With more than 25 years of experience in contract aseptic fill/finish (F/F) manufacturing, contract bulk drug manufacturing, and aseptic F/F outsourcing of bulk drug product, I have identified a number of pitfalls that tend to trip up potential clients during their search processes. In this article, I will discuss common oversights and how to remedy or avoid them.
Step 1: The RFP
It should come as no surprise that the first step involves putting together a Request for Proposal (RFP) that will be presented to potential contract aseptic F/F sites. The importance of this step is highlighted by the fact that a quick Internet search using the keywords “RFP, Pharmaceutical Outsourcing, and Manufacturing” will yield over 70,000 listings of papers and seminars explaining the details and how-to’s of RFPs.
However, for the sake of this paper, putting together an RFP for contract aseptic processing should, at minimum, detail the following:
- Description of the final drug product and its intended use
- Project scope (i.e., is the project just fill/finish? Will testing, stability studies and/or development work be included?)
- The proposed aseptic manufacturing sequence
- Any special “considerations” (e.g., thermal, light, shear sensitivities that the product may have, incompatibilities with certain materials, etc.)
- The required number of vials
- The expected date the product is needed
- Testing requirements
The key word in the preceding paragraph is detail. In many cases, when details are improperly given in an RFP, processing problems will result. The most prevalent error at this stage involves providing unintentional misinformation about the process and/or product in the RFP.
For example, let’s consider a product destined for use in a Phase I clinical trial. Up to this point, the majority of manufacturing effort and cost has been spent on developing synthetic routes for the API or, in the case of biopharmaceuticals, looking for ways of expressing and purifying the active biologic. A significant amount of time and money also has been spent on evaluating additional parameters (e.g., efficacy, profile studies and formulation issues).
A critical mistake is to present this limited history in the RFP as if it were the definitive process or history. Remember, a good contract aseptic F/F site will have the necessary experience to help you identify areas that may pose concerns. An example would be a bench-scale formulation process that does not lend itself to easy transformation into a cGMP formulation process. If the bench-scale process is presented in the RFP as the sole way to formulate the product prior to aseptic processing, the resulting CMO bid prices could be extremely high and incorporate unnecessary processing steps.
It’s much more important to clearly describe the work that has been done and the extent to which it has been done. This will allow the aseptic F/F contractor to assess the project fully and come back with questions and/or suggestions.
Using the same case in point, additional considerations that must be addressed during the drafting of an aseptic F/F RFP include:
- Product hold times — Usually this parameter is not controlled during bench-scale formulation studies. It is a given that not only will the larger cGMP-scale studies take more time, but the level of process control also will be greater.
- Product contact materials — Typically a factor during lab-scale development work, material specifications may be affected by the availability of what is on hand at the time. For example, this could be very expensive if Teflon is specified when polypropylene would work just as well.
- Container closure systems — Closures are almost always overlooked and taken for granted. Query the various contractors vying for the project for suggestions.
- Timing — Be realistic. A fast-tracked, first-time aseptic fill/finish project will take at least 10 to 12 weeks to get into a CMO’s shop after the service agreement has been signed.
- Quantities — Don’t forget to factor in process losses, in-process samples, release testing samples and stability study samples.
- The possible inclusion of an engineering run — This is extremely important for first-time processes involving formulation steps that have no/minimal history.
Evaluating the Contractor’s Proposal
Once the RFP has been drafted, it is sent to potential contractors for their review, questions and responses. A good CMO will always respond to the RFP with a formal proposal. Usually, this is in the form of a Statement of Work (SOW) or similar document. It’s important to review these proposals to ensure that each contractor clearly understands the project’s scope. Beware of the contractor who, after being allowed to ask questions, puts additional requirements into the SOW that were not present in the RFP.
Another positive characteristic of a well-written proposal is that all assumptions made in the response are clearly stated. These assumptions must relate directly to the final project cost, which should be included in the proposal.
It’s important for the client to pay special attention to the pricing. Proposals will generally be firm/fixed-price or based on some form of time and materials. Briefly, the “firm/fixed-price” model provides the client with a project cost based on all activities that will be performed as described in the contractor’s proposal. The “time and materials” model allows the contractor to charge the client for facilitation and/or personnel at a stated rate for as long as the project takes. Typically, materials are charged at cost, plus some additional processing fees.
It is very difficult to compare proposals with different pricing structures. For processes that are not yet optimized, the firm/fixed-price model usually is better for the client. It allows for budgets to be set and, as importantly, indicates that the contractor is comfortable enough with the client and project to assume the risks inherent in this pricing model.