Contract Manufacturing / Aseptic Processing

Choose Wisely

Selecting a contract manufacturing organization (CMO) for aseptic processing of injectable final drug product (FDP) is no simple matter. Here are some do’s and don’ts.

By John Dobiecki, Microtest Laboratories

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
  • Stability
  • Shipping

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.

Based on the proposals received and the interactions and conversations during the preliminary search, a selection of potential vendors can be made. The next step involves site visits.

The Site Visit

Typically, two types of site visits occur. The first involves a more technical review of the project by both parties. During this meeting, the tires get kicked and a preliminary assessment is made of the contractor’s and client’s capabilities and how well those fit together.

This is also the time when the second most common error is made. At this point (if it hasn’t been done during the RFP development phase), the client needs to appoint a Project Manager who will be responsible for coordination of all internal and external project-related activities and associated timelines. Failure to have a point person will inevitably lead to multiple unnecessary delays that drive additional cost and timeline creep.

The second part of the site visit process is the formal site audit. This can be combined with the first site visit or covered in a second visit. In either case, client attendees for the formal site audit should include personnel representing the following disciplines: Project Management, Process Development, Quality Assurance and Quality Control. This mix of disciplines helps avoid another very common mistake — the unintentional misrepresentation of the product/process to the CMO made by a client representative with only a superficial understanding of the project. Having this mix of personnel representing the client helps minimize this occurrence and allows for more rigorous questioning of the contractor during the audit process.

Because these audits generally require one day, a well constructed agenda will result in an efficient and successful meeting. Typical agenda items include:

  • Contractor’s presentation (including an overview of its history, facilities and capabilities)
  • Site inspection histories (from both U.S. and European agencies)
  • Review of any other registrations, licenses, etc.
  • CVs of key personnel
  • Review of site master plans, drug master files, etc.
  • Review of the contractor’s quality manual
  • Review of the client’s SOPs
  • Facility tour
  • Documentation audit

The audit should be conducted in a formal manner. The contractor should expect a brief wrap-up describing any observations or findings as well as a commitment by the client to issue a formal, written report. Additionally, the client will let the contractor know when a formal response to any audit findings is expected.

The Selection

The last step of the selection process is just that — the selection. The decision must be made carefully, based on all the tangible and intangible information gathered. Be very critical of the audit findings and the experience base of key personnel. The overall capabilities of the contractor must also figure into the choice. Generally, an organization that can internally support all RFP requirements will be easier to manage than an organization that must subcontract some of the work.

Be sure to assess personalities when making the decision. It’s a given that the selected contractor will be working for the client. But the prospects for project success will increase if all parties believe the contractor will also be working with the client. Good contractors understand that successful first projects generally result in an extended manufacturing relationship.

The Biggest Mistake

The biggest mistake potential clients can make during the selection process occurs when the contractor’s pricing becomes the determining factor in the selection decision. When appropriate, attempt to match the proposals’ pricing “apples to apples.” However, if this is difficult, feel free to contact the contractor for further clarification. Any contractor you want to work with should be amenable to further discussions on pricing.

Once you’ve done your homework, suffered the associated hours of angst, and made your decision, remember this: You are the product expert and owner. Questions and decisions about the product are your responsibility. However, the contractor is the process expert. Let the contractor’s project team guide the product along a mutually agreed-on process path.

Contractors also are your partners. They are an untapped resource for advice. Use their experiences with other drug products and processes to support your decision-making process.

 


About the Author
John Dobiecki is vice president of manufacturing operations for Microtest Laboratories. He has been involved in the manufacturing and quality control of pharmaceuticals, medical devices, and biologic products for over 25 years. His experience includes preparation of INDs, NDA/ANDAs, CMC sections, Pre-Approval Inspections (PAI) and U.S. and European regulatory inspections.

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