A WHITE PAPER

By John Dobiecki

SELECTING AN ASEPTIC FILL/FINISH CONTRACT MANUFACTURER:Avoiding the Most Common Mistakes

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A WHITE PAPER

SELECTING AN ASEPTIC FILL/FINISH CONTRACT MANUFACTURER:Avoiding the Most Common Mistakes

INTRODUCTIONThere have been many seminars and papers whose topic focuses on the proper selection process for choosinga Contract Manufacturing Organization (CMO). This paper focuses specifically on the unique steps involved inselecting and working with an aseptic processing CMO to produce injectable Final Drug Product (FDP). In addi-tion to providing guidance on the selection process, common mistakes made by potential clients will also bediscussed. These common oversights and their remedies are sourced from a collective experience base thatcovers contract aseptic Fill/Finish (F/F) manufacturing, contract bulk drug manufacturing, and aseptic F/F out-sourcing of bulk drug product.

RFP - THE FIRST STEPIt should come as no surprise that the first step involves putting together a Request for Proposal (RFP) that willbe presented to potential contract aseptic F/F sites. The importance of this step is highlighted by the fact that aquick Internet search using the keywords “RFP, Pharmaceutical Outsourcing, and Manufacturing” will yield over70,000 listings involving 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 minimally shoulddetail the following:

1. Description of the Final Drug Product and its intended use.

2. Project scope (i.e., is the project just Fill/Finish? Will testing, stability studies, and/or development work beincluded?)

3. The proposed aseptic manufacturing sequence.

4. Any special “considerations” (e.g., thermal, light, shear sensitivities that the product may have, incompatibili-ties with certain materials, etc.).

5. The required number of vials.

6. The expected date the product is needed

7. Testing requirements

8. Stability

9. Shipping

The key word in the preceding paragraph was detail. Many times the way the detail is given in an RFP results inmultiple mistakes being made on the part of the potential client. The most prevalent error involves providingunintentional misinformation about the process and/or product in the RFP.

For example, let’s examine a product destined for use in a Phase I Clinical trail. Up to this point, the majority ofmanufacturing effort and cost has been spent developing synthetic routes for API or, in the case of biopharmaceu-ticals, looking for paths of expressing and purifying the active biologic. A significant amount of time and moneyhas also 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 being the definitive process/history. Remember,a good contract aseptic F/F site will have a sufficient experience base to help you identify areas that may be of aconcern. An example would be a bench scale formulation process that does not lend itself to easy transformation

John Dobiecki

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into a cGMP formulation process. If presented in the RFP as sole way to formulate the product prior to asepticprocessing, than the resulting CMO’s bid prices could be extremely expensive and result in unnecessary pro-cessing steps.

It’s much more important to clearly describe the work that has been done and the extent to which it has beendone. This will allow for the aseptic F/F contractor to fully assess the project and come back with questionsand/or suggestions.

Using the same case in point, the following are some other considerations that need to be addressed during thedrafting of an aseptic F/F RFP:

• Product hold times - Usually this parameter is not controlled during bench scale formulation studies. It is agiven that not only will the larger cGMP scale take more time, the level of process control will be greater.

• Product contact materials - Typically a factor during lab scale development work governed only by the avail-ability of what is at hand at the time. This could be very expensive if Teflon® is specified when polypropylenewould have worked just as well.

• Container Closure Systems - This is one factor that is almost always overlooked and taken for granted. Querythe 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 toget 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 stabilitystudy samples.

• The possible inclusion of an engineering run. This is extremely important for first time processes involving for-mulation steps that have no/minimal history.

EVALUATING THE CONTRACTOR’s PROPOSALOnce the RFP has been drafted, it is sent to potential contractors for their review, questions, and responses. Agood CMO will always respond to the RFP with a formal proposal. Usually this is in the form of a Statement ofWork (SOW) or similar document. It’s important to review these proposals and ensure that the contractor clearlyunderstands the project’s scope. Beware of the contractor who, after being allowed to ask questions, puts addi-tional 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 clearlystated. These assumptions must relate directly to the final project cost, which should also be part of the proposal.

It’s important that the client pay special attention to the pricing. Proposals will generally be firm/fixed price orbased upon some form of time and materials. Briefly, the firm/fixed-price model provides the client with a proj-ect cost based upon all activities that will be performed as described in the contractor’s proposal. The time andmaterials model allows the contractor to charge the client for facility and/or personnel at a stated rate for aslong as the project takes. Materials are charged at cost with (usually) some additional processing fees.

It is very difficult to compare proposals with different pricing structures. Generally for processes that are still notoptimized, the firm/fixed-price model is better for the client. It allows for budgets to be set and (as importantly)intimates that the contractor is comfortable enough with the client and project to assume the risks inherent withthis pricing model.

Based on the proposals received and the interactions and conversations during the preliminary search, a selec-tion of potential vendors can be made. At this point, site visits are the next step in the process.

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THE SITE VISITTypically, 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’scapabilities and fit.

This is the time when the second most common error is made. At this point (if it hasn’t been done earlier dur-ing the RFP development phase), the client needs to appoint a Project Manager who will be responsible forcoordination of all internal and external project related activities and associated timelines. Failure to have apoint 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 orcovered separately in a second visit. In either case, client attendees for the formal site audit should include per-sonnel 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 mis-representation of the product/process to the CMO made by a client representative with only a superficialunderstanding of the project. Having the above mix of disciplines representing the client helps minimize thisoccurrence and also allows for a rigorous questioning of the contractor during the audit process.

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

• Time for a contractor’s presentation/overview of the company history, facilities, and capabilities.

• Site inspection histories (from both US and European Agencies)

• A list of any other registrations, licenses, etc.

• CV’s of key personnel

• Review of site master plans, drug master files, etc.

• Review of the contractor’s quality manual

• Review of all the client’s SOPs

• Facility tour

• Allotted time for documentation audit

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

THE SELECTIONThe last step of the selection process is just that... the selection. Careful decisions are based on all the tangibleand intangible information gathered. Be very critical of the audit findings and the experience base of the keypersonnel and staff. The overall capabilities of the contractor must also weigh heavily on the choice. Generallyan organization that can internally support all RFP requirements will be easier to manage than the organizationthat must subcontract some of the work.

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

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THE BIGGEST MISTAKEThe biggest mistake in the selection process occurs when the contractor’s pricing becomes the gating factor inthe selection decision. Attempt to match proposals’ pricing “apples for apples” when it is appropriate. However, ifthis is difficult or can’t be easily done, feel free to contact the contractor for further clarifications. The contractorsyou want to work with will also be amendable to further discussions on pricing.

Lastly, once you’ve completed your homework, suffered the associated hours of angst, and finally made yourdecision, remember this: You are the product expert and owner. Questions and decisions regarding the productare your responsibility. However, the contractor is the process expert. This is their business. Let them guide theproduct along a mutually agreed upon process path.

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

About the Author

John Dobiecki is Vice President of Manufacturing Operations for Microtest Laboratories. Mr. Dobiecki has been involved in the

manufacturing and quality control of pharmaceuticals, medical devices, and biologic products for over 25 years. His extensive

experience includes preparation of IND's, NDA/ANDA's, CMC sections, Pre-Approval Inspections (PAI) as well as multiple U.S.

and European Regulatory Inspections.

For more information, contact:

info@microtestlabs.com

(800) 631-1680

www.microtestlabs.com