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To outsource or not? That is the question.
Q: Can you provide some insights into choosing a contract manufacturing organization? How do I ensure that the partnership will meet my goals?
The continuing debate for mature, emerging, and virtual biopharmaceutical companies remains whether to outsource production to a contract manufacturing organization (CMO) or not. At its core, the issue is brand protection. While outsourcing can minimize your capital and labor costs, your challenge lies in the process of evaluating CMOs to identify the right one to serve as your manufacturing partner.
How can you minimize the potential for negative consequences, including damage to your brand and loss of market share and revenue?
How can you minimize the risks to product quality, while you ensure that the equipment, processes, and procedures used in manufacturing will maintain the intended strength, integrity, safety, purity, and quality of the drug product?
And how can you do it all within budget?
While the answers to these questions will be specific to each company and its drug products and processes, below are some key factors to help you make the right decision if you do turn to a CMO. Keep in mind, these factors need to be in line with your business goals and ultimately get your product to market in a safe, compliant, and cost-effective manner.
A CMO that already has clients may have a small window in which to produce your drug product. To determine the CMO's ability to fit you into its production schedule, questions to ask include:
  • Does the batch size and length of time required to produce your drug product on the CMO's machines increase your risks of not having your drug product when you need it? For example, might the CMO not be able to provide sufficient throughput to meet demand? A quick calculation would be to divide the batch size by the machine's speed per hour to determine the approximate amount of time to manufacture your drug product. This measurement doesn't account for total production time such as what a calculation of overall equipment effectiveness (OEE) would provide.
  • Does the speed of the CMO's machines match the speed needed for your batch size? Based on the machine's ability to fill at a particular rate, i.e., units per minute or hour, can the machine produce the number of final units per batch in the time required?
  • Will your batch size and number of lots be a small fish in a large pond, making your needs the last to be fulfilled, or will they possibly overwhelm the CMO's production schedule because they are so large?
  • If an upset occurs in manufacturing, will the CMO postpone your manufacturing date? If you are small fish in a big pond, the CMO may postpone your manufacturing time to accommodate a customer with a larger volume of product. You would either need to have resources dedicated at the CMO's site to act as advocates on your behalf, or the CMO should provide you with notification if this scenario occurs.
If you are manufacturing for a specific period or for seasonal distribution, and you miss the date, you could lose your market share. You must determine the CMO's technical competence, available machinery, and resources. To do so, consider the following issues:
  • Is its equipment built to reduce rejects? You should assess the CMO's technologies and capabilities during the technical and commercial due-diligence period and during the initial audit activities for quality compliance.
  • Does the equipment have the dose-accuracy control to meet your patients' requirements? You have the legal and regulatory responsibility to meet all label claims; therefore, you need to verify that the drug product contains the dose stated on the label. For example, a 100-mg unit cannot contain 90 mg of drug product. If a final product unit is dose-dependent and is not accurate, then a patient could receive too much or too little of a drug product, potentially causing harm or providing a less-than-effective dose. From a business perspective, you also don't want to be giving away drug product.
  • Can the bulk of a batch be preserved if a machine failure occurs?
  • Can the CMO's staff provide feedback on developmental or troubleshooting work they have successfully executed? Does is seem likely that they can handle any such needs for your drug product?
Observations by regulatory agencies
Because pharmaceutical manufacturing facilities are built to protect the operators, drug products, and patients, quality systems and facility and equipment design are critical. When considering a CMO, research the company's history with regulatory agencies, its documentation practices, and its process and testing procedures, including responsiveness to problems and corrective and preventive actions (CAPAs) previously documented:
  • Are the CMO's operators trained well? CFR Part 211 and various Guidances require training of staff and documentation of training. You should evaluate training records as part of the initial quality compliance audit. Furthermore, you should observe and assess training as part of your technical evaluation during the due-diligence period.
  • Does its staff understand current good manufacturing practices (cGMP) and will they comprehend the reasons why your procedures are written the way they are? Training should include general GMP training and any special training related to your product, your standard operating procedures (SOPs), and your analytical methods to allow the CMO's staff to manufacture your product and determine if it's acceptable for use. This training should include identification and understanding of the following criteria: Critical Quality Attributes (CQAs), Proven Acceptable Ranges, Critical Process Parameters, Critical Operational Parameters, and other product specifications.
A search on the FDA's website for the CMO's previous inspection observation summaries can provide relevant information [1]. Ask the following questions to help you determine whether the CMO's compliance with regulatory agencies is satisfactory:
  • When was the CMO's last inspection?
  • What were the findings?
  • What were the CMO's responses to remediate the observations?
  • Were the responses accepted and the corrective actions completed and verified?
Personal interviews
You can't just rely on the CMO's industry reputation and experience; you must conduct personal interviews with the CMO's executives, management, and current staff on site before signing a contract. You need to interview previous and existing customers and rely on vendors' feedback.
When touring a facility, ask about the equipment, its history, and any requirements for new equipment:
  • How old is the equipment? See the section on equipment reliability and lifecycle below.
  • What drug products has the company produced on the equipment and does its staff have any experience with drug products similar to yours?
  • What is the reject rate for a given batch size? Are the rates satisfactory for your drug product?
  • Will any new equipment need to be purchased for your runs?
  • Will such equipment be included in the quoted price?
  • What is that equipment's delivery lead time?
  • When will that new equipment be qualified?
  • During the last process simulation on the new equipment, what were the findings? Did the process have any issues?
Also, ask if the CMO has had any recalls, and if they have, why, what the root cause was, and if they have corrected the problem.
Technology and equipment capacity and capability
Each drug product has a unique set of CQAs and process parameters that you need to consider to determine if the CMO has the correct fit of technology and expertise.
  • Does your drug product have special handling or temperature requirements?
  • Is it susceptible to foaming or clumping?
  • Is it shear-sensitive?
  • Does it require some type of mixing or blending?
  • What is its sensitivity to bio-decontamination or cleaning chemicals?
  • Is it highly viscous or temperature-, light-, or oxygen-sensitive?
  • Is it a controlled substance?
In addition, find out whether the CMO is set up to handle your type of end product:
  • Does the CMO have the right in-line process equipment?
  • What does that process cost? You need to determine the costs, in time and money, to modify production equipment to meet your requirements and the requirements of the process to manufacture good product.
  • Is the process included in the proposal cost? The CMO must prepare a proposal and present that proposal to the you. You need to assess it as part of the bid tab or contract evaluation.
  • How automated will the process for developing your drug product be?
  • What controls are in place to prevent excursions?
  • How much experience does the CMO have with the required technology or type of drug product? For example, your process may use vision systems, laser sensors, analytical equipment like an optical density meter to monitor homogeneity, flow meters, gravimetric systems, and decontamination systems. Suspension products and high-viscosity products require different knowledge and experience as compared to solution products. Highly potent and cytotoxic products require another set of skills and experiences to maintain a safe environment for operators.
Contamination prevention
Because CMOs may run 2 days of product for one client and then 2 days for another, cross-contamination prevention is key:
  • If the facility produces any highly hazardous compounds, how are they controlled and contained? Are the CMO's methods sufficient for handling your drug product?
  • What are the cleaning procedures between products? Are those procedures adequate for your drug product?
While each facility should have its own containment strategy, a pharmaceutical company contemplating using a CMO may still want to have a set of equipment-format and product-contact parts to be used exclusively for its runs. Drug products created for specific high-risk populations may have additional containment requirements. Make sure that the CMO can accommodate your requirements.
Equipment reliability and lifecycle
Manufacturing equipment is advancing very rapidly, especially in the area of microelectronic sensors, vision systems, and analytical instrumentation. That advancement is occurring so fast, in fact, that equipment more than 5 years old is likely to be obsolete for achieving all of your requirements. Equipment even older than that may not have the sensors or instrumentation to detect many of your critical defects in-line. This lack translates into lost product and lost revenue.
When touring a facility, ask how old the equipment is and ask to see it run. Inquire about the equipment manufacturer and any problems that the CMO has had with the equipment. Maybe it has been in a storage room for 4 years, but when you examine it, you find out it is actually 20 years old:
  • How available are spare parts for it? How will the CMO replace a part if needed?
  • Are the controllers on the machine even available for purchase or is the CMO shopping online bidding sites trying to find replacement parts?

Christa Myers is senior pharmaceutical engineering specialist and Kevin Debbs, CPIP, is process specialist at CRB USA.

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