Pharmaceutical and biotechnology companies making products for human use have an obligation to ensure that their products are safe, effective, meet established regulatory expectations and licenses, and are available to the patients who rely on them. Pharmaceutical change management processes extend to the materials and services employed to manufacture and test drug products, necessitating the need for an effective supplier-initiated change (SIC) management process. This article provides an overview of the pharmaceutical SIC process, including a discussion on the need for control of SICs, a review of change notification scope and content, and a summary of how SICs are typically evaluated, managed, and closed.
Notification of Change
Biotech and pharmaceutical products, if defective, have a high potential to cause harm to the patients who are using them. As a result, companies making these products perform extensive studies to validate that the materials, equipment, and processes used for manufacturing consistently produce products that meet specifications upon release and throughout their labeled shelf life.
One of the cornerstones of consistency in any process is change control. Pharmaceutical manufacturers’ change-control systems are designed to ensure that any changes to raw materials, product contact materials, manufacturing methods, product tests, and production equipment among others are understood, evaluated, and approved prior for use in manufacturing. In addition, drug manufacturers must ensure that regulatory authorities (e.g., FDA, European Medicines Agency [EMEA], and other Boards of Health) are updated on changes associated with their manufacturing licenses and product dossiers.
Suppliers providing services or materials that are employed for manufacture of human use products are also expected to have an established change-control system. These systems should provide for reporting applicable changes to their pharmaceutical customers. These change notifications, when received, are evaluated to determine the impact on the manufacturing process for the drug or biologic product.
Change Notification Scope and Content
In general, biotech and pharmaceutical manufacturers need to be aware of any change that might alter the properties or performance of a material used in manufacturing or testing, or which will impact manufacturing-related documentation. These changes need to be known prior to implementation so that manufacturers can fully evaluate them and have time to plan for and qualify the change.
To ensure that requirements for reporting of changes are understood and agreed to, pharmaceutical and biotech manufacturers will typically require suppliers to enter into an agreement, sometimes referred to as a supplier-initiated change or SIC agreement, as a pre-requisite for doing business. In some cases, it may take the form of a quality agreement, which is discussed later. An example generic SIC agreement is included in Figure 1. This agreement establishes the need for and timing of reporting. The types of changes that are subject to be reported are specific to the material or services purchased, and include but are not limited to the following:
• Change in address or location (manufacturing, testing, and warehousing among others)
• Change in ownership
• Change in company name
• Use of a new subcontractor for purchased materials or services
• Change in certification or accreditation status by standard setting body or regulatory agency (e.g., International Organization for Standardization [ISO], FDA, EMEA, American National Standards Institute [ANSI]).
Material suppliers (including product-contact disposables)
• Change in raw material supplier or source in packaging configuration or components
• Chnage in packaging confirmation or components
• Change in part number
• Change in product documentation (certificate of analysis, certificate of compliance, product drawing, content on the primary container label)
• Change in raw material supplier or grade (e.g., United States Pharmacopeia [USP], National Formulary [NF], multi-compendial, etc.)
• Change in manufacturing process (e.g., addition/deletion of unit operations, significant change in qualified equipment), including but not limited to:
o Changes in process or chemistry that result in a physical property change
o Changes in purification and/or isolation steps where the result is a less pure product going into the final isolation/purification step
o Changes in manufacturing process that causes a change to the end product impurity profile
• Discontinuation of a material
• Change in specification
• Change in storage condition or shelf life
• Introduction of other processing, such as non-pharmaceutical products, penicillin, hormones, pesticides, or other potent compounds (including phthalates and heavy metals) into multi-use equipment or building
• Changes in sterilization, including “like-for-like” equipment, changes to cycle, criteria, or methods
• Change that results in the potential for cross-contamination a purchased item, including the introduction of a new product or grade of product on equipment that was previously dedicated
• Change to the animal-origin status of a material, change to the country of origin or tissue of an animal-derived material.
Testing Laboratory or Calibration Service Provider
• Failure or out-of-tolerance (OOT) condition of a standard or instrument used for calibration or testing of equipment or material
• Change in test method or documentation
• Re-qualification or re-validation of a test method.
Material Distributor or Warehousing
• Use of a new facility for storage or distribution of materials
• Change in processes or qualified equipment impacting storage and distribution of product
• Failure of equipment that may impact storage or distribution of materials.
In addition to the items above, SIC agreements will define the method for reporting of changes. Typically, it will be an e-mail address to which change notifications and the supporting documentation can be forwarded. Some companies may also choose to have changes reported to a specific individual or department, either by electronic or hard-copy means. Some suppliers have customized mechanisms for ensuring that their customers are notified of changes. For example, a supplier may require that customers sign up for change notification announcements through an automated web form or similar tool. It is important that appropriate communication takes place between suppliers and customers to ensure that each other’s needs and systems are understood and met.
Step 1: The pharma client receives the change notification from the supplier per the SIC agreement, or other governing document, and an initial evaluation is performed. This evaluation usually involves a search of the enterprise resource planning (ERP) system and production documentation (e.g., specifications, standard operating procedures [SOPs], test methods) to determine where/how the supplier’s materials or services are used. If it is determined that the material or service is not employed by the manufacturer, in some cases the SIC can be closed, and the supplier notified if required, without further action required.
Step 2: The change is evaluated by the appropriate users and subject-matter experts to determine impact. If necessary, additional data or input may be requested from the supplier to support evaluation of the change. This change evaluation may be performed by multiple sites or user groups, for example, in the case where a change impacts multiple operating sites of a large company.
Step 3: The change is managed via approved change-control procedures, which define the specific elements of the change that need to be addressed. This process is typically risk-based, and defines the evaluations and outcomes that need to be managed, as well as the specific deliverables required to establish that the change has been implemented. These deliverables may include, but are not limited to:
• Receipt of additional information from the supplier
• Execution of qualification studies or review of supplier validation summaries
• SOP/specification updates
• Material qualification
• Supplier audit or questionnaire
• Regulatory filings.
Step 4: Following completion of the defined deliverables, the SIC is closed. If required, notification to the supplier may be performed.
Additional Concerns for Critical Suppliers
For materials or services with a high potential to affect product quality and/or patient safety, a more formal and detailed contract may be required to delineate the responsibilities of each party with regard to control of the quality aspects of the supplier-purchaser relationship. These critical suppliers are typically required to enter into a formal quality agreement. Suppliers subject to quality agreements may include contract manufacturers, manufacturers of APIs, custom or critical raw materials (e.g., animal-derived) or final product contact containers/closures, or manufacturers whose materials and services are referenced in regulatory filings.
In addition to requirements for change notification, a formal quality agreement will typically define the requirements for quality management of other important aspects of the supplier-purchaser relationship, for example:
• Right to audit
• Responsibilities for regulatory inspections, filings, and communication
• Management of documentation and records
• Timing and mechanism for reporting of deviations and out-of-specification (OOS) results
• Qualification requirements for methods and/or manufacturing operations
• Process/timing for handling, archive, and destruction, or records
• Mechanisms for escalation or resolution of quality issues.
The change reporting requirements for critical suppliers are almost always more stringent than those for standard materials. Given the potential impact of the suppliers’ goods/services on product quality, timelines for change notification are typically extended so that drug manufacturers can perform in-depth evaluation/qualification of the changes, which may include evaluation of multiple lots/batches of material, formal technical evaluation, and site audit among others. In some cases (e.g., for APIs and pharmaceutical excipients), specific industry guidance (1) may be included as a standard reference for change reporting.
Pharmaceutical manufacturers and the suppliers that they rely on operate in a world of continuous improvement, and any improvement will result in change. The objective of continuous improvement must be balanced with the recognition that all changes; even those that may seem innocuous require resources to evaluate, plan, and implement. By establishing a good understanding of the needs of each partner, fostered by communication and a clear understanding of expectations, suppliers and drug manufacturers can ensure that their collaborations improve the product while avoiding unnecessary product or supply risks to the patients who depend on them.
1. The International Pharmaceutical Excipients Council of the Americas, Significant Change Guide for Bulk Pharmaceutical Excipients, Revision 2, March 2009.