Contract manufacturing organizations (CMOs) are used by many pharmaceutical and medical device companies and for a wide array of uses. These uses may be singular in nature or include all aspects of product development, manufacturing, and distribution. CMOs can be subsets of large multinational companies, or a service subset of a clinical research organization (CRO), providing limited support to research efforts. Some are a single site company that provides manufacturing and packaging services. No matter the size or the limits of use, using contracted supports requires a system to manage the various aspects of the usage.

Managing any activity or support should not be chaotic. The management system adopted by the contracting company (referred to as “the company”) should have a defined structure that is utilized consistently. The approach doesn’t change just because the CMO, product, service, or location changes. The system should reflect the life cycle of the products supported, even if the support only reflects a minor part of that lifecycle. Poorly managed CMO efforts will result in higher internal costs and efforts, and increase risks to the product supply and compliance. This article discusses the CMO System for managing external production or product supports.

A CMO System includes four aspects of the product lifecycle: regulatory, technical, compliance, and operations. The first three ensure the product’s quality and legal status; the last ensures supply. All are interdependent and any gaps impact the whole, requiring increased efforts to achieve the goals. The primary responsibility for each part, and the supportive roles in execution, are dependent on the relationships—contract and personal—established between the company and the CMO. It is in the company’s interest to ensure all systems are established and effective. Poor systems increase effort and risk.

Regulatory and technical
Regulatory and technical documents give CMOs and their quality group the information needed for the contracted effort and compliance oversight. Examples of information for exchange, within appropriate confidentiality controls, are:

• Formula and specifications (API, materials) and test methods, standards
• Process and product specifications, controls, and test methods
• Container closure systems, with specs, test methods
• Stability information (API, product)

Information alone is not sufficient for product or control purposes. The company should establish CMO Master Control Records (specifications, test records, etc.) similar to internal QC documents. Company master records help communicate requirements and help the CMO establish internal documents to meet their internal systems requirements. Share information based on the supports provided. General information sharing ensures both organizations understand requirements and can support decision-making.

The CMO may have been selected because they are technical experts for a product or process, or the company may have inherited the CMO, as occurs with acquisitions of products or companies. It doesn’t matter if the company or the CMO is the expert, what matters is equal access to technical information. Sufficient sharing of technical information helps both organizations support the efforts and make decisions.

The company and the CMO need to agree on the technical requirements, especially those that impact compliance. These agreements need to be documented through procedures or reports for future reference. This helps address changes of personnel or ownership, where new participants don’t have the benefit of history. The topics for agreement are dependent on the contracted supports. Examples are:

• Equipment and facility qualification
• Validation and controls (process, product, analytical)
• Stability

Qualification of the facility and equipment is a CMO responsibility and likely predate any company/CMO relationship. The company assures the CMO approach is adequate, but shouldn’t expect or require them to adopt company procedures. The addition of products or processes should require supplemental qualification efforts based on the impact of the products on the facility or equipment. A non-compliant system or execution of qualifications should be discussed with the CMO head of quality. The project team may not be in a position to address major deficiencies, or the company and the QA representative could be wrong about the requirements or status.

The company should be clear in defining validation expectations. If the CMO validation system—SOPs, protocols—is compliant and adequate, it should be used. This ensures needs are met without disrupting the CMO process. Providing the CMO historic protocols and reports, or suggested draft protocols and reports, is a good way to communicate information and expectations. Differences in format or language are typical roadblocks, and are overcome by open discussions. Disagreements reflect a lack of understanding, caused by poor communication, inexperience or misuse of technical language.

Controls include using procedures and master records to define acceptance ranges or limits, and specific supplies or equipment settings. Controls include knowledge and tools for safe handling and practices to protect the employee and the environment. Controls apply to:

• Material and supplies (specifications, manufacturer,packaging, and storage conditions)
• Analytical (methods, validation, transfer, qualification,standards)
• Equipment/environmental (ranges, calibration, cleaning)
• Process (ranges, limits, sampling, testing)

The development and establishment of controls reflect the regulatory application and the technical experiences of the company and CMO. Stability profiles—conditions, container/closure—impact materials, in process, and finished products. Stability information from manufacturers or development should be shared to ensure proper controls are established.

The company should establish formal systems to ensure proper regulatory and technical information is available, shared, and serve as the controlling aspects of a product/ project. These systems should include master documents that are created and controlled for the CMO projects and products. These documents should reflect the regulatory submissions that serve as the basis of approval, and reflect the technical history and experience of the product within the company.

In addition to the master documents, requirements documents should be created and maintained, to ensure the specific controls and expectations are well defined and communicated. Often these documents need to be a discussion point, based on the company needs as matched against the CMO use, structure, and their business needs. While a single universal document may seem efficient for use with all CMOs, the reality is that any expectation should be based on the specific relationship between the company and the CMO.

Compliance
Compliance should reflect the requirements for the support and the operating environment of the CMO. An ideal condition is where the CMO has the capability and capacity to meet all compliance requirements, so compliance is assured without the company oversight. An audit of the CMO quality systems can determine if they can operate autonomously or semi-autonomously. If not, then improvements to get to this state should be established. This is more efficient than piecemeal management of compliance on an ongoing basis, and may result in better cost controls.

There should be a written agreement establishing the quality roles, and the limits of the roles. Industry believes this is resolved through formal Quality Agreements. Quality agreements are written to meet contractual or compliance guidance requirements, and are not suitable for working agreements for day-to-day execution. This becomes obvious where each CMO provides different services for different products. Most day-to-day items are based on oral agreements between the initial project teams or quality groups. Changes in personnel can dilute historic oral agreements. Over time these changes and conditions can lead to poor working relationships and unmet expectations.

The following quality topics should be defined and agreed on to ensure proper use of quality personnel at both organizations:

• Quality systems: general expectations based on supports provided
• Change control: guidance with specifics on what changes require internal change controls, and what changes require company change control and approvals. Good communications can offset change control constraints.
• Documents/master records: a procedure defining the review and approval process, including position responsibilities. Formatting should be based on the CMO record systems, as multiple formats within a site can impact quality.
• Records review and approval—batch, analytical: defines who conducts reviews, what it entails, and who approves the records. Example: Batch record: the company reviews critical entries and test results, but doesn’t repeat the CMO’s line-to-line record audit.
• Training system: how personnel are trained and qualified for the supports provided. The company does not need the names of people that are approved for specific actions, only that a system is in place.
• Investigations: a primary source of conflicts and delays. Like change control, good communication can address most issues. Identify specifics and what investigations require approvals.

Use the CMO procedure and format. The company assures adequacy and conclusions, but does not manage the CMO process or records. If the CMO lacks the knowledge or experience then the company should conduct the investigation and not just manage it from afar. Oversight of an inadequate condition is not feasible, so this needs to be corrected over time. Establish a path to elevate investigations in each quality organization in the event of disagreements with conclusions or responses.

Establishing compliance expectations through company systems can address most issues before discrepancies occur. Using established systems helps prevent inconsistent application, or migration to an out of compliance state. Maintaining these expectations through formal systems helps address the impact of personnel or company changes.

Ongoing operations
Companies and CMOs will pursue new project and product efforts with gusto. The adequate support and experience assigned to the project help ensure success. Once the routine gets underway, both sides assume all requirements are in place and cutting a purchase or work order is sufficient to “press on”. This is rarely true.

Inadequate systems in the daily activities reveal themselves in different ways, such as timing constraints, slow responses, or new people. Overwork or inexperience can be a primary contributing factor. Instead multitudes of minor infractions that occur in the daily activity become the focus of investigations. The longer this continues the more negative the consequences to both organizations. Establishing operating systems does not guarantee elimination of process or personnel issues—within or between organizations. Properly established systems do provide a blueprint to address issues, and provide direction to pursue corrective actions. This becomes additive, and the approaches used become more effective and efficient.

Teams are needed to manage the functional actions between the company and CMO. These teams should comprise individuals from each company. They should meet to manage the actions, and to develop the communication that is distributed within both companies. Examples include:

• Operations: inventory, schedule and changes
• Quality: product release, investigations, projects, and changes
• Project management: T&E status and plans

In the event specific issues arise or decisions are needed, the teams can meet to resolve or mutually agree to elevate within the companies.

Similar to the need to establish a quality agreement, there should be an operating agreement to define the operating roles. The CMO’s systems should be used as the basis of the agreement, since they are responsible for activity at their site—and it needs to support all of their clients. Examples of topics include:

• Materials management, including labeling: ordering, use of non-critical local supplies, local ERP system requirements.
• Inventory: rotation, investment levels, storage
• Planning/scheduling: based on lead times, finished good inventory levels decisions, routine production rates, accelerated rates and overtime
• Production: daily scheduling based on planning agreements, to target efficiency, effectiveness, and output rates
• Shipping: logistics providers, conditions, status of shipped goods
• Complaint handling: addressing non-product company or CMO complaints

Communication standards between the company and CMO can pre-empt significant issues and keeps everyone informed. Informational communications should be sent to applicable teams and management at both companies. Examples of topics include:

• Schedule: inventory levels, open POs and work orders,
• testing schedules, releases, and shipping schedule
• Projects: T&E status
• Changes: future events and status of changes

Innovation
The opportunity for innovation exists at the company and the CMOs. Both should establish a means of identifying and pursuing innovative efforts that improve the supports—costs, equipment, controls—and the people—training, communication, software, etc.—This helps both companies realize additional returns on their business and interpersonal investments.

CMOs can offer many opportunities for companies and products. Achieving those opportunities are dependent on the working relationships and successes of each. Establishing appropriate systems within and between each will improve their opportunities and successes. These systems should address regulatory, technical, compliance and operations. Identifying and pursuing innovation should be included. 

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Phil Burns has worked in the Pharma industry over 30 years, with technical and senior management roles in quality and operations. He has served as the head of quality, technical support, quality control/regulatory, and production at multiple companies. He is the co-founder of CRO-Consulting, providing compliance, regulatory and operations consulting to the pharmaceutical and medical device industry. He can be reached at phil@cro-consulting.net.