API Manufacturers Compete through Process Optimization

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The pharmaceutical contract manufacturing market is expected to hit revenues of $80.5 billion in 2019, according to a report by business intelligence provider Visiongain (1). A notable trend is that pharmaceutical companies will continue to outsource more drug production operations. For several years, API manufacturing has formed the largest share of the pharmaceutical contract manufacturing market, driven by the increased use of generic drugs worldwide, the rise of biologics and biosimilars, and the growth of emerging markets such as India and China (1).

To remain competitive in an increasingly demanding pharmaceutical market, contract service providers are constantly striving to increase the capacity and efficiency of their manufacturing activities. Pharmaceutical Technology spoke to industry experts about process optimization in API manufacturing. Participants in this roundtable discussion include Joshua P. Van Kley, corporate sales and sales operations manager, Cambrex; David Goeddel, PhD, group leader, Process Development, MilliporeSigma; 
Andreas Stolle, vice-president, Process Development Services API, and Peter Poechlauer, innovation manager, who are both based in Linz, Austria, which is currently Patheon’s largest API manufacturing site.

Developing an API manufacturing process

PharmTech: What factors should be taken into account when developing an API manufacturing process? What guidelines have regulators provided?

Van Kley (Cambrex): When developing an API manufacturing process, there are a number of important considerations from a practical and logistical standpoint. Firstly, can the chemistry be performed at the manufacturing site in terms of handling the necessary solvents and reagents, and does the plant have the capabilities to accommodate the temperature ranges of the process? It is also important to evaluate the specific hazards and safety implications of undertaking the process.

Availability of key raw materials must be evaluated to ensure that they are readily available from existing suppliers, or whether new suppliers can be established, to avoid a situation where you are limited by supply of a key raw material or unable to import it.

It is also important to look at the process from an environmental point of view, to ensure that all waste can be handled and disposed of properly, and also to ensure that the process is scalable from laboratory through to the commercially projected scale. Hazards, by-products, and waste products that are not as consequential at smaller scale can become major issues at large scale, thus, it is important to factor these considerations in from the beginning.

There are also many other considerations that come into play, such as clinical phase, cycle time, the control of the product’s particle size, polymorphism, and handling issues such as the filterability of steps within the process. All these factors can have an impact on the quality of the product as well as cost of goods, therefore, it is important to bear them in mind when providing a quality product as well as meeting the customer pricing demands.

Goeddel (MilliporeSigma): Several factors should be taken into account when developing the manufacturing process for an API. Careful focus should be placed on ensuring that the overall purity, purity profile, and individual impurity levels are at acceptable levels to ensure the safety of the patient. Guidance has been provided in this area by the International Council for Harmonization (ICH) on threshold limits for impurity identification and qualification in API drug substances--ICH Q3A. In addition to organic impurities, process chemists should also pay close attention to residual solvent levels and elemental impurities when developing a process for API manufacturing. This factor is particularly important when metal catalysts are used in the API synthesis, and remediation techniques (scavengers, charcoal, or crystallization) are often required to reduce these impurities to the acceptable levels outlined in ICH Q3D.

In addition to impurities, another aspect that needs to be taken into consideration when developing an API process is the potential reactive hazards. Performing a thorough safety evaluation and modifying the chemistry as appropriate will enable the API to be made safely, which will help prevent operator injuries, plant or equipment damage, and potential supply-chain interruptions. The raw material supply chain is another important factor. Not only does the vendor need to be qualified, but they must also be able to ensure the long-term timely delivery of needed raw material quantities in the required quality.

Finally, throughput is another important factor that should be taken into account when developing a process. Improvement in yield lowers API cost and reduces waste, which will consequently benefit the patient, company, and the environment.

API purity, impurity levels, raw material supply chain, yield, and process safety are all important factors that should be taken into account when developing a process for API manufacturing. Focusing on those key areas will help secure both patient and employee safety while completing efficient chemical syntheses that reduce cost and minimize the impact on the environment during API production.

Stolle and Poechlauer (Patheon): The development of a 
pharmaceutical manufacturing process has to meet different requirements depending on the development phase of the product:

• In early clinical development (CT I), the primary goal is to deliver the required amounts of material quickly and in reproducible quality.

• Later on (in CT II), when the route is frozen, the production process must be reliable, well understood, and again deliver the product in the required quality. The appearance of potentially genotoxic byproducts in the final product must be excluded in a safe and scientifically sound way.

• Finally, the process for the final clinical trials (CT III) and launch of the product must be scalable to deliver the required product volumes with predictable quality, and it has to be environmentally benign and economical on resources.

• After product launch, the process must have room for continuous improvement without major changes.

In addition to the process figures, the following factors must be taken into account:

• Availability and safe supply of starting materials in constant quality

• Investments in equipment to operate the envisaged process at the desired scale

• Start-up time and time demand for capacity changes

• Easy process transfer between different manufacturing sites to meet local demand and support supply-chain optimization.

The current regulatory environment supports advancing regulatory science and innovation, which may include abandoning some traditional manufacturing 
practices in favor of cleaner, more flexible, and more efficient continuous manufacturing. Regulatory authorities in the three ICH regions and beyond are encouraging the industry to adopt new technology as supported by ICH Q8(R2), Q9, Q10, and Q11; and the introduction of quality-by-design (QbD) concepts, emphasizing science and risk-based approaches to assure product quality. The regulatory expectations for assurance of reliable and predictive processing, which is technically sound, risk-based, and relevant to product quality in a commercial setting, are the same for batch and continuous processing.

Optimizing process chemistry

PharmTech: How do you optimize process chemistry in API manufacturing? What are the key considerations?

Stolle and Poechlauer (Patheon): Our key considerations in optimizing process chemistry are driven by optimizing the service to our clients. This approach comprises considerations such as:

Chemicals and reagents:

• Are the involved chemicals and reagents reliably available?

• Is their price acceptable in view of the target product price?

• Are the solvents recyclable?

• Does the generated waste pose a problem?

• Is it biodegradable?

Process conditions:

• Can we develop a sufficiently detailed process 

• understanding?

• Do the chosen conditions allow quick and safe scale-up?

• Is the process easily transferable between sites or does it require specialized equipment?

Batch-wise versus continuous processing concept:

• Will the process yield/throughput profit from continuous manufacturing techniques?

• Will process control profit from continuous manufacturing?

• What are the options for rework?

Process control:

• Can we develop a sufficiently quick and easy process control system?

• Are the chosen analytical methods reliable and easily transferable?

• Does the process control system support continuous process verification?

Our optimization strategy comprises both classical determination of proven acceptable ranges (PAR) values and, in tight collaboration with clients, strategies of multivariate analysis and other elements of process analytical technologies. In addition to technical aspects of optimization, there are aspects related to client requirements, such as use of innovative but proven technologies to provide maximum value.

Van Kley (Cambrex): Initially, the process is carried out in its current state using the conditions provided by our clients. This approach allows us to observe the chemistry and get a feel for how it performs. From there, the next stages of development investigate ways to reduce solvent volumes, increase yields, reduce cycle times, lower raw material costs, and lower waste costs. These steps are crucial to improving product quality and the economics of the process, which allows us to pass efficiencies and qualityon to our clients. Most of this work is undertaken in the chemical development laboratory prior to going into production. Once in production, the chemist and engineer assigned to the program will further work on optimization of the process based on observations made during production. In addition, our continuous improvement/six sigma group will also contribute to the optimization process once the program is in validation or commercial launch. The group will help in managing the lifecycle of the program along with looking at ways to continually improve the efficiency of production by data mining.

Typically, we will see programs that have chromatography steps within the process, high volume issues, filtration issues, and/or long cycle times. Our development efforts are centered on removal of any chromatography processes if present for scaling purposes, volume reductions, faster filtrations, and cycle time reduction, either for efficiency or the possibility of telescoping steps to reduce unnecessary isolation steps if the process lends itself.

Goeddel (MilliporeSigma): We strive to perform phase-appropriate process optimization for API manufacturing. Process optimization means very different things for Phase I clinical programs compared with programs that are entering validation. For an API that will be entering Phase I, the key objective is usually to rapidly develop a process that can safely yield the required API with the necessary quality attributes. This way, clinical evaluation of the API can begin quickly, which is important for both drug developers and patients who seek successful treatment. As the program advances toward validation and commercial launch, greater emphasis is placed on improving yield and gaining greater process understanding to support process validation and eventual launch.

No two programs are the same, but there are some consistent factors that generally apply to most programs. We consider several factors when deciding whether the incoming synthetic route can be used or if a new synthesis should be developed. Raw material supply chain, process safety, projected future API manufacturing costs, likely commercial scale, and timing all play an important role in the decision-making process. After a route is selected, proof-of-concept studies are performed to determine whether or not the proposed route can generate the API. We then optimize the process to reliably and safely generate API in adequate quality. This objective is achieved by building process understanding through many techniques, including impurity origin and control, identifying critical parameters, and setting appropriate limits on operating ranges. We develop this chemistry with an eye on the intended commercial manufacturing scale, because APIs that will be manufactured on a smaller scale will have more processing options available than those that will be made on a larger scale. During the final phase of optimization, experimentation is performed to determine if the API can consistently be manufactured with the required quality attributes. Statistical design of experiments is a particularly useful technique for these studies, because interdependent variables can readily be identified. The successful completion of these phase-appropriate process optimization efforts enables us to deliver high-quality clinical batches and commercial supply in a timely manner, which is important for our customers and their patients.

Ensuring API quality

PharmTech: How can manufacturers ensure that APIs of the intended quality are consistently produced?

Goeddel (MilliporeSigma): Manufacturers take steps that span from early research and development through commercial manufacture to ensure that APIs of consistent quality are produced. The general pathway for this process is outlined by FDA and involves three phases: process design, process qualification, and continued process verification.

During the process design phase in development, great effort is made to understand what parameters are critical. Building upon that knowledge, the process is optimized as necessary to enable the desired quality attributes to be consistently achieved. Manufacturers then perform a failure modes effects analysis (FMEA) on the process to identify processing risks that could impact quality attributes. From that exercise, additional experiments can be designed to address risks identified in the FMEA to ensure that the critical quality attributes are reliably met. During this stage of development, manufacturers perform stress testing, stability studies, design of experiments, and range-finding studies to help ensure that the intended quality is 
consistently produced in subsequent manufacturing.

The process qualification phase involves an assessment of whether or not the process is reproducible. There are two major components to process qualification. The first part involves the qualification of the plant and equipment to ensure everything works as intended. The second part involves the qualification of the process itself through an activity known as process performance qualification (PPQ). PPQ involves drafting a protocol, execution of the protocol for the specified number of batches under current good manufacturing practices (cGMPs), and issuance of a report. Following successful completion of the process qualification, the process can be used for commercial supply of the API.

The process to ensure product quality does not end with product launch. Manufacturers use systems that enable them to track process data and identify any sort of trend that may require intervention. Furthermore, an adequate facility and equipment maintenance program ensures that the plant and equipment are functioning at the desired level. By performing all of the aforementioned activities, manufacturers can ensure that APIs of the intended quality are consistently produced.

Stolle and Poechlauer (Patheon): The key to consistent quality product is a sound process understanding combined with effective process control. Process understanding suffers if the features of the processing equipment mix with features of the actual chemical reaction, blurring them and interfering with precise process control. Consistent production of APIs of intended quality starts with a kinetic and thermodynamic analysis of the synthesis reaction. The rate, energy balance, and kinetics of by-product formation and factors such as equilibria of phase distribution determine the requirements of the process. They in turn determine the features of the processing equipment and ultimately the equipment selection. They also determine the control strategy to effectively safeguard consistent product quality. A sound process understanding allows the 
conscious choice of proven acceptable ranges for reaction parameters and intermediate product quality. It avoids overly narrow parameter ranges or unnecessary tight intermediate product specifications and thus allows for continuous improvement without putting API quality at risk. In many cases, continuous processing simplifies the precise control of process conditions even for processes that are very exothermic or require quick mixing to establish the correct stoichiometry and avoid byproduct formation.

Continuous processing equipment can be tailored to meet the respective requirements of a chemical reaction or work-up section with moderate effort. Its combination with state-of-the art methods of continuous analytics allows precise and reliable control of product quality.

There appears to be a paradigm change: instead of slowing down the chemistry to a degree to allow large-scale batch processing equipment to cope with heat evolution etc., the developer determines ideal conditions for the respective chemical transformation and defines (or if necessary constructs) suitable processing equipment and control instruments. This approach leads to more modern ways of processing and, as the PAT guideline (2) stipulates, ‘development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance.’

Van Kley (Cambrex): An important step is performing critical process parameter studies. A critical process parameter study is initiated to identify those critical parameters in the process that affect the final product quality and reproducibility. Typical critical parameters to be investigated at each step requiring validation may include: temperature, charge ratios, pressure, vacuum, time (duration), flow rate, cooling rate, and agitation speed, among others.

Critical process parameters are usually identified and studied after initial laboratory work, or after initial manufacturing campaigns, when the chemists can observe the behavior of the chemistry at scale. Our customers typically dictate when they want this work to be performed to tighten up the operating parameters.

From a quality perspective, Cambrex follows ICH Q7 guidelines. In addition, we have a strong analytical method validation program in place for all analytical methods, including cleanout methods for each isolated intermediate as well as finished goods. The validated cleanout methods not only ensure quality for the current product being manufactured, but also ensure the quality and integrity of the plant for the next product to be produced, as we operate a multipurpose facility with non-dedicated production streams.

References

1. Visiongain, “Pharma Contract Manufacturing Services Market Will Reach $80.5 Billion in 2019,” accessed July 19, 2016. 
2. FDA, Guidance for Industry, PAT--A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004).