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There is a trend emerging in drug discovery for new compounds to be increasingly more selective in their pharmacological activity. The manufacturing activities associated with highly potent compounds are becoming more difficult to manage with respect to safe handling of the compounds and also achieving reproducibility of dosing. Many companies are consequently choosing to outsource the development and manufacture of highly potent drugs to contract development and manufacturing organizations (CDMOs) with the necessary skills and capabilities in this area. But what should one look for in a CDMO if they wish to outsource the formulation development of a highly potent drug?  It is almost impossible to find every box ticked by a CDMO; therefore, building a risk-based approach to selection is required. The following five key areas should be considered when deciding to outsource a high-potency project.


	When selecting a CDMO, the first thing to check is that they have the necessary infrastructure for ensuring safe handling of highly potent compounds. Many organizations are now choosing to conduct a safety audit of a CDMO’s facility in addition to the usual technical and quality audits. In particular, the following should be checked:

 It has become common practice within the industry to define the handling requirements for a drug according to an occupational exposure banding (OEB) system (1). Typically, OEB systems categorize compounds from low potency to high potency and define the handling/containment requirements dependent upon the OEB category. Banding systems are often used in cases where there is insufficient data available to define an occupational exposure limit (OEL) for a compound (e.g., new potential drug candidates). Depending upon its pharmacological attributes (e.g., dose and toxicology), a compound can be placed into an OEB category that defines the implications for operator exposure and the actions required for safe handling. An example of a typical potency classification system is shown in 

.With this in mind, it’s worth checking what risk assessment process is followed by the CDMO for the introduction of a new project, particularly one involving a highly potent compound, and whether the outcome of each risk assessment is documented.

 Are there suitable containment practices in place to prevent operator exposure and cross-contamination within the facility? The industry preference is for “containment at source” rather than reliance on personal protective equipment (PPE). The activities where the drug is being handled (e.g., preparation of formulation or analytical samples) should be conducted in suitable isolators or extraction cabinets (2, 3). Procedures for handling contaminated waste materials should be in place.

	In many cases, the project will progress to current good manufacturing practice (cGMP) manufacture of product for clinical trial use. Consideration should, therefore, also be given to the containment practices within the manufacturing facility. Is the manufacturing equipment that would be required at the next phase able to be appropriately contained?  

High potency generally means low dose, and formulation development for low-dose products usually demands particular knowledge and skill. The main challenge is often achieving satisfactory drug content uniformity per unit dose. The CDMO’s track record in developing low-dose formulations is, therefore, a factor that must be taken into consideration. Ask about the experience and technical skills of the people who would be responsible for the project from the initial development of an appropriate formulation to the clinical manufacture. Ultimately, for clinical manufacture, it is important that appropriate training procedures are in place for safe handling of potent materials. No matter how well designed the facility is for containment, the weakest link will always be the people using it. More than anything, you need to feel confident in your CDMO partner.


	Formulations for highly potent compounds will often contain only a few milligrams of drug and could contain as little as a few micrograms of drug substance. For very low dose requirements, it may be appropriate to consider dissolving the drug in a liquid vehicle and filling into capsules (4). Alternatively, to maximize the drug-to-excipient ratio, minitabs may be an option. Another option is to pre-dissolve the drug in a suitable liquid vehicle and to spray this solution onto carrier particles to produce coated granules. One crucial consideration is whether the potential CDMO has the requisite development expertise and range of processing capabilities for developing such low-dose products.

	When outsourcing a formulation development project to a third party, most vendors will prefer for the CDMO to also be responsible for provision of products for clinical trial use. It is, therefore, worthwhile to confirm that the CDMO has capability for scale-up of processes from benchtop to early-phase cGMP manufacture. In reality, most CDMOs will have a maximum scale they can produce with respect to equipment capabilities, the flexibility of the facility, and resource availability. Discuss with your CDMO potential tech-transfer and/or scale-up options should the project continue to expand.


	Formulating and manufacturing for potent/low dose products is challenging, but so too is the analysis of these products. Detection of very low concentrations of drug in the product can be an issue. If the drug molecule contains a strongly absorbing chromophore, then analysis of unit doses for drug content and degradation products can be achieved using standard high-performance liquid chromatography (HPLC) ultraviolet (UV) detectors. However, for determination of degradation products or drug residues for cleaning verification purposes, it may be necessary to achieve levels of detection at nanogramme or even picogramme levels. For very low-level detection, liquid chromatography-mass spectroscopy (LC-MS) is the most appropriate analytical method for cleaning verification purposes (5). Consider the CDMO’s analytical techniques for low-level detection and what criteria are used for cleanliness verification for processing equipment.

	The International Society for Pharmaceutical Engineering’s Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) process (6) is being widely adopted to manage the risk of cross-contamination to achieve and maintain an appropriate balance between product quality and operator safety. Furthermore, a recent EMA guideline (7), based on the principles of Risk-MaPP, introduces the practice of determining the permitted daily exposure (PDE) of a compound for calculation of acceptable residue levels for equipment following cleaning. This approach replaces the traditional practice of applying 1/1000th of the lowest clinical dose or 10 ppm to derive acceptance criteria for cleaning limits. Ask whether the CDMO is familiar with these guidelines and how they are used.


	Even if a CDMO has what appears to be the required blend of skills, experience, and processing capability, it does not necessarily guarantee your project will be in safe hands. One aspect that can have the most influence on a successful outcome (or otherwise) of an outsourced development programme is project management. Enquire how projects are typically inducted, run, and completed by the CDMO. Who will be your point of contact and who will be the project team members? Work closely with your CDMO to create an outline of how the contract partner visualizes the breakdown of the programme of work and how each stage will be scheduled to ensure you are both aligned. Agree on means and frequency of communication as well as expected response times upfront to help manage expectations.


	Although the five points given in this article may provide some guidance in assessing potential vendors for a formulation development project, the reality is that no CDMO is likely to meet every need perfectly, and early discussions to find appropriate options is advised. Away from the technical aspects, there are many other softer selection criteria that are more difficult to define and quantify. For instance, how engaging and enthusiastic are the representatives from the CDMO at initial discussion stages?  Do the technical discussions provide a sense of trust in the ability of the CDMO to fulfil the requirements of the project brief and to work collaboratively to meet the yet unforeseen hurdles?

	Handing over any project to a third-party contractor includes risks, and outsourcing development of products containing highly potent drugs is particularly risky, both from a safety aspect and also because of the technical challenges. Ideally, your chosen CDMO will not only tick many of the more mechanical selection criteria, but will also demonstrate an enthusiastic and collaborative attitude to helping reach your project goals.


	1. J.P. Farris,  A.W. Ader, and R.H. Ku,

 24, 5-10 (2006).
	2. D. Bormett, “High-Potency APIs: Containment and Handling Issues,” 

Pharm. Technol., Pharmaceutical Ingredients Supplement

 (September 2008).
	3. M.J. Faber  et al.,   Chemica Oggi - 

 32 (3) 34-38 (2014).
	4. J. Carey and A. Dixon, “Challenges in the Secondary Manufacture of Encapsulated High-Potency Drugs,” 

 Analysis 43, 1206-1212 (2007).
	6. ISPE, 

ISPE Baseline Guide: Risk-based Manufacture of Pharmaceutical Products

Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

Pharmaceutical Technology European Outsourcing Outlook


	When referring to this article, please cite it as R. Harris, “Outsourcing Formulation Development for High-Potency Compounds," 

Pharmaceutical Technology European Outsourcing Outlook 

Features

The author lists five key areas to consider when selecting a CDMO to develop highly potent formulations.

Outsourcing Formulation Development for High-Potency Compounds

As the biotech industry evolves, there are mounting concerns about the transportation, security, and robustness of cell-culture media, intermediate, or bulk drug substance (BDS). Safe, stable, and closed systems are needed when sterile products are shipped in single-use bags (1). In this article, the authors look at the limitations of the validation for a single-use shipping system and provide a perspective on what shipping validation means.

The increasing need for shipping product in the biotech single-use market
	

The complexity of biopharmaceutical manufacturing processes requires continuous improvement. The expansion of manufacturing capacity worldwide has resulted in the multiplication of links between production facilities as well as the increasing need for storage or transportation of media, intermediate, BDS, and drug products.

	Outsourcing to contract manufacturing organizations (CMOs) offers a solution to the capacity constraint. CMOs bring to the biopharma industry valuable technical expertise and flexible capacity and reduce the total risks associated with building internal capacity; however, a robust and validated manufacturing process (2), including product transportation between facilities, is required.

	Single-use technology (SUT) continues to expand because of its potential for reducing both capital and operating expenses (3). The growing adoption of single-use, especially in critical process steps, has increased the need for product quality, robustness, and integrity. The biotechnology industry is now expanding its implementation of single-use bags into all bioprocess steps for applications including cell-culture preparation (4), filtration (5), purification (6), storage (7), mixing (8), freeze-thaw operations (9), and fill-finish (10).

	Depending on the manufacturing process organization and the level of outsourcing, the challenge of safe and robust BDS transportation becomes a crucial step from a risk analysis point of view (11, 12).


	To comply with modern manufacturing requirements, SUT must offer similar levels of security and robustness as multi-use technology (MUT). A MUT shipping container is designed to withstand the different static and dynamic forces to which it is subjected during transportation, handling, and storage operations. The shipped product must also be protected from climatic conditions, such as temperature and humidity (13). Reusable products must:

		Be robust in terms of providing protection to the shipped product against rigorous environmental and handling conditions

Stainless-steel tanks for bulk freezing and distribution between drug substance sites and drug product sites were the processing units of choice until recently, when the technology was challenged by SUT (9, 14, 15). It is important to note that there is a simpler supply chain with SUT shippers because there is no need to manage the return of empty tanks or to clean and verify them.

	In addition to the aforementioned standard requirements, shipping with SUT requires the following additional needs:

		Maintenance of the structural integrity of the single-use bag (i.e., no leaks)

		Qualification of product in contact with the single-use material (i.e., extractable and leachable testing).

While SUT shipping can offer substantial advantages compared to MUT shipping, there are challenges with SUT shipping as summarized 

. Several considerations are related to the material of construction of SUT. Moreover, the end-users’ requirements for shipping depend largely on the application as shown in 

(TR) N°66 (16), the supply of process solutions in large-volume bags, from point of manufacture to point of use is a well-established practice that involves the following elements:

		A bag designed to fit a rigid wall outer container

		A rigid wall outer container such as a plastic drum or tote or a stainless-steel bin

		Secondary packaging materials (e.g., dunnage) and lids or other mechanical devices to suppress the fluid wave action in the bioprocess bag.

	Transportation of process solution in small-volume bags (nominal volume lower than 20 L) is also a common process that requires less complex packaging solution (16). The exception is the transportation of frozen materials that necessitates temperature-resistant materials and cold-chain logistics (17).

	Shipping systems must be qualified for their intended use through proper design and testing in consultation with a packaging engineer. The International Safe Transit Organization (ISTA) (18) and the American Society for Testing and Material (ASTM) D4169 (19) are good references for testing standard. These standards are complex with many different protocols, and the selection of a relevant protocol linked to an application is not trivial. It must be analyzed with a packaging and transport expert. The following are some key considerations for end-users:

		What is the shipping unit (size, weight, and form of construction)?

		What are the shipping routes: intercontinental (truck/air/boat), national (long-distance truck), or continental (short-distance truck)?

		What is the assurance level that should be established? Level I > level II > level III

		Define the lifecycle phases of the shipped unit (storage, transport, handling, transport, use)

		What are the associated environmental conditions for each phase of the lifecycle (temperature, humidity, compression, vibration, shock, free fall, bump, and pressure)?

		What are the handling conditions (forklift, tarmac, roads)?

		What are the type of shock, shake, and vibrations associated with the shipping routes?

		What is the appropriate number of samples for validation?

		What is the adequate severity of the simulated shipping test?

		What are the acceptable safety margins?

		What are the acceptance criteria: product is damage-free, package is intact, or both?

	Based on the projected distribution, the end-user should define a test plan using the distribution cycle (DC) defined in 

 of the ASTM D 4169 (19). The DC chosen should correlate with the projected lifecycle phases of the shipped unit (20).

	In addition, many pharmaceutical or biotechnological products are temperature sensitive and require specific precaution during storage and transportation (21). Transport and storage conditions have to be determined considering the risks of product degradation (22, 23).

	PDA TR N°66 has highlighted specific factors of importance for transportation that must be considered by end-user (16). These factors are:

		Dimensional factor (i.e., volume to be shipped and dimensions of the shipper)

		Mode of transportation, whether it’s ground, air, rail, boat, or combination of more than one mode of transportation. Metrics must include hold time on tarmac.

		The associated environmental conditions (temperature, humidity, pressure, and variation)

		Functionality (i.e., forklift access, stack ability of outer container, access to fill and drain port, secondary container to collect leak)

		Room classification such as fill and drain procedure to maintain sterility

		Logistics (e.g., external shipper, cold-chain logistics).

	In addition to PDA TR66, the analysis of the regulatory requirements and relevant references can be summarized as follows:

		The transportation routes must be defined for international shipment. A risk assessment for vibration, handling, delays, and seasonal variation should be established (11).

		The suitability of the containers (compatibility, safety, robustness) and of the container-closure system (material of construction, integrity, interaction) must be defined as well as a rational for the choices of the material, the barrier properties, the compatibility, and the safety (13).

		Recommendations are given to define storage and shipping conditions, to assess risk of the environmental parameter variation, to define labeling, and to assess short-term excursion outside storage conditions according to the International Council on Harmonization (ICH) accelerated testing (24).

		Qualification and validation of the shipped product can be performed in real shipment with monitoring (25-27) or in simulated shipment according to ASTM D4169 (19) or ISTA (18).

		In addition, precautions for transport of hazardous materials and dangerous goods are also described in additional regulations. The Economic Commission for Europe has defined regulations applicable to road transportation of chemical dangerous goods (28). Part 3 of the documents lists the chemical entities considered as dangerous goods for which special precautions are required.

		The United Nations has established regulations for any type of transports (air, road) of biological and infectious substances (29).

		The International Air Transport Association has established regulations applicable to safe air transportation of dangerous goods (30).

	Shipping is indeed complex and users should verify the vendor’s claims about some regulations. It is important for the end-user to understand what is behind the claim and the relevance to its application. As discussed in this article, shipping validation protocol for mechanical constraints needs to be carefully defined with parameters setting linked to the application in close collaboration between end-users and suppliers.

	It is a requirement of the US Food and Drug Administration (FDA) (12, 31), EMA (32), the European Union (11) and other drug regulatory agencies that the process produces consistently similar and reproducible results that meet the quality standard of the product. According to FDA, validation is “Establishing documented evidence that provides a high degree of assurance that a specific process--including shipping--will consistently produce a product meeting its pre-determined specifications and quality attributes” (33). A properly designed system will provide a high degree of assurance that every process step, including shipping, has been properly evaluated before its implementation.

	In the biopharmaceutical industry, qualification and validation are intended to demonstrate that the manufacturing process provides the desired level of product quality and specifically its activity, sterility, and potency. Qualification of a shipping system and shipping equipment is part of the validation.

A SUT shipping system composed of a bag and a stainless-steel bin should ensure safe shipment (i.e., no loss of integrity and no loss of product sterility). It can be granted by the mechanical robustness of the shipper. The objective is to verify that no leaks occur during transportation. According to Tull, “Product quality can be defined in terms of the ability of a product to perform its desired function despite the stresses to which it has been exposed before and during its intended use” (23).

	Bag leakage can be analyzed following methods described in the PDA TR N°27 (34). This document, however, describes high-sensitivity methods adapted for final packaging and not necessarily for intermediate or BDS. More global test methods such as diffusion of a dye, detection of a liquid leak, or damage of the bag (films and seals) may be more relevant (35).

The authors provide their perspectives on shipping validation.

Pharmaceutical Technology Europe-03-02-2016

Pharmaceutical Technology Europe 2016 Outsourcing Supplement (PDF)

Outsourcing Formulation Development for High-Potency Compounds

Qualification and Validation of Single-Use Shipping Systems