A Framework for Managing Supply Chain Integrity and Supplier Quality

• Pharmatech Associates

Ensuring supply chain integrity today in the global market requires integrating risk management for a physical and a virtual supply chain. An approach that ensures supplier quality and performance and supply chain integrity is very important. The issuance of HR3204 Drug Quality and Security Act (DQSA) has set the timeline and metrics for demonstrating supply chain integrity for the next decade. To set the scene, today there are more than 70 countries that have either implemented or plan to implement some form of serialization as a key component of efforts against drug diversion or adulteration.

Serialization, et al

In the U.S., some significant FDA guidances to standardize track and trace solutions and serialization have already been released. In March of 2010 the FDA issued guidance on Serialization Number Identifiers (SNIs)¹ to establish a standardized numbering scheme for all drug products shipped within the U.S. The SNIs consisted of a 10-digit National Drug Code (NDC) and a 20-character alphanumeric or numeric serialization code. This guidance also specifically identified Radio Frequency Identification (RFID) and 2-Dimensional bar coding as track and trace technologies to consider when managing supply chain risk. In October 2011 “Guidance for Industry Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting”² advocated the addition of non-functional components to an individual drug therapy as a deterrent to counterfeiters.

The most significant development in supply chain integrity was the passage of HR 3204 in 2013 that describes the Drug Quality and Security Act (DQSA). Up until this time many states had their own state-level set of regulations for interstate commerce that made establishing a cohesive serialization scheme difficult. Embedded within the DQSA is the Drug Supply Chain Security Act (DSCSA), which defines the specific timelines and deliverables for the phased implementation.

Addressing drug manufacturers, wholesale distributors, dispensers, and re-packagers, the DSCSA program defines a phased approach for a standardized information-tracking scheme that ensures the chain of custody. The law was intended to go into effect in January 2015 but has been delayed until May 2015 because the industry was not ready to implement the first level of traceability. The three largest wholesalers in the US, McKesson, Cardinal and AmerisourceBergen have asked for the initial information from their customers to demonstrate compliance with the law as of June 2014, and have threatened to embargo any shipments that do not comply.

DCSCA Commitments

The initial requirements focus on establishing a system for maintaining the transaction history, transaction information, including lot number and creating a transaction statement that will reside with the product as it moves through the supply chain. The additional performance requirements for each supply chain partner required as of May 2015 through full deployment are summarized in Table 1:

Table 1. DCSCA Requirements

From Table 1 it is clear that the expectation is to establish systems, potentially an electronic system, capable of providing the full pedigree for the product as it moves through the supply chain.

This is no small task as the components of a global supply chain can vary greatly. A migration to an electronic means of data gathering, communication, and data integrity requires establishing a model framework for data management often called a Master Data Management Strategy. This strategy seeks to characterize what data is already captured through existing operational IT systems such as ERP or Order/Entry and to link them to a detailed track and trace strategy.

Master Data Strategy Questionnaire

In linking these systems an organization may ask:

• What new Master Data (MD) is required for global track and trace?
• Product MD
• Customer MD (Country Specific)
• Partner/Channel MD (Company Info)
• As the company serializes to meet new country mandates, how do I identify and collect new Master Data?
• In what systems will this new track and trace Master Data be maintained?
• What are the supporting track and trace systems that will be the consumers of the Master Data and which classes of Master Data is required for each?
• Packaging line systems
• Serialization management systems
• Regulatory compliance and reporting systems
• The simplest way to attack this problem is to map existing processes with the intent of capturing chain of custody information, such as:
• Where there is physical movement of inventory?
• Where are the SNI’s assigned?
• Where are there state changes in the physical inventory that do not impact track and trace considerations?
• Where are there physical movements that require a SNI change?
• Where are there physical movements where SNI changes are optional?

This information will allow the user to identify the types of systems that will be required to satisfy HR3204 when fully implemented.

Implementation Roadmap

Meeting the expectations of DSCSA will vary from organization to organization and there is no single solution that fits all companies. A simple checklist of activities might consist of the following:

Internal Business Processes

• Map your current business operating Supply Chain (buy, sell, drop ship, transfer, repackage, dispense)
• Identify business process interaction points and systems that trigger compliance activities (sale, shipment, receiving, etc.)
• Identify production, transaction, partner and shipment information business systems which must be integrated
• Determine non-critical but beneficial information that you may want to capture or share to drive operational efficiency or business performance (Product expiry, invoice/PO number, etc.)
• Analyze exception points and develop required SOPs for handling these activities
• Ensure all Change management elements are addressed for hardware, software, data and documentation processes

Supply Chain

• Compile a list of all downstream supply chain trading partners to whom you sell drug product or drop-ship product including company information, license information, key contacts
• Compile a list of packaging sites and contract partners that produce saleable product, e.g. products produced, markets served, serialization/packaging technologies
• Compile a list of all upstream supply chain trading partners from whom you buy saleable drug product
• Identify the status of the drug products that you acquire, e.g. originally manufactured, purchased from direct source, purchased from indirect source, repackaged
• Determine internal capabilities and preferences for exchange of compliance data with external partners
• Survey trading partners to determine their capabilities or preferences for providing or receiving compliance data
• Analyze change management risk (frequency of partner change, B2B change, new market introduction, etc.)
• Following this basic framework will correct the major issues associated with creating a secure supply chain network. It is important to consider the physical supply chain but also the cyber-supply chain, which conveys the critical information being generated and communicated throughout the supply chain.

Supplier Quality

Of course integrity of the supply chain is moot if you cannot manage supplier quality. Supplier quality issues are in the forefront of the news whenever contaminated or adulterated drug substances and drug products make their way into the U.S. market. Many companies realize that their approach to supply chain management has been rendered obsolete by the changes brought about by globalization. The times when new shipments of goods were accepted just based on Certificate of Compliance (CoC) or Certificate of Analysis (CoA) are over and a more systematic risk management based approach is strongly recommended.

Quality Risk Management (QRM) and ICH Q9 provide general guidelines and recommendations on how to apply risk management tools and assessment procedures as part of the drug development life cycle. These guidelines emphasize the importance of integrating QRM activities within the company’s Quality Management System (QMS).

In evaluating the product development lifecycle there are many opportunities to leverage QRM to reduce overall program risk and drive supplier quality. Activities that have proven to be highly effective in driving supplier quality range from questionnaires to models, as below:

• Supplier Questionnaire: Supplier evaluation questionnaires are an effective first step to screening potential contract service providers. One common mistake some organizations make is to seek out a supplier that can support product development from early development through commercial. In reality the skill set of early service providers is often different from later stage service products when it comes to commercial manufacturing and support. Tailoring the questionnaire to this requirement and selecting a supplier that is established in the market and can provide references related to their performance with other customers is an effective way of focusing the evaluation criteria.
• Establish Clear Technical Requirements: Develop clear and comprehensive raw materials specifications along with corresponding methods of analysis to use. Include draft manufacturing procedures, sampling plan and acceptance criteria. The specifications should also address any material attributes that could affect the quality of the drug product if outside of acceptable ranges. This effort is an ongoing activity, particularly during early drug product development. Significant importance should be given to documentation control to assure that raw material provided conforms to the evolving set of specifications.
• Supplier Audits: Utilize a multidisciplinary team to conduct supplier audits to better evaluate a supplier’s capability and risk from multiple perspectives (i.e. quality, regulatory, manufacturing, etc.).
• Master Supply Agreements: Develop Master Supplier Agreements (MSAs) as the product moves to late stage development, to begin discussions regarding supply and quality issues that will be the foundation for commercial manufacturing.
• Raw Material Characterization: Evaluate the raw materials in control runs under experimental protocols to quantify the impact on product performance and process stability of different lots of raw materials with different material attributes. Utilize risk assessment tools such as cause and effects analysis or pre-hazard analysis to determine which material could have a significant impact on the drug product. The use of design of experiments (DoE) is highly encouraged when there is a need to evaluate the impact and contribution of multiple raw materials in a relatively short period of time.

We recommended communicating the findings to the suppliers to increase their awareness of the importance of the material attributes that can affect the drug product quality. This will help translate the findings and information into an effective control strategy for the different units of operations, particularly to any units that define the material attributes that affect drug product quality attributes.

• Boundary Limit Studies: Challenge the raw material suppliers to produce product at the edge of their proposed ranges. Include these “extreme” lots during the process development activities to assess the sensitivity of the drug product process to raw material variability.
• Commercial Quality and Supply Agreements: Develop a program to encourage suppliers to comply with the elements of the MSAs. Framing agreements where the suppliers are rewarded for consistent quality, cost and delivery schedule helps build a long-term relationship.
• Distribute Responsibility for Quality: Work with suppliers after they demonstrate capability and compliance. Streamline the evaluation of new lots of raw materials by using the supplier’s capability to sample and test prior to shipment. The end goal is moving to using the suppliers’ own quality control data.

Overall, it is vital to emphasize a product lifecycle approach to supplier quality because, inevitably, changes will occur in the supply chain. Significant product knowledge and optimal supplier-client relationship can make the difference between remaining as a viable provider of drug products or potentially losing market share to competitors who are more agile and effective in dealing with changes.

Summary

Ensuring quality and integrity in the global supply chain today is a complex undertaking. It involves working with evolving, disparate requirements. Establishing a framework to manage integrity and quality helps to understand and control current systems and meet the supply chain integrity requirements for the U.S. and most major global markets. In combination with measuring and monitoring suppliers against agreed-upon performance metrics, this is the best way to reduce overall risk and drive the performance of the global supply chain.

References:

1. March 2010 Guidance for Industry Standards for Securing the Drug Supply Chain - Standardized Numerical Identification for Prescription Drug Packages.http://www.fda.gov/ RegulatoryInformation/Guidances/ucm125505.htm
2. October 2011 “Guidance for Industry Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting http://www.fda.gov/downloads/Drugs/Guidances/UCM171575.pdf
3. November 2005 Quality Risk Management ICH Q9

Mr. Chatterjee, President and Chief Scientific Officer for Pharmatech Associates, has been in the bio-pharmaceutical, pharmaceutical, medical device and diagnostics industry for over 30 years. He has guided the successful approval of over a dozen products across U.S. and Europe and is a frequent speaker at industry and regulatory events.

Mr. Basso, VP of Product and Process Development for Pharmatech Associates has over 30 years of experience in engineering, automation, process development and validation of discrete and continuous pharmaceutical processes and medical device operations. He has held engineering management and validation leadership positions in start-up and Fortune 500 companies.