One of the more important tools in the quality assurance (QA) toolbox when working with contract manufacturing organizations (CMOs) is the QA vendor audit. An audit can help identify appropriate service providers and ensure that current service providers are maintaining appropriate quality standards. An effective vendor audit covers four stages, including audit planning and preparation, conducting the audit, the audit report, and audit responses and follow up.

When using contract manufacturing organizations (CMOs), one of the key concerns of the quality assurance (QA) department of the company contracting out the work is how to demonstrate adequate oversight of the activities at the CMO. Additionally, the contract giver must have demonstrated assurance that the CMO has adequate facilities, personnel, and systems to deliver the services for which they have been contracted in compliance with current good manufacturing practices (cGMPs). This requirement is even more prevalent in today's climate with the proliferation of "virtual" companies and startups, which do not have manufacturing capability of their own. 

When working with CMOs, the QA vendor audit is an important tool, because it ensures that current service providers are maintaining appropriate quality standards.  

There are a number of stages in conducting an effective vendor audit. For the purposes of this article they have been grouped into four sections, following the chronological path:  

It is important that all stages of the audit be given an equal measure of attention. Too often, all the effort is loaded toward the middle of the process (the execution), without adequate attention to planning or ensuring timeliness with respect to reporting. This often is combined with a 

 attitude toward responses once received. When that happens, corrective and preventative actions (CAPAs) produced in the original audit often are not acted on until the next CMO audit is scheduled.  

There are several key questions to ask when planning an audit, the answers to which will drive the focus, extent, and scope of the audit preparation. These include: 

The "when" mainly depends on the purpose of the audit, and this can be one of or even a combination of the following: to identify a suitable service provider; to conduct a routine audit of an active service provider; to perform a cause audit, resulting from a significant compliance problem; or to validate readiness for process validation or a pre-approval inspection (PAI). 

Most quality or technical agreements provide for an annual two-day audit of the relevant facility. It is also expected that an audit to assess the suitability of a service provider would not exceed two days. However, in the case of a mock PAI or an audit designed to assess readiness, it would be appropriate to request a longer duration. When significant travel is involved, it is common to see an audit length of two and a half days to allow for a full two days for the actual audit, followed by final discussions and a close-out meeting the morning of the third day. 

The size of the audit team should, wherever possible, be kept to a minimum. The ideal  team consists of two experienced auditors with complementary backgrounds to facilitate coverage of the major areas of concern or interest. However, when there is a significant scope to be covered, we recommend a team of three with varying specialities (identified when the purpose of the audit  is determined and during preparations). 

Audit preparation should involve the whole team, who should agree on the focus and purpose of the audit, based on any previous audit reports and other available data.   

The proposed audit agenda should then be drafted and agreed upon by the team before being communicated to the auditee along with the request to audit. A typical audit agenda includes the following:  

qualification of equipment used in manufacturing drug substance 

change controls or engineering change orders

vendor qualification and technical agreements

environmental monitoring results and trending

equipment, qualification, maintenance, and calibration

It is essential that before the audit, a lead auditor is chosen, who will be responsible for organizing the audit and collating the observations raised. Also, the lead auditor usually is the most appropriate person to be the primary author of the audit report. 

An introductory meeting is an essential and useful part of the audit because it gives the audit team an overview of the company and facility that are being audited. This meeting will set the tone of the audit, so it is essential that this meeting be given its due importance and not be seen as something to be endured before the "real" audit. There is often important and useful information to be gleaned from this initial meeting of the respective parties. 

During the facility tour, the audit team can get an early impression of the strengths and weaknesses of the company's procedures and its commitment to quality. It is critical that the audit team listen carefully to what the staff ask and have to say, and also to take the time to observe the condition and status of rooms and equipment, as this is often an indicator of the status of the relevant systems in place at the facility. 

The facility tour is sets the scene for the rest of the audit and its value should not be underestimated. 

Articles

It is important that all stages of the audit be given an equal measure of attention.

Effective Auditing of CMOs

A process harmonization assessment (PHA) is an efficient tool to thoroughly assess the differences between separate sets of equipment processing a specific molecule. The main components reviewed in a PHA include: process flow, process parameters, equipment capability, and raw materials. A PHA document evaluates the risk to the technical success of a technology transfer by understanding the important process and equipment-related issues early in the process. A PHA document also discusses when differences between sets of equipment may affect critical design parameters for the process such as mixing, heat transfer, column flow rates, and gradient control. Early process development and scale-up may not need every aspect of a PHA document, but node-to-node transfers generally realize great benefit when complete assessments are performed.

Technology transfer consists of the transfer of technical information about a process from the laboratory to pilot-scale, pilot- to commercial-scale, and commercial node-to-node transfers. Each transfer has varying levels of data and restrictions. A node-to-node transfer has the largest breadth of process data, but also has the highest restrictions caused by critical process parameters and other process and equipment parameters defined by a registered process. When contemplating a technology transfer, a well thought out process to assess the inherent differences between facilities and equipment sets must be followed.

	One of the most efficient ways to do this is by conducting a process harmonization assessment (PHA). The PHA compares process and engineering parameters from the current process facility and equipment set to a proposed facility and equipment set. The main components of a PHA include the review and comparison of process flow, process parameters, equipment capability, cleaning, and raw materials. Each of these components also includes a discussion of differences in parameters between the facilities. Action items may be created to understand the impact of the differences. These action items may include mixing studies or additional laboratory data to support the changes to the process that are required as a result of the transfer. 

	Technology transfers early in the development cycle have fewer strictly designed process steps and few if any critical process parameters (CPPs). A simple assessment of the most basic process flows, process parameters, yields, and purities may be enough for a PHA at this development stage. After process development reaches pilot-scale or production-scale, further details in the assessment are critical to reduce risk from unknown variables and ensure both the receiving site and sending site understand the process and the equipment that is being transferred. A PHA document may undergo revisions over the course of a technology transfer as the design progresses, and will continue to be revised as the process changes.

	The process flow review section of a PHA establishes how the receiving site will fit the process into its major pieces of equipment. This is the earliest portion of the PHA that can be completed. In many cases, a process flow review is completed during due diligence or the initial process fit. Each piece of equipment is selected to enable the major process steps to flow with approximate equipment capacity, product flow through the facility, and process timing. This section may take the form of a process equipment diagram with the process flow shown in a basic process and instrumentation diagram. The process equipment flow creates the inventory of equipment needs at the receiving site and will be the basis of any initial capital project needed to procure major equipment, if necessary.

The inclusion of process parameters in the PHA serves primarily as a communication tool to ensure that the receiving site knows the important parameters to control and monitor. This list includes not only any CPPs, if defined, but also any other parameters that are likely to affect product quality, yield, or consistency, such as pH, temperature, conductivity, product concentration, and intermediate step purity and yield. The receiving site will be able to assess whether its equipment set is capable of achieving the required process control. This also is an opportunity for the receiving site to ask questions about process parameters it has observed to be important in other processing experiences. Table 1 shows an example of a process parameter table for an ion-exchange process step. Bold text is used to denote CPPs or other quality parameters that must be maintained.

	Table 1 shows that there are differences between the sending site's process parameters and the receiving site's parameters. As with all sections of the PHA, it is important to have a summary to discuss areas of concern that may need more development.

The process parameters also include important scale-up parameters. These parameters may not be directly controllable parameters, but may be significant in attempting to reach comparability. Table 2 shows a list of some of the process parameters that are critical for scale changes.

	The equipment capability section of the PHA compares the mechanical and instrumentation capability of the pieces of equipment used for the execution of each process step. Equipment capability is a critical assessment, whether the scale of the process changes or not. When transferring a process, there will be many differences between the equipment used to execute the same process step at two different locations. It is important to determine where the differences are in critical design features. Critical design features may affect the ability of the equipment to control or achieve the important process parameters listed in the previous section. Differences in process scale, and what scaling factors were used in the design, should also be included. Table 3 shows an example of an equipment parameter table comparing a piece of equipment used for the same process step at two different manufacturing sites.

Two of the most critical equipment capabilities are buffer capacity and process mixing. When calculating comparable scales between the sending site and the receiving site, buffer and process volume comparisons must be performed. The amount of additional buffer needed is dependent on process transfer line size, flush volumes, and lower height equivalent to a theoretical plate (HETP) values for larger chromatography columns. Larger columns may need more buffer column volumes to equilibrate because of natural inefficiencies with larger columns. Directly scaling buffer volumes from the sending site must be done carefully to account for the differences in the receiving site's tank capacities. In many cases, buffer makeup and storage capacity may be the limiting constraint on process scale-up. Companies can easily purchase larger portable columns, but installing capacity in buffer hold areas can be extremely expensive and result in long lead times. If a process involves any critical reactions or rapid pH changes, it is critical to assess the mixing characteristic between the sending and the receiving site. It is much easier to obtain well mixed environments at smaller scales. Blend time calculation is an easy way to perform an initial comparison, but other comparisons may be required for crystallizations, viscous fluids, or other complex scenarios. In one instance, what was thought to be slow mixing at a pilot-scale was actually faster than what could be obtained at production-scale. Many software packages are available for these analyses.

	Transferring a process to a new facility typically will require a different set of preferred vendors for raw materials. If the raw materials have been registered, the sourcing of new raw materials must meet the registered specifications of the original supplier. If the raw materials are not registered, a side-by-side assessment should be done to ensure comparable quality. If comparable raw materials are not available, Design of Experiments with the new raw materials should be performed to assess the impact on the process. Depending on the number of raw materials, this section may be incorporated into a separate document to facilitate review and approval.

	A process harmonization assessment (PHA) is a useful tool to compare various equipment sets proposed to manufacture a single product. PHA compares the process flow, primary process parameters, equipment sets, and raw materials between the two sites involved in technology transfer. Any technology transfer can benefit from the methodology of PHA. Node-to-node transfers benefit the most from the high level of detail contained in a PHA document. Technology transfers in early development can benefit from the documentation of the important parameters and initiate the development of these documents for future transfers. Technical resources at both the sending site and receiving site are involved to enhance the communication and technical expertise of both sites.

 is an associate senior consultant engineer in Indianapolis API Engineering Servces at Eli Lilly and Co., Indianapolis, IN, 317.433.0545, rockabrand@lilly.com

A process harmonization assessment can aid in smooth technology transfer by comparing data across equipment and sites.

Process Harmonization Assessments for Technology Transfer

Insourcing contract staff allows pharmaceutical companies to reduce fixed headcount expenses while ensuring sufficient staff are on hand to get the work done. This flexibility is particularly useful in processes that have natural peaks and troughs. It also allows the company to retain greater control than if the work is outsourced. Before insourcing personnel, however, managers should consider the potential pitfalls and how to avoid them.

In most industries, outsourcing non-core functions has long been the norm, and the pharmaceutical industry is no exception. Outsourcing makes effective use of limited funds and helps retain key expertise in-house.  

There are times, however, when the remaining in-house resources are not sufficient to complete critical tasks, especially in processes for which resourcing demands vary throughout the lifecycle of a project. Clinical research is one such area, where activity at the start of a trial is higher, lower during post-patient recruitment and monitoring, then followed by a flurry of activity toward close-out as data are managed and reports are generated. Similarly, demands for in-house analytical scientists can vary as candidate drugs reach different stages of development.  

A growing trend is to turn to outside providers to fill these gaps by "insourcing" skilled staff. In some cases, just a few staff members are brought in, while in others,  an entire job function can be handed off to suppliers in either a managed team or functional service arrangement. 

In insourcing arrangements, the insourced staff are not employees of the pharmaceutical company. A third-party supplier retains responsibility as the employer of the insourced staff, while the pharmaceutical customer is responsible for their day-to-day supervision during the project.  

The benefits of these types of arrangement are numerous. Reducing fixed headcount expenses is the most obvious. Such arrangements offer excellent flexibility, because early termination clauses allow the client to easily "switch off" the additional resource should the demand be reduced suddenly, for example, if a clinical study closes early or if development on a drug candidate ends because of unfavorable clinical results. In such cases, there may be a need to quickly reduce headcount to save costs. Insourcing staff also can be used to fill short-term resource gaps caused by planned absences such as maternity leave. 

Another benefit of insourcing staff that often motivates large companies is that it allows the client company to retain tighter control of the work involved than if the work were contracted out. 

A further benefit of working with insourced staff is that not only does the hiring manager get the pick of the best available qualified staff from across many sources, but the time a contract staffer spends on site also can serve as an extended interview. When headcount positions become available, contract employees often apply, removing a large degree of uncertainty for the hiring manager. In addition, should these insourced employees have worked with the client for a considerable time, there may be minimal take-on fees, thus making this a very cost-effective recruitment solution. 

In the clinical trials arena, insourcing experienced staff also has an advantage over contracting out a study when the product is close to commercialization: The insourced staff represent the pharmaceutical company with key opinion leaders and investigators, thus retaining relationships with future potential prescribers. 

When considering personnel insourcing, there are several pitfalls and a few simple rules to consider. 

Contractor retention may be a concern, because insourced staff do not have the same degree of loyalty to the company and can, in theory, leave at any time. This concern can be mitigated, however, by clauses in the insourced staff's contract with the staffing supplier. For example, insourced staffers, as employees of the supplier with associated company benefits, have notice periods and are subject to the supplier's human resources (HR) processes. 

Another concern raised by pharmaceutical customers is that integrating insourced staff into the company's regular business meetings and required project training, and offering career development opportunities could create an employer–employee relationship with insourced staff, which can have legal ramifications, particularly  in the EU and Australia, where employment legislation is tight.  

Pharmaceutical companies often wish to integrate contract employees as much as possible into their operations, to ensure the staff are properly trained and have all the information they need to do their jobs effectively. Likewise, all staff want career development and it is natural for a manager to want to aid and develop the best and brightest. However, when these people are not your employees, providing too much integration or development assistance may mean that the "employer–employee" line will be deemed to have been crossed.  

Therefore, the pharmaceutical company should evaluate carefully whether it is necessary and appropriate to include insourced employees in any meeting or event that is not project related. The pharmaceutical company's legal counsel may wish to weigh in on this. 

These risks also can be mitigated by working with a supplier who fully employs, manages, trains, and supports the staff on contract to you. Insourced staff should have career development discussions with the supplier's industry-experienced line manager. Supervisors at the pharmaceutical company should provide input into performance appraisals and career development plans through the supplier manager of the insourced personnel, but not hold these meetings directly with the insourced personnel. 

The assigned supplier manager not only has responsibility for the staff's career development, but also for ensuring that client needs and timelines are met. Therefore, you also should work closely with the assigned supplier manager to set meaningful project-related objectives that are timed to coincide with the insourced personnel's probationary periods. 

If you work with a company that does not fully employ the contract staff but instead provides access to a freelance network, you should verify that these freelancers are set up as limited companies and not "sole-traders," to mitigate the risk of co-employment. 

When choosing a supplier of contract staff, there are some basic questions that all hiring managers should ask about the supplier's corporate stability, pricing, track record, and ability to resource for the specific roles in question. Other important questions include:  

How long is the average time to provide appropriate resumes once a job requisition has been received?

How quickly can candidate interviews be arranged?

When will the candidates be available to work? (Bear in mind that notice periods of up to three months may apply).

The customer also should ascertain how the contract staff will be supported by the supplying company. Key questions include:  

Does an established and appropriate line management system exist?

Are there HR processes and procedures that support both the insourced employee and the sponsor company?

Is the customer involved in setting objectives for the insourced employee?

Is there a probationary period that protects the customer?

Are the company benefits offered to the insourced employee competitive enough to aid retention during the project?

How is good behavior encouraged and outstanding performance recognized?

Should there be a need, does an early release clause enable you to downsize in a short time without major financial penalties?

As companies get comfortable with working with contract staff, complacency can set in. Just as we see "project creep"' when running a study, so there has been "employment creep" over the past few years when working with contract staff, as companies often start including contract staff in non-project-related activities and begin to cross the employer–employee line.  This can be avoided by ensuring you have a positive answer to the above questions. Another way to avoid employment creep is to contract an entire function to a trusted supplier, thus accomplishing all project goals while driving down fixed costs.  

In summary, insourcing contract staff offers pharmaceutical companies an alternative to outsourcing work when volume demands exceed internal capacity, and allows the company to maintain greater control than if the work were outsourced. Insourcing also provides excellent flexibility to expand and contract staff quickly as needed. 

A few risks are associated with insourcing, but they can be mitigated easily by ensuring the employer–employee line is not crossed, working closely with the supplier to manage staff performance and development, and ensuring the contract contains key clauses to protect the client. By following these guidelines, pharmaceutical companies can gain significant benefits from insourcing with minimal risk. 

is the vice president of i3 Pharma Resourcing, London, UK, +44 07812 148086, 

Insourcing is new outsourcing. Here's how to do it right.

How to Reap the Benefits of Insourcing Contract Staff While Minimizing the Risks

To ensure reliable delivery and optimize outsourcing costs, it is essential to partner with a contract manufacturing organization (CMO) that uses multidimensional strategies. Older models of project management were not focused on client satisfaction and did not account for the organization's needs. More recent models in project management blend and integrate these objectives. They leverage best practices from different arenas to integrate the needs of the client, project, and business. This article presents a model for conducting work based on three core methodologies: project management principles, customer service, and Lean methodologies.

In this troubled economy, fewer companies are manufacturing their pharmaceutical products in-house.

  More and more companies are working with contract manufacturing organizations (CMOs), or are actively looking for CMOs to partner with. To ensure reliable delivery and optimize outsourcing costs, it is critical that your CMO relationship yields the best possible value to your organization. To achieve optimal results from your outsourcing, it is essential to partner with a company that uses multidimensional strategies, integrating best practices from project management, customer service, and Lean methodologies.  

A CMO worth spending your money on must do more than just produce your product. It must serve as an expert partner to help maximize your product's potential. Like any customer, you want the CMO to treat your project with care and commitment. Older models of project management were not focused on client satisfaction, and did not account for the organization's needs. More recent models in project management blend and integrate these objectives. They leverage best practices from different arenas to integrate the needs of the client, project and business. Blending best practices from project management, customer service, and Lean can provide optimal results for clients.  

The role of a project manager at a CMO has evolved to encompass a broader set of stakeholder expectations, including delivering excellent customer service and driving leaner processes. Traditional project management models focused on the success of the project only in terms of the constraints of time, scope, and quality. Today's project managers must deal with increasing complexity and offer their stakeholders the optimal strategy for the project. A systems approach is essential to identify and manage all constraints. Additional metrics must be created and monitored, such as customer satisfaction surveys and measures of process efficiency. When selecting a CMO, consider how facile their project managers are at analyzing tradeoffs among the constraints. Do they have tools and processes in place to provide you with this critical information? If you are considering a process change, will it mean that you won't be able to operate as efficiently down the road? When problems arise, will the project manager address them within the organization, or will they inform you and include you in the resolution process?  

Not only are biopharmaceutical companies looking for state-of-the-art facilities, reliable quality systems, and technical know-how, they also are looking for CMOs that will manage their projects well. Biopharmaceutical companies must look for CMOs that deploy repeatable project management best practices and processes to drive down project cycle time. They also should look for CMOs that work toward eliminating the "accidental" project manager assignment through training, coaching, and mentoring. This includes development and use of tools, templates, and checklists, as well as establishing metrics to measure performance and risk. Project management certification is one means of assessing an organization's dedication to effective project management. Although certification is not a guarantee of effective project management, it is a positive indicator of organizational commitment to project management knowledge and skills. 

Customer service is not only about having a pleasant relationship with your CMO partner, it also is about timely communication, effective resolution of issues, response to changes you need, and product delivery when requested. We all know good and poor customer service when we experience it, so what you really need when evaluating a CMO partner is a way to peer into the organization and get a good idea of what your service experience will be like after you sign the contract. There are some recent trends in customer service in the CMO industry that offer you a predictive tool. These include customer service agreements, dedicated project teams, and mutual alignment on objectives and consequences. Service agreements explicitly spell out "how" the client and CMO will work together, while dedicated cross-functional teams consisting of representatives from key functions (manufacturing, technical services, and quality) offer focused and responsive communication for your project.  

Lean is a win-win strategy that is customer-focused, while providing cost saving benefits to the organization. As biopharmaceutical companies continue to struggle with increasing cost pressures, regulatory burden, and more challenging drug development timelines, the value of Lean operations and efficient execution has become more important.

  Sayer and Williams best summarize Lean as ". . .  a philosophy and a proven long-term approach that aligns the business to deliver increasing customer value.  It's about focusing people and systems that continuously deliver value to the customer by eliminating waste and deficiencies in the process.  Lean is an everyday practice at all levels to perform consistently, as well as to consistently improve performance."

  The logic of Lean methodology echoes what has been stated earlier regarding project management best practices and a focus on customer service. It concentrates on identifying and exploiting shifts in competitive advantage. It encourages individual initiative and the flow of information highlighting defects, operator errors, equipment abnormalities, and organizational deficiencies. Operationally, it standardizes workflow and focuses on problem identification, hypothesis generation, and experimentation in a relentless pursuit for process improvement. 

Table 1 provides an integration matrix of best practices from project management, customer service, and Lean methodology in terms of process, tools, training and development, and sustainability. Below are two examples of how blending these best practices provide optimal results for clients adding value to their organizations.  

Table 1. Lean, customer service, and project management integration matrix 

A client metric scorecard (Figure 1)—a customer service tool—is part of the daily accountability process (Lean) tracking performance of the client's project and is presented at quarterly client business meetings. The scorecard contains key project metrics important to the CMO and the client, such as on-time delivery, incident rate (exceptions in the manufacturing process), and yield. It is a visual control (Lean) that also satisfies the monitor and control stage of the project, and provides an effective communication tool for customer service. As the client, you can feel confident about how your project is being managed, and you and your CMO have a common understanding of the status.  

Figure 1. An example of a client metric scorecard 

A risk assessment (Table 2)—a project management process—is done as part of the technology transfer phase of your project. The risk assessment document contains the list of risks, the probability of occurrence, the impact should the risks occur, and the project team response to each risk to mitigate it and build contingency plans. This project management practice identifies potential waste that can diminish value creation (Lean), while it helps manage mutually agreed expectations (customer service). The result is that risks are better managed, so there are fewer issues and costly mistakes in the process.  

Table 2. An example of a risk-assesment document (red: risk plan is needed; yellow: consider a risk plan; grey: risk plan completed) 

Project managers should leverage best practices from project management principles, customer service, and Lean. This helps integrate the needs of the client, project, and the CMO, focusing on timely delivery of your project to yield the best possible value to your organization. 

 is a senior director of program management and 

is a manager of project management office, both at Baxter BioPharma Solutions, Bloomington, IN  812.355.5247, 

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http://www.reuters.com/article/pressRelease/idUS104649+10-Jun-2009+BW20090610

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8. Baxter International. Baxter BioPharma Solutions Process 360. Customer service. Available from: 

http://www.baxterbiopharmasolutions.com/content/about_bbps/process_360.html

Partner with a contract manufacturing organization that integrates best practices from project management, customer service, and Lean.

BioPharm International-04-02-2010

Effective Auditing of CMOs

Process Harmonization Assessments for Technology Transfer

How to Reap the Benefits of Insourcing Contract Staff While Minimizing the Risks

Strategies for Optimizing the CMO-Client Relationship