Quality Challenges in Drug Delivery

The role for quality by design and excipients

Annie Zhang,  Wooensdag Sales Manager Pharmaceuticals IMCD China

Alen Guy,  Technical Director

This article deals with how some companies have adapted to the Quality by Design (QbD) environment, and also looks at some of the core elements of solid dose drug delivery and the raw materials used. The context for this latter part will look at how drug delivery companies can work with excipient suppliers to strengthen the robustness of their technology through better understanding of the supply chain.

Drug delivery companies and the products borne from them are often characterised by complex partnerships between companies, with licensing agreements and strategic relationships. The challenges they seek to face and overcome rely upon strong technology delivering drugs to targeted sites in the patient.

Outsourcing of opportunities has dramatically increased over the last decade. As a result, drug delivery companies (large and small) have found themselves closer to the early stages of a drugs development. This has landed there technology firmly in the quality by design QbD sphere.

This article deals with how some companies have adapted to the QbD environment, but also looks at some of the core elements of solid dose drug delivery and the raw materials used. The context for this latter part will look at how drug delivery companies can work with excipient suppliers to strengthen the robustness of their technology through better understanding of the supply chain.

Drug delivery companies are an increasingly important part of drug product development as pharmaceutical companies have required more outsourced expertise.

A ‘classic’ drug delivery company builds its value around intellectual property in a number of ways. There is typically a platform of technology related to improving API properties, drug product compliance or combinations of added value properties.

Whether the platform(s) utilised are targeted at solubility or bioavailability improvement, alcohol-resistant controlled release, drug-abuse or compliance benefit through novel dosage form, the need and use of excipients is inevitable and widespread.

The examples given in table 1 show a small selection of the companies involved in oral drug delivery worldwide. All of these companies apply proprietary technology or significant know-how to the successful formulation of drug products. However, the proprietary nature of formulation platforms essentially requires them to use a limited number of excipients to achieve their aims. In the current regulatory climate and the drive towards QbD in the largest markets the drug delivery companies face some interesting challenges.

Many drug delivery companies seek to develop products that are differentiated from innovator products or designed to increase product lifecycle for the innovator, thereby keeping generic competition at bay! Whichever route they take the regulatory pathway will take them through, most often, an ANDA route. In a few cases a completely new submission with fresh clinical data will be undertaken. In either case a QbD route can lay before them.

Is QbD attractive for drug delivery companies?

The real point of QbD lies in creating a quality and risk management system that minimises the need for costly inspection-based quality, as well as providing significant knowledge to support the submission in such a way that the manufacturer can safely adjust the process during the manufacturing stages without the need for costly regulatory work.

A drug delivery company, often, not only creates the opportunity and formulation, but also controls the manufacturing, raw materials and the outputs to the drug company. This in itself means advanced companies have a lot of data regarding what does and does not work for their technology. In other words, they should have de facto carried out many risk analyses regarding critical quality attributes of formulations with respect to excipient properties and process parameters.

Does this mean drug delivery companies undertake regular assessments of excipient suppliers? In my experience this is often not the case. Normally it might be imagined the drug delivery company has a robust system that can tolerate a range of suppliers for excipients such as mannitol, microcrystalline cellulose, lactose, HPMC etc.

What about other pressures? The current economic climate is such that even areas that have very little impact on the final cost (especially Excipients) come under cost strain. Sourcing groups seek to optimise and create lean supply chains, minimise outgoings and stock handling. This might mean certain suppliers appear more attractive to them than they might to the R&D group and formulators.

So, QbD should be attractive to drug delivery companies, as their entire technology platform should have been designed to predict and understand the elements of risk associated with formulations and the processes they own. From the standpoint of attracting new customers, this element of their knowledge should be utilised and exploited. Can and should a drug delivery company incorporate a full raw materials assessment into their development program?

Catalent gives consideration to QbD principles quite openly through its activities with dry powder inhalers, but also most recently with multiparticulate oral controlled release development. This was announced (June 21, 2012) as part of its alliance with Bend Research in Oregon. Indeed, catalent also published in the Journal for Patient Compliance, coining or using a phrase ‘Adherence by design’ an approach derived from QbD principles. However, this is a drug delivery construct that is best intentioned towards more targeted delivery, where the design element is more about drug product design rather than quality that has been designed into a process to meet a desired outcome.

However, the acceptance of the principles as being important is key here when considering your drug delivery partner.

Skyepharma makes no implicit statement regarding QbD but their commitment to inhalation projects ensures they will have quality managers concerned with ICH and QbD guidelines.

Aptalis, Flamel nor Orexo make any QbD assertion in an open manner. SPI Pharma doesn’t either, but this is not surprising given they are more specialised in providing materials for the customer to formulate rather than manufacturing finished products in their own facilities.

Bend Research does, however, makes a lot of assertions with recent press releases with Catalent and Dow Chemical, as well as highlighting their commitment to process engineering and Quality-by-design on their website.

When looking at these companies I see some distinctions appear quickly. I can summarise them in the following, Table 2.

Some drug delivery companies are more likely to have their own QbD programs for a variety of reasons. Primary among them is that they are either 1) large-scale manufacturer of finished goods or 2) Process-driven and scientific innovators or 3) both. How this is distinct from the classic model is that they are not bound by their platforms, they are freed by the fact they utilise whatever means they can to yield a desired outcome as per the original reasons stated regarding the purpose and goals of drug delivery companies.

Classic single platform drug delivery companies are trying to fit the optimal drugs into the constraints of the technology they are utilising and are covered by the IP they possess.

What can a drug company or potential partner / licensee do to ensure that QbD principles are being partially or wholly executed when working with a drug delivery company?

  1. Decide, during the strategic development phase, whether a QbD approach is both viable and desirable. This will be dictated by lifecycle expectations, value and ultimately the regulatory drivers prior to submission, such as OGD desire for QbD with Generic submissions from January 2013.
  2. Really question the company about the robustness of the technology! When the composition of a typical drug product is given, ask about the sourcing management and validation of the raw materials. It must be clear that the excipients utilised have a verifiable provenance. It is more preferred if the excipient supplier has its own QbD program, rather than a supply chain dedicated to a simple adherence to specification or monograph.

This is easier said than done. However, the potential benefits to the partners in such an agreement are numerous.

  1. The DD company understands more about its technology platform. It might be surprised at how versatile it could be. More IP could be discovered this way.
  2. The cost structure during manufacturing will have been optimised.
  3. The post-approval regulatory framework will be easier to navigate
  4. The licensee / partner will have much more confidence in the stability and safety of the product for long-term supply. This infers a presumed lower risk of product recall due to failures in dose uniformity and contamination.

A number of excipient companies are looking closely at their input to QbD. This could have far-reaching impact on drug and drug delivery companies.

Such organisations look to excipient companies to provide a stable product, with a solid history of production. Now, however, QbD and a greater emphasis on regulation of excipients has led to a higher degree of scrutiny by personnel dealing with approving products.

Take, for instance, the guidance of an IR generic drug product. The example set forth in this guidance highlights the need to be fully aware of the potential impacts on the critical quality attributes of the formulation and product and how these relate to and meet the requirements of the Quality target product profile!

The drug delivery company’s knowledge of API aspects tends to be very high and in some cases deliberately managed, through milling or nano-sizing or polymorphism and salt selection. However, knowledge of excipient variance is still basic in many cases. Excipients most often come from natural sources–Cellulose, starch, lactose, minerals, other vegetable and animal products. As such, they have some inherent natural variability.

It has been shown in many studies that in certain processes the particle size of the excipient, water-binding capacity and shape can be a big factor in areas such as roller-compaction and direct compression.

If this is the case, any sensitivity to large changes (within monograph specification and in specifications not listed) could have a dramatic effect on the drug product outcome. These may not show themselves until the process scales-up and go unobserved at the bench or pilot scale. These are the unknown unknowns paraphrased from Donald Rumsfeld(x).

In such a case if the QbD guidance was to be followed expplicitly, the drug delivery company submission would be subjected to a QbD type assessment of its technology. It is at this point that some may baulk at the idea.

However, a DD company that proceeds with a QbD approach ahead of time and identifies general QTPP for products it wishes to develop, can then proceed with identifying typical CQA and as such have a solid template. A knowledge space and a likely design space may well be sketched out before an active has been selected. This could significantly shorten the QbD DOE time and not unduly delay drug product development.

Summary

Drug delivery companies are seeing a rich opportunity from outsourced R&D activity and the patent cliff a lot of innovatie companies face. Generic medicines that can be differentiated from the pack are being seen as potentially highly valuable to the marketplace. However, regulatory bodies in the major markets are paying ever closer attention to the raw materials used in drug products, not just the active ingredient. This will mean, for some, that QbD considerations will have to be put into development programs.

Clearly some DD companies already have QbD principles embedded in their mission or philosophy, but others seem slow to adopt even the language of QbD.

It is likely that this space will have some time before it will fully need to comply, but by starting now the drug delivery companies could yield significant benefit in the medium-long term

Excipient suppliers should explore this space carefully and with an eye to increasing awareness and the knowledge of the DD companies.

Drug product licensees and DD partners must include the potential requirements for QbD before selecting their development partners.

Author Bio

Annie Zhang

Annie Zhang is a Technical Sales Manager at Pharmaceutical Business Unit of IMCD Group, based in Shanghai, China. She joined IMCD in 2011 to spearhead the Group’s pharmaceutical business in China. Ms Zhang began her pharmaceutical career as a formulation development and research fellow at China’s renowned–Shanghai Institute of Materia Medica-Chinese Academy of Sciences in 1997. During her tenure at the Institute, Ms. Zhang was responsible for formulation screening and optimisation for finished products, quality analysis and preparation of submission documents to SFDA etc.

Alen Guy

Alen Guy joined IMCD in 2010 as the Technical Director in the IMCD Business Group Pharmaceuticals. Dr Guy started his academic career in the field of high performance liquid chromatography where he learned much about how good health and general well-being work together. He has presented at numerous drug delivery and pharmaceutical conferences on topics such as co-processing of active ingredients and excipients, excipient innovation, orally disintegrating tablet technology, taste-masking and solid dose development.

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