However, because the stakes are very high and there is little room for error when manufacturing a biopharmaceutical product, a better approach to CMO oversight would involve the client serving as an active participant in the execution of the campaign and rely less on periodic updates via web/teleconference. Working together as a team on manufacturing preparedness, the CMO and client establish lines of communication that wouldn’t necessarily exist if the client took a hands-off approach. In turn, this deliberate and direct engagement decreases the risk of an error or misunderstanding related to the client’s production process at the CMO. The client’s involvement provides an extra level of review that could prevent a potentially catastrophic failure leading up to or during the manufacturing operations. This thoughtful and proactive review of the components and systems involved in biopharmaceutical production can be referred to as manufacturing readiness.
The Oxford Dictionary defines readiness as, “The state of being fully prepared for something.” As it relates to biopharmaceutical manufacturing, the definition can be refined as: The active review of all processes and procedures of a manufacturing campaign at a CMO so as to ensure successful manufacture of the product on time and within budget.
This article presents a blueprint for client readiness evaluations that are based on a simple, systematic process that ensures the active participation of the client’s manufacturing representative(s) in the manufacturing campaign at the CMO.
Readiness areas of interest
Readiness for a biopharmaceutical manufacturing campaign involves focusing on specific areas of interest that are essential to the manufacturing operation. By defining these areas up front, the readiness activities can be systematically executed. The specific areas of interest for a biopharmaceutical manufacturing campaign are:
- Raw materials and consumables
- Manufacturing operations
- Quality control
- Packaging and labeling
The readiness process
Figure 1 outlines the sequence of readiness activities that are typical leading up to a biopharmaceutical manufacturing campaign; these are discussed in more detail later in this article.
The timing of the readiness visit will depend on what process step is being performed (i.e. bulk drug substance (BDS) manufacturing versus drug product (DP) manufacturing versus packaging/labeling) and the level of risk at that specific process step. Moreover, it is recommended that the client perform a risk assessment for the entire manufacturing process and determine when to start readiness activities and when to perform the readiness visit(s) for their specific product. If necessary, more than one readiness visit may be needed for a given campaign. In a typical biopharmaceutical BDS manufacturing process that involves inoculum scale-up, bioreactor production, and downstream processing, a client may decide to only perform the readiness visit during the days leading up to the bioreactor inoculation and at some point during the purification process because the risk of failure at the inoculum scale-up step is low and would have little impact, but a failure in the bioreactor or purification steps may have a higher likelihood and would have a higher impact. In this case, the readiness activities would be comprised of periods of remote and on-site activities until the production operations are finished.
Drug product manufacturing, however, which usually occurs as a one or two-day operation, requires a readiness visit at least a few weeks in advance of the scheduled manufacturing activity to ensure everything is in order prior to the operation. A failure at the drug product manufacturing stage likely has a much more severe consequence for the client’s drug supply needs than a failure during BDS manufacturing. Thus it is imperative that a readiness visit be planned and conducted in advance of the scheduled fill activity.
The readiness checklist
A successful readiness visit can only be accomplished with proper planning, and an essential tool needed for the planning and execution of the readiness activities is the readiness checklist. This checklist (see Table 1), which is structured like a questionnaire, helps ensure all aspects of the manufacturing operation are covered. The goal at this stage of the planning process is to derive a comprehensive listing of the items to be evaluated. The more thought and preparation the client puts into preparing the checklist, the greater certainty the client will have that the CMO is prepared for the manufacturing campaign.
Each of the readiness areas of interest are reviewed in more detail in the following text, and examples of checklist questions and line items are provided.
- Are the batch records approved, effective, and issued?
- Is the product specification approved, effective, and issued?
- Have all planned changes been incorporated into the batch records and have all change control actions been closed?
- Is the stability protocol approved?
- Are all materials and components available in sufficient supply, have they been QC released, and will they be within expiry by the time they are used? It is helpful to have a complete list of all raw materials and consumables along with the quantity needed. If the CMO utilizes an enterprise resource planning (ERP) software, they should be able to provide a complete list and may even be able to run an “Exception Report” to show which items are not in stock or which ones are in stock but are not yet released.
- Have there been any requirements/specification changes with any of the raw materials or consumables and have these been incorporated into the specifications?
- Have there been any vendor notices for any of the raw materials or consumables or have there been any vendor complaints filed within the past 6 months?
- Are all critical manufacturing equipment current in calibration, preventative maintenance, and qualification? A complete list of critical equipment along with the due dates for calibration, PM, and re-qualification is essential for this readiness step. This should include supporting equipment such as washers, autoclaves, depyrogenation ovens, cold rooms, and freezers. All equipment that the raw materials, process intermediates, and final product is exposed to during manufacturing and storage should be considered.
- Are there sufficient spare parts on hand for critical process equipment? Spare parts are very important for equipment with moving parts prone to failure for which there is no backup. For example, this could include components of a filling machine, bioreactor, or chromatography skid. A risk assessment may help determine where equipment failure has the highest impact. In many cases the CMO probably has already conducted this evaluation.
- This part of the checklist is usually reserved for process-specific questions or follow-up items. For example, “Review the column performance data for the Protein A column with the manufacturing team.” This requires some pre-planning but can really be valuable and can lead to insightful discussions.
- Is the HVAC system current in calibration, preventative maintenance, and qualification?
- Are room differential pressure sensors current in calibration, preventative maintenance, and qualification?
- Have the environmental monitoring results for the facility been trended for the previous 3, 6, and 12 months and been reviewed by management? This should include the monitoring results from clean steam and water systems, if applicable. It is helpful to review these environmental monitoring reports and pay attention to any trends that may indicate the facility is not in control.
- Are all personnel performance trained on the process(es) and are they up to date on all of the training in their curriculum?
- Are all internal and external QC labs and personnel aware of the in-process and release testing schedule for the product? How is this information communicated to the QC teams?
- Are all test reagents in stock and within their expiration date?
- Have there been any changes in the test methods or reagents and have these changes been incorporated and approved by quality?
- Are all QC instruments current in calibration, preventative maintenance, and qualification? Like the manufacturing equipment, it is helpful to have a list of instrumentation used in the testing of the product.
- Is there adequate reference standard in stock at all test labs, including subcontractors, to support the testing of the product in-process and release?
- Is the final container in stock in sufficient quantity; is it released and within expiry?
- Have the final labels been approved by quality assurance?
- Is there a procedure in place for final product pack-out for shipment?
- Have all shipping personnel been trained on the pack-out of the final product?
- Has the shipment been arranged with a carrier?
The readiness agenda
Clients should notify their CMO of their plans for readiness activities in advance of the readiness visit. It is helpful to communicate the specific areas of interest, including the documentation, records, facilities and systems that the client representatives will be focusing on so that the CMO staff can be prepared; this ensures that the client will achieve an efficient readiness visit.
Another crucial part of the readiness visit agenda is listing the CMO subject matter experts (SMEs) that client wants to meet with during the visit. The client’s CMO colleagues need time to plan for their role in the readiness visit; clients should notify CMO leadership well ahead of time to ensure that client staff can meet with critical CMO personnel. These details should all be outlined in the readiness agenda; an example is provided in Table 2. Sending this agenda at least two weeks in advance of the readiness visit is usually adequate; however in some cases, clients may want to provide more notice. For increased transparency, clients may choose to include the entire readiness checklist in addition to the agenda so it is absolutely clear what client staff will be focusing on. Finally, clients should highlight what records they would like the CMO to prepare or produce during the visit so it can be as streamlined as possible.
The readiness visit
In order to focus on critical areas of interest in the time leading up to a manufacturing campaign, it is necessary to always perform an on-site readiness visit. In many cases the CMO will not be able to share all of the documentation and records necessary to perform a thorough readiness check via email or a secure website, due to their proprietary nature. Therefore, it is critical that the appropriate client representative visits the CMO. This is the best way to be an active participant in the readiness for manufacturing. The readiness visit should be handled differently than an on-site audit of the CMO, and clients should have this discussion at the beginning of the planning process so as to avoid the tension a client visit can cause. It is important to convey to the CMO colleagues that the readiness activities are just as much to their benefit and that any “findings” will be addressed jointly and do not constitute audit observations. The client and the CMO are one team with the same goal: successful execution of the manufacturing campaign.
The timing of the readiness visit is important and it should be scheduled with enough lead time to allow correction of any potential issues that are identified during the readiness activities but not too far in advance where the client may not be able to see the approved documentation and up-to-date records, such as calibration and environmental monitoring reports. Longer manufacturing campaigns may require multiple visits to accomplish a thorough readiness process. Clients should schedule the readiness visit in coordination with the CMO project manager assigned to them.
There is no better way to gain a thorough understanding of how a client’s process is performed at a CMO than by having client representatives on the manufacturing floor alongside the manufacturing personnel. Thus, while on site performing the readiness visit, client staff should make sure to leave time to enter the manufacturing facility to observe the production operations as allowed by the CMO’s policies. This may require specific training on gowning and personnel flow, so clients should leave enough time at the beginning of the visit to satisfy these requirements.
Readiness visit follow-up
Depending on when a readiness visit is performed, there will likely be activities that will take place leading up to, during, and even right after the manufacturing operation occurs. This is where the readiness checklist is helpful. Anything not confirmed on site can be handled via email or teleconference. The CMO can likely provide client staff with objective evidence in the form of scanned pages or simply an email reply. It is recommended that clients utilize their CMO’s project manager for these follow-up activities.
As previously mentioned, there are certain records and documents that cannot be shared electronically (i.e. CMO-specific procedures and records), so it is important to make it a priority to review these while on site. Readiness does not begin or end with the on-site visit, so it is imperative client representatives remain engaged throughout the whole process.
In addition to the readiness checklist as a record of the client’s readiness activities, it is helpful to summarize the activities in a readiness report. This report can be a valuable reference when planning for future readiness visits or when deciding what areas need (or do not need) focus during a compliance audit. It may be helpful to provide a copy of this report, or a summary of it, to the CMO; they will likely want to know their client’s impressions of their readiness.
The production of a client’s biopharmaceutical at a CMO is complex and is best done when the client is involved and engaged in the process from start to finish. The insight clients gain regarding the systems and processes employed by their CMO will be very valuable for future interactions. If issues or shortcomings are discovered, they can be addressed jointly and proactively. Furthermore, knowledge of the CMO’s systems will allow clients to strictly focus on compliance issues during compliance audits and may in fact help reduce on-site audit time and follow-up activities.
It should be noted that the readiness activities can be a windfall for the CMO as well. A client’s engagement in the manufacturing readiness can illuminate weaknesses in the supply chain or support systems. An engaged client, through their readiness activities, may identify something the CMO’s team has overlooked, such as a wrong part number, a material shortage issue, or a training deficiency. Additionally, the face time spent between the client and the production and support teams helps build relationships and engenders trust. After all, successful execution of a biopharmaceutical production lot is in everyone’s best interest, especially the patients we serve.
Finally, while the readiness process provides benefits for both parties, it is important that the client and CMO agree upon the terms of these activities before entering into a manufacturing agreement. Discussing this early and making it part of the contract promotes the same spirit of open communication and transparency that is fostered by the readiness process itself.
Jason Condon is a senior CMC project manager at Vaccinex, Inc. in Rochester, NY and an adjunct assistant professor in biomedical engineering at the University of Rochester. He has also held roles in biopharmaceutical manufacturing and process development at Bristol Myers Squibb and Janssen R&D. His expertise in cell culture and cGMP manufacturing has aided him in developing manufacturing processes for monoclonal antibody, cell therapy, and vaccine production throughout his 13-year career in the industry. A significant portion of this work has involved continuous (perfusion) bioreactors and hollow fiber filter cell retention devices. Jason is currently responsible for the clinical supply chain at Vaccinex and oversees drug substance and drug product manufacturing and testing, as well as the packaging, labeling and distribution of the finished product.