When a firm embarks upon a contract manufacturing relationship with a third party, the questions that inevitably arise are: “Who is ultimately responsible for compliance? And what happens if and when a non-compliant situation arises?” The worst thing that can happen is to confront this question after a non-compliant situation occurs. A firm needs to know, from the beginning, who is responsible for each regulatory component.
In order to limit the scope of this article, only the Investigational New Drug Application (IND) and its related components will be discussed.
The regulatory component (for a U.S. study) referred to in this article consists of:
• The document necessary to initiate a clinical study in the U.S. This is the IND and it is comprised of several distinct sections. Each section must be complete in order to submit the document to the Food & Drug Agency in support of a new investigational drug product. However, we will focus on the Chemistry, Manufacturing, and Control (CMC) section.
• A mechanism for reporting changes to such aspects as formulation, manufacturing process and analytical methods.
• A mechanism for reporting on-going stability work.
• A designated person (or persons) to serve as the authorized contact with the FDA.
• An audit of the contract manufacturing facility and its systems in terms of current Good Manufacturing Practices (cGMPs) to make sure the sponsor is not wandering blindly into a nightmare.
• A designated person (or persons), often in the Quality Assurance department, who is the authorized escort in the event of FDA inspections.
Regulatory Overlaps Quality Assurance
Companies with limited human Resources (virtual companies in particular) may contract with a firm that provides regulatory document preparation and review services, as well as project management and product development services. These consulting firms are the in-between parties: they are “in-between” the client who has developed or licensed a product and the contract manufacturer who is responsible for producing it. The consulting firm is often responsible for making sure that the regulatory components are considered and that the appropriate submissions are made to the FDA. The problems start to surface, however, when it becomes evident that the client has not established boundaries, or even roles, with both parties. This can become apparent when a manufacturer acts wide-eyed and bewildered when asked to put together the CMC section for an IND. Some contract manufacturers have minimal involvement with these documents while others offer this as a service to the client.
Typically, however, the client or the consulting firm creates and assembles “the submission.” The client relies upon the contract manufacturer to provide the Master Production Record and the necessary information about the facility. The client does not always need to see the final product as long as the information provided by the contract manufacturer is accurate and the information is accurately transferred into the CMC format. Sometimes, however, depending upon the nature of the relationship between the client and the contract manufacturer, the client may be asked to review and approve the CMC section of the document prior to submission.
Believe it or not, a plan for preparing the documents, reporting the data, and performing the work is often not in place at this point. Though it may sound like oversimplifying the process to suggest it, there are only two pieces that need to be fixed at this point: (1) a delineation of responsibilities and (2) a group of people who are experienced enough to understand what to do or to know when the time has come to ask. Assembly of the Gantt chart (and there will be at least one) will come next, after the firm and the contract manufacturer determine what actually needs to occur (and when) in order to submit the documents, manufacture the product and ship it to the sites.
Avoiding the panic and chaos that occur in the wake of a “bad inspection” or an “agency re-quest” is certainly possible. Delineating the roles and having a plan that defines the communication chain are the most important pieces. The next most important piece is agreement by management that the plan will be used and the established roles will be kept. Often, management jumps in and determines that the only way to resolve the potential crisis is to take matters into its own hands. Unfortunately, management does not always have all the knowledge and experience needed to make sound regulatory decisions. That’s why regulatory specialists exist. Regulatory issues can create huge stumbling blocks for firms. A regulatory contact must be able to grasp the severity of an issue addressed by the FDA. If the agency poses a question about a test method or a packaging component, it must be taken seriously. It doesn’t matter if you think “everyone” should know the answer to the question. Keep in mind that the FDA deals with a multitude of products and companies and that there any many ways to comply with the cGMPs.
When a sponsor deals with a set of systems everyday in its facility, the management starts to think that everyone should know how the systems work. It is normal to assume that every other system works the same way. Sometimes, I run across a system in a facility that is unique. And since FDA investigators visit more facilities than I do, it is likely that they will encounter a unique system every now and then.
I once worked for a company that had what we called a “near-miss compliance crisis.” And even though a mechanism was in place for handling a compliance crisis, senior management decided to steer the boat. The people closest to the crisis (those who would ultimately be the ones to resolve the issue) were relegated to sitting, listening and answering questions when called upon. As a result, the crisis resolution process dragged on much longer than it should have. It didn’t surprise anyone when the people who ultimately resolved the issue were those closest to the problem.
It needs to be clearly noted that management must be well informed in the event of a compliance issue. This does not mean, however, that management should create a plan of action, along with new roles and responsibilities, in the face of a potential compliance issue.
Delineating Roles and Responsibilities
If I were to suggest a plan for the organization of the activities and responsibilities that I listed earlier, it would look something like Table 2 (please reference print version of Contract Pharma for this table):
The pieces that have the potential for disaster are shared between the client and the contract manufacturer.
It is evident from the tables above that the client is responsible for just about everything. Even though the company that owns the product (i.e., the client) contracts specific functions to another party, the company that owns the product is still responsible. Granted, the contract manufacturer is responsible for making sure that the facility is operated in compliance with cGMPs. However, if a cGMP audit sponsored by the client reveals what are considered to be cGMP violations, it is the client’s responsibility to ensure that the observations are resolved satisfactorily.
If the contract manufacturer believes there isn’t a problem, but the client and/or the consulting firm disagrees, then the client needs to consider the available options. Moving to another contract manufacturer is not that easy. It can be done, but it involves additional time and money, both of which are usually limited. This is especially true when a clinical study is looming on the horizon and the amount of money allocated to manufacture the product is fixed.
If the contract manufacturer provides a response that the client believes is satisfactory and the client decides not to pursue the observation further, then the contract manufacturer needs to take no further action. But if this same observation becomes an issue during an FDA investigation and the contract manufacturer cannot successfully convince the FDA investigator that there is not a issue, then the contract manufacturer will receive the observation in the form of a FDA 483. Both parties (and let’s not forget the consulting firm, if that party performed the audit), however, have a problem.
The Contract Manufacturer’s Side of the Story
Because the contract manufacturer’s income is derived from manufacturing, the company has every hope that the product it has agreed to produce will be a huge success. Most contract manufacturers will agree to produce small batches (i.e., clinical batches) with the understanding that the owner of the product will stay with them for commercial manufacturing. This is a reasonable expectation, since very little profit, if any, can be made from manufacturing the clinical product. The profits are in commercial manufacturing.
There are, of course, companies that specialize in the formulation development of clinical supplies. With these companies, commercial production is not a concern, since the facility and systems are designed for small-batch production.
Every contract manufacturer probably has a client or two that has presented new and different “challenges” for them. These clients are the ones that disagree with the way the facility is operated and managed. Sometimes, the clients are right. Other times, they are wrong and should not try to tell a contract manufacturer how to operate a facility. In either case, neither party can afford a strained relationship. A consulting firm can serve to ease the tensions on both sides of the equation. In fact, this skill should be within the consulting firm’s area of expertise. If a consulting firm is contracted by the owner of the product to manage the project from beginning to end, then the consulting firm should have the ability to understand manufacturing and compliance issues and be able to participate in problem-solving with the contract manufacturer on behalf of the client.
Earlier I noted that a contract manufacturer was caught wide-eyed and bewildered when asked to provide the CMC section of an IND for a small innovator company. This story was related to me by a very busy and successful contract manufacturer. The primary issue was that IND preparation had never appeared on the contract manufacturer’s menu of services. Somehow it was “assumed” by the client that the contract manufacturer would provide it. When the contract manufacturer informed the client that this was not an option, the client was puzzled and asked the contractor how they could “get it done.”
Time constraints are typically the biggest cause of tension between the client and the contract manufacturer. The client needs the product right now but the manufacturer does not have an opening for two to three months. Sometimes, through savvy scheduling, a manufacturer may be able to find an opening just large enough to manufacture the product, but it leaves no room in the event that the process does not go exactly as planned. If the manufacturing glitch is just significant enough to lose the batch, then the clinical schedule is disrupted. The manufacturer then has to try frantically to satisfy the customer by making a new slot in the schedule that isn’t too far into the future. This paves the way for a strained relationship between the two parties, unless they can salvage the relationship by understanding that problems occur and that reasonable people will do whatever is in their power to resolve the problems and get the project back on track.
There are many success stories involving multiple parties. I have participated in a project that involved, in addition to the innovator, a consulting firm to provide regulatory and QA assistance, as well as a contract manufacturer, a contract packager and a contract laboratory. There were miscommunications and overlaps in responsibility from time to time, but the product met the launch target and is now on the market.
Other projects I have worked on, both as an employee of a pharmaceutical manufacturer and as a member of a consulting firm, haven’t fared quite so well. In some cases, the problems were due to failure to define roles and to allow the responsible people to do what they had been assigned to do. In other cases, the responsibilities were defined and the plan was in place, but the product simply didn’t work out.
As more companies engage in contract manufacturing relationships, and more parties are involved in a given project, a new batch of creative ways to handle compliance issues will undoubtedly emerge. In the end, however, the company that owns the product is ultimately responsible for ensuring that every task on the Gantt chart, especially if regulatory-related, has been completed.