of development and strategies for API development must align with these. A simplified approach can help. During early development and pre-proof of concept, what’s the most efficient way to deliver product to answer the key clinical question(s)?

  • Clean yes/no to the key question, minimal risk of inadequate performance
  • Minimal resource to manufacture (cost, time, effort)
  • Minimal evaluation effort (first intents have value in this respect)
  • Consideration of patient benefit and full development/ commercial efficiency

During full development (proof-ofconcept to launch), what’s most efficient to deliver a fully understood (QbD) product to launch?

  • A minimal number of process steps
  • A minimal process complexity
  • A minimal number of parameters studied in experimental design (including the number of components)
  • The number of parameters that are critical for optimal product performance (likely critical quality attributes)
  • Simplicity of scale-up (continuous manufacture)
  • Minimal investment needed to manufacture on a production scale
  • Consideration of patient benefit and commercial efficiency

For commercial manufacturing, what is most efficient to manufacture on an ongoing basis?

  • A minimal number of process steps
  • A minimum delay between process steps, suitability for parametric release
  • A minimal risk of batch failure
  • A minimal wastage from losses and sampling

The simplification paradigm for drug formulation development can help support all of these stages. A key requirement for simplifying the formulation development process is a stronger relationship between the chemical development team and drug product development, since the simpler the formulation and the manufacturing process demands, the better the performance from the API. In other words, the critical quality attributes of the API have to be assessed and kept to a minimum at each development phase to avoid impact on clinical performance (for PK exposure extent and consistency). The CQAs of the API have to be assessed and possibly minimised in order to slim down the dependency of the PK profile and its reproducibility upon the variation in API batches, or to track the effects on the PK versus the identified CQAs.

In the simplification paradigm, dosage form attributes differ for investigational stages versus commercialisable stages. The formulation drivers also differ: clinical questions for the investigational dosage forms (even if the subject compliance is anyhow relevant), and the drivers being the patients and marketing requirements for commercialisable stages (see Table 1)

A useful approach for formulation strategy is ‘fit-for-purpose’ versus ‘tactical’ (see Figure 1). A general trend appearing is that the big pharma companies are more prone to consider both approaches, while the small to medium companies tend to progress the fit-for-purpose approach as long as possible.

A fit-for-purpose formulation is designed to get the available drug into the body as rapidly as possible, and it is recommended when a high attrition is expected. Typically the gap in attributes versus the final target product profile is significant. A tactical formulation designed to get the available drug into the body with a dosage form that mitigates the properties of the API can be used up to proof-of-concept and potentially ‘converted’ into a commercialisable formulation.

A ‘fit-for-purpose’ approach is well-suited to answering questions related to safety and tolerability, as the resources and time required to accomplish this target are significantly less than for other more conventional approaches


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Massimo Bresciani started his career in 1989 in a start-up pharmaceutical company targeting the potential for applying advanced physical pharmacy concepts to advanced drug delivery. During his 22 years of experience in the pharmaceutical field he has covered many roles in different sectors. He has 15 years of experience in pharmaceutical dosage forms development, drug delivery systems, and in formulation and technology development, enriched by the knowledge of key concepts in pharmacokinetics and biopharmaceutics. Massimo is currently Director and Head of CMC Business Unit within the Medicines Research Centre at Aptuit Verona in Italy. Email: massimo.bresciani@aptuit.com

After her PhD in Chemical Science, Patrizia Ghiotti started to work in pharmaceutical companies in 1998, specifically in pharmaceutical development, focusing on drug development activities throughout the compound development process, from candidate selection to early/late clinical phases, up to market launch. Patrizia is currently Product Development Senior Manager at the Medicines Research Centre at Aptuit Verona. She is accountable for the pharmaceutical development of finished dosage forms with required quality and productivity, coordination of DP development and supply activities, as well as being responsible for ensuring state-of-the-art results in small molecule formulations, from laboratory through to transfer and commercial manufacturing sites. Email: patrizia.ghiotti@aptuit.com

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Massimo Bresciani
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Patrizia Ghiotti
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