Introduction
Over the past couple of decades, the pharmaceutical and biotech industries have trended towards increasing outsourcing of clinical and commercial materials and services. This is driven largely by an effort to streamline costs – particularly capital investments – and timelines for creating clinical products. At the same time the number of nonconventional and complex products has steadily risen as technological advances have been made in the worlds of drug discovery, biologics, and drug delivery. If special attention is not given to the outsourcing of these types of products, then neither sponsor nor contractor will be able to succeed. In this paper we will walk you through some of the best practices for outsourcing complex formulations and processes.
Outsourcing Models
It’s important to recognize that outsourcing goes beyond producing cGMP drug product. It really starts with the development effort often years before a manufacturing campaign. To ultimately outsource the clinical and commercial supply of a complex product, it is important to develop a robust understanding of both the product characteristics and the manufacturing process. By using a Quality by Design (QbD) approach, critical product attributes and their relationship with biological performance can be clearly defined2 . Once in vitro/in vivo correlations are developed and a quality target product profile is defined, critical quality attributes and acceptance criteria can be developed that are biologically relevant, and the relationship between input parameters and product quality can be identified. The input parameters should include formulation or recipe parameters, process parameters, and raw material attributes. At BIND we’ve decided to perform these very important pre-clinical development exercises in-house and accordingly have invested in extraordinary laboratory capabilities and personnel with the appropriate expertise. Depending on the complexity of the product and development requirements, it’s also possible to outsource this development effort.
Outsourcing starts far upstream of drug product in the supply chain. Raw material sourcing is critical for everything that’s produced and used in support of the drug product. Even for formulations using all conventional excipients, the critical raw material providers must be effectively qualified and managed. Even if the materials are all commercially available and compendial, the specifications may not be perfectly suited to your product and clinical trial phase, so some level of customization may be required. Non-compendial excipients that are especially complex to deal with can require a lengthy process of vendor selection and analytical development activities. You’ll want to be aware of any raw material attribute changes that might impact your product by writing change notifications into your supply agreement.
Drug substance is often a huge component of outsourcing. If you are developing a new chemical entity (NCE) then there will be a substantial CMC effort required to develop the processes for the synthesis and purification as well as a significant analytical effort supporting process monitoring and material characterization. BIND has historically used generic active pharmaceutical ingredients (APIs), so this is more of a negotiation and vendor qualification exercise, but now that we have in-licensed a number of NCEs there is a more concerted effort in this area.
Characterization and material release is a very large effort and often the most visible to regulatory agencies as reflected in the large number of FDA 483s associated with laboratory activities. This includes release testing of raw materials, drug substance, intermediates, and drug product. A complex formulation often comes with some non-conventional test methods. These methods need to be developed and transferred into the testing lab in a manner akin to the manufacturing process itself, and hence this can become a large part of the scope of technology transfer activities, particularly if more than one laboratory must be used to accommodate specialized testing needs.
Finally, distribution of product requires active management. At BIND this is handled by the clinical operations department, but a larger company with multiple clinical and commercial products will likely require entire supply chain departments to manage their clinical and commercial product distributions.
How deeply you manage your suppliers should be commensurate with how critical the material or activity is. Certainly being aware of your contract manufacturers’ suppliers is a must from a vendor management and product quality perspective. There is much talk these days about managing three levels down – to your suppliers’ suppliers’ suppliers3 .
Perhaps the most important thing you can do as a sponsor company is to hire a technically competent staff to manage the outsourcing effort. In addition to the functional competence of your scientists, engineers, business, and legal personnel, experience interfacing with vendors is a key skillset. This staff needs to build and administer flexible internal systems to supervise those vendors, the associated projects, and all the contracts, project plans, documents, and individual tasks, typically across multiple external partners.
CMO Evaluation and Selection Process
Before managing contractors, you have to select them. This is perhaps the most critical step in outsourcing, because these decisions will lead you into (hopefully) long-lasting relationships that have significant impact on the products you are developing. Because the number of candidates could appear overwhelming to begin with, it’s best to whittle the list down to a manageable number before initiating contact. Create a list of specific requirements for your product that can be discussed in a non-confidential manner. Focus on those that are nonstarters – meaning that the failure of the CMO to meet those needs would be reason in and of itself to be a no go. For BIND, some of these requirements include:
- Availability of a large, Grade C/Class 10,000 compounding room flexible enough to accommodate our customized process equipment.
- A WFI system capable of delivering thousands of liters of tempered WFI on-demand for a very water-intensive bulk process.
- The ability to handle and lyophilize cytotoxic APIs.
- A liquid fill line and lyophilizer in a Grade A/Class 100 area to perform an aseptic fill/finish.
- Flexibility in scheduling since we have both compounding and lyophilizing processes that take several days.
You may have some of these same demands or others not on this list, such as fill line speed requirements, lyophilizer capacity, geographical location (and any associated local regulations), the absence of certain types of APIs or materials being handled in the facility, and special plant utilities such as vacuum, compressed gases, or glycol. The most important thing is that you identify the needs upfront so that you don’t initiate the confidentiality disclosure and request for proposal (RFP) process with a CMO that doesn’t qualify. Identifying these potential show-stoppers early will save valuable time required for the proposal process for both you and the CMO. Once you have confirmed that the CMO meets all of your high level needs, it is advisable to create a technical questionnaire around general facility capabilities and practices that are important to your process.
Narrowing the field of candidates to a handful, around three to six, prior to submitting a formal RFP will allow for a more manageable selection process. The RFP, along with the proposals that follow, needs to be very clearly written to avoid any confusion and ultimately extra charges later, and to receive comparable proposals. CMOs that submit acceptable proposals should be visited to perform a formal due diligence. The technical visit should include representatives from both manufacturing and QC. Performing a technical visit ahead of and separate from the quality audit is advised, but the two visits can be combined if necessary. It is important to have technical representation at the quality audit to review equipment qualifications, procedures and other technical documentation that may be outside of the auditor’s experience and provide a more holistic view of an organization’s compliance program.
Complex processes will require more extensive interaction between the CMO and sponsor; therefore the CMO’s initial effort and ability to understand the process, their willingness to work through potential issues, and their communication style are particularly critical in the evaluation process. The responsiveness to the questions asked during the questionnaire and the level of detail involved in the technical discussions are usually good indicators of how responsive the organization will be as a whole when working with them on a tech transfer. If they are not responsive and enthusiastic when trying to get your business and putting their best foot forward then it is a good idea to steer clear. As has been reported for CROs, once you start working with them you’ll find that their dedication to the project and sense of ownership is as important as any attribute in determining success4 .
Figure 1. Risk assessment matrix for CMO selection. Prioritize categories by assigning category weights to the different criteria. Those attributes most important to your product should be assigned a 10, and so forth down until the least important attributes. This weight can be multiplied by the individual scores and then the products added up for an overall rating.
When making the decision, it is important to focus on the categories and attributes that are most critical to your company and to compare apples to apples. This should happen naturally if the RFP was well written, but may require follow-up questions if the proposals were not clear in their scope or substance. Using a risk assessment matrix such as that described in Figure 1 can be helpful with the decision. Even if the decision is obvious in the end, such a matrix can be a comforting validation and also serve as justification for the decision to your superiors. Remember to also consider your long-term supply needs. While the RFP may be focused on a single manufacturing campaign that meets immediate needs, most manufacturing endeavors are not just one-offs but will be part of an extensive clinical and ultimately commercial supply strategy5 .
Quality systems are one of the most important attributes to compare. Therefore, standards should be defined to evaluate them. An obvious one is their regulatory history. All formal inspection reports should be provided by the CMO. Sometimes sections related to specific clients are redacted, but the observations and main points should remain apparent. Additionally, the organization’s familiarity with progressing products through the clinical development lifecycle to commercialization is imperative. A CMO with minimal regulatory experience could be a liability or require substantial coaching and oversight from your quality organization. Conduct an evaluation of SOPs (e.g. deviations, data integrity, training, equipment qualification, validation, vendor management, etc.) and the quality manual since the purpose is to judge the CMO’s operational compliance in the absence of firsthand experience. Finally, from a manufacturing perspective, getting a sense of their timeliness to review documents, release batches, and close deviations is important.
Even after the decision-making process, do not fully inform the contractors that didn’t make the cut until it’s a certainty—meaning contracts are signed. And, unless you’ve been absolutely convinced that you would never use a CMO in the future, be sure to explain the decision, depart amicably, and leave the door open for future partnerships, as things can change quickly in this world. Remember that your backup CMO is one warning letter away from becoming your primary supplier.
When you have made your decision and are in the contracting phase, it’s important to remember that everything is negotiable. An important point for BIND, given the complexity of our manufacturing process, has always been to have man-in-plant privileges. For our early-stage products run on our small-scale, manually-intensive process, that means having our engineers on the floor and interacting with the operators during the compounding process. That right is written into our master services agreements.
CMO Management
Like most relationships, effective communication is the key to managing your contractors. Once tech transfer has started, it is important to have frequent meetings. Weekly has worked well for BIND, but we often increase the frequency during periods of high activity or add additional focused meetings on an ad hoc basis. We also make many site visits leading up to batch production to assist with training and method transfers, or just to have an eye witness verify what we’re being told.
It is very important to have an in-house project manager on the team. Do not rely solely on Project Management of the CMO as that is a sure way for tasks to fall behind schedule. With a complex process there are many tasks to juggle and whether it be from a staffing perspective, technical understanding, or general organization, CMOs may not be equipped to handle such complexities. Therefore, a small team is needed to complete the tech transfer and interface with the respective departments at the CMO. BIND normally has at least four team members from the manufacturing group as well as representatives from our Analytical, Supply Chain Management, and Quality Assurance departments.
Conducting an effective technology transfer is the critical first step in your new CMO relationship, and requires appropriate internal effort. Of particular importance is development of a comprehensive technology transfer package, including process knowledge, analytical methods, equipment, materials, documentation, and specifications. Be prepared to allocate appropriate resources and time to bring the CMO up to speed. One way to effectively convey the key elements from the extensive development work you have done to ensure a robust process is to develop, in combination with CMO personnel, a failure modes and effects criticality analysis (FMECA). This important risk assessment tool can really highlight process complexities to your new partner, help them understand how you’ve developed the process, where key risks lie, and enroll them in your success. Maintaining a sense of engagement and partnership with the CMO is particularly critical for complex projects, as the time and effort requirements are likely to be disproportionately significant for your project, with the potential for frustration.
The CMO will often give you the option to be the reviewer on most quality documents written for your product. This option is actually something that should be specified in the General Quality Agreement (GQA). Take the opportunity to review as many documents as you can make time for or dedicate resources to. Prioritize if needed, but the more you review the better handle you will have on the activities happening with your product in their shop. Always keep copies of your documents in your own quality systems as these can be very handy down the road when transferring into new facilities, reviewing the history of a process, and preparing for regulatory inspections.
Consider using a phase-appropriate approach to a variety of aspects of contracting out. While everyone is aware of phase-appropriate method qualifications and specifications, you can apply similar principles to the tech transfer and process. This starts with equipment qualifications— conduct only basic IQ/OQs in early-stage processes when the process and equipment set is bound to change, and save the full commissioning and validation for later-stage programs. An important area for BIND is operator training. In early development, we work with CMOs who allow BIND staff to be trained in their systems so that we can help run a very complex and manually-intensive process with engineers who are fully adept at it. We try to avoid the complete hands-off approach of running the process until Phase III, at which time the process is ready to be validated and runs on more automated and user-friendly equipment. One important note is that, for a sterile product, there is nothing phase appropriate about sterility assurance – complete validation of the sterilization process and testing is expected.
Conclusions
To summarize the most important points, the first thing you need to do is staff the project with a strong technical team, starting from the evaluation phase all the way through commercial manufacturing. Every aspect of the outsourcing process, from sourcing raw materials to clinical distribution, requires active management.
For manufacturing of anything complex or unusual, there is no replacement for having staff on site. That usually means a technical representative to handle manufacturing questions, perhaps one for analytical questions, and a quality representative. No matter how well- prepared you are, something will go wrong. It is far easier to deal with problems and make game-time decisions when you’re on site and have all the information.
Finally, don’t get too lost in the trees and forget to pull back and see the forest. Oftentimes small changes in details in certain aspects of the tech transfer may impact the entire schedule, but it won’t be too obvious if you don’t have a detailed Gantt chart that you’re checking for critical path. For example, a delay in establishing a simple spec sheet could delay the ordering of a raw material. Late delivery will then delay release and availability of that material needed for a certain batch schedule. Having a technically competent project manager who is also responsible and detail-oriented will help ensure project needs are managed appropriately so that project timelines are achieved.
Using these best-practice approaches, including a QbD development and active management of contractors, BIND Therapeutics has successfully moved a promising academic concept with a small amount of data into potentially game-changing therapeutic products.
References
- Hrkach et al; Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile; Sci Transl Med 4, 128ra39 (2012)
- ICH Harmonised Tripartite Guideline: Pharmaceutical Development Q8(R2)
- Outsourced Pharma http://www.outsourcedpharma.com/doc/amgen-three-deep- with-suppliers-lilly-making-medicine-together-0001?sectionCode=Editorial&templ ateCode=Single&user=2708474&source=nl:42954&utm_source=et_6214173&utm_ medium=email&utm_campaign=OUTPH_2015-05-06&utm_term=35197D1E-2CBD-462A- 85C0-4B03D14776D2&utm_content=Amgen%2bThree-Deep%2bWith%2bSuppliers%253b %2bLilly%2b%2522Making%2bMedicine%2bTogether%2522
- Glass HE, Beaudry DP. Key factors in CRO selection. Applied Clinical Trials. April 1, 2008
- Pharmaceutical Outsourcing https://www.pharmoutsourcing.com/Featured-Articles/172751-What-to-Look-for-in-Selecting-a-CRO-CMO-and-How-to-Ensure-the-Right-Choice-A-Quality-Assurance-Perspective/
Greg Troiano directs the formulation development, process development, and manufacturing of BIND’s proprietary Accurin TM drug delivery technology. Prior to joining BIND Therapeutics, Mr. Troiano was Associate Director of Process Development at Alkermes, where he lead a team to develop, optimize, commercialize, and scale up microsphere and other drug delivery technologies. Mr. Troiano received his MSE in Biomedical Engineering from The Johns Hopkins University. He holds over 15 patents and 5 scientific publications in drug delivery.
Donald Parsons directs the synthetic chemistry and analytical development groups at BIND, including the sourcing of complex, custom-manufactured excipients as well as characterization services. Prior to joining BIND Therapeutics, Dr. Parsons held positions of increasing responsibility at Warner Chilcott Pharmaceuticals and Procter & Gamble Pharmaceuticals. Dr. Parsons received his Ph.D. in Physical Chemistry from the University of Wisconsin – Madison, and is the author of 5 scientific publications.
Christina Van Geen Hoven directs the manufacturing of BIND’s proprietary Accurin TM drug delivery technology. Prior to joining BIND Therapeutics, Mrs. Van Geen Hoven was a Lead Engineering Associate at Alkermes where she worked on developing and scale up of microsphere drug delivery technologies. Mrs. Van Geen Hoven received her B.A in Biology from Boston University and holds 4 patents and 1 scientific publication in drug delivery.
Stephen Tuller directs the quality assurance organization at BIND. Prior to joining BIND Therapeutics, Mr. Tuller was Associate Director at Vertex Pharmaceuticals responsible for batch release, vendor management and hosting third party inspections. Mr. Tuller received his B.S. in Chemistry from East Tennessee State University.
Jagannath Dey leads development, project management and tech transfer activities for BIND’s proprietary Accurin TM drug delivery technology. Prior to joining BIND Therapeutics, Mr. Dey was an Associate Scientist at Georgetown University where he focused on developing targeted nanoparticle therapies for the treatment of Type 1 Diabetes. Mr. Dey received his M.S in Biomedical Engineering from University of Texas, Arlington. He holds 1 patent and has authored 7 scientific publications.
Lia Brigida works on the manufacturing and project management of BIND’s proprietary Accurin TM drug delivery technology. Prior to joining BIND Therapeutics, Miss Brigida was a Senior Research Associate at Millennium: the Takeda Oncology Company where she focused on development of small and large molecule sterile formulations and technology transfers to CMOs. Miss Brigida received her B.S. in Biochemistry from the University of Massachusetts Amherst.
