Anil Kane

	Oral solid-dosage forms (typically, tablets and capsules) are manufactured using conventional manufacturing processes such as direct blending or granulation techniqueswet granulation, dry granulation/roller compaction, or fluid bed granulation followed by fluid bed drying, milling, compression, and coating. It is important to understand the critical processing parameters (CPPs) that impact critical quality attributes (CQA). The CQAs that impact the final outcome (i.e., the therapeutic efficacy of the drug product) usually are parameters such as in-vitro dissolution and drug product stability. In-vitro dissolution of the drug can influence the rate and extent of drug absorption. Drug substance properties such as particle size, morphology, dosage strength, and drug loading have a big impact on the blending process and can influence the homogeneity of the drug substance in the blend. Blending is a critical process that needs to be optimized and is considered a CPP that can impact the potency of the finished product. Similarly, each of the granulation techniques has a processing step that could cause variability and has the potential of impacting the CQAs. Key parameters that need to be optimized (see Table I) will depend on the API properties, its stability, dose, drug loading, and other factors.

	Table I: Process and critical process parameters that require optimization.

					Number of revolutions of the blender

	A typical process optimization methodology includes a systematic identification of CQAs, CPPs, and a risk assessment to identify the critical selection of key parameters. A plan can then be drawn up, using a statistical design of experiments (DOE), which can be a full- or partial-factorial design, based on the availability of API and the number of runs that can be manufactured. The DOE experiments involve running parameters at high, medium, and low values, as well as running a defined number of control runs at target parameters. By analyzing the data from the DOE runs, a design space can be identified. Knowledge of the design space enables a control strategy to be defined for the manufacture of the product.

	A similar approach is taken for formulation optimization, in which critical functional formulation excipients are evaluated with high, medium, and low levels, and the impact of these variables is studied on output parameters of that functionality (e.g., disintegrant levels studies can be done with the rate of disintegration of tablets as the output).

	A systematic DOE to optimize the formulation composition in an oral solid-dosage form is important for two main purposes:

		To ensure the optimum level of a functional excipient in the formulation. In an immediate-release tablet formulation, excipient levels of binder, disintegrant, and lubricant can be varied and the functionality challenged. A partial or full factorial DOE can evaluate multiple excipients at different levels of the excipient. For an extended-release tablet formulation based on a hydrophilic gel matrix, polymer levels will affect the release rate of the drug from the tablet. Hence, the level of polymer is selected based on the specifications or the target release profile.

		To optimize the drug load in a formulation to reduce the pill burden, especially for a large dose drug product. Many oral solid-dose products need to be formulated in doses above 100 mg per unit tablet or capsule. There are quite a few new chemical entities that need a much higher dose up to a 500 or 750 mg per unit dose. Fixed-dose combination therapies are becoming more popular, due to synergistic therapeutic effects and as a lifecycle management strategy. The number of actives and the dose per unit tablet are increasing. Thus, there is a need to formulate such products in a way that the tablet size is reasonable to swallow, especially for geriatric patients. It is important, therefore, to optimize the formulation so that the drug load in a tablet is as high as possible, which also means that there is little room for inert excipients. Selecting the right functional excipient in the right quantity thus becomes more crucial.

	Products with multiple doses use a “dose weight proportional” strategyâusing the same formulation composition (drug to excipient ratio) and compressing the larger dose into a larger tablet size. This strategy has the benefit of avoiding a separate stability study as the drug to excipient ratio is the same; however, the disadvantage is that the higher dose becomes a large tablet, which may present “patient compliance” issues because of difficulty in swallowing. The limited time available for developing clinical trial formulations often makes optimization of drug load and tablet size a low priority.

	During this stage, however, it is important that the choice of excipients, level of excipients, the drug load, and reduction of pill size and burden are optimized. Polypharmacy is a huge problem, and patients would benefit greatly if better drug products that are easier to swallow can be developed. Optimizing the formulation at the right stage in the development program by increasing the drug load per unit tablet or capsule, thereby, reducing the pill burden, would be beneficial.

	Anil Kane is executive director, Global Head of Formulation Sciences, Pharmaceutical Development Services at Patheon.

	When referring to this article, please cite it as A. Kane, “Key parameters to be optimized in the development and manufacturing of oral solid-dosage forms” sidebar to “Designing Optimized Formulations," 

Articles

Anil Kane, executive director, Global Head of Formulation Sciences, Pharmaceutical Development Services at Patheon discusses key parameters in the development and manufacturing of oral solid-dosage forms.

Key parameters to be optimized in the development and manufacturing of oral solid-dosage forms

Pharmaceutical companies walk a tightrope in early drug development. They have to balance speed, quality, scientific risk, and API cost. Compromising on any one of these four crucial elements can prove fatal to a product candidate.

	While advancing from preclinical through Phase II trials as quickly as possible, developers must make a number of important decisions about product formulation and process design. Over-engineering a Phase I or Phase II drug that ultimately fails in the clinic could be a costly waste of resources. Neglecting sound science during early formulation and process development, however, could mean that a promising Phase II drug poised to enter Phase III trials may not have a manufacturing process that is scalable or commercially viable.

	The competitive and hard-changing healthcare market certainly demands expeditious and efficient drug development from pharmaceutical companies. Key stakeholders (e.g., shareholders,  senior management, and board members) want a “go/no go” decision at the earliest possible stage. Every single product candidate, however, requires an investment in formulation and product design just to reach a point where its clinical and commercial potential can be evaluated.

	A key milestone occurs when preliminary evidence of efficacy in a relevant patient population becomes available, typically during or immediately after Phase II trials. A study in 

 showed that slightly more than two-thirds (68%) of experimental compounds fail at this pivotal Phase II juncture. Failure rates are 35% and 40% for Phase I and Phase III compounds, respectively (1). For the roughly one-third of Phase II candidates that do advance, a scalable and commercially viable manufacturing process and formulation must already be in place or costly, game-changing delays could arise.

	All drug developers--from virtual and small firms through mid-sized and top-20 pharmaceutical giants--face the same challenge of being prepared to develop their fraction of viable product candidates efficiently no matter their business models or exit strategies for an asset. The following strategies can help companies navigate the drug development tightrope and advance product candidates with maximum efficiency:

Practice sound science and build in quality from day one


	Although FDA and the European Medicines Agency (EMA) introduced pharmaceutical quality by design (QbD) in international guidelines more than five years ago, most drug developers remain unaware that the real benefits of sound science go beyond smoothing the regulatory pathway. A science- and risk-based approach to drug development and manufacturing, QbD is an opportunity to add value by building quality into products and thereby gaining a business advantage. It is not a mere line item expense.

	Adopting a QbD approach at the formulation design stage has become essential as iterations toward the target product profile are minimized, and the overall risk to the project is reduced (see 

practices that create value and mitigate risk include statistical design of experiments (DoE), a branch of applied statistics that deals with planning, conducting, analyzing, and interpreting controlled tests; and failure mode and effects analysis (FMEA), a systematic, proactive method for evaluating a process to identify where and how it might fail and how to correct the problems.

	For example, FMEA can provide a rigorous up-front “set-up” of problems. Relying on the unbiased analyses enabled through FMEA experimentation and modeling, issues surface that are not limited to ones that could have been predicted based solely on experience. By identifying and correcting the root causes of problems early in the design phase of the process- and product-development cycle, companies can cut the risk of later stage quality, yield, and supply-chain issues.

Two recent cases highlight the hazards of neglecting the scientific method


	A drug company recently developed a tablet formulation for a large-dose antiviral drug. The formulation had a high drug loading. The formulation and process development was performed at an approximate scale of 10 kg. The process worked for this scale of operations as the run time for compressing the tablets was short. To supply enough product for pivotal clinical trials, however, the process had to be scaled up hastily to approximately 300 kg. However, a systematic scale-up study was not performed and critical process parameters (CPPs) were not identified. Despite the risks, the process was scaled up to 300 kg.

	During compression of the tablets at 300 kg, granules adhered to the tooling, and the tablets could not be compressed after the initial run. An investigation revealed that the granules had a sticking tendency and formed a film on the tablet turret and tooling. Also, the materials could not be compressed at higher speeds of compression. A systematic DOE study of the compression behavior, compressibility, and speeds of compression at a pilot scale would have identified the problem, and the issue could have been addressed by formulation, process, or engineering solutions.

	Another company formulated a potent drug substance into a low-dose, solid oral tablet. The process involved direct blending and compression. As the formulation had an extremely low percentage of API, the blend and content uniformity of the API were crucial. But the Phase II formulation and process was scaled up to approximately 150-200 kg without proper process understanding or risk assessment. When that happened, the batch no longer met the necessary criteria for blend uniformity or content uniformity. A systematic study of the impact of particle size distribution of the API in the blend, or particle size of other major excipients, would have been invaluable to identify the CPPs. A study of the influence of various blending times on the blend and content uniformity could have helped to better characterize the material properties, as well as process parameters.

	Even small companies--where the exit strategy is to out-license an asset at Phase I or Phase II--will profit from the QbD toolkit. In recent years, diligence conducted on acquisition targets increasingly includes a thorough chemistry, manufacturing, and controls (CMC) review, in addition to a clinical efficacy review. Licensees are well aware that many products fail late in development due to CMC deficiencies and/or an unfavorable cost of goods profile, a reason why CMC experts are now at the table in licensing negotiations.

	Companies that offer QbD-generated data demonstrating knowledge of the drug substance, its physicochemical properties, characterization, raw material and excipient interactions, and variability--and how these all affect the dosage form design, target product profile, and shelf-life stability--often can realize a premium on deal terms. Conversely, companies that develop assets using short-term, seemingly cheaper methodologies may be forced to accept less rewarding terms for valuable assets.


	Developers must perform cross-disciplinary analyses at regular checkpoints to assess the scientific, clinical, regulatory, and commercial risks for a given product, and their strategies may need to change as a result of these reviews. Gated reviews that build in quality and bring science to the table offer advantages to all companies.

	The window between Phase II and Phase III is crucial. For example, one company recently had a stellar, small molecule lipid-lowering compound that in several head-to-head Phase II studies showed promising clinical superiority over existing therapies. Poised to enter a highly competitive cholesterol-lowering market estimated to be worth more than $100 billion, the company developed its drug quickly. Clinical trials were supplied with a batch production process optimized for small- and intermediate-scale manufacturing.

	Now the company needs to conduct two much larger, global Phase III clinical efficacy trials simultaneously, plus a 5000-patient long-term safety study; the firm is struggling to produce the larger batch sizes needed for the Phase III study. This wholesale  process change could mean that regulators will require the reformulated drug to start all over again at Phase I.

	The moral of this cautionary tale? Phase II development is the correct point at which to evaluate the scalability of manufacturing processes and the potential regulatory impact of any changes, not the brink of launching Phase III. In cases where a product’s formulation needs tweaking prior to a Phase III trial, a bridging study can be conducted to demonstrate pharmacokinetics equivalency between the old and new products.

Apply the right standards and-product upgrades at the right time


	Over- or under-engineering a product for its stage of development is a common, costly error. The key is to understand phase-appropriate specifications. For example, a Phase I product can have impurity levels, stability limitations, and 

 dissolution release profiles that are markedly different (and significantly looser) than commercial products. Similarly,  formulating a product with a three- to four-year shelf life for a Phase I trial is an obvious waste of resources.

	Phase II products also can have looser specifications. Performance standards, however, will tighten by Phase III and launch. For example, for a controlled-release drug, an acceptable release profile might be to deliver 30-60% of drug within 4-6 hours (note the 30% delta). By Phase III, the release criteria for the same drug could be tightened to release 40-50% of drug in 4 hours, with assurances to regulators that these will be the final batch-to-batch quality specifications. By the time this drug hits the market, it will fail quality tests if it releases, say, 36% at 4 hours, instead of 40%. That’s how tight the margins could become with justification.

	With a control strategy grounded in systematic scientific evaluations including gated reviews (see 

), specifications can be tightened in a stepwise fashion as a product advances from Phase I to Phase 

III to launch. Through early integration of science in formulation and process development, companies can create a detailed technical transfer plan, bringing on new equipment capabilities as required, and ensuring plant availability to deliver when requested. As standards are adopted throughout the development process, from formulation through commercial manufacturing, a firm gains the ability to choose options at each stage that are both fit for purpose and best in class.

Science-driven formulation reduces risk and creates lasting value


	Use of sound science appropriately applied at critical junctures is the only sure route to improve efficiency in the high-wire act of drug development. QbD and other scientific tools should be viewed as opportunities that deliver benefits to patients, in the form of safe, effective drugs, and to companies, in the form of quality products that will generate value throughout their lifecycle. Phase-appropriate, science-driven formulation and process design:

		Adds value to an asset and boosts return on investment for every business model and exit scenario

		Mitigates risk at every stage of development

		Allows for efficient success and (often as importantly) efficient failure

		Minimizes iterations from pilot product to target product profile

		Reduces the probability of regulatory delays by providing justification for all CMC decisions

		Creates the ability to tighten product standards in a stepwise fashion.

	In today’s hypercompetitive healthcare market--populated by increasingly sophisticated buyers of both approved and experimental drugs--companies can no longer afford to reduce costs by skimping on science, which raises the risks of drug development to an unsustainable level. Rather, the solution is to build a science-based foundation of quality into products and processes and then layer on ever-tightening standards and upgraded features appropriately as a drug wends its way toward market.

. 2014 Jan;32(1):40-51. doi: 10.1038/nbt.2786. Supplemental Info: www.nature.com/nbt/journal/v32/n1/extref/nbt.2786-S1.pdf  

:
	When referring to this article, please cite it as A. Kane, "Phase-Appropriate Formulation and Process Design," 

Appropriate use of sound science applied at critical junctures will improve efficiency in the high-wire act of drug development.

Phase-Appropriate Formulation and Process Design

Quality by design (QbD) is based on sound science and quality risk management through which quality is built into products. Although the benefits of QbD are obvious, the industry has been relatively slow in adopting the concept because QbD often falls low on the list of immediate priorities. With product development and manufacturing increasingly being outsourced to contract development and manufacturing organizations (CDMOs), however, a strategic partnership between the sponsor and a CDMO can help realize the benefits of QbD. The author discusses how a CDMO helps in gaining process understanding and in developing robust, high-quality products and processes.  

Whether the product and process is developed at one contractor's site, transferred from one contract developer to another, or transferred from a sponsor development unit to a contract development and manufacturing organization (CDMO), knowledge transfer, an in-depth process understanding, identification of critical process parameters, and determination of proven acceptable process ranges (PAR) are crucial to successful development. By failing to identify and correct the root causes of problems early in the design phase of the process- and product-development cycle, organizations risk quality, yield, and supply-chain issues. Quality by design (QbD) should be viewed as an opportunity that brings value and business benefits to both the sponsor and the CDMO.

A CDMO supports the development of hundreds of molecular entities in different stages of clinical programs with small or large molecules in sterile and nonsterile processes. A wealth of knowledge and experience resides with a CDMO that could be leveraged by a sponsor for new projects. Drawing on knowledge gained from experience, a CDMO can move quickly in identifying critical steps, building a robust model to plan, and designing experiments to address problems. We often find that when sponsors have changed hands due to licensing of new chemical entities,  some information and documentation does not get transferred. A CDMO can help the sponsor orle001anize information, determine gaps, and work to build the program to meet the quality and regulatory requirements. QbD requires a solid base of knowledge of the drug substance, its physicochemical properties,  characterization, raw material and excipient interactions and variability, and how all these impact the dosage form design, target product profile, and shelf-life stability. A CDMO can leverage its inventory of knowledge and experience, work with a sponsor to lay out a plan, and apply the principles of ICH Q8, Q9, and Q10 to develop a QbD strategy that adds value to the sponsor's program (1–3). 

A CDMO develops products for virtual companies, biotech, specialty, mid-size, large pharma, and generic drug companies, and sees different philosophies and strategies adopted by sponsors in applying QbD to product development. As key players in industry, CDMOs need to move the QbD initiative forward by helping sponsors and clients see potential benefits, so they will give QbD a higher priority and understand the risks of not using the QbD toolbox.  

The benefits of using QbD at various stages of development have been well documented. In a live poll conducted during a QbD conference, the majority of representatives from the industry felt that it is "never too late" to adopt QbD and generate data to get an in-depth process understanding (see 

Figure 1: When is it too late to adopt a quality-by-design approach to your product at a CDMO? (Ref. 4).   			

In a 2008 survey, 58% of the respondents said that their QbD initiatives were only in the ideas and vision stage (5). In 2010, at another QbD conference represented by the small, medium, large pharmaceutical, and generic drug sectors, results of a live poll, shown in 

, indicated that more had moved on from this stage (6). 

Figure 2: At what stage are quality-by-design initiatives in your organization? (Ref. 6). 			

Organizations have been slow in thinking about the best way to implement the principles of QbD in their development programs as a part of their corporate strategy. When asked about the biggest obstacles, poll respondents' answers, shown in 

, indicated that pursuing QbD did not fit into the priorities of many organizations (6). 

Figure 3: What is the biggest obstacle to pursuing quality by design in your organization? (Ref. 6).  			

Based on various discussions, Patheon has compiled comments from the sponsors' perspective as to reasons for not adopting QbD in their programs: 					

"Our process is well developed and scalable. There may not be any need for additional process development to set appropriate design space."

"We need to meet aggressive timelines to ensure continued funding. For virtual to small organizations, proof of concept and moving quickly to the next phase of the clinical program are of top priority."

"Our goal is to have a product that will be successful in clinical trials. We can always optimize the process after the clinical phase is done."

"This product will be partnered or sold post Phase 2b; why invest in QbD now?"

"There are regulatory risks associated with conducting QbD experimentation and the risk of delays due to large experimentation and possible reformulation in the late stages of development. This could also lead to an additional bioequivalence study, which is costly and time-consuming." 

"We are reluctant to share development or proprietary information (e.g., filing or historical data)."

On the other hand, comments from CDMOs, compiled by Patheon from various discussions, offer a different perspective on why QbD is worthwhile:  					

"Many transferred processes are not well defined. Selection of excipients and their levels are not scientifically justified. Processes are scaled up to provide larger quantities of clinical trial supplies without sufficient data."

"The failure rate in clinical trials is high. Using sound judgment and a calculated risk-based approach, however, will help move the clinical program forward by balancing the scientific approach with capital investment." 

"Often there is no time to optimize products in later phases, which has impact on the cost of goods and security of supply." 

"Failed batches and additional regulatory scrutiny will cause more delay than doing a systematic study correctly now."

"A well-understood, stable product developed using sound QbD principles adds value to robust development, and the product is more attractive to potential partners for out-licensing." 

 show that, when considering conducting QbD with a CDMO, respondents are concerned about project delays, cost, information sharing, and the expertise of the contractor (4). As more and more product development is outsourced to a CDMO, however, sponsors will have to partner with CDMOs in pursuing the QbD strategy.  

Figure 4: What is the biggest concern you have in conducting a quality-by-design approach using a CDMO? (Ref. 4). 			

In recent years, Patheon has seen an increase in the number of sponsors/clients asking for QbD. Sponsors would like to know what strategy a CDMO would propose to proceed with this exercise and the experience level of the CDMO in designing a QbD work plan. More organizations are now conducting statistical design-of-experiment (DOE) studies to understand the design space for critical process steps in solid oral and sterile dosage manufacturing operations. 

CDMOs will typically have worked with a larger variety of complex processes and challenging molecules than their counterparts in individual sponsor organizations. The knowledge base gathered during many years and the experience gained in resolving complex problems can immensely help the sponsor through the steps in the QbD process (see 

Figure 5: Steps in the quality-by-design process. 			

A CDMO can design a phase-appropriate QbD strategy to build quality into the product being developed. An experimental plan should conserve API and consider time and cost. A CDMO can help in performing an in-depth scientific risk assessment that will help in justifying the investment in a QbD exercise. 

Because the financial investment in QbD to a small or medium sized organization can be huge, it is important for the CDMO and sponsor to jointly build a business. It is not always possible to put a financial value on everything we do. There also are business risks to this investment, such as the possibility of the project costing more, taking longer, or even failing due to a variety of developmental reasons. 

A case study illustrates the QbD process wherein Sponsor X developed a drug product and process in partnership with  Patheon, by using QbD principles to ensure desired safety, efficacy, and quality of the product. 

depicts the overall QbD strategy that was used.  

Figure 6: Quality-by-design process flow for a drug product (DP). 			

A combination of prior knowledge and experimental assessment during development were used to identify performance requirements (i.e., Stage 1), develop process understanding, and conduct the criticality analysis. In Stage 2, critical quality attributes (CQAs) of the drug product were defined. An initial risk assessment was performed in Stage 3 to determine which process steps and materials could control product CQAs. Stage 4 included a detailed criticality analysis which evaluated the functional relationship between critical and key process parameters and CQAs to establish the design space. The design space included the control ranges of the key processing parameters and in-process parameters (IPCs) used to meet the CQAs for a safe, efficacious, and chemically stable drug product. The design space defined by normal operating ranges (NORs) and proven acceptable ranges (PARs) in conjunction with material and product CQAs formed the basis of manufacture of the drug product. Process failure mode and effect analysis (FMEA) was conducted (Stage 5) prior to validation (Stage 6), followed by continuous verification and improvement during commercial operation (Stage 7). 

A detailed criticality analysis was conducted on each material attribute. Each aspect of the material was designated as critical, key, or noncritical based on its potential to impact a CQA as illustrated in 

Figure 7: Criticality analysis process flow. CQA is critical quality attribute. 			

Using the above systematic approach based on sound science and quality risk management, Sponsor X filed a QbD-based new drug application that was subsequently approved, and the product has been successfully launched in the marketplace. 

As pharmaceutical companies partner with CDMOs for development, clinical, and commercial programs, the CDMO will play a critical role in jointly developing a QbD strategy to develop robust processes and quality products. Due to the wealth of knowledge gained by working on multiple, challenging molecules, processes, and products, CDMOs are well positioned to support the sponsor in building a business case, justifying the investment, and applying risk assessment to drive QbD implementation. 

 PhD and MBA, is executive director of global science and technology for pharmaceutical development services at Patheon, 2100 Syntex Court, Mississauga, ON L5N 7K9, Canada, tel: 905.812.6874. email: 

 4.  S. Closs, presentation at FDA/Xavier University Global Outsourcing Conference (Cincinnati, OH, 2011). 

 6. A. Kane, presentation at FDA/Xavier University Global Outsourcing Conference (Cincinnati, OH, 2010).  

The author discusses how a CDMO helps in gaining process understanding and in developing robust, high-quality products and processes.