Every family has a favorite recipe that‘s been passed down over the years. Yours might be a prized chocolate chip cookie recipe that your grandmother made, and then your mother, which was eventually passed down to you. But how was that recipe passed down? Family recipes like these may be passed down by word-of-mouth or may undergo some adjustments as various family members put their own spin on it. The result may be a delicious chocolate chip cookie, but one that is difficult for others to recreate or is vastly different from its origins.

The situation is even more acute in U.S. Food and Drug Administration (FDA) and ISO environments. In a marketplace in which consumers continue to demand products at breakneck speed, manufacturers must be quick to meet those demands while maintaining stringent regulatory requirements. Consider the fiercely competitive pharmaceutical industry. According to a recent study in the Journal of Health Economics, only 12% of potential medicines investigated by American research-based pharmaceutical companies survives the rigorous FDA approval process.¹ Moreover, it takes pharma manufacturers about 10 years at a cost of more than $2.6 billion before a new medicine is approved, the study adds.

In a highly competitive, high-stakes regulatory environment, nothing can be more devastating to a life sciences manufacturer than a product recall. Product recalls can happen for several reasons, but one of the most common occurrences is unregulated changes in the manufacturing process. In 2019 alone, the FDA has issued over 200 recalls to date.² In this context, any production change that affects the “purity” and effectiveness of the approved product is critical.

Definition of Change

In the manufacturing environment, change refers to any modification in equipment, manufacturing materials, facilities, utilities, design, formulations, processes, packaging/labeling, computer systems, and all associated documentation (SOPs, quality manual, etc.). A change may be a simple adjustment brought on by a new customer specification, an updated document, a part replacement, or other production need. It may be caused by a deviation from an approved regulatory filing or written procedures. A change may be temporary or permanent, routine or emergency, innocuous or serious enough to shut down production.

The fact that change in manufacturing is inevitable makes control a critical factor, especially in FDA and ISO environments, where inappropriate or "uncontrolled" changes could affect the safety and reliability of products and directly impact public health and safety.

In the summer of 2018, the FDA announced a voluntary recall of a single-use resuscitation device produced by Vyaire Medical, Inc.³ Vyaire recalled the resuscitation device due to a manufacturing error which may cause extra plastic material in the oxygen output connection that reduces or blocks the flow of oxygen to the patient. The FDA noted than an undeclared change to the manufacturing process of the resuscitation device likely led to this production error. This illustrates the critical implications of change in the manufacture of medical devices or any other life sciences product. Whether the product is a cookie, a car or a pacemaker, the goal of regulatory bodies is to protect public safety by ensuring the highest quality standards. For this reason, the concept of change control is closely interwoven with FDA and ISO compliance.

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Regulatory Requirements

Change control requirements for medical device companies are outlined in the 21 CFR Part 820.30 (design changes), 820.40 (document changes), and 820.70 (production and process changes). Twenty-one CFR Part 820 requires that manufacturers establish written change control procedures that describe company-approved procedures.

For pharmaceutical companies, written procedures are considered part of FDA Current Good Manufacturing Practice (CGMP) outlined in 21 CFR Parts 210 -211. Any changes in production and processes must be controlled — meaning recorded, reviewed and approved by the quality control unit. CGMP requirements are meant to prevent harm by building quality into the development and production of medicines. Manufacturers certified to ISO 9000:2000 and ISO 13485 standards are required to ensure that any changes affecting the quality management system (QMS) — including product requirements, design, and development changes — should be controlled.

The underlying message in these regulations is that all changes should be made according to approved (approval implies successful testing or thorough review/investigation) written company policies and procedures. Change control procedures must be documented and recorded as a way of standardizing instructions. Documented procedures (particularly electronically documented procedures) are also more reliable compared with passing on information verbally. “Uncontrolled” change in this context refers to modifications made without review and approval of the quality control unit and other departments affected by the change.

In FDA and ISO environments, strict adherence to approved policies and procedures is a key factor in keeping manufacturing operations in a state of control and why change control is a crucial point across the product life cycle management.

Elements of Change Control

Change is typically introduced by an initiator or originator. Depending on the company and industry, the initiator may or may not be the person who will carry the change through implementation. Initiating a change usually involves filling out a change request form, which then moves through a process or system of review and approval. Most organizations have a change control committee or board, which may be a single entity for an entire company, or there may be one for a company's manufacturing site (s). The committee usually includes representatives from different departments involved in production, such as quality, manufacturing, regulatory affairs and engineering. Depending on the change, the committee may also involve the legal, sales or marketing departments.

For pharmaceutical companies, CGMP requires that all changes should be reviewed and approved by the quality control unit. In these companies, there may be a “change administrator,” a role usually assumed by the quality unit.

Change control records usually cover: identification of the item/entity being changed, a description of the change, identification of the affected documents, signatures of the approvers, approval date, and effective date.

In the medical device industry, each modified device, accessory, labeling, packaging and process must be thoroughly verified and/or validated by the appropriate department. The change control committee then reviews the test results and other pertinent information.

Challenges

A change control system is necessary to prevent inappropriate modifications. While this sounds simple, implementation can be complex and an inadequate system can cause internal confusion, noncompliance, or worse, a product recall or a product liability lawsuit. What makes change control so challenging? There are many factors, but the following are the most common issues:

1. Poor communication - Lack of communication between departments, failure to follow up or escalate change requests, and delayed or inappropriate notification of changes made by suppliers are some of the communication-issues that impact the change control process. Companies using a manual, paper-based change control system are likely to rely on face-to-face exchanges, such as change control board meetings, to discuss changes. The effectiveness of these meetings depends on their frequency and the availability of members to meet as emergency changes arise.
2. Poor turnaround - Timeliness can make or break a product's chances of succeeding in the market. Companies that rely on a manual QMS to generate data and to route and track submissions and change orders are likely to have poor turnaround for change implementation because the system requires more time and effort. The problem becomes worse when there is an unexpected change — a deviation — and supporting data is not generated in a timely manner. Delays may also result because of failure to recognize the urgency of a change and the absence of a contingency plan for certain types of changes.
3. Ineffective documentation - A manual or hybrid data system makes it more difficult to update documentation, including revision history, and to find or retrieve necessary data to support a change. The proposed change may be delayed when an outdated record does not show revision history, or testing may be duplicated because documentation has not been updated with results of a previous testing.
4. Training not integrated with change - Adequate training of personnel is a prerequisite in both FDA and ISO environments. When training control is not connected to the rest of the quality process, such as in manual systems, keeping training current with procedures that have changed can be difficult. Training tasks can easily fall through the cracks if employees are not vigilant in seeking them.

A digital QMS can help you avoid all of these challenges by providing your organization with real-time production data that is accurate, accessible and compliant, thereby assuring that all your production changes, approvals and signatures are entered correctly and helping you avoid costly delay and deviations that prevent product from getting to market quicker. Most importantly, with an automated change control system, you can properly document change control data and avoid the slow turnaround times and error-prone documentation that a paper-based system produces.

Conclusion

Whether its cookies or medical devices, consumers have become more concerned about and aware of product quality, and they’re demanding more transparency from manufacturers. In response, manufacturers have adjusted their processes to meet consumer demand. Customer satisfaction and continuous improvement of product quality have become the objectives not only of regulatory bodies, but also of manufacturers themselves. At the operational level, the focus is moving from error detection to prevention. Companies recognize that it's their primary responsibility and in their best interest to proactively determine if a proposed change might affect the safety or effectiveness of a product rather than being the responsibility of an FDA inspector or ISO auditor. Manufacturers increasingly realize that effective change control is integral to continuous quality improvement, which can ultimately help them increase customer satisfaction and prevent product recalls, product liability actions, and regulatory observations.

References

1. “A Tough Road: Cost to Develop One New Drug Is $2.6 Billion; Approval Rate for Drugs Entering Clinical Development Is Less Than 12%,” by Thomas Sullivan. Policy and Medicine. March 21, 2019. https://www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html
2. “Recalls, Market Withdrawals and Safety Alerts” U.S. Food and Drug Administration. April 26, 2019. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts
3. “Vyaire Medical, Inc. Recalls AirLife Resuscitation Devices Due to Manufacturing Error Preventing Oxygen Delivery” U.S. Food and Drug Administration. August 10, 2018. https://www.fda.gov/medical-devices/medical-device-recalls/vyaire-medical-inc-recalls-airlife-resuscitation-devices-due-manufacturing-error-preventing-oxygen

Connor White is a member of the content team at MasterControl. He has worked in the advertising, marketing and property management industries before coming to MasterControl. White has a bachelor’s degree in strategic communications from the University of Utah.