Change Control Tests Contract Manufacturing Relationships
(From PDA Journal Article)
Walter Morris and Emily Hough, PDA
Of the many challenges facing contract manufacturers and their clients, change control can be one of the toughest to handle and require the most effort.
Strong change management is a fundamental principle of a robust quality system, and while the concepts behind change management are relatively simple, the globalization of the pharmaceutical industry and the borderless supply chain supporting it create complexity. The program committee for the 2007 PDA/FDA Joint Regulatory Conference dedicated two breakout sessions to the topic, with speakers representing regulatory authorities in the United States, Canada and Japan and the industry.
The added challenges of co-managing change control when working in a contract manufacturing arrangement was also addressed. Luisa Paulo, GMP Compliance, Hovione, discussed the matter from the contract manufacturer perspective, and Randall Tlachac, past Program Director, Molecular and Cellular Therapeutics, spoke from the perspective of a “virtual” firm.
Both speakers indicated that the parties involved in a contract manufacturing relationship need to focus resources and personnel on ensuring that the partnership works. These resources must work together to manage hurdles such as different corporate cultures, barriers to communication, divergent views and perspectives on issues such as deciding what is important and regulatory interprestions. Failure to do so can jeopardize the effectiveness of the relationship and its long-term viability.
Changes to the manufacturing process, equipment and supplies, whether initiated by the drug product licensee or the contract manufacturing organization (CMO), greatly test how effectively both parties work together.
Changes required by the licensee seem to occur in the early phases of the partnership, according to Hovione’s Paulo. “Usually…when [the clients] propose changes it is always at the beginning of the campaign. It is two weeks or one week before the campaign starts, and we need to rush in order to have everything in order for the campaign.”
Oftentimes, the sense of urgency is compounded by a pending marketing authorization. The licensee should understand changes “give rise to new versions of the documents always, at least batch records,” Paulo said. “We have time constraints and we have a lot of iteration issues between all the areas and with the client.”
CMOs Must Work with Various Cultures
Contract manufacturers need to be adept at working with various corporate cultures. According to Paulo, in some companies either no one makes a decision or decisions are delayed until the last minute. Other companies, she said, make many decisions and end up providing too much information to the manufacturer.
Sometimes companies place added stress on the CMO as a result of the “huge pressure to have products to get results.” Because of this pressure, some firms place many people on the same project, she said, “but they are not very well organized in terms of hierarchy—and this is an issue we handle with customers.” Hovione must work hard to manage information when the customer has multiple representatives working on the project. Although her firm might have one QA and one QC person on the project, customers have sent information from various sources, including QA, development, the validation team, etc. “So we need to have discipline and have a very well-defined organization,” said Paulo.
In some situations, the customer does not fully appreciate the differences between the three phases of product development, according to Paulo. “Another point is that products under development have three distinct phases and the controls should increase from phase 1 to phase 3. “This sometimes is difficult to be accepted by the customers.” Sometimes customers “ask us for everything” in phase 1 as if it were a commercial product. “This is something we also need to discuss with the client in terms of changes.”
Paulo has seen situations where the licensee fails to provide enough information to the CMO to support the change. “What we also have to take into consideration is that sometimes the changes are required by the client but without rationale, and we need to take care of this.” This can cause problems when the regulators visit the CMO for the preapproval inspection. “We know that at the time of the preapproval inspection, FDA will ask us, ‘Okay, you have changed—why you have changed?’” Stating “‘because of client requests’ is not the best rationale we can have. So this is something we need to handle also when we evaluate the change control or the changes in the manufacturing.”
Varying perspectives among the parties to the contract manufacturing arrangement can be ameliorated with a strong quality agreement. For instance, Paulo described how clients often take a short-term view of the process, usually in light of the urgency to receive marketing approval. “Clients always think of the present movement; they do not think of the long term view,” she said. “Sometimes it happens because the timing for clients is the filing of the NDA.” By contrast, the CMO has a longer time horizon which includes the marketing authorization and at least the first five years post approval, Paulo said.
When the CMO proposes changes, it should not discount the important role that the licensee should play in evaluating the proposed changes, said Paulo. Typically, the licensee is in a better position to assess the impact of change on the safety and effectiveness of the drug product and on the filling.
“When you work in contract manufacturing, the client is the most important piece. If you want to change something, you need to have the client on your side to give support for the changes.” The client “can help assess the changes that you want to perform in terms of formulation, because he knows everything about the formulation in terms of the safety and effectiveness of the drug product and of the filing.” However, the licensee needs to respect the manufacturer’s knowledge, said Paulo. “We know the product. We know the process. We know the problems we face during the manufacturing of the product.”
Discuss Change Control in Quality Agreement
A strong change control procedure built into the quality agreement along with solid lines of communication between the two parties can help the parties overcome these challenges.
Paulo noted that change control is a “formal process used to ensure that a product, service or process is modified in line with the identified necessary change.” She suggests defining in quality agreements which changes need to be reviewed and approved by customers. “These are issues that we need to handle, and we need to quantify all this work.”
Molecular and Cellular Therapeutics’ Tlachac also advocated developing a tight change control procedure in the quality agreement. For virtual firms, the more comprehensive the procedure, the better. “When I speak of a virtual firm, of course, they take on many different forms and are many different sizes.”
Tlachac’s presentation addressed the needs of a virtual firm undergoing its first experience with a contract manufacturing arrangement. “It is very difficult sometimes for them to understand what they are exactly dealing with. So the meaning of change management for virtual firms, I believe, is the task of managing the change and most importantly the relationship between your firm and the CMO. It’s the process of risk evaluation and assessment and includes the definition of the level and detail of information that has to be shared between the two parties—and also an understanding of procedures and mechanisms for effectively managing change. [Change management] involves an assessment of the systems that both firms use to enable change in a risk-based manner while allowing for innovation, process improvement and optimization while ensuring quality by design and all the time focusing on relationship building.”
Such firms face a number of unique challenges, according to Tlachac. When it comes to change control, they must manage two quality systems and changes both within the control and outside the control of their organization. “Often times you have to use your best skills of influencing to accomplish your goals. You need to identify the interfaces and differences between your elements of the quality system and the CMO’s and recognize that each firm sees risk in a different way. And often times, especially if you have a large CMO, change may primarily be viewed as a cost and may not be something they’re particularly interested in at the outset.”
Tlachac advises virtual firms to self-evaluate whether or not they will be anticipative or reactive when it comes to change. “By that,” he said, “I mean whether they can truly act in a proactive role with the CMO. In some cases it may be better for [virtual firms] to take a reactive position to the CMO, especially if they have greater capacities than your firm has.”
Tlachac notes that virtual firms must learn to understand how they and the CMO interpret the regulatory impact of various manufacturing changes and “master parallel review cycles.”
First, licensees must “recognize that different firms have different processes for the regulatory interpretation of changes, and this gets to be very important in areas you may not think of, such as minor changes in processes or minor changes in equipment that were not even anticipated….Examine carefully the philosophy and the process for the CMO interpretations, ensure that you have a good agreement in how changes are interpretated and ask specifically the questions regarding process equipment, method and procedural changes and how they are processed.”
Second, “it is very important to try and achieve efficient parallel reviews at both firms, and often that means the virtual firm must perform at a very effective pace in order to keep the process going.” If possible, Tlachac added, the virtual firm should consider utilizing the CMO’s process and achieve equivalent risk assessment mechanisms.
Real-Time Data Sharing Helps Relationship
To facilitate document review, Hovione’s Paulo urges the use of an electronic change control management system with a World Wide Web interface. Hovione utilizes a Web interface which allows the customer “access to the information on real time.”
Tlachac acknowledged that Web-based systems for document review is becoming more common. “So when I talk about the basis for regulatory approval, we are talking about what information is transferred from the virtual firm to the CMO. And this of course can occur at various levels, depending on when the process and product is actually transferred.”
Data sharing can be initiated by the CMO in the form of a questionnaire or a technology transfer package. Either way, “it certainly relies on the documentation from the CMC, including specs, batch records, protocols and summaries.” The licensee must understand and identify “key differences” in how the CMO prepares documents and to integrate those differences.
Tlachac used stability reports as an example: “It might be how the CMO reports stability in a summary, and the licensee might find that stability summary does not include all the information it would like to be report to FDA, so it may convert that summary to its own document.”
To deal with all of these issues, like Paulo, Tlachac emphasized that the quality agreement needs to be comprehensive and items need to be spelled out such as roles and responsibilities, points of control, documentation change control, risk management, and deviation and out-of-specification procedures. In addition, “ensure that provisions are in place for evaluation of regulatory changes for both parties and agree on timelines and expectations for evaluation and risk assessment.”
Tlachac continued, “A good quality agreement will maintain involvement and understanding. It will define changes a manufacturer may make using the risk management process. It will identify raw material, component, process and product controls within the design space to create requirements or a guideline against which change management, risk assessment and audits may be preformed. Periodic onsite reviews to evaluate deviations, CAPA and outcomes of joint actions are important—primarily from the standpoint of examining performance between the two groups.”
In general, Tlachac explained, “change control systems should be dynamic enablers for optimization, and I think we have all experienced cases where change control seems to be a break in the entire process transfer or process improvement.” Paulo agreed noting that “change cannot be avoided.” She said that whenever a contractor is working with a client to develop a process, changes “should be looked upon as opportunities to gain knowledge and further support of the design space.”
Virtual firms should seek to establish relationships with operators and analysts at the CMO to encourage understanding and participation in the change control process, advised Tlachac. “You can do this in a variety of ways—getting to know them as a part of your onsite reviews or by asking the CMO to include [those] personnel…on the project teams. Certainly, to identify and avoid the potential for disincentives for change, [the inclusion of] many people on this team, you will be doing exactly that.”
Ultimately, the success of a contract manufacturing arrangement rests on the culture of the two organizations and the relationships that have developed.
These relationships will have the greatest impact when problems arise. This is especially important, Paulo said, “when we are producing. When we are manufacturing, of course problems arise and sometimes big problems arise. Sometime we need to call the client and say, ‘Oh sorry, but we have a problem—we lost some kilos or we have the product contaminated or we whatever.’ Problems always happen and if we have not built a good relationship with our customer, we will have problems….And this can be the start of a good relationship or could be the end of the relationship with the client.”
Both Paulo and Tlachac indicated that the benefits of an effective contract manufacturer relationship are vast for virtual firms and the CMO. To make that a reality, a vision and plan for achieving change, developing and implementing a communication plan, establishing standard meeting times for participants, awards and incentives are needed.
Quality Systems has brought numerous firms and contract manufacturers successfully through the product development process. Creating and anticipating the regulatory pathways for new products is what we do. Contact us to learn more.
Announcements
Randall Tlachac is participating in the PDA subcommittee efforts to provide guidance for Quality Agreements