Traceability and Sourcing
TRACEABILITY
Traceability refers to the ability to determine (trace) what materials have been brought into the facility, which materials, equipment, and personnel were used to manufacture a specific batch of finished product, and where the finished goods were distributed for commercial sale. To achieve complete traceability, companies must have systems in place to record the receipt and use of materials, by unique identifier (either a batch or control number), that go into the manufacture of the drug product, and systems for identifying where the finished product batches were distributed. Good documentation is key to meeting the traceability requirements and ensuring, in the case of a recall, that all impacted product is identified and can be removed from the field, if necessary. The United States Food and Drug Administration (FDA) good manufacturing practices (GMP) regulations illustrate the concept of traceability throughout a finished dosage form facility.
Raw Materials and Components
Before a raw material or component arrives at the receiving dock of the pharmaceutical company, it is imperative that the company has done its homework on the material and the vendor that supplies the material. Establishing the quality and integrity of the raw materials and components that are used in manufacturing and packaging the drug product begins with an understanding of how these materials are manufactured and packaged by the vendor. It is important to qualify vendors to ensure the receipt of quality raw materials and components. It is also important, through the qualification process, to verify that the vendor has mechanisms in place to trace the manufacture of its products, and that the product label is a unique identifier that can be traced forward into the manufacture of the finished dosage form.
Proper receipt of raw materials and components is crucial from a traceability perspective. When materials and/or components arrive on the dock, a verification of the vendor’s bill of lading should be conducted. Upon receipt, GMP regulations require that the finished dosage form manufacturer assign a unique code (batch or control number) to each lot of incoming materials, for each shipment received. The vendor’s unique identifier (batch or lot number) should be recorded to allow traceability back to the vendor in the event of a problem. The regulations direct the pharmaceutical company to verify the vendor’s packaging, labeling, and tamper-evident seal (if applicable) to ensure that the material received is legitimate and not counterfeit. Finally, it is important to understand that multiple shipments of the same batch of material require unique batch or control numbers to be assigned to each receipt. It is not acceptable to assign the same batch or control number to multiple receipts of the same vendor-supplied material or component batch.
Product Manufacturing and Packaging
GMP regulations require that each manufactured batch is assigned a unique identifier, typically a batch or lot number, that is specific to the product being manufactured. As raw materials are weighed and dispensed for use in manufacturing, the batch or control number of the raw materials must be recorded. As these materials are charged into the manufacturing equipment, their identity (by batch or control number) and quantity must be recorded on the manufacturing batch documentation. It is important to note that the addition of raw materials to the batch is typically viewed as a critical step and, as a result, requires two individuals to verify that the correct materials were added and to record the correct batch information on the associated documentation.
As manufacturing progresses, appropriate documentation of the manufacturing process (for example, the equipment used, personnel involved) is needed. The use of processing aids (for example, lubricants) should be documented. If individual batches are blended together to produce a single, larger batch for further processing, there should be traceability to the individual batches that were used to manufacture the larger batch. Batches should only be combined in this manner according to preestablished procedures and validated processes. Batches that failed to meet required specifications should not be combined with batches that have met specifications in hopes of producing a larger batch that meets the predetermined specifications for the product.
Water is a raw material that is commonly used in a number of pharmaceutical dosage forms and manufacturing processes. Documentation of water usage, and traceability to the water used, is always a bit of a problem as most companies use a continuous flow loop for their process water. A specific batch number or unique identifier can not be easily applied to the water that is used in the manufacturing process. As a result, traceability with respect to water is typically time-based, and any issues that arise with the quality of the water have the potential of impacting all of the batches that used the water since the date of the last acceptable testing results.
Finally, similarly to the requirements during manufacturing, each batch or control number of the packaging and labeling components must be recorded on the batch documentation to meet traceability requirements.
Finished Dosage Form
GMP regulations require the identification of each packaged lot of product with a batch or lot number that permits the determination of the history of the manufacturing and packaging operations, as well as the control and testing of the batch.
Distribution Practices
GMP regulations require the maintenance of distribution records containing at a minimum:
• Name and strength of product
• Name and address of the consignee
• Batch or lot number of the finished drug product shipped
• Quantity shipped
• Date shipped
These distribution records enable the tracking of each finished drug product, and should include shipments to commercial customers, transfers to internal departments (for example, samples for quality control [QC] testing), as well as samples to physicians or other healthcare providers. A system should be in place to account for 100% of the packaged finished dosage form and allow for complete notification of customers in the event of a product recall.
BIOLOGICAL AGENTS
Transmission spongiform encephalopathies (TSE) came to the forefront in the mid- 1980s with the identification of the bovine form (bovine spongiform encephalopathy [BSE]) in British cattle. This discovery of mad cow disease, and the risk of transmission to humans, highlighted the need for greater controls over the sourcing of animal-derived materials for use in the pharmaceutical industry.
The ideal situation when sourcing raw materials for the manufacture of drug products would be to avoid the use of bovine-derived materials or materials from other animal species in which TSE naturally occurs. Therefore, when a pharmaceutical company has a choice between materials of animal or nonanimal origin, the materials of nonanimal origin are clearly preferred. Unfortunately, sourcing materials of nonanimal origin is not always possible and, as a result, it is critical for a pharmaceutical company to take steps to minimize the risk of transmitting animal TSE through their drug products.
The European Medicines Agency (EMA) identifies mechanisms to minimize the risk of transmitting TSE:
• Sourcing materials produced from animals residing in geographic areas of low risk for the disease
• Cleaning and control procedures that minimize the risk of cross-contamination between production batches
• Removal or inactivation of TSE agents during production processing
Of these activities, the well controlled souring of animal-derived material materials is the most critical as this prevents the introduction of TSE into the drug manufacturing facility. To ensure that the materials used in the manufacture of the finished dosage form do not contain these types of biological agents, defined steps are recommended (Figure 40.1).
GMP regulations place responsibility for ensuring the quality of the materials used to manufacture drug products squarely on the shoulders of the pharmaceutical company. The globalization of the pharmaceutical supply chain, and the increasing use of materials manufactured in emerging countries (from a pharmaceutical perspective) such as India and China, has made this responsibility increasingly difficult to achieve.
Over the last few years, much debate and discussion has occurred regarding the establishment of a drug pedigree to ensure the integrity and authenticity of each and every drug product that enters the pharmaceutical supply chain. Much of this discussion has arisen as a result of the increase in counterfeit pharmaceutical products entering the supply chain and putting consumers and patients at significant risk. It is imperative that every organization involved in the pharmaceutical supply chain does their part to minimize or eliminate the introduction of counterfeit materials or products.
PHARMACEUTICAL SUPPLY CHAIN
A typical supply chain for a pharmaceutical company is shown in Figure 40.2. Inputs (for example, raw materials, packaging components) into the finished dosage form manufacturing process typically are purchased from outside suppliers. Once the finished dosage form is manufactured, packaged, tested, and released, it is shipped to a wholesaler who may store it for a period of time. The wholesaler may sell the product to a chain drug store (which requires the product to pass through the chain drug store warehouse before reaching the pharmacy) or directly to a pharmacy customer. The finished product typically passes through a number of hands before it reaches the end customer or patient.
