Sophisticated Cleaning Methods
Approaches to consider when manufacturing multiple drug formats

By Patty Frey and Martha Sloboda

In an increasingly competitive global economy, it is vital for the pharmaceutical manufacturing industry to effectively utilize fixed capital assets as frequently and cost-effectively as possible. Depending upon available equipment, contract manufacturers may choose to leverage their assets by producing multiple dosage formats and products on the same equipment train as opposed to purchasing and installing additional dedicated production lines for each format. In these cases, a robust cleaning approach addressing the compliance aspects and the need for increased manufacturing flexibility must be in place to eliminate the risk of cross-contamination while ensuring product safety. Robust strategies to support manufacturing flexibility and the cleaning requirements associated with this approach must work hand-in-hand as new products are developed and commercial products produced.

By treating the cleaning process as a strategic imperative — in both the development of an approach for new compounds and in the ongoing implementation of established approaches — it becomes an enabling element for successful and efficient project execution. In fact, CMOs can ensure ongoing manufacturing flexibility and productivity by leveraging their cleaning systems as a strategic risk mitigation tool and a point-of-differentiation among competitors.

One industry approach to cleaning employs a multi-arm assessment that facilitates streamlined movement of a product through its life cycle to span feasibility, development, scale-up, commercialization, growth, and decline. This approach enables manufacturers to produce multiple drug delivery formats, ranging from oral and topical dissolvable films to adhesives and transdermal drug delivery systems, on shared equipment trains with minimal dedicated manufacturing systems for each format. Maximizing the use of capital assets provides enhanced flexibility to formulate unique drug delivery systems while extending the efficiency and cost savings of this strategy to our clients.

We shall provide an overview of a multi-drug platform manufacturing process, the potential cleaning implications of producing multiple dose formats on the same equipment train, and how adhering to the three pillars of cleaning — matrix, minimizing and proceduralize — provides manufacturing flexibility to expand the product portfolio.

Case in Point

One industry where it is feasible for CMOs to produce multiple drug delivery formats on a shared equipment train can be seen in adhesive and specialty coating manufacturing. The liquid casting technique used to produce transdermal adhesives can also be applied to the production of transmucosal, and oral thin film (OTF) products. The production of polymers, coatings, adhesives and dissolvable films is based on a multistep, tightly controlled process utilizing liquid casting or 100% solids extrusion techniques¹. Essentially, a liquid formulation is prepared in the form of a solution, dispersion or emulsion, and cast onto a moving web of support material. The cast product is run through a series of heated dryers with various in-line controls and heating capabilities. The dried product is wound into large rolls for further converting and packaging. All steps within the process — from material pre-weigh to mixing, coating and finishing — are processed in segregated rooms to minimize any risk of cross-contamination.

These manufacturing systems have demonstrated the ability to hold extremely tight tolerances across and down the production chain, with content uniformity maintaining a relative standard deviation of 1-2%². This control is ideal for many products, including those with narrow processing windows and potent compounds.

Cast production, because of its inherent ability to produce a multitude of different products, offers developers a large spectrum of raw materials from which to select when formulating and delivering active pharmaceutical ingredients (APIs) or other molecules. These material sets present varying degrees of solubility and volatility profiles and the breadth of these characteristics impacts the scope of any cleaning initiative.

To address the cleaning challenges presented by producing multiple dosage formats on shared equipment, a well-understood and comprehensive cleaning strategy was created. This approach delivers two key outputs:

1. a thorough, defendable documentation package for compliance, and
2. an approach that is appropriate in scope and scale for any developmental initiative

The cleaning strategy recognizes the evolving needs of global clients and the associated regulatory authorities. To be effective, the cleaning strategy must be organic to adapt to the latest guidances and best practices issued. For example, when the FDA issues its upcoming guidance on cross-contamination³, there must be an immediate assessment and incorporation of the recommendations into daily practice.

Matrix-based Approach To Cleaning

A key element of the cleaning strategy is a matrix-based grouping system for materials and compounds used in the manufacturing of products based on their level of difficulty to clean. This is not a unique approach, however it enables new materials to be screened and classified efficiently into categories of proven and well-understood cleaning approaches for compounds of a similar nature. It is also a reference tool for formulators as they look to leverage existing materials in new formulations.

The cleaning matrix thought process goes beyond simply considering the active ingredients to be removed. It identifies the types of cleaning agents most appropriate for removing specific compounds, establishes acceptable post-use hold times, and evaluates different safety factors based on published acceptable carry-over levels for all possible compounds manufactured on shared equipment. By creating a “worst-case scenario” or benchmark that exceeds the published industry standards, minimum therapeutic dose, and safety-based limits for all compounds used on one’s equipment, the manufacturer can be confident the equipment train is secure, eliminating risk at even the most difficult level.

The matrix should be viewed as a dynamic tool that may be revised or expanded as needed. For example, as products are discontinued, their impact is removed from the matrix. Likewise, as new products are added to production, the cleaning class levels within the matrix may need to be adjusted. The overall benefit is that this tool provides the structure whereby the overall risk of a new compound can easily be assessed because it establishes acceptable levels of carry-over for compounds in both new and existing programs.

Understanding the matrix can benefit strategic sales planning efforts. This tool provides overarching guidelines for the compounds that may be well-suited for a CMO’s existing processes, therefore providing insight regarding products that can potentially move to production scale more quickly. This approach cannot address the overall technical feasibility of producing a product, but provides teams rapid access to evaluate manufacturing viability and challenges.

Equipment Selection

An important consideration in avoiding cross-contamination starts with the appropriate selection and design of equipment for cleanability. For example, if the goal is to minimize the number of dry and wet surfaces that make direct contact with a product, the equipment should be selected not only from a technical capability standpoint, but also for ease of disassembly to clean and inspect internal components. Equipment design impacts cleanability; sharp corners, cut-aways, and threaded fittings can trap small amounts of unwanted materials. Selecting smooth, concave surfaces improves rinsability. Utilizing disposable parts can aid in the cleaning process.

Minimize Exposure, Minimize Risks

Facility design and flow is an equally critical consideration. While it is a well-known industry standard during early-stage development to segregate manufacturing steps to avoid cross-contamination, it may not be realistic to segregate smaller production runs in separate full-scale manufacturing rooms. In these cases, room-within-room segregation approaches may be employed. Not all product programs will lead to commercialization, so when determining the technical feasibility of these initiatives, small-scale versions of production equipment are often substituted for the mixers or other equipment at risk for the highest exposure. Also, developmental activities can be staggered, even grouped as several sequential events, a technique that is useful when developing products that are not intended for human or animal use.

Proceduralize the Developmental Process and Ongoing Production

Cleaning is a key component of any developmental process from the beginning stages of any project launch. Once initiated, the project development team is able to quickly assess the project’s active compound and potential excipient sets, as well as all available equipment options capable of technically producing the desired dosage format. Through a collaborative approach, the group can then refine the needs of the equipment train to evaluate the requirements for the given developmental stage. For example, early-stage proof-of-concept runs may utilize small-scale mixing equipment with disposable components to create a representative sample without compromising the entire equipment train.

As the program grows and expands, the cleaning approach is further defined. Early-stage activities may leverage smaller-scale processing options, but ultimately scale-up expands the equipment train. Verification may be used in a project’s early-stage development, while cleaning validation will be confirmed with process validation. As Dr. Gary Baker suggested in his May 2010 article in Contract Pharma, cleaning validation is most efficiently conducted with process validation⁴.

Maintaining Flexibility

The primary objective for any custom-developer or contract manufacturer is to provide the most innovative products and services to the market. Proving these capabilities frequently requires quick demonstration of technical success, production viability and manufacturing flexibility. Some elements that can contribute to maximizing this flexibility include:

• On-site laboratory capabilities – On-site, focused analytical and environmental testing can aid rapid turnaround. However, the scope of this capability must be assessed and adapted based on evolving business needs to avoid underutilized and costly capacity.
• Strong supplier relationships – Understand the developments and evolving capabilities of providers that specialize in cleaning, cleaning agents, and the latest recovery techniques. Forming healthy relationships with these providers extends a manufacturer’s expertise and capability toolbox when taking on new programs.
• Strong equipment maintenance program and standard operating procedures SOPs – A robust, proceduralized approach facilitates rapid machinery clean-up, timely status reports, and assures that all working parts are operational at all times. A strong program also promotes opportunities for streamlining cleaning initiatives such as staggering cleaning activities to avoid equipment downtime.
• Dedicated cleaning team – Ideally, members from different functions within the manufacturing process evaluate efforts on an ongoing basis. When new programs are initiated, this focused group can quickly respond with functional insight to develop a plan for execution.
• Engagement with executive management – Ongoing dialogue with management provides an opportunity to discuss successes, challenges and opportunities for enhancing cleaning systems, as well as the impact these have on the business. Project needs and focus can change, so early engagement of the cleaning team enables more effective planning and adjustment. These ongoing discussions help to accelerate funding approvals to increase cleaning efficiency, throughput, and capabilities — an important consideration when new classes of compounds or equipment are being brought on-line.

Cleaning is a vital component of any manufacturing operation. It provides assurance of a safe and quality product while minimizing overall risk for the organization. Failure to develop and support rugged and proven cleaning systems, frankly, is not an option in this industry. However, as organizations grow and diversify their product offerings, they must also view cleaning as more than only a regulatory necessity. It is an opportunity for CMOs to differentiate and diversify. Companies that establish a cleaning mindset that extends beyond compliance to enable rapid utilization of equipment, and quick developmental assessment for internal teams, will have the opportunity to capitalize on their cleaning systems as an invaluable strategic asset.

References

1. B. Vondrak and B. Barnhart, “Dissolvable Films for Flexible Product Format in Drug Delivery,” http://pharmtech.findpharma.com/pharmtech/Drug+delivery+Article/Dissolvable-Films-Dissolvable-Films-for-flexible-P/ArticleStandard/Article/detail/505380, accessed August 15, 2010. [return]
2. S.D. Barnhart, “Thin Film Oral Dosage Forms,” in Modified Release Drug Delivery Technology, 2nd ed., Vol. 1, (Informa Healthcare; New York, NY 2008) 209-216. [return]
3. http://www.fdanews.com/newsletter/article?articleId=123953&issueId=13374, accessed August 30, 2010. [return]
4. G. Baker, “Only You Can Prevent Cross-Contamination,” http://www.contractpharma.com/articles/2010/05/only-you-can-prevent-crosscontamination, accessed July 26, 2010. [return]

Patty Frey is director of Operations at ARx, LLC. She can be reached at pfrey@arglobal.com. Martha Sloboda, MBA is business manager at ARx LLC. She can be reached at msloboda@arglobal.com.