This article discusses the manufacturing and process development approach taken from an early development stage through scale-up and tech transfer to commercial manufacture. It includes discussion of cold fill and pressure fill technology, both of which are effective and have their specific advantages. It also cites comparisons and points to consider when assessing and selecting cold fill or pressure fill for the manufacture of pressurized metered dose inhaler (pMDIs).

Ideally, projects can be developed quickly and inexpensively, meet customer preferences without impact on the expectation of a single cycle review, are easy to routinely manufacture and batch release, and tick all of the boxes that allow a product to be well marketed and available to patients at a competitive price to the health care provider.
In order to achieve these aims, it is important that the product development scientist and process development scientist work synergistically to develop a thorough understanding of what is required to realize a successful commercial product. Holistic technical and, indeed, business decisions throughout the development cycle facilitate a smooth transition through product and process development, scale-up, commercial manufacture and launch.

Recent guideline changes and the introduction of Quality by Design (QbD) initiatives¹ further emphasize the requirement to understand the relationship between input raw materials, formulation, process design and product performance. These factors, risk assessed and investigated appropriately, together, result in a validated commercial manufacturing process that is both robust and flexible.^2,3 This approach brings advantages such as a greater understanding of design space and process controls, enabling efficient technology transfer of new products and processes into the commercial environment, where they can supplement such things as lean manufacturing, continuous improvement programs and sustainability initiatives.

The role of the process developer is integral in this environment because, very often, scientists can gravitate to working in isolation, focusing on their specialism without appreciation of all stakeholders and their value to each other. This is a characteristic that lends itself well to deep concentration and study, but unfortunately can be a hindrance in the multi-stage development of a new drug product where all aspects of a successful commercial project must be considered. The role of the process developer, therefore, is to facilitate communication along all the touch points of the development commercial spectrum, and to ensure that the right data are being generated at every stage.

One metaphor that may be useful in understanding process design and development is that of designing a kitchen. It is entirely possible and unfortunately common for a kitchen to be designed that looks impressive, with top-quality equipment and advanced features, but for the kitchen to still function poorly. When the person who designs the kitchen is not the person who will spend decades cooking in it, there will be an obvious disconnect in what each party envisions. A simple detail, such as the direction a door opens in, may make the difference between a room that is a pleasure to use and one that is a nuisance. The only remedy for this problem is for the designer and the user to communicate closely from the very beginning of the concept stage and to ensure that the final product is one that will be both functional and beautiful. In pMDI development, a process developer serves as the intermediary between the “designer” and “user” to help avoid the problems that each of them could not anticipate alone and to develop a culture going forward of ‘integrated engagement’.

Exploring this kitchen metaphor further, we can consider what would happen if the kitchen were designed to make only one kind of dish, day-in and day-out. The floor plan and appliances could of course be optimized for that particular dish, but it would still be crucial to consider the ongoing sourcing of raw materials to ensure consistency and quality. Cleaning must also be considered, as it too plays a role in the product’s quality. The pharma industry often prioritizes product development over process and cleaning development, because the product is the end result that can be seen and felt. However, it is the process that makes the product. Product and process development must align so that changes in process settings that will influence the product’s performance can be understood and controlled.

An overview of the development cycle
The role of the process developer encompasses work at each of the three stages of manufacturing. The processes and equipment may differ for each stage, making it important for someone to plan for the continuity from one stage to the next. Each of the three stages are summarized here:

Feasibility stage
Early phase batches are typically manufactured at lab scale, filling anything from single containers to small-scale batches of hundreds of units. It is at this stage of the project that product and process scientists should give consideration to all factors that may influence product and process viability, providing valuable insights to enable future risk management.

Pilot scale
To bridge the transition between lab and full scale, pilot scale batches of thousands of units are manufactured on equipment more representative of the commercial manufacturing process. At this scale, multiple batches can be manufactured and equipment cleaning experiments can be performed without the need to use the commercial manufacturing facility, resulting in reduced project costs and mitigating future risks. This is particularly effective where new and novel materials are both expensive and potentially in short supply.

Commercial scale manufacturing options
It is the expectation that the product and process development scientist will manage and mitigate all significant risks through laboratory and pilot scale development to allow seamless introduction of new and /or novel processes into the commercial facility. This allows for the completion of equipment designs and fabrication and qualification of manufacturing equipment specific to product needs. Strategic project planning is critical to ensure that the right experiments are performed at the right time and knowledge is transferred throughout the development program.

pMDI Manufacturing Process Overview
In the manufacturing of pMDIs, developers have two major approaches to choose from: cold filling and pressure filling.⁴ Both processes are an effective means of commercializing products and have their advantages dependent on the nature of the product or formulation being manufactured. See Table 1 for points to consider.
In addition, two major types of formulation exist, namely suspension and solution, and each demands consideration of different factors to enable successful commercialization. Both approaches require careful development and understanding to establish critical process parameters, which need to be optimised, justified, measured and controlled throughout the manufacturing process.

The general principles of manufacture for pMDIs involve 5 main stages:

1. Propellant batching
Since the propellants used in pMDIs are gaseous at normal temperature and pressures, they must be liquefied to enable manufacturing equipment to process them efficiently. Liquification can be achieved either by lowering the temperature, (cold filling) or by applying pressure (pressure filling).

In the cold filling process, volatile propellants are liquefied by chilling below their boiling point in a refrigerated vessel, where typical temperature ranges from -50°C to -60°C.

For pressure filling, pressure is used to condense the propellant. The propellant is held in a pressurized vessel in liquid form, typically at 100 psi.

2. Concentrate preparation
This stage involves the creation of a concentrate by mixing the active pharmaceutical ingredient (API) with a solvent or carrier that is liquid at room temperature. This is transferred to the batching vessel on completion. Consideration should be given to the stability of the input raw materials (physical and chemical), so that appropriate choices can be made regarding routes and orders of addition and whether to formulate the concentrate as either a suspension or solution. Additionally, in the case of cold filling, it may be appropriate to manufacture the concentrate as a chilled liquefied propellant mixture.

Typical factors that are considered at this stage include material handling and isolation, rates, orders and methods of addition, temperature ranges, pressure ranges, mixer speeds, pump speeds, etc.

3. Canister filling
Cold Filling: The concentrate is pre-mixed with the volatile propellant at low temperature within the batching vessel, formulation is dispensed directly in a single filling step into the empty pMDI canister, and the metering valve is then crimped into place. Cold filling does not require any formulation to be driven through the valve.

Pressure Filling: There are two main variants of pressure filling: the two-stage method and the single stage method, though the industry is currently almost entirely single stage.

In the single stage pressure filling method, the concentrate is pre-mixed with the volatile propellant under pressure within the batching vessel, and formulation is then injected through a pre-crimped metering valve and canister.

In the two-stage pressure filling method, a concentrate of active drug and excipients are filled into the empty canister. A valve is then placed and crimped to the partially filled canister and the volatile propellant injected through the metering valve.

Both two-stage and single-stage pressure filling rely on a step in which material is driven backwards through the valve at high pressure, as opposed to the normal patient-use operation in which the valve opens to allow formulation out of the canister.

4. Post filling activity
The post-filling stage for products manufactured by either the cold-fill or pressure-fill method involves typical process controls of fill weight and crimp dimension checks, as well as heat stress challenge and function testing before through batch units are sampled for product release testing according to the specification.

5. Equipment cleaning
Cleaning development is an integral part of the process development phase⁵, with the expectation that equipment design considers clean ability and cleaning data is generated at an early part of the project. It is a truism among process developers that if you can’t clean it, you can’t make it, and therefore cleaning must never be treated as an afterthought. Dedicated equipment must be verified as visibly clean, including any hot spots. Non dedicated, shared equipment must be verified as clean to an Acceptable Residual Limit, which considers the toxicity of the API and excipients and cleaning materials used as well as the nature of the follow-on products. Cleaning methods are developed, optimized, confirmed and validated.

Conclusion
Modern process development demands a dynamic approach to enable efficient and effective outcomes that will produce reliable high quality product with low risk, satisfying high regulatory standards and the ever-changing demands of the commercial world. By adopting this approach, companies can increase their opportunity for success. Thoughtful process development reduces project risks, facilitates a robust and flexible manufacturing process, and allows a high quality product to be consistently produced on target, on budget and on time, meeting the expectation of the business and all stakeholders. 

References:

1. A Regulatory Perspective on the Current and Future State of Pharmaceutical Quality, International Conference on Drug Development, Austin, TX, Feb 26, 2013.
2. Dynamic Design Space as an Integrated Component of Quality by Design – Benoit Igne, Zhenqi Shi, Sameer Talwar,Carl A Anderson, James K Drennen, Duquesne University Centre, of Pharmaceutical Technology, Pittsburgh, PA, USA. January 2011
3. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, January 2011.
4. Metered Dose Inhaler Technology, Tol S Pureval, Informa Healthcare, 2007
5. Validation of Cleaning Processes (7/93) Food and Drug Administration Pharmaceutical “Quality by Design” (QbD): An Introduction, Process Development and Applications
6. Inhalation Manufacturing: Cold Fill, Pressure Fill and Finding the Right Partner. Ross Errington. www.ondrugdelivery.com Copyright © 2012 Frederick Furness Publishing

3M is a trademark of 3M Company.© 3M 2016. All rights reserved.

---

Steve Haswell is a process development specialist for 3M Drug Delivery Systems. He has been with 3M for 16 years and his current role has a focus on pMDI process technology. His team of scientists and technologists are responsible for process and cleaning development and technology transfer from R&D into commercial operations.