Supporting GMPs During the Product Life Cycle in Contract Manufacturing

According to its final report in September 2004, Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach, the US Food and Drug Administration's guiding principles now include risk-based orientation, science-based policies and standards, integrated quality systems orientation, international cooperation, and strong public health protection. Per the guidance, FDA reviews include risk-based approaches, quality-systems approaches, enhanced internal regulatory coordination, international collaboration, and a strong analysis of current good manufacturing practices (CGMPs) requirements. Because "sterile drug products are a major component in FDA's risk-based inspectional program, FDA hopes to facilitate the application of good science and modern technology, and thus eliminate avoidable risks from aseptic operations" (1).

This approach is found in the agency's recent draft publication, Guidance for Industry INDs: Approaches to Complying with CGMP During Phase I (2). Recommendations for compliance include suggestions for personnel, quality control functions, facility and equipment, control of components, production and documentation, laboratory controls, container closure and labeling, distribution, and record-keeping. Many of these recommendations are useful for supporting all phases of pharmaceutical manufacturing because the structure required to implement and support these recommendations for Phase I products is beneficial for all CGMP activities in the production of quality and efficacious pharmaceutical products.

CGMPs: interpretations and applications. The proper application of CGMPs requires more than following a set of rules to ensure a drug product is of adequate strength, purity, quality, and efficacy. CGMPs are an overall approach in both theory and practice that must permeate the entire process. CGMP regulations should never be viewed as extensively as roadblocks or as simply as documentation practices. They should be viewed as a mindset or the best method to produce quality pharmaceutical products.

The interpretation and application of CGMPs are problematic for any pharmaceutical company. They are especially challenging in the world of a contract manufacturing organization (CMO) where processes are not always well defined and requirements vary based on the stage of the product in question (e.g., toxicological material, clinical trial material, Phases I, II, III, registration, or commercial).

Each client has a unique set of requirements for the successful manufacture and release of its product. These requirements range from process scale-up assistance and batch-production record assistance to lyophilization cycle development and analytical-method validation. Moreover, every client has a unique level of experience with its product and with CGMPs. Some clients are virtual companies that rely heavily on consultants with varying degrees of experience to provide guidance. Still others are from large pharmaceutical companies with a specific set of expectations for quality assurance and documentation practices. Complicating the process further is a range of experience levels and multiple client styles with varying interpretations of CGMPs in the client/product life cycle.

Strong project management. Given the complexities involved, a strong project-management system is the best way to provide individual customer service while maintaining a reasonable level of infrastructure, meeting required deadlines, and fulfilling all CGMP requirements. It is essential that the project management system be robust with decision power at all critical levels. It must also be well maintained and work simultaneously with timely and consistent communication.

Project-management systems work most effectively with equal participation between the client and the CMO. Multidisciplinary project teams from each company must meet frequently and have a working communication style and decision power that moves the project forward. To meet aggressive timelines associated with contract manufacturing, the level of communication required may include information sharing between consultants or third-party laboratories.

A project-management system developed by contract manufacturer HollisterStier meets clients' multifaceted needs by acting as a framework for the manufacturing process. This system is most effective when executed with precision. All projects have multiple moving parts, thus making it challenging to meet time frames. Moreover, integrating CGMPs into each cycle of production in a uniform manner is complicated. Using a well-defined set of project-management guidelines that outline a successful project widens the opportunity for success. It is helpful to identify the following criteria before beginning the project:

• project schedule;

• quality requirements;

• budget;

• team members and leaders;

• customers (internal and external);

• regulatory compliance requirements;

• risk assessment;

• required project documentation adequate to facilitate future communications with customers, equipment maintenance and trouble-shooting, and facility modifications.

Establishing a project team

It is important to create a multidisciplinary team with representatives from business development, validation, regulatory affairs, engineering, and manufacturing. The team should include representatives from quality assurance, quality control, and product development departments to ensure project accuracy. These team members should meet weekly as needed with a corresponding client project team via conference calls.

A team leader is established as the contact point on both sides of the equation. All communication flows through the team leaders. When required, team members from the client team and the CMO team may communicate with each other for specific project needs. These needs include quality control for analytical method support. The project leader should be copied at all times.

The project leader is responsible for team-meeting minutes and project record-keeping. A project binder is maintained throughout the project and may be passed to a new project leader, should the need arise. This is especially helpful when a project changes scope during the project life cycle. For example, a project may require the building of a specialized facility. In this case, an engineer is often the best choice to lead the project for this phase. Once the building is complete, a process development representative may be better suited to lead the project. When the change occurs, the project binder is simply passed to the new leader for a seamless transition.

Finally, once a project is completed, a closeout meeting is held to assess the project's success. Updated project guidelines ensure lessons learned are passed along to the next project.

Creating a timeline to support CGMP documentation requirements

Project status. Timelines are closely managed by Microsoft Project and customized databases with communication to senior management on a daily basis in morning production meetings. A monthly project meeting also is held to provide project updates during an informal question-and-answer session. In support of this meeting, project leaders provide detailed updates to a project database and present status reports to upper management.

Requirements checklist. Support groups that are well trained in CGMPs feed the project-management engine. They provide the project leader with background information by giving guidance when necessary.

A well-established Contract Manufacturing Documentation Requirements checklist serves as guidance for the project leader when communicating with clients. This checklist covers all areas affecting the project, including general information such as material safety and waste requirements, sterilization, lyophilization, manufacturing, validation, quality control, quality assurance, regulatory issues, engineering, maintenance, metrology, and business development.

Recommendations in the checklist are based on the following guidelines: CGMP 21 CFR, the Guidance for Industry documents available, the International Conference on Harmonization of the Technical Requirements for Registration of Pharmaceuticals (ICH), the United States Pharmacopeia (USP), the European Pharmacopoeia (EP), and the Japanese Pharmacopoeia (JP). Relying on these resources and previous manufacturing and regulatory filing experience are critical. They support the checklist, thereby providing a means for both the client and the CMO to be on the same page. The entire process depends on the communication process to keep teams informed and the project on track.

Trusting and flexible client–CMO relationships. Mutual trust and flexibility are integral to the process. A CMO can supply support and guidance to customers based on strong regulatory history and audit experience. Agency, customer, and internal audits provide assurance that a CMO is compliant and provide the opportunity to improve the process constantly. For example, since 2000, HollisterStier has hosted more than 100 client audits, seven preapproval inspections (PAI) audits, and eight general agency facility audits, including FDA, European, Japanese, and other international regulatory agencies. These audits support all regulatory needs, including product-flow diagrams; drug master file authorization; chemistry, manufacturing, and control;and PAI support. Customer notification is distributed through an automated database system, thereby allowing for timely and accurate project and product information delivery.

Risk management: component and excipient identification

In addition to a regulatory notification system, each client and the facility should be protected by the fundamental practice of identifying every component or excipient that enters production areas. This procedure is not only a good manufacturing practice, but it also protects clients and CMOs from possible contamination that could take much longer to address than issues arising with known substances where cleaning methods are established. Applying the practice of using dedicated or disposable equipment for product-contact equipment and parts saves time and energy with cleaning validation.

Case study examples

The following case studies describe a variety of project challenges and successes. The studies demonstrate the adaptation and application of several CGMPs in a project-management system, including the corresponding support systems to provide customers with timely and quality service.

Case study 1: communication in proper equipment handling. Client A had a new process requiring a state-of-the-art facility with more than 40 aseptic connections. This project required a highly specialized compounding–filling suite. A project team was assembled and set to work. Six months from the project's start date, the facility was ready and the process transfer began. The process, however, was fraught with problems because scale-up and process development modified the scope of the project several times. CGMP regulations dictate:

Appropriate equipment (is required) that will not contaminate the product or otherwise be reactive, additive, or absorptive with the product and that is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals following written procedures (1).

In this case, the primary CGMP challenge was taking equipment from several locations around the country and literally putting the pieces together on-site. Discussions began by determining how to ship each piece of equipment, transfer them down the hallway, and complete proper installation, operation, and performance qualifications. The project teams from the client and CMO worked very hard to resolve the problems and manufacture the product aseptically within CGMP guidelines. The client was on-site for several months as this project took place.

Key to this successful project was timely and consistent communication. Many process development steps were fine-tuned within the Contract Manufacturing Documentation Requirements checklist during this project.

Case study 2: label crunches and temporary staff. Client B had a commercial diluent project. At first glance, this project was simple. But, 13 product lots needed to be produced over a three-month time frame. Labeling became the critical path for this project.

Because of the aggressive timeline and label-vendor supply issues, CGMP labels were not available as quickly as required. When the labels became available, the packaging and release of the product lots (nearly 2 million vials) were completed in one month. This project was completed with a skilled staff and effective use of local temporary employees. The 21 CFR 211.130 (a) "Packaging and Label Operations" and 211.25 "Personnel Qualifications" guidelines both apply in this case and the support thereof was critical. Efficient and specific CGMP training programs provide CMOs the ability to use temporary staff when specialized nonroutine projects arise.

Case study 3: multiple projects for the same client with different originating sites. Client C had several small clinical trial material projects run by three different groups or sites in its large pharmaceutical company. Because one can interpret and implement CGMPs in many ways, the project was a true test of the project-management system's consistency. Several small, yet very important, projects with different client project leaders (each with different styles) and short timelines tested the system's ability to repeat the process with overall project uniformity and application of Subpart I-Laboratory Controls (21 CFR 211.160 General Requirements).

A solid pattern was established for transfer requirements, but flexibility in applying the pattern was the key to providing support for the client's individual project leader's needs. A management oversight committee was established to meet routinely to discuss successes and possible improvements. This client appreciates the well-defined documentation system, the project-tracking system, and the CMO project team's preparedness at weekly teleconferences. As a result, multiple projects have been completed successfully. In this case, flexibility fostered a great working relationship and ensured continued business.

Case study 4: method transfers from non-CGMP facilities. Client D had a very aggressive timeline for a project with underdeveloped analytical methods from a non-CGMP facility. According to 21 CFR 211.165 "Testing and Release for Distribution" (e):

The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 211.194(a)(2).

Meeting this specific requirement often becomes a critical path for many projects. After redefining the project scope, developing assays, and writing the validation protocol, the method was validated at an outside laboratory. To complete the validation in time for scheduled batches, the contract laboratory used the CMO's validation protocol. This demonstrates a need to meet customer requirements by having several CGMP-compliant contract laboratories qualified to perform on-demand outsourcing requirements. It also shows that sharing information may be the best course of action to complete a project on time.

Case study 5: third-party laboratory transfers. Client E, a virtual company, required a complicated analytical method transferred from a third-party laboratory where communication was extremely challenging. Differing opinions in the application of validation criteria and CGMP timing requirements (method validation must be complete before stability-study commencement) were the primary challenges. The method included extensive system-suitability criteria with secondary standards. It also required in-house, laboratory-prepared molecular weight markers using eight chemicals and more than 36 hours of hands-on labor. Patience, persistence, and several three-way technical conference calls were required to complete this transfer. Once transferred, an excellent laboratory training system allowed this method to be performed by four scientists in support of final container and stability testing requirements.

Case study 6: old product revivals. Client G had a unique problem: bringing back a product that had been off the market for more than 20 years. This project encompassed antiquated methodologies and processes, lost product historical information, and different raw material suppliers. In addition, there were a huge regulatory risk and multiple issues requiring the redefinition of the project's scope. Ultimately, applying CGMPs to this project required a complete change in approach, timeline, and the addition of clinical trials demonstrating that producing a quality-compliant product comes first.

Case study 7: client interaction. Client H presented its project with a very aggressive timeline. Nonetheless, the client's project and regulatory strategy had not been thoroughly examined. As the project was defined, the client allowed the CMO to draw on the prior expertise of the CMO's project team.

More than 1.5 million vials for a large Phase III clinical trial were produced in time to begin the associated study, thus saving the client time and money. Although basic in nature, the 21 CFR 211.22 responsibilities of the quality control unit apply in this case. The key to success with this project was willingness on the part of the client to learn, understand, and accept the CMO's quality systems.

Without a strong quality unit and well-established systems in place, the client would not have trusted the CMO to the extent necessary to complete the project within the desired timeframe. Together, CGMP issues were identified, discussed, and applied using CMO-established systems. A long-standing relationship has ensued with many additional projects completed at the CMO.

Conclusion

A successful contract manufacturing organization (CMO) must clearly identify the goals of a project, establish a plan, and then effectively execute accordingly. Knowing that each project includes diverse companies, personalities, phase requirements, and a large variety of products helps project leaders decide what communication style can most successfully move the projects forward. CMOs that empower their project teams by providing them with decision-making authority and direct access to senior management result in teams that operate quickly and with flexibility. Using the aforementioned strategy with a uniform application of current good manufacturing practices, allows CMOs to continue their role of producing high-quality and efficacious pharmaceutical products.

Sandra A. Lueken is the senior manager of quality control at HollisterStier Laboratories, LLC, 3525 N. Regal, Spokane, WA 99207, tel. 509.489.5656, sandra_lueken@hollister-stier.com

References

1. US Food and Drug Administration, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach (FDA, Rockville, MD, 2004).

2. FDA, Guidance for Industry INDs: Approaches to Complying with CGMP During Phase I (FDA, Rockville, MD, 2006).