By Kara Quinn and Ewelina Flamm

In Part 1 of our two-part series Balanced Sourcing of Custom Media/Buffer Formulations, we discussed the case for outsourcing, identifying three logical reasons to outsource, with key considerations. In Part 2, we are flipping the proverbial coin to discuss key considerations in the case for vertical integration, or insourcing. While our case for outsourcing highlighted cost-effectiveness, it’s the inherent technical challenges that might lead a biopharmaceutical manufacturer to conclude for themselves that just because you can doesn’t mean you should.

3 Practical Reasons For Vertical Integration And Sourcing From Within

1. Parenteral Drug Product Safety Regulations

Individuals processing incoming materials in biopharmaceutical manufacturing may at some point have noticed a common disclaimer found on the certificate of analysis (CoA) of a preformulated sterile media/buffer, “Not for use in humans. For downstream processing only.” Invariably this statement strikes fear in the hearts of less experienced biopharmaceutical employees as they realize the purchased media/buffer will be dispensed into the aseptic process of a sterile injectable human drug product!

But preformulated media/buffers used in parenteral product manufacturing are always intended for downstream processing only. Manufacturers of licensed drug products must abide by purity and sterility standards detailed in the regulations for general biological products (21 CFR Part 610) as well as finished pharmaceuticals (21 CFR 211.165). It is the licensed manufacturer that carries the ultimate accountability for the safety of a parenteral drug product.

Manufacturers that choose to outsource the formulation of their custom media/buffer excipient cannot also defer the design controls and rely solely on the supplier’s sterilization method alone. Parenteral drug product manufacturers must understand that the controls employed by a third-party formulator certify the sterility of the media/buffer for the supplier’s intended purpose: downstream processing only. Third-party suppliers are not licensed as parenteral drug product manufacturers and cannot manufacture products for human use. It is incumbent upon the parenteral drug product manufacturer to further process a media/buffer excipient by validated sterilization techniques at the point of use. A simple 0.22 micron in-line filter might seem redundant and post-use bubble point testing an unnecessary hassle, but it’s a small investment in licensure obligations. The alternate option would be to formulate in-house under the design controls of a licensed and inspected drug product manufacturer.

2. Functional User Requirements

In biopharmaceutical development, the discovery of custom proprietary drug products invariably demands a novel or unique combination of raw material ingredients. Custom media/buffers are frequently a necessary by-product in development, which begs the inevitable question: when or where to formulate? Strategies for formulating in-house might include make-and-use in-line, make-and-hold in-line, and make ahead, test, release, and store until use, depending on capacity and shelf-life. If none of these options sound appealing, outsourcing demands a technical transfer of the custom proprietary formulation, manufacturing instructions, ingredient supply chains, and potential analytical methods to a third party. Whichever formulation strategy a manufacturer chooses, there are several technical challenges that require consideration:

Optimal Nutrient Availability

Culture media/growth medium supplies all critical nutrients a biological organism needs to survive or thrive in an in vitro environment. Under axenic¹ processing conditions, biopharmaceutical manufacturers deliver the nutrients to a specific biologic organism to the exclusion of all others. Therefore, in liquid formulations, the sterility of culture media, or absence of unwanted microbial organisms, is paramount to the intended function from the moment of formulation whether achieved through aseptic manufacturing conditions, terminal sterilization, or by 0.22 micron in-line filtration. Generally, the shorter the distance between growth medium formulation and sterilization to the axenic process, the better.

An inconspicuous breach in the post-sterilization packaging, shipping, or handling of a growth medium container (i.e., an errant twist-tie pokes a pinhole in manifold tubing) not only violates GMPs by challenging purity requirements but creates conditions in which an environmental organism might consume the critical nutrients intended for axenic manufacturing, replacing them with waste products. The risk is not just to purity/sterility at this point but to the functional user requirements of the validated manufacturing process.

Third-party suppliers considered in the formulation of custom growth media should be assessed not only for their ability to formulate but also package and effectively ship the volumes needed on a routine basis. A reliable supplier must have sufficient controls in place to address the many potential sources of contamination post-manufacturing, including but not limited to, the container closure integrity, sampling, the shipping process/handling, and the additional sampling/testing upon receipt.

Shelf-Life Stability

The quality, analytical, and functional attributes considered essential to the release of a preformulated custom media or buffer upon its receipt are expected to be met through its date of expiry. Shelf life, the period of time a material can be stored under labeled conditions and still meet the essential characteristics reported on the certificate of analysis, is established through repeated CoA testing on the same batch over time. A custom formulated media or buffer, by definition, does not have a known shelf life. Without data, there is no guarantee that the combined ingredients will serve the very same function on Day 365 as they do on Day 1.

If a custom formulation is determined to have a very short shelf life, the biologic product manufacturer may have no other choice but to formulate in-house. As an example, L-glutamine, an essential amino acid that delivers nitrogen necessary for protein synthesis in the rapid division of cells, is notoriously unstable in unfrozen aqueous solutions (i.e., formulated growth medium). L-glutamine quickly degrades into toxic by-products within a matter of hours to days.² While various synthetic versions of L-glutamine have been developed to extend this shelf-life constraint, cell-line compatibility and cost remain relevant factors in whether a full replacement is feasible in industry.

Prior to outsourcing, a biopharmaceutical manufacturer must understand the custom media/buffer formulation’s stability and expiry along with how much of that time might be eaten by shipping and release. For materials with already short expiries, outsourcing could significantly shorten the clock of usable time and put stress on manufacturing schedules. In-house supplementation offers biopharmaceutical manufacturers both the control over time-zero addition and post-supplementation degradation at each stage of medium addition/replacement.

Analytical Development

A woefully overlooked consideration when outsourcing formulated custom solutions is the analytical complexity required to test and release for both the third-party formulator and the drug product manufacturer. Regulatory standards allow for the acceptance of partial or full testing results from the supplier’s CoA in lieu of on-site testing by the drug product manufacturer; however, at a minimum, per-batch identity testing must be performed. Industrywide identity testing serves to broadly and consistently affirm that materials received from non-regulated supply chains are in fact what they are purported to be, which adds a profound layer of protection to patients by way of a comprehensive screen of common supply chains for potential adulteration, mislabeling, or mix-up. It’s an understandable and relatively straightforward principle, except when you need to quickly identify each of the surprisingly “clear, colorless” preformulated solutions that are purchased and delivered to your docks.

When formulating in-house, drug product manufacturers purchase the individual raw material ingredients directly and often prioritize sourcing well-known chemically defined, pure, shelf stable materials manufactured to compendial grade standards determined by pharmacopeial monographs. Pharmacopeial monographs overwhelmingly simplify acceptance testing for incoming ingredients because not only are the required material attributes aligned and predetermined but the specified analytical methods are already validated and the acceptance criteria set. Preformulated custom solutions have no pharmacopeial monographs. It is incumbent upon the drug product manufacturer that developed the custom “cocktail” to determine the unique and specific manner in which the solution can be identified. In a sea of clear, colorless solutions, differentiating between two that differ only in concentration of sugar is no small task.

While outsourcing preformulated solutions may alleviate the burden on manufacturing floor resources, there is likely a transfer of burden to analytical development resources. Depending on how subtle the various purchased formulations may differ, it is important for biopharmaceutical manufacturers to acknowledge the up-front investment that might be required to differentiate their custom solutions before celebrating the longer-term savings on in-house capital, capacity, and expense. Analytical investment is not an insurmountable technical obstacle, but it does require forethought, unique technical expertise, and time for development and validation, which, if not already built into decisions on outsourcing, quickly becomes an obstacle capable of derailing project timelines at a very inopportune time.

3. Proprietary Formulations

Raw material variability and process robustness are two sides of the same coin. Given the inherent variability in biologic systems, every cell line, virus, monoclonal antibody, gene, etc., is likely to respond quite differently to the artificial conditions created in their ex vivo or in vitro experience. It is not uncommon for the exact same process using the same raw materials and operating parameters to yield different results for different organisms. A biopharmaceutical manufacturer must thoroughly understand its process capabilities before making a definitive decision on supply chain strategy. More often, however, the process development and scale-up move at a speed dictated by the promises of clinical performance. This means that at the time a sourcing decision is needed, it’s not entirely clear whether the process is robust enough to deliver consistent yields despite preformulated media/buffer variability or, as is often the case, the process robustness yields to the variability of the critical media/buffer. It goes without saying that if your biopharmaceutical process is particularly sensitive to performance variability, having the flexibility to formulate in-house is a significant advantage.

But if outsourcing a custom formulation is to be considered at all, the contract between the third-party supplier and the biopharmaceutical manufacturer requires special considerations. Custom formulations, including the specific ingredients, source, grade, concentration, and process, are all proprietary to the biopharmaceutical manufacturer and drug product through licensure. Management of the original recipe and sourcing of the ingredients are deciphered in-house during clinical development, which provides the manufacturer the greatest amount of oversight and control over formulation. This is no small task for some processes as it is not uncommon for a growth medium to comprise ~80 to 100 individual ingredients sourced from a wide variety of suppliers.

Notably, the inactive ingredient components that make up the excipient buffers/stabilizers/adjuvants become part of the proprietary drug product formulation. A detailed identification of origin, source, concentration, quality, and manufacturer is correspondingly delineated within the product license/dossier submitted to health authorities. A change to any one of the filed attributes, including the formulator, requires a level of notification (i.e., prior, concurrent, or annual) to the corresponding health authority by statute. Excipient buffers/stabilizers and their individual ingredients are also held to more stringent regulations pertaining to current good manufacturing practices (cGMPs). Inactive ingredient manufacturers are not “licensed” by health authorities and are therefore not beholden to drug product cGMPs by anyone other than the license holder. Regulations dictate that it is the drug product manufacturer’s responsibility to ensure the necessary cGMPs for drug product quality are applied to the inactive ingredient and manufacturer. This standard applies to both the formulated buffer/stabilizer and the individual ingredients. When final excipient formulation is performed by the drug product manufacturer, however, the corresponding cGMPs employed are typically commensurate with the final formulation of licensed drug product verified prior to approval as well as routinely. 

Deciding to outsource formulation of proprietary solutions extends the oversight expected of the license holder to a third party, requiring confidential disclosures and a decrease in direct communications with the ingredient sourcing supply chain. Confidential disclosures are not difficult to manage through non-disclosure agreements (NDAs), etc., although instances do arise that seem to limit drug product supply chain flexibility when contract manufacturers intend to source the proprietary preformulation without a three-way NDA in place. Managing the effects of an indirect supply chain arrangement with the source ingredient manufacturers has the potential to turn into a long-term product life cycle management hurdle that might significantly outweigh the benefits of outsourcing, if not expressly articulated in contract agreements. Custom formulations demand greater oversight, data trending, process control, and supply chain visibility for the obvious reason that process development specifically identified the formula, its ingredients, and concentrations as essential to the defined efficacy, safety, or quality of the biological process; otherwise, an off-the-shelf formulation would have sufficed. The significance of custom formulations and the purpose for their development should be readily evident to all stakeholders and, therefore, adequate due diligence should always be a consideration in the decision to outsource custom formulations.

The Happy Medium

By now, the world is acutely aware of the havoc a pandemic can wreak on supply chain management. In the effort to rapidly respond with both prophylactic and therapeutic treatments, the biopharmaceutical industry, in particular, experienced the costs of premature sourcing decisions, constraints on third-party supply options, and the limited flexibility a manufacturer has without a balanced strategy for media/buffer sourcing. In those moments it was hard not to appreciate the value of a good old-fashioned stainless-steel tank, a reliable WFI system, and some readily available shelf-stable ingredients. Post-pandemic, the industry continues to move toward a lean facility-of-the-future consisting of modular designs and single-use disposable process materials. But if the pandemic taught us anything, there is great value in flexible manufacturing strategies that take advantage of the best of in-house formulation and outsourcing. A facility designed solely to accommodate the idealistic vision of reliance only on outsourced support functions is a facility incapable of the agility necessary to urgently respond to the next relevant demand.

Having been tasked with sourcing custom media/buffers in times of both feast and famine, we recommend manufacturers take a strategic, proactive approach to sourcing strategies at the earliest stages of process development. It is the point at which the process is being defined that affords the greatest in-depth opportunity to assess the effect a specific formulation or who, when, or where the formulation occurs will have on process performance. In the fall of 2019, we participated in an industrywide development of a raw material risk assessment process and tool through the BioPhorum Group. The assessment and its corresponding tool were designed to accommodate the entire product development life cycle. However, the power of this risk assessment methodology was by far realized when applied in the earliest possible product development stages.

There are three tenets to the risk analysis, which compare the user requirements (1) versus the unique material attributes (2) to the available supply chains in the current marketplace (3). While there is no one-size-fits-all, the tool is a “living” assessment that considers: the process (i.e., user requirements, quality attributes, robustness, material variability, etc.); product development timelines and complexity including technology transfer and analytical development; facility design, capacity, and support functions; and the complexity and criticality of the formulation, its ingredients, and the corresponding oversight warranted both initially and throughout the product life cycle. The cross-functional analysis should inform the decision to manufacture in-house versus outsourcing liquid media or buffers. The cross-functional team may include technology teams, the process development team, analytical support groups, engineering solutions, safety, and procurement, with the ability to consult other groups (such as regulatory) as appropriate. 

As always, regulatory guidance asserts that it is the medicinal product manufacturer’s responsibility to determine the level of supervision required to establish and maintain the qualified status of a procured raw material, as well as the stringency with which GMPs are to be applied. Oversight of raw materials should be proportionate to the risks posed by the specific material to its unique designated function and purpose. While there are some safer bets when it comes to deciding which formulations to outsource (i.e., simple buffers used for ancillary purposes that are not present in quantifiable amounts in the formulated drug product or intended to serve a function in drug product delivery as an excipient), outsourcing of buffers reduces the ability to have direct oversight over the buffer inputs; therefore, consideration must be taken when selecting potential candidates.

References

1. axenic. (n.d.) Collins Dictionary of Biology, 3rd ed. (2005). Retrieved November 25, 2023, from https://medical-dictionary.thefreedictionary.com/axenic
2. Yousefi Taemeh et al. Journal of Cell and Molecular Research. Effect of Glutamine Stability on the Long-term Culture and Line Establishment of Chicken Primordial Germ Cells. (2021) 13 (I), 44-53. Accessed Nov. 27, 2023 through https://jcmr.um.ac.ir/article_40565_6de8ea4c24257289a3a4b75c0a5d83d9.pdf.

About The Authors:

Kara Stockett Quinn, M.S. in regulatory science, has worked in the biopharmaceutical industry for 30 years. She has developed subject matter expertise in end-to-end product development, technology transfer, validation, commercialization, pre-approval licensure, manufacturing launch, and supply. She has held positions of increasing responsibility in nonclinical/clinical development, process technology, and quality systems and operations while gaining extensive experience in direct health authority facilitation and regulatory communications. Quinn was instrumental in facilitating industry alignment in raw material risk assessment best practices, qualification standards, and novel excipient characterization. Her work as a thought leader in raw material qualification and supply chain management continues through periodic authoring/co-authoring of relevant industry articles.

Ewelina Flamm is an associate director at Merck and is a subject matter expert in Merck's Incoming Material Center of Excellence Group supporting large molecules. With 17 years of experience, she advances incoming material knowledge with key focus in clinical and commercial technical risk assessments (fit for function alignment), origin of materials, incoming material lifecycle management strategy, and improving access to electronic supplier data.