The benefits of outsourcing manufacturing are well known within the biopharmaceutical industry. Small companies can benefit greatly from working with a CMO by minimizing capital outlays, shortening lead times for bringing capacity online, accessing manufacturing and development expertise, and leveraging project management skills. Larger companies are also using outside capacity to bridge shortfalls in internal capabilities or to off-load their older, lower-margin products, which can free up capacity for newer products. Additionally, CMOs can offer certain types of capacity that the innovator company lacks.

 Karen Walker (Abgenix, Inc.) and Marc Puich (Tefen, Ltd.) 

As with any partnership, working with a CMO can be complex. The level of trust and cooperation between both organizations needs to be extremely high due to the sensitive nature of the product technologies and the crucial timing involved with running clinical trials and supplying needy customers. A key aspect to managing this relationship is forming a joint quality culture and establishing strong communication plans at all relevant levels. Building the successful relationship requires formal agreements with key milestones and responsibilities. These agreements include the actual product manufacturing and supply agreement and should also include a quality agreement.  The quality agreement solidifies the quality structure and culture and  serves as a tool for manageability with respect to quality issues. 

Before creating any framework for the quality relationship, both parties involved in the partnership need to understand the extent to which they have developed a quality culture. Creating a quality culture requires focus in three main areas: 					

regulatory and business environment understanding.

Through dialog and initial audits, a company looking to outsource can gain a fairly clear understanding of their outsourcing partner's quality philosophy and evaluate how it might fit with their own. Understanding where there might be gaps in these quality cultures and learning to adapt them to the needs of the partnership is a difficult part of the process. This is where the quality agreement becomes so important. Because of different regulatory interpretations and internal quality systems, the agreed upon language and quality relationship needs to be formalized to assure total understanding of roles and expectations on both sides of the partnership. The joint quality culture, and therefore the elements of the quality agreement, is built on the mutual understanding of the needs of the partnership and requires planning, execution, and continuous review and revision.   

Different regulatory agencies have slightly different views on the need for stand-alone quality agreements. FDA does not explicitly define that one is required but references something similar in concept in several guidance documents, including "Cooperative Manufacturing Arrangements for Licensed Biologics"(Draft 1999).  

Chapter 7 of the EU GMPs also defines the need for clarity on product control and on how the qualified person releasing the batch can assure compliance with regulations but does not state that a quality agreement is a necessary instrument.  

The ICH regulations are the most explicit in defining the need for a stand-alone quality agreement. Section Q7a lists the following requirement:  

There should be a written and approved contract or formal agreement between the contract giver and the contract acceptor that defines in detail the GMP responsibilities, including the quality measures, of each party. 

The quality agreement is usually developed in conjunction with the overall supply agreement. The supply agreement, a legal document, defines pricing methods, milestones, the workplan, forecasts, and other terms and conditions of the relationship. Some would argue that the quality plan should simply be an addendum to the supply agreement, not necessarily held to the same level of legal scrutiny. The reasoning is that it doesn't define terms of payment or milestones. Others would contend that the quality agreement is contractual, due to its definition of clear roles and responsibilities and its use in reducing ambiguity if challenges arise. Regardless of how it is viewed, having it as part of the negotiation and final agreement is vital to strengthening the ties between partners. 

The quality agreement should have several key parts to it. First, it should define the level of cooperation when working with the following quality systems: 					

Defined for each of these should be elements such as: the communication strategy for when events occur, the level of oversight by the innovator, audit frequency and rights, approval rights, access to information systems and documentation, and a clear definition of when issues need to be escalated to the client. 

Additionally, the quality agreement should include the communication plan with regulatory authorities. This plan should clarify the specific set of actions (and involvement) of the client during regulatory inspections at the CMO. It should also define the appropriate structure for managing and responding to regulatory commitments.  

A final part of the quality agreement should define ownership of regulatory filings and responsibility for notifying regulatory authorities about changes. 

The format of a quality agreement can vary. However, one needs to keep in mind that it will be referenced on a regular basis. In many contract manufacturing relationships, certain products may be produced only a few times a year. As a result, the need for a clear and useful document to remind both parties of the process for managing the manufacturing and release of product is critical. There are several design elements that can help the quality agreement achieve this goal: 

The document should be written in plain language. Not all of the individuals referencing the document will be quality (or legal) experts. 

It should be able to stand alone as a document. Even if it is included as an addendum to the overall supply agreement, it may be referenced separately. There should be sections that summarize the scope of the document and the general relationship between the parties. 

It should include flow charts of key business processes, such as release and deviation investigations. These flow charts can visibly show (through color coding or dividing lines) the path and ownership of certain process steps. 

It should include a section with roles and responsibilities in tabular format. At a glance, parties can easily understand where they fit in the overall process.  

Areas of joint responsibility are further clarified in accompianing narative text associated with the tabular format. 

The quality agreement is one of the most critical aspects of developing a strong relationship between a contract manufacturer and an innovator company. By jointly developing this document, companies will take the first steps to defining a working relationship built on a foundation of communication and negotiation. Although it is not yet a required element by every regulatory agency, the quality agreement should be seen as key to any developing strategic relationship. 

Articles

Quality Outsourcing

As with any partnership, working with a CMO can be complex. The level of trust and cooperation between both organizations needs to be extremely high.

Managing Quality While Outsourcing

The fundamental goal of technology transfer is to implement a process in a different place, whether from preclinical to cGMP manufacturing, between two sites, or from one company to another. The reasons to transfer a process include considerations of capacity, scale, facility availability and compliance, and production economics.

Technology transfer is always challenging, even in organizations with years of experience in cGMP manufacturing, and if care is not taken to ensure meticulous planning and execution, it can be wrought with unpleasant and costly surprises. Further, a thorough understanding of the manufacturing requirements throughout the development pathway — from research, through clinical development, to commercial manufacturing — is fundamental to successful biopharmaceutical drug commercialization.  Diosynth Biotechnology is dedicated to delivering products and services with the highest level of quality. It is with that in mind that the company developed standards in the form of a Standard Operating Procedure (SOP)

  to clearly define all requirements from early process development through commercial manufacturing of recombinant proteins. Diosynth has implemented this product development process SOP to help ensure that a customer's product enters the company's system at the most appropriate stage. 

The process is divided into five stages that serve as guidelines to streamline process transfer and development. It is a uniform approach to cGMP manufacturing and quality operations that ensures seamless production within and between the manufacturing sites in Research Triangle Park, North Carolina and Oss, The Netherlands. This approach also helps Diosynth Biotechnology and its customers in evaluating, developing, and executing high-quality, efficient manufacturing processes by ensuring that the most appropriate program and development stage is assigned to each product.  This not only saves up-front time but  also helps avoid the costlier delays in redevelopment later in the clinical trajectory. 

While every project is unique, a formalized approach to process development allows rapid progress during preclinical and early clinical testing. To ensure that each program and product enters Diosynth's system at the optimal stage, process development and technical services specialists initially evaluate the process fundamentals, regardless of whether the product is in preclinical development or approved for the commercial market. If the process and analytical methods are robust, transfer to cGMP manufacturing areas can occur rapidly, though process and method refinement are often requested by the customer or are required to fit the customer's process into the company's facility and equipment. By gaining familiarity with the molecule and the process, process development scientists are well prepared to support further refinement and development during the development trajectory, including support of validation through small-scale modeling and experimentation. 

The product development process is divided into five stages. 

The objective of this stage is to determine whether the proposed biotechnological process can be executed. 

Marketing and sales (M&S) is typically the first department to be in contact with a potential sponsor concerning a proposed program. The M&S representative records information presented by the potential sponsor and presents it to the Diosynth Biotechnology Global Portfolio Review Board. This group reviews the information and determines whether the proposed program conforms to the company business model. If this group approves the program, the process development, operations and quality/regulatory departments review the information and comments on the technical feasibility of the work proposed. A resource estimate and timeline are provided. The process development staff also evaluates, with environmental, health and safety personnel, the effect of the potential program on human safety and the environment. 

During development of the Statement of Work (SOW), Diosynth forms a project team. Representatives from the quality, process development, and operations technical management departments and a program manager comprise the project team. The purpose of the project team is to ensure that the program is executed according to the SOW. The project team assembles the appropriate resources to execute the program on an as-needed basis as the program proceeds through the development process. 

The objective of this stage is to generate a prototype manufacturing process at a laboratory scale. The starting point for research is a cell line that produces the molecule of interest. 

The duration of effort in this stage depends on the extent and suitability of a sponsor's previous work. However, each process transferred to or developed at Diosynth Biotechnology is confirmed first at an ~10-L production (fermentation or cell culture) scale in the process development laboratory. During this confirmation, significant process parameters are identified and provisional operating ranges are established or confirmed. 

The final laboratory step of this stage is the demonstration of the process at an ~100-L production scale. Draft batch records in Diosynth Biotechnology format document this production. After this demonstration is complete, including testing the product by appropriate analytical methods, a process description is prepared. This document provides a list of raw materials used, the sequence of operations for the process, provisional operating ranges for process parameters, in-process controls, and provisional acceptance criteria for the product. Preliminary stability information on API is generated to support the suitability of the research batch for the intended use. Packaging materials are investigated.  

Analytical methods that test product safety, identity, strength, purity, or quality are developed, appropriately evaluated, and used to test product from small-scale and research batches during Stage II. The method evaluations are performed under protocols that are reviewed by the quality department. These methods are used to establish provisional specifications for the product. On a case-by-case basis, Diosynth develops/transfers in methods designed to test the potency of the product. An interim reference material is made available before method evaluation begins. 

Raw materials, starting materials, process consumables, and other process aids are specified for the process during this stage. Compendial raw materials are selected unless compelling process reasons exist for the use of non-compendial materials. Raw materials, starting materials, process consumables and other process aids used in this stage and subsequent stages are selected, as applicable, from the standard list of approved raw materials at Diosynth. These materials are procured from the company's approved vendor list. If a necessary material at this stage is available only from a vendor not on the list, that vendor is added to the list when the quality department approves the vendor. 

A research technical summary report is prepared at the end of this stage. The report describes the experimental justification for the process description, with references to original data, and a preliminary rationale for each unit operation and analytical methodology used. The report also outlines additional work that needs to be performed to complete the process and product characterization and contains a process flow diagram. Additionally, a Process Transfer Package (PTP) is generated which consists of the following five components: a detailed process description (DPD), process flow diagram (PFD), bill of materials (BOM), equipment list (EQL) and sampling plan (SP). The PTP fully defines a process as it is to be manufactured under cGMP conditions at a specified scale at Diosynth Biotechnology facilities. It is a lifecycle document that fully describes scale-dependent and scale-independent process parameters. 

The objective of this stage is to implement the process developed in Stage II at manufacturing scale. The starting point for this stage is the research summary report.  

Evaluation of analytical methods in anticipation of method validation continues during this stage. The method evaluations are performed under protocols that are reviewed by the quality department. Where in-process control and test results dictate manufacturing decisions for the batch, appropriate test methods are developed and evaluated by the same standards used for product release methods. Approved written analytical methods are used for testing product from this stage. Provisional product specifications and a reference standard are established before API manufacturing begins. 

Critical attributes of raw materials, API starting materials, process consumables, process intermediates, and other process aids are identified, and appropriate methods are developed to test for these attributes. In some instances, the suitability of a raw material may be determined in small-scale reactions — use testing — rather than by analytical testing alone. 

At the end of this stage, development batches of the product are produced.  Batch records are prepared by process development staff and reviewed and approved by the appropriate operations and quality assurance personnel. The batch records in this stage are flexible and consistent with assuring the quality of the product. SOPs specific for the process are prepared and approved and staff training is completed. Raw materials and supplies are procured, tested, and released by quality assurance. Testing methods for intermediate release are developed where appropriate. 

The effectiveness of cleaning procedures is demonstrated on process equipment. The demonstration includes, at a minimum, swab, visual, and rinse data.  These data are generated at the beginning of the manufacturing campaign(s) for this stage and are summarized in the manufacturing campaign summary report. The cleaning procedures are finalized so that the equipment is suitable for production of material for human use.  Sterilization cycles and glasswash cleaning cycles are fully qualified prior to use in the manufacture of API for use in humans. 

The process description is revised to reflect the refinement of the process during this stage. The research technical summary report from Stage II is appended to justify the process and testing changes that have been implemented during this stage. The report references original data and also outlines remaining work that needs to be performed to complete the process and product characterization, as well as additional work identified during this stage. 

The end of this stage is reached when the quality assurance department has dispositioned product from the manufacturing batches. Additionally, the appended research technical summary report, the revised process description, and the description of additional work needed to complete the process and product characterization are generated, and the PTP is updated. 

The objective of this stage is to verify the choices made during the previous stages and to demonstrate the consistency of the process and the methods used to test the product. The starting point is the development report from Stage III, supplemented with the approved batch records from the pilot manufacturing campaign. 

The rationale for each unit operation is expanded to include the quantitative description of the specific impurities removed or generated by the process. Additional methods are developed and evaluated for testing API and intermediates. Characterization of product and process-related impurities are completed during this stage. 

Scale-up studies are performed if the Stage IV manufacturing scale is greater than the Stage III manufacturing scale. These scale-up studies evaluate the relevance of Stage III operating parameters to the larger-scale equipment. Performing at least one engineering batch using draft batch records provides additional assurance that the API manufactured meets its predefined specifications and presents an opportunity to correct deficiencies in equipment performance, manufacturing instructions, or operator training. The results of these studies are described in a scale-up summary report. 

Production of verification batches occurs in a controlled environment using appropriate production and control procedures to ensure the quality of the drug substance. Personnel trained in the specific unit operations perform all manufacturing and testing activities, actively assisted by process development personnel as required. Each batch is approved or rejected by quality assurance, applying appropriate GMP concepts. 

A stability study of the API and selected intermediates is initiated. The design of the stability study is appropriate for the intended use of the API. Expiration or retest dating is established for product from the verification batches. 

At the end of this stage, the process description is revised to reflect the refinement and additional characterization of the process. The process is controlled under critical change control procedures and is not subject to change after the end of Stage IV. The development report is appended to justify the process as it is defined in the process description and describes any additional work needed to begin commercial manufacturing. The report forms the basis for the commercial regulatory applications. The report also identifies unsuccessful approaches to developing the manufacturing process. Additionally, the PTP is updated to reflect any changes that might have been made during this stage. 

Diosynth prepares the Project Master Plan (PMP). The PMP describes the general plan for process and cleaning validation for the project. Preparation of the PMP components is the responsibility of the appropriate validation departments and is executed during Stage V. 

The objective of this stage is to demonstrate that the manufacturing process, when executed within the constraints of specified process parameters, yields a product that reliably and reproducibly meets its predetermined acceptance criteria. The PMP is used to direct this demonstration. 

The PMP has two components: process validation and cleaning validation. Process validation is performed under protocol during a minimum of three consecutive successful manufacturing batches (validation batches) at commercial-manufacturing scale. Cleaning validation is performed concurrently under protocol for three consecutive manufacturing batches, and it may be continued to monitor the effect of routine production on the suitability of equipment cleaning procedures. Execution of the protocol is typically the responsibility of the operations department. 

Each protocol describes the acceptable operating limits of the process and equipment that, if met, ensure that the product will meet its predefined quality attributes. Execution of the process validation protocol demonstrates that the equipment can direct and control the process within the established limits. Execution of the protocol also demonstrates that the process, as performed by operations personnel, yields a product that meets its predetermined specifications. For cleaning validation, execution of the protocol demonstrates that the cleaning methods ensure contamination and carryover are maintained below predetermined acceptable levels. 

After the validation protocol has been executed, the respective validation department prepares a validation summary report. This report is reviewed and approved by quality assurance. The operations department assumes responsibility for routine production. Process performance is monitored and additional data are gathered to monitor process trends and to provide data on resin and membrane lifetimes. 

During routine commercial manufacturing, critical parameters are monitored and trended to ensure that the process is still operating in a valid manner. Reprocessing or rework is allowed at this stage if such processes are being validated under protocol or if such processes have already been validated. Reprocessing or rework requires approval of the sponsor. 

Implementation of this procedure for process development and transfer enables Diosynth and its customers to use a common language to manage expectations for contracted work. 

Diosynth Standard Operating Procedure SOP#80GN1327: Evaluation, Development and Execution of Manufacturing Processes at Diosynth RTP 

Tech Transfer

The objective of the feasibility stage is to determine whether the proposed biotechnological process can be executed.

Technology Transfer: A Contract Manufacturer's Perspective

Traditionally, continuous improvement (CI) activities at Lonza were carried out and managed by staff who were also responsible for the delivery of product to internal and external customers. The CI projects usually competed for resources with product delivery. To address this issue, the potential benefit of having dedicated resources focused on improving working practices and procedures was often discussed. Separating direct accountability for product delivery from CI efforts alleviated this conflict. 

In May 2003, Lonza restructured the manufacturing department and created two full-time, dedicated positions focused on CI activities in manufacturing. The new roles provided a resource for CI projects designed to achieve specific business goals. To highlight the importance of the projects, the CI leads reported directly to the head of operations. 

The CI lead role was envisaged as a long-term secondment, allowing the skills and knowledge obtained from executing CI projects to ultimately be transferred back to the product delivery teams. This was done to ensure that CI did not become just the job of the CI leads, although the CI leads were responsible for driving and ensuring successful project execution. To allow the CI leads to be successful in their roles, training and coaching  on CI techniques was provided by an in-house Six Sigma Master Black Belt. As well as executing projects, part of the CI lead's role was promoting the CI philosophy and encouraging the use of various CI techniques throughout the organization. By exposing as many staff as possible to the philosophy, Lonza hoped that CI would become part of the staffs' everyday work to ensure that the company continues to deliver value to its customers.  

Lonza's CI philosophy is based on five main principles. 

The first principle of the philosophy is understanding process variation and emphasizing on-target performance with minimal variation. Control charts are useful tools for monitoring process variation over time and determining if a process is in control (stable, predictable, and exhibiting only random, "common cause variation") or out of control (unstable, unpredictable, and showing "special cause variation").

  Traditionally, the number of deviations reported from one manufacturing batch was compared to the number reported for the previous batch. If the current batch generated more deviations than the previous batch, an investigation was carried out to try to understand why. Conversely, if the number of deviations generated was less than the previous batch, the teams were considered to have performed particularly well. In the past, there was no way to determine the typical level of variation in the process and, therefore, how many deviations could be expected. Control charting is now used to monitor the number of deviations generated by each batch. This has allowed Lonza to target investigations at batches that truly have special cause variation rather than wasting time investigating random and expected variation. 

Figure 1.  This control chart shows a shift in the process performance (a reduction in the mean number of deviations generated per batch) after implementing an on-plant review of documents.  New control limits will remain temporary until more batches are completed using the new process.  

Control charting also helps track and evaluate process performance over time. This is particularly useful after process improvements have been made to ensure the changes have a beneficial effect. For example, changes were recently made to the timing of batch record reviews. The review of manufacturing batch records now takes place in the plant, usually on the day they are completed. Before, the documents were reviewed in an office several days after they were completed. The improved process has reduced the time between document completion by manufacturing and the subsequent review by an independent lot review group and quality assurance (QA). One anticipated benefit of this change was reduction in the number of deviations generated per batch by having QA input available at the plant as batches are being processed. As control charts were already being used to monitor the process, the effects of this change in procedure were quickly evaluated. Changing the timing of the document reviews resulted in a reduction in the mean number of deviations generated per batch (Figure 1). 

The successful use of this technique has led to the introduction of control charts to track the performance of other processes. For example, the number of process alarms generated during manufacturing is now monitored using this tool. 

The second principle of the CI philosophy is preventing errors — not just applying corrective actions once they have occurred. This has been achieved using a technique called failure mode effect analysis (FMEA). FMEA is a risk-based prioritization tool that helps to identify known or potential failure modes within a process or system.

  FMEA has been successfully used for one of Lonza's fermentation harvest systems. The technique helped identify and prioritize areas requiring CI focus, engineering investment in the plant, additional operator training, and opportunities for standard operating procedure improvement. A secondary benefit of using FMEA is that the team (consisting of representatives from fermentation, engineering,  and pilot and QA compliance) has enhanced its understanding of the harvest system. The team felt that the knowledge they gained would be useful to them in their normal roles.  

Figure 2.  Drill blanks have been mistake-proofed by attaching the correct size tubing for which the blanks are intended to be used.  This helps to ensure that the correct size blank is used for the appropriate size tubing.  

The third continuous improvement principle promoted at Lonza is using structured problem solving to help identify root causes of problems more rapidly. Cause and effect analysis has been used to structure problem solving by graphically displaying all possible causes of a problem. Brainstorming sessions are held with members of the relevant teams to generate the list of potential causes. It is essential to involve the people working on the system or process as they possess the best knowledge of likely causes of the problem. It is also useful to include an "outsider" at these sessions because of their ability to ask "obvious" questions that people with in-depth process knowledge frequently overlook. Once a cause-and-effect diagram has been generated, all the possible causes of a problem are investigated. Potential causes are only discounted if factual evidence can be found to back-up that decision. This helps remove subjectivity from investigations. Previously, individuals often presented their opinions as facts, leading to unsubstantiated conclusions being drawn about the actual root cause of a problem. 

As well as a more rapid determination of root causes, this technique is also a useful method of documenting an investigation. This helps with the closure of associated manufacturing deviations as it provides clear evidence that an event has been fully investigated. The tool is now a standard problem solving and investigative method in manufacturing.  

Once root causes of problems have been identified, it is essential that actions are taken to ensure that they cannot recur. Root cause elimination is the fourth CI principle used at Lonza. Root cause elimination is achieved by using mistake-proofing techniques that have already proved successful in the automotive and aerospace industries.

  Mistake-proofing allows systems and procedures to be designed or modified to help avoid the opportunity for error. 

Figure 3.  Instrument port blanking plugs used in fermenter vessels have been color coded to ensure that the correct plugs are used and that the plugs are correctly aligned.    

For example, the root cause of a pump tubing split at Lonza was attributed to the incorrect setting of pump roller gaps. Gap measuring devices (blank drill bits) are now being used to ensure that pump rollers are set to the correct operating distance. These gap measuring devices were developed so that it is obvious which size tubing should be used (Figure 2). This has helped reduce opportunities for the wrong operating distance to be used when pumps are set up. 

The mistake-proofing technique has also been successfully used to ensure that the instrument port blanking plugs used in fermenter vessels are correctly positioned and aligned prior to commencing a manufacturing batch (Figure 3). Now that the mistake-proofing system is in place, it is obvious to operators, at a glance, if a plug is correctly oriented. 

The final principle in Lonza's CI philosophy is the transfer of key learning and knowledge to other systems, processes, and people. Transferring information can potentially prevent the same issue from occurring in other departments or facilities. This transfer of information helps reduce the resources that other departments and facilities spend trying to resolve the same or similar issues. This has been particularly beneficial where multiple facilities perform similar operations. 

Due to the success of the manufacturing CI leads over the last 12 months, two new positions for engineering CI leads have been established at Lonza's UK operations. After a 10-month secondment, the two initial manufacturing CI leads moved to work on Six Sigma Black Belt projects and were recently replaced by two new manufacturing CI leads. Despite the relatively short time that the CI lead role has existed, the benefits of having dedicated resources are clear. Lonza is convinced that this investment in dedicated resources has produced and will continue to produce real returns in improved operational efficiency and effectiveness.  

Wise SA, Fair DC. Innovative control charting: practical SPC solutions for today's manufacturing environment. Milwaukee (WI): ASQ Quality Press; 1988. 

London A. BioPharma Operations Excellence. 

Continuous Improvement

Continuous Improvement requires a sound philosophy. Is your company following the correct principles?

BioPharm International-09-15-2004

Managing Quality While Outsourcing

Technology Transfer: A Contract Manufacturer's Perspective

Applying Continuous Improvement (CI) Manufacturing