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Security of Bioprocess Consumables Supply
Chapter 53
Security of Bioprocess Consumables Supply Jeffrey R. Carter*, Daniel Nelson*, David G. Westman† *
GE Healthcare Life Sciences, Marlborough, MA, United States, †GE Healthcare Life Sciences, Uppsala, Sweden
53.1 INTRODUCTION Biopharmaceutical manufacturers rely on consumable materials to manufacture their drug products. In cases such as cell culture media or chromatography resins, the consumables are intrinsic to the manufacturing process. In cases such as single-use manufacturing equipment, they represent alternatives to traditional manufacturing strategies, (e.g., alternatives representing advantages in speed to market or manufacturing flexibility). Along with the benefits of these consumables are the attendant risks that derive from reliance upon them. One of these is the risk of an interruption to the supply of these consumables, which in turn jeopardizes the supply of drugs to the marketplace. Consumables supply disruptions may occur due to events that are within the control of the participants in the supply chain (e.g., Ref. [1]), or to force majeure events. Recent natural disasters, such as the volcanic eruption in Iceland in 2010 and the earthquake and tsunami in Japan in 2011, brings the latter point into relief. Such realization has fueled concern over supply chain risk management by suppliers, drug manufacturers, and regulators alike. In marketing drugs to the public, drug manufacturers make a commitment to actively manage their supply chain to minimize risk to the uninterrupted supply of safe and efficacious drugs. This is realized through the active management of a Security of Supply (SoS) program. The concept of SoS may be viewed in the context of the more common term, “supply chain management” (SCM), which is “the systemic, strategic coordination of the traditional business functions and the tactics across these business functions within a particular company and across businesses within the supply chain, for the purposes of improving the long-term performance of the individual companies and the supply chain as a whole” [2]. SCM elements include, but are not limited to, raw material sourcing, manufacturing, logistics, business continuity, information systems, and risk management within each element. Whereas SCM relates to the general “performance” of the supply chain, SoS is a more focused concept describing a state in which the relevant SCM elements have been harmonized to minimize risk of supply chain disruption (Fig. 53.1). Managing SoS is resource-intensive. A survey [3] found that while elements of SoS described in this chapter are incorporated into many companies’ procedures, they are sometimes not fully followed. Limitations in time, resource, or budget are often cited as causes, where cross-functional representation in the due diligence process is absent. Managing SoS of several consumables product categories is also complex. In some cases, the products are still evolving in terms of materials and design. The supply chains of these products may be intricate and include suppliers whose focus is not biomanufacturing. Commonly, even large drug manufacturers and their suppliers are minor consumers for some raw materials. As examples, single-use film resins comprise less than 1% of the plastics market, serum is a byproduct of the meat and dairy industry, and cell culture nutrients such as amino acids are used in the sports drink industry. This translates into difficulties in negotiating appropriate quality standards and requirements on the raw material suppliers, especially when there are multiple tiers within the supply chain (see Fig. 53.2). With the complex and diverse nature of the consumables’ designs, materials, supply chains, and application requirements, it is not surprising that SoS strategies should be equally diverse. One size does not fit all. This chapter discusses four main elements to SoS: material selection, supplier selection, risk management, and communication. It explores considerations for three consumable segments (single-use manufacturing equipment, cell culture media, chromatography resins) illustrating both similarities and differences in SoS challenges and strategies.
Biopharmaceutical Processing. https://doi.org/10.1016/B978-0-08-100623-8.00053-0 © 2018 Elsevier Ltd. All rights reserved.
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QbD: material characterization
Sourcing and quality control
Security of supply
Communication
Risk management
FIG. 53.1 Diagram depicting the interplay among several business practices required to effect security of supply. “Sub-tier supplier”
“Supplier”
Plastic resin
Film
Single-use supplier
Stabilizing agent
Connections
Cell culture media supplier
Sterilization
Chromatography supplier
“Drug manufacturer”
Drug manufacturer
FIG. 53.2 Diagram of supply chain complexity. This abbreviated picture shows that the drug manufacturer will interface with several suppliers. As shown for the single use supplier, the supply chains branches at each tier in the supply chain. The same will be true of the other suppliers’ supply chains.
53.2 MATERIAL AND PRODUCT SELECTION The first, and arguably the most critical, step to SoS is to identify critical quality attributes (CQAs) for raw materials that will be used to manufacture the final consumable product. Each raw material may vary in chemical, physical, mechanical, or rheological properties and may change during processing (e.g. synthesis, extrusion, and molding) or sterilization (e.g., irradiation). Therefore, it is paramount that each product development cycle begins by establishing clear material specifications, and closes with verification studies to confirm material appropriateness. Material considerations for three consumable product groups are in Table 53.1.
53.3 SUPPLIER SELECTION This section addresses the rigor that must be applied to selecting the supplier of the product or materials. This selection process can be considered the same for both a drug manufacturer selecting a supplier, or a supplier selecting a raw material supplier (sub-tier supplier). Supplier selection is complementary to material selection, as the supplier is responsible for managing the lifecycle of the material or product. This encompasses rigor in such areas as product design, manufacturing controls, procurement, and documentation. During the selection process, suppliers should be evaluated with respect to general business practices and financial soundness. Assessment of business practice-related items such as those in Table 53.2 will help to create a supplier profile that can be examined for risk attendant in the choice of that supplier. The ability to consistently provide products that meet applicable regulatory and drug manufacturer requirements is sustained through a supplier’s quality management system (QMS). Most suppliers are compliant with the ISO 9001 Standard
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TABLE 53.1 Critical Quality Attributes to be Considered for Each of the Three Consumable Product Segments Material Category
Description
Chromatography
Single-Use
Cell Culture Medium
Manufacturability
Processing or conversion into finished products
Minimal lot-to-lot variations
Extrusion, machinability, weldability
Particle size distribution, homogeneity, solubility, filterability
Application
Robust performance within drug manufacturer operating parameters
Efficient purification of target molecule
E&L, temperature (freezing, heat inactivation, etc)
Support of anchoragedependent cells, suspension cells, virus or protein production, cloning support
Criticality/Risk
Sole/single source, manufacturing difficulty, IP limiting
Often single sourced, ligand leakage
Sterile device, components in product contact, essential to function or safety, use in validated process or product, single or sole source
Proprietary formula, second source availability, impurity profile, adventitious agents
Chemical
Chemicals that may alter the composition of fluids exposed to the test article
Alkaline stability for cleaning in place
Extractables, pH shift, TOC, oxidizable substances
Animal or non-animal sourced constituents, chemical impurities, compatibility with downstream process
Physical
Physical properties of the product
Porosity, particle size distribution
Tensile strength, elongation, burst, tear, puncture, durometer, vapor transmission
Flowability, particle size distribution, filterability
Functional
Specific functional attributes of the product, which indicate windows of operation
Capacity, alkaline stability, porosity, selectivity
Shelf life, particulate generation, flow rate, pressure rating, brittleness
Cell growth and productivity, pH balance and buffering capacity
Biological
Biologically active compounds that may be released from the product
Endotoxin, microorganisms
Biological reactivity in vivo, in vitro, endotoxin, hemolysis
Endotoxin, adventitious agent (virus, prion, mycoplasma) risk
Regulatory
Quality attributes that impact fitness for use versus regulatory requirements
Ligand leakage, animal origin
Animal origin, BSETSE (bovine spongiform encephalopathy, transmissible spongiform encephalopathy), biocompatibility
Animal derived materials, adventitious agent risk, chemically defined
Process Compatibility
Ability of the test article to maintain its performance while exposed to certain physical or chemical conditions
Alkaline compatibility, pressure flow properties for optimal productivity
Chemical and temperature compatibility
Growth promotion during fed-batch and perfusion processes; downstream compatibility
on Quality Management Systems. More stringent standards, such as ISO 13485 may be adopted. Rigorously operated companies have comprehensive QMSs that govern all functions that contribute to product quality. Although it is not the intent of this chapter to detail the specifics of a QMS, the following discussion (Table 53.3) highlights product-quality mechanisms that should be governed by QMS. Product design. Products should be designed to meet documented drug manufacturer requirements and to ensure that the resultant product has appropriate performance attributes. The technical teams must understand the fundamentals of the materials being using and actively contribute to the technical aspects of lifecycle management (e.g., material changes, complaints, drug manufacturer technical discussions). Moreover, products should be designed for manufacturability, as difficulty in manufacturing is a risk factor for quality or reliability issues. Common practices to accomplish this include design
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TABLE 53.2 Business Criteria to Evaluate Suppliers Item
Discussion
Organization Strategy
Financial stability, leadership engagement, technology innovation, responsiveness, knowledge of role in biopharmaceutical industry
Business Continuity Management
Established and committed to risk mitigation activities (e.g. business continuity plans such as ISO 22301, inventory levels, and second source programs)
Business Focus
Assure that suppliers and sub-tier suppliers understand specific quality and regulatory needs and routinely are committed to meeting those standards
Manufacturing Capacity and Capabilities
Quality management systems to assure consistent and improved quality over time. Capacity planning aligned with market trends
Change Management Program
Ensure that changes are rigorously qualified and that notification time is sufficient for all affected parties to qualify the changed part
TABLE 53.3 Quality Management System considerations for consumable segments Points to Consider
Discussion
Incoming Inspection
Single-use: film material verification (e.g., FTIR), component specifications Cell Culture: material origin, authenticity, and purity Chromatography: material origin and verification
Manufacturing Space
Single-use: clean room design qualification and maintenance, particulate reduction, operator training Cell Culture: animal component free, humidity Chromatography: bioburden control (microorganism), validated manufacturing methods to minimize lot to lot variation
In-Process Controls
Single-use: weld settings, integrity assurance, design and defect checks Cell Culture: particle size distribution, heat generation, homogeneity Chromatography: porosity, particle size distribution
Product Release Tests
Single-use: sterilization qualification and verification, destructive tests (e.g. burst test on lot samples), endotoxin testing Cell Culture: growth promotion, contamination Chromatography: binding capacity, pressure flow properties, ligand density, microorganism control
and process failure mode and effect analysis (DFMEA, PFMEA). Concurrent with product design are the establishment of analysis methods that will be used in incoming inspection, in-process testing, and product release. Incoming inspection. This step represents the first opportunity of the supplier to detect a nonconforming material or part. As such, the inspection strategy should be designed to detect nonauthentic materials or parts that do not meet documented specifications. Numerous technological, analytical, data collection, and statistical tools exist to aid in this. Manufacturing. Robust manufacturing requires standard operating procedures that are followed by well-trained operators. Additionally, equipment should undergo routine preventive maintenance, and measuring devices should be calibrated. In-process monitoring and testing should be in place as needed to assure process control, quantify process variation, and assure conformance to specifications. To this point, well-designed automated processes, such as cell culture media raw material milling, will generally have greater control over variability than manual operations. The manufacturing environment should be commensurate with the need to maintain product cleanliness. This may range from clean rooms for singleuse components and assemblies, to well-maintained chemical process plants for chromatographic ligands or cell culture nutrients. Product release. Release testing should be performed by qualified operators and should be designed to confirm critical quality attributes. Sampling and test plans, and their rationale, should be thoroughly documented. Some release tests are destructive and require randomized selection within lots, while others can be performed on each item. An example of a new, more challenging control is single-use equipment integrity testing, which is increasingly receiving more attention.
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Corrective and Preventive Action. Suppliers should have an active CAPA program, as this is a key mechanism for managing quality issues and identifying potential issues for remediation.
53.4 RISK MANAGEMENT Risk management has been defined as “the implementation of strategies to manage both everyday and exceptional risks along the supply chain based on continuous risk assessment with the objective of reducing vulnerability and ensuring continuity” [4]. The previous sections highlight material- and supplier-related items that, in effect, may be viewed as inputs to a drug manufacturer’s risk assessment. The output of this may be used to determine which risk mitigation options, if any, should be implemented. These options are delineated in the following section. The many options available highlights that a one-size-fits-all approach will generally not be efficient or effective. Risk mitigation tactics should be scrutinized to ensure resource allocation is commensurate with the level of risk.
53.4.1 Supplier Auditing One of the most effective and commonly used mechanisms to manage a supply chain is to audit a supplier’s quality management system. Section 53.3 delineates some major elements of a QMS that relate to SoS. In this context, the supplier audit is intended to confirm and document that the supplier’s QMS contains these elements and that the supplier is performing effectively against them. The premise is that performance issues may presage a high-impact supply incident. Various management methodologies can be used to strategically allocate audit program resources to greatest effect. For example, an audit schedule can be developed with inputs such as criticality of materials, criticality of supplier, supplier audit and performance history, susceptibility of disruption, and the probability of disruption. Supplier audit meetings can lead to subsequent meetings related to corrective action or to collaborative discussions in which risk mitigation becomes a shared issue. Building collaborative relationships will ensure a common understanding of user requirements and of supplier capabilities. It will also support the transfer of the drug manufacturer’s requirements from suppliers to sub-tier suppliers. Ultimately, these discussions should lead to establishment of legal agreements on supply conditions and audit frequencies. Strict change control sections should be included in supply agreements.
53.4.2 Multi-Sourcing Unexpected disruption in a supply chain often necessitates emergency measures: (1) to identify a new material and supplier, (2) to qualify the material and supplier, and finally, (3) to implement use of the new material and supplier (Table 53.4). From the drug manufacturer’s perspective, this is true whether they are multi-sourcing suppliers or their supplier is multi-sourcing materials. Each of these steps takes time, which is at a premium in such an emergency situation. Therefore, to mitigate risk, it may be appropriate to perform one or more of these steps proactively. The first two are intermediate steps to the ultimate measure of dual-sourcing or multi-sourcing. Because each risk mitigation step consumes resources, the decision to activate any risk mitigation step involves balancing resource spend with risk reduction. One should note that any company within the supply chain can use such risk mitigation steps. The first of the three steps is second-source identification. In this step, one or more candidate materials, which are potentially interchangeable with the material under discussion, are identified. These may be acquired for a technical assessment and to determine if a candidate material is likely to be a successful replacement. The second step is material qualification, the main goal of which is to assure that the critical quality attributes are met when the alternative raw material is used. The third step is the actual multi-sourcing, which implies that the second supplier and replacement material are fully qualified and the replacement material is being implemented along with the original material. Thus, the two materials are considered to be interchangeable. Note that these three steps do not have predefined boundaries; one can choose to take specific measures as one sees fit. For example, although “implementation plan established” is placed under “part implementation” in Table 53.4, one may choose to create that plan without an immediate intent to implement the part. Multi-sourcing can be effective if three conditions are met. (1) The material or component from a second source is fully interchangeable, with respect to all quality and performance attributes, with the original part. The proprietary nature of some raw material formulations complicates this effort. Such is the case with single-use films. Moreover, even though a material meets established specifications, it may not perform identically to the material it is intended to replace. Chromatography resins are an example, as they comprise complex biological materials with unique binding properties and purification profiles. Additionally, cell culture medium may have contaminants at micro levels, which adversely affect cell culture performance.
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TABLE 53.4 Risk Mitigation Steps Taken to Implement a Redundant or Alternate Raw Material or Product Step
Actions
Identification
Material specification Technical Assessment of material—proof of concept
Qualification
Sub-tier supplier approval Material qualification: critical quality attributes are met Risk assessment of the change to the new material
Implementation
Implementation plan established Supply agreement Quality agreement Qualification to verify process and product compatibility Operator training Procedural items (e.g., incoming inspection) Protocol revisions to reflect use of the new material Change notification executed (for suppliers) Regulatory notifications executed as needed (for manufacturers)
(2) The supply chain from two sub-tiered suppliers must be independent. For example, if two sub-tier suppliers share the same raw material suppliers, then the redundancy of the supply chain is directly compromised. (3) The supply chains from two redundant suppliers (e.g., finished products), must be independent. If the two suppliers share the same material sub-tier suppliers, then the redundancy of the supply chain is partially compromised. For example, multiple cell culture media suppliers were affected by a global shortage in folic acid in 2014 [5]. Full implementation of a second, redundant supplier, is a relatively aggressive risk mitigation strategy that should be used only after the costs and complexity to qualify, validate, and manage multiple sources are fully understood [6]. Table 53.5 provides common issues related to three product categories.
TABLE 53.5 Considerations for Multi-Sourcing Materials/Suppliers Consumable Category
Discussion
Single-use
• Chemical differences in functionally equivalent parts may require substantial qualification. • Forms of functionally equivalent parts may require training in the use of the redundant part. • Different plastics require fully redundant qualification work (processing conditions, shelf life, irradiation compatibility, extractables characterization). • Standard vs Custom: suppliers often have lists of standard materials, often chosen due to sub-tier detailed characterization, business stability, or purchasing power. Custom material runs the risk of lacking one of the above features. • If a material or part is IP protected, it can be challenging to negotiate transference during a time of crisis.
Cell culture media
• Proprietary or custom media platform formulations are often controlled by the supplier who won’t release exact details, requiring the drug manufacturer to start from the beginning in development. • Raw material chemical impurity profiles from different suppliers may also adversely effect product outcome. • Media format: suppliers produce media in different formats (e.g., powder or complex granulation) which are intrinsic to the manufacturing process.
Chromatography resin
• Complex raw material such as protein ligands and base matrix material need thorough characterization for confirmed interchangeability. • Regulatory hurdles to prove multi-sourced chromatography media have the same purification profile with unaltered effect on safety and efficacy of purified product. • Potential for increased variability, e.g., lot-to-lot variation on the end product. • Process complexity of validation/verification for two chromatography media sourced from the same supplier (two manufacturing facilities). • Cost/complexity of validation/verification concerns for sourcing two chromatography media from the different suppliers.
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Common drawbacks to multi-sourcing are as follows: ●
●
●
●
Sourcing a redundant supplier/material implies that they must be managed with the same attention as the primary source for critical products, and this requires resources. Sourcing a redundant supplier/material implies that they should be qualified for use. This implies the need for a risk assessment on the use of the redundant part, and the possible need to evaluate such resource-intensive issues as extractables and leachables testing, and drug substance/product stability. Often, this issue leads to multi-sourcing being implemented only when other risk mitigation strategies are deemed ineffective. Sourcing a redundant material/supplier may result in the need to set up two different processing steps to use the two different raw materials. For example, two different aseptic connectors, although viewed as functionally interchangeable, will require two dedicated instruction sets for use. It is difficult to engage in fruitful, collaborative relationships with suppliers when the sourcing volume is low. Difficulties can ensue with respect to quality or supply chain performance, such as with change notifications and predictability of delivery times.
53.4.3 Manufacturing Facility Risk Several elements of QMS work in tandem to keep manufacturing processes consistently delivering products to predetermined quality specifications. However, even the most well-run supplier manufacturing site is subject to events such as contamination, equipment failure, or force majeure events, which can lead to manufacturing interruption or shut-down. To manage this risk requires firstly an understanding of the manufacturing risk profile, followed by prioritization of high risk elements, and lastly, action plans that incorporate one or more risk-mitigation strategies. These steps are critical. Underestimating or ignoring the likelihood of disruptions exposes the supplier’s manufacturing facility to undue vulnerability, whereas overestimating risk can lead to undue time and resources spent on risk mitigation implementation. This chapter will focus on the considerations a drug manufacturer should make when evaluating an individual supplier’s manufacturing risk management. Three leading concepts for manufacturing risk management will be discussed: (1) multi-site considerations, (2) business continuity planning, and (3) safety stock.
Multi-Site Considerations Multi-site manufacturing is a strategy taken by a supplier to build redundant manufacturing capability. Although this is often driven by business needs such as capacity expansion or cost reduction (e.g., transportation, labor, and tariffs), it has the added effect of insulating both the supplier and drug manufacturers against disruptions in one of the supplier’s manufacturing sites. In this sense, multi-site manufacturing is analogous to multi-sourcing, but with certain intrinsic differences, benefits and liabilities (Table 53.6). The contrast between multi-site implementation by the supplier, and
TABLE 53.6 Considerations for Single Supplier Multi-Site and/or Multi-Supplier Approach Issue
Multi-Site
Multi-Suppliers
Supplier identity
Only one supplier to manage; two sites to be monitored
Two or more suppliers to manage and monitor.
Capacity
Transfer to the second site could lead to capacity limitations and delays, e.g., overseas shipping
Transfer of capacity to the second supplier could lead to capacity limitations.
Raw materials
Commonly the same raw materials are used, but this should be confirmed. If true, then redundancy is achieved
Many raw materials will differ, but this should be confirmed to document supply chain redundancy.
Product and Processes
Ideal state is that the processes should be identical, but critical to quality attributes should be evaluated to confirm identity
Considerable validation and regulatory requirements to treating the suppliers and “interchangeable.”
Business continuity
Based on minimal or no risk for the full manufacturing site to be incapacitated
A second supplier will provide “true” redundancy. This is based on the presumption the facilities are not affected by the same disruption or event.
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multi-sourcing implementation by the manufacturer, highlights that a given risk element may be more effectively managed by either the manufacturer or the supplier. This in turn reinforces the benefits of close communication between the two parties. A multi-site manufacturing strategy is often an integral part of the supplier’s business continuity plan where during a disruption, the second manufacturing site can be leveraged to supply the market demand until the primary facility is fully functional. Drug manufacturers may consider the risk to be reduced by knowing that their supplier has this capability. However, to fully benefit from this strategy it is prerequisite that (a) they have qualified or can qualify the second site, (b) the second site has complete, redundant manufacturing qualifications and capabilities, and (c) there is flexible capacity at the second manufacturing site to meet the demand. Unsurprisingly, due to process complexity or equipment costs, even though a secondary site is operational it may not have full capabilities to manufacture from start to finish. Therefore, when evaluating a supplier’s multi-site approach, it is important to enquire about the full breadth of capabilities to ensure no bottlenecks exist segregated the manufacturing chain. Most manufacturing disruptions or events are not catastrophic in nature and occur in isolated portions of the manufacturing facility. Considering this, a supplier may establish redundant manufacturing capabilities on the same site and take special precautions to keep the two manufacturing lines within from each other. The major benefit to this strategy as compared to having two separate manufacturing sites are that the same infrastructure is in place regarding water quality, air supply, organic solvent supply, quality management system, and trained and experienced operators. With these redundancies, the validation effort associated with manufacturing transfer within a site may be lesser than that associated with transfer between sites. The multi-site and multi-sourcing strategies may be contrasted as follows. In short, the consumables manufactured by multiple sites are intended by the supplier to be identical, whereas consumables sourced from two different suppliers are not identical. At best, they may be qualified by the drug manufacturer as being “interchangeable.” Suppliers undertake rigorous assessments to ensure likelihood and success in achieving consumable identity during a second site institution. From a drug manufacturer perspective, the level of supplier qualification and the level of validation and qualification efforts required in a multi-site sourcing strategy are often lower than that which is required in a multi-supplier sourcing strategy. However, a rigorous assessment of consumable criticality should be used to determine the effort required in second-site qualification. At times, one may need simply to process a supplier change notification through a risk assessment but without need for experimental work. In situations of high consumable process criticality, the qualification work could be extensive, and close to the effort required to source from a second supplier. Note that multi-site sourcing is not only a consideration for manufacturing, but also with service providers. Two common examples are providers of analytical chemistry and microbiology testing services, which can be a part of product release testing, and sterilization service providers, which are effectively a part of the manufacturing process for sterile products. While this chapter does not discuss these services in detail, they play an important role in the supply chain and merit attention when evaluating suppliers.
Business Continuity Planning The loss of a manufacturing facility can be devastating to a business and can have severe effects on its customers. Business continuity planning (BCP) is an ongoing and structured mechanism that “identifies an organization's exposure to internal and external threats and synthesizes hard and soft assets to provide effective prevention and recovery for the organization, while maintaining competitive advantage and value system integrity” [7]. Especially if they produce single- or sole-sourced materials, organizations should have a structured business continuity plan to ensure risks for supply and manufacturing interruptions are managed. BCPs consists of several complementary elements including communication, disaster recovery, business recovery, business resumption, and contingency planning. Organizational Business Continuity Management Systems (BCMS) practices can be developed at a corporate level holistically, but require tactical execution to be implemented locally based on the product and market needs. During an incident, a BCP is often executed by dedicated emergency response teams and crisis management teams to respond, recover, and ensure continuity. An ongoing part of BCP is to identify and evaluate risks to critical manufacturing assets and the anticipated impact to drug manufacturer and supplier. These plans seek to adopt preventive measures and to minimize damage if a disaster does occur. Additionally, plans are maintained, updated and tested as business processes change. Established industry standards serve as guidelines for BCPs, and often call for audits from certified external organizations. Historically, the framework is based upon the British Standard BS25999-1. In recent years, a more robust ISO 22301 certificate for business continuity management has been established.
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Safety stock The BCP often coincides with a safety-stock program. Safety stock programs mitigate risk by maintaining reserve inventory based on demand forecast. Stocking volumes are established on a case-by-case basis, and with inputs from supplier and drug manufacturer, considering: – – – –
Product impact and criticality to the drug manufacturer application or process Anticipated time to recover or replace the source Anticipated time for the drug manufacturer to qualify new materials or manufacturing site Forecasts of material utilization
Safety stock may be warehoused by the supplier or the drug manufacturer. In either case, safety stock programs can have a large financial impact, and they are naturally only considered for critical or high-risk materials and consumables. This financial impact, whether on supplier or drug manufacturer, may be warranted as a mechanism to assure uninterrupted supply of drug product to the patient population. In unusual circumstances, when supplier and drug manufacturer do not align on risk tolerance, one option is a supply agreement for a private safety stock service. When safety stocks are drawn upon, a controlled order intake and prioritization process governs which drug manufacturers will receive products and how much they will receive. These prioritization plans favor the immediate use in manufacturing processes for approved pharmaceuticals to prevent a lapse in patient treatment. Depending on the severity of the disaster, less critical operations such as research labs may experience shortages.
53.4.4 Supplier Agreements Drug manufacturers can minimize risk for quality- or supply-based interruptions through formal quality and supply agreements with suppliers. The quality agreements should stipulate items such as implemented quality management system, change controls, and information transfer between the organizations. For critical raw materials, commercial contracts should be executed. This is especially important in cases where the raw material is sole-sourced and there are no suitable alternatives. The commercial agreements can include safety stock agreements, last-time-buy options, stable forecasting processes, and process or technology transfer in the case of a disruption. Regardless of approach, the risk mitigation effectiveness will be enhanced with collaboration and shared vision between manufacturer and supplier.
53.5 COMMUNICATION Leaders in the biopharmaceutical industry have come to understand that risk mitigation of their supply chains, as described above, is best achieved when communication between companies is strong. Primarily, communication of critical information tends to flow from supplier to customer, a natural consequence of the drug manufacturer’s need for supplier information to feed risk assessments and to practice ongoing monitoring of the supply chain. This open flow of information to drug manufacturers has come to be termed “transparency” (e.g., Ref. [8]). Transparent communication has commonly involved the transfer of heretofore confidential information such as identity of suppliers, identity of raw material part numbers and specifications, and ranges of manufacturing process steps. Information such as this has come to be seen as important input into SoS (as well as initiatives to manage process variation). The general call for this kind of information has led to increased focus on supply chain mapping, which lends visibility, for example, to the geographical distribution of suppliers. Such visibility then allows one to monitor for disturbances worldwide and to alert one to the possibility that a supplier might be susceptible to a disruption. Presently, the biopharmaceutical industry is still developing best practices and the trust required to make this level of transparency the norm in the industry. Historically, drug manufacturers have had reservations about sharing process or forecast information, which is sometimes exacerbated by imperfect forecasting abilities or concerns about how suppliers may leverage the information. This hesitation to share information encourages a transactional relationship of order placement and order fulfillment with suppliers. Relying on this order fulfilment paradigm, suppliers’ forecasting, capacity planning, and future expansion plans hinge on their ability to anticipate demand with inadequate data. This in turn puts the drug manufacturer at risk, as suppliers are reticent to build capacity in the absence of demand for it. Recognizing this kind of dynamic, more advanced drug manufacturers are now practicing transparency, sharing proprietary information regarding business plans and manufacturing strategies with their key suppliers. The premise is that suppliers will be more willing to share information if they understand the need, and they will be more able to offer well-targeted support if they understand the problem. This is the essence of the benefit to engaging in a partnership with key suppliers.
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53.6 CONCLUSION Ushering modern SoS practices into biomanufacturing creates the opportunity for drug manufacturers and suppliers to work closely together long before and after materials and sub-tier suppliers have been selected, and manufacturing protocols and conditions have been defined. Their joint objectives should be to collaborate and communicate to deliver safe and efficacious therapies to the market. This partnership model enables true security of supply from raw material to drug manufacturing, allowing the drug manufacturer and regulatory bodies to develop trust and consider their primary suppliers both capable of and responsible for monitoring and managing the supply chain and risks. In conclusion, the diversity and complexity of supply chains and the risk profiles associated with the several consumable segments require drug manufacturers and suppliers to carefully plan and execute the various selection, sourcing, manufacturing, and risk mitigation strategies discussed in this chapter.
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Security of Bioprocess Consumables Supply Jeffrey R. Carter*, Daniel Nelson*, David G. Westman† *
GE Healthcare Life Sciences, Marlborough, MA, United States, †GE Healthcare Life Sciences, Uppsala, Sweden
53.1 INTRODUCTION Biopharmaceutical manufacturers rely on consumable materials to manufacture their drug products. In cases such as cell culture media or chromatography resins, the consumables are intrinsic to the manufacturing process. In cases such as single-use manufacturing equipment, they represent alternatives to traditional manufacturing strategies, (e.g., alternatives representing advantages in speed to market or manufacturing flexibility). Along with the benefits of these consumables are the attendant risks that derive from reliance upon them. One of these is the risk of an interruption to the supply of these consumables, which in turn jeopardizes the supply of drugs to the marketplace. Consumables supply disruptions may occur due to events that are within the control of the participants in the supply chain (e.g., Ref. [1]), or to force majeure events. Recent natural disasters, such as the volcanic eruption in Iceland in 2010 and the earthquake and tsunami in Japan in 2011, brings the latter point into relief. Such realization has fueled concern over supply chain risk management by suppliers, drug manufacturers, and regulators alike. In marketing drugs to the public, drug manufacturers make a commitment to actively manage their supply chain to minimize risk to the uninterrupted supply of safe and efficacious drugs. This is realized through the active management of a Security of Supply (SoS) program. The concept of SoS may be viewed in the context of the more common term, “supply chain management” (SCM), which is “the systemic, strategic coordination of the traditional business functions and the tactics across these business functions within a particular company and across businesses within the supply chain, for the purposes of improving the long-term performance of the individual companies and the supply chain as a whole” [2]. SCM elements include, but are not limited to, raw material sourcing, manufacturing, logistics, business continuity, information systems, and risk management within each element. Whereas SCM relates to the general “performance” of the supply chain, SoS is a more focused concept describing a state in which the relevant SCM elements have been harmonized to minimize risk of supply chain disruption (Fig. 53.1). Managing SoS is resource-intensive. A survey [3] found that while elements of SoS described in this chapter are incorporated into many companies’ procedures, they are sometimes not fully followed. Limitations in time, resource, or budget are often cited as causes, where cross-functional representation in the due diligence process is absent. Managing SoS of several consumables product categories is also complex. In some cases, the products are still evolving in terms of materials and design. The supply chains of these products may be intricate and include suppliers whose focus is not biomanufacturing. Commonly, even large drug manufacturers and their suppliers are minor consumers for some raw materials. As examples, single-use film resins comprise less than 1% of the plastics market, serum is a byproduct of the meat and dairy industry, and cell culture nutrients such as amino acids are used in the sports drink industry. This translates into difficulties in negotiating appropriate quality standards and requirements on the raw material suppliers, especially when there are multiple tiers within the supply chain (see Fig. 53.2). With the complex and diverse nature of the consumables’ designs, materials, supply chains, and application requirements, it is not surprising that SoS strategies should be equally diverse. One size does not fit all. This chapter discusses four main elements to SoS: material selection, supplier selection, risk management, and communication. It explores considerations for three consumable segments (single-use manufacturing equipment, cell culture media, chromatography resins) illustrating both similarities and differences in SoS challenges and strategies.
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QbD: material characterization
Sourcing and quality control
Security of supply
Communication
Risk management
FIG. 53.1 Diagram depicting the interplay among several business practices required to effect security of supply. “Sub-tier supplier”
“Supplier”
Plastic resin
Film
Single-use supplier
Stabilizing agent
Connections
Cell culture media supplier
Sterilization
Chromatography supplier
“Drug manufacturer”
Drug manufacturer
FIG. 53.2 Diagram of supply chain complexity. This abbreviated picture shows that the drug manufacturer will interface with several suppliers. As shown for the single use supplier, the supply chains branches at each tier in the supply chain. The same will be true of the other suppliers’ supply chains.
53.2 MATERIAL AND PRODUCT SELECTION The first, and arguably the most critical, step to SoS is to identify critical quality attributes (CQAs) for raw materials that will be used to manufacture the final consumable product. Each raw material may vary in chemical, physical, mechanical, or rheological properties and may change during processing (e.g. synthesis, extrusion, and molding) or sterilization (e.g., irradiation). Therefore, it is paramount that each product development cycle begins by establishing clear material specifications, and closes with verification studies to confirm material appropriateness. Material considerations for three consumable product groups are in Table 53.1.
53.3 SUPPLIER SELECTION This section addresses the rigor that must be applied to selecting the supplier of the product or materials. This selection process can be considered the same for both a drug manufacturer selecting a supplier, or a supplier selecting a raw material supplier (sub-tier supplier). Supplier selection is complementary to material selection, as the supplier is responsible for managing the lifecycle of the material or product. This encompasses rigor in such areas as product design, manufacturing controls, procurement, and documentation. During the selection process, suppliers should be evaluated with respect to general business practices and financial soundness. Assessment of business practice-related items such as those in Table 53.2 will help to create a supplier profile that can be examined for risk attendant in the choice of that supplier. The ability to consistently provide products that meet applicable regulatory and drug manufacturer requirements is sustained through a supplier’s quality management system (QMS). Most suppliers are compliant with the ISO 9001 Standard
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TABLE 53.1 Critical Quality Attributes to be Considered for Each of the Three Consumable Product Segments Material Category
Description
Chromatography
Single-Use
Cell Culture Medium
Manufacturability
Processing or conversion into finished products
Minimal lot-to-lot variations
Extrusion, machinability, weldability
Particle size distribution, homogeneity, solubility, filterability
Application
Robust performance within drug manufacturer operating parameters
Efficient purification of target molecule
E&L, temperature (freezing, heat inactivation, etc)
Support of anchoragedependent cells, suspension cells, virus or protein production, cloning support
Criticality/Risk
Sole/single source, manufacturing difficulty, IP limiting
Often single sourced, ligand leakage
Sterile device, components in product contact, essential to function or safety, use in validated process or product, single or sole source
Proprietary formula, second source availability, impurity profile, adventitious agents
Chemical
Chemicals that may alter the composition of fluids exposed to the test article
Alkaline stability for cleaning in place
Extractables, pH shift, TOC, oxidizable substances
Animal or non-animal sourced constituents, chemical impurities, compatibility with downstream process
Physical
Physical properties of the product
Porosity, particle size distribution
Tensile strength, elongation, burst, tear, puncture, durometer, vapor transmission
Flowability, particle size distribution, filterability
Functional
Specific functional attributes of the product, which indicate windows of operation
Capacity, alkaline stability, porosity, selectivity
Shelf life, particulate generation, flow rate, pressure rating, brittleness
Cell growth and productivity, pH balance and buffering capacity
Biological
Biologically active compounds that may be released from the product
Endotoxin, microorganisms
Biological reactivity in vivo, in vitro, endotoxin, hemolysis
Endotoxin, adventitious agent (virus, prion, mycoplasma) risk
Regulatory
Quality attributes that impact fitness for use versus regulatory requirements
Ligand leakage, animal origin
Animal origin, BSETSE (bovine spongiform encephalopathy, transmissible spongiform encephalopathy), biocompatibility
Animal derived materials, adventitious agent risk, chemically defined
Process Compatibility
Ability of the test article to maintain its performance while exposed to certain physical or chemical conditions
Alkaline compatibility, pressure flow properties for optimal productivity
Chemical and temperature compatibility
Growth promotion during fed-batch and perfusion processes; downstream compatibility
on Quality Management Systems. More stringent standards, such as ISO 13485 may be adopted. Rigorously operated companies have comprehensive QMSs that govern all functions that contribute to product quality. Although it is not the intent of this chapter to detail the specifics of a QMS, the following discussion (Table 53.3) highlights product-quality mechanisms that should be governed by QMS. Product design. Products should be designed to meet documented drug manufacturer requirements and to ensure that the resultant product has appropriate performance attributes. The technical teams must understand the fundamentals of the materials being using and actively contribute to the technical aspects of lifecycle management (e.g., material changes, complaints, drug manufacturer technical discussions). Moreover, products should be designed for manufacturability, as difficulty in manufacturing is a risk factor for quality or reliability issues. Common practices to accomplish this include design
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TABLE 53.2 Business Criteria to Evaluate Suppliers Item
Discussion
Organization Strategy
Financial stability, leadership engagement, technology innovation, responsiveness, knowledge of role in biopharmaceutical industry
Business Continuity Management
Established and committed to risk mitigation activities (e.g. business continuity plans such as ISO 22301, inventory levels, and second source programs)
Business Focus
Assure that suppliers and sub-tier suppliers understand specific quality and regulatory needs and routinely are committed to meeting those standards
Manufacturing Capacity and Capabilities
Quality management systems to assure consistent and improved quality over time. Capacity planning aligned with market trends
Change Management Program
Ensure that changes are rigorously qualified and that notification time is sufficient for all affected parties to qualify the changed part
TABLE 53.3 Quality Management System considerations for consumable segments Points to Consider
Discussion
Incoming Inspection
Single-use: film material verification (e.g., FTIR), component specifications Cell Culture: material origin, authenticity, and purity Chromatography: material origin and verification
Manufacturing Space
Single-use: clean room design qualification and maintenance, particulate reduction, operator training Cell Culture: animal component free, humidity Chromatography: bioburden control (microorganism), validated manufacturing methods to minimize lot to lot variation
In-Process Controls
Single-use: weld settings, integrity assurance, design and defect checks Cell Culture: particle size distribution, heat generation, homogeneity Chromatography: porosity, particle size distribution
Product Release Tests
Single-use: sterilization qualification and verification, destructive tests (e.g. burst test on lot samples), endotoxin testing Cell Culture: growth promotion, contamination Chromatography: binding capacity, pressure flow properties, ligand density, microorganism control
and process failure mode and effect analysis (DFMEA, PFMEA). Concurrent with product design are the establishment of analysis methods that will be used in incoming inspection, in-process testing, and product release. Incoming inspection. This step represents the first opportunity of the supplier to detect a nonconforming material or part. As such, the inspection strategy should be designed to detect nonauthentic materials or parts that do not meet documented specifications. Numerous technological, analytical, data collection, and statistical tools exist to aid in this. Manufacturing. Robust manufacturing requires standard operating procedures that are followed by well-trained operators. Additionally, equipment should undergo routine preventive maintenance, and measuring devices should be calibrated. In-process monitoring and testing should be in place as needed to assure process control, quantify process variation, and assure conformance to specifications. To this point, well-designed automated processes, such as cell culture media raw material milling, will generally have greater control over variability than manual operations. The manufacturing environment should be commensurate with the need to maintain product cleanliness. This may range from clean rooms for singleuse components and assemblies, to well-maintained chemical process plants for chromatographic ligands or cell culture nutrients. Product release. Release testing should be performed by qualified operators and should be designed to confirm critical quality attributes. Sampling and test plans, and their rationale, should be thoroughly documented. Some release tests are destructive and require randomized selection within lots, while others can be performed on each item. An example of a new, more challenging control is single-use equipment integrity testing, which is increasingly receiving more attention.
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Corrective and Preventive Action. Suppliers should have an active CAPA program, as this is a key mechanism for managing quality issues and identifying potential issues for remediation.
53.4 RISK MANAGEMENT Risk management has been defined as “the implementation of strategies to manage both everyday and exceptional risks along the supply chain based on continuous risk assessment with the objective of reducing vulnerability and ensuring continuity” [4]. The previous sections highlight material- and supplier-related items that, in effect, may be viewed as inputs to a drug manufacturer’s risk assessment. The output of this may be used to determine which risk mitigation options, if any, should be implemented. These options are delineated in the following section. The many options available highlights that a one-size-fits-all approach will generally not be efficient or effective. Risk mitigation tactics should be scrutinized to ensure resource allocation is commensurate with the level of risk.
53.4.1 Supplier Auditing One of the most effective and commonly used mechanisms to manage a supply chain is to audit a supplier’s quality management system. Section 53.3 delineates some major elements of a QMS that relate to SoS. In this context, the supplier audit is intended to confirm and document that the supplier’s QMS contains these elements and that the supplier is performing effectively against them. The premise is that performance issues may presage a high-impact supply incident. Various management methodologies can be used to strategically allocate audit program resources to greatest effect. For example, an audit schedule can be developed with inputs such as criticality of materials, criticality of supplier, supplier audit and performance history, susceptibility of disruption, and the probability of disruption. Supplier audit meetings can lead to subsequent meetings related to corrective action or to collaborative discussions in which risk mitigation becomes a shared issue. Building collaborative relationships will ensure a common understanding of user requirements and of supplier capabilities. It will also support the transfer of the drug manufacturer’s requirements from suppliers to sub-tier suppliers. Ultimately, these discussions should lead to establishment of legal agreements on supply conditions and audit frequencies. Strict change control sections should be included in supply agreements.
53.4.2 Multi-Sourcing Unexpected disruption in a supply chain often necessitates emergency measures: (1) to identify a new material and supplier, (2) to qualify the material and supplier, and finally, (3) to implement use of the new material and supplier (Table 53.4). From the drug manufacturer’s perspective, this is true whether they are multi-sourcing suppliers or their supplier is multi-sourcing materials. Each of these steps takes time, which is at a premium in such an emergency situation. Therefore, to mitigate risk, it may be appropriate to perform one or more of these steps proactively. The first two are intermediate steps to the ultimate measure of dual-sourcing or multi-sourcing. Because each risk mitigation step consumes resources, the decision to activate any risk mitigation step involves balancing resource spend with risk reduction. One should note that any company within the supply chain can use such risk mitigation steps. The first of the three steps is second-source identification. In this step, one or more candidate materials, which are potentially interchangeable with the material under discussion, are identified. These may be acquired for a technical assessment and to determine if a candidate material is likely to be a successful replacement. The second step is material qualification, the main goal of which is to assure that the critical quality attributes are met when the alternative raw material is used. The third step is the actual multi-sourcing, which implies that the second supplier and replacement material are fully qualified and the replacement material is being implemented along with the original material. Thus, the two materials are considered to be interchangeable. Note that these three steps do not have predefined boundaries; one can choose to take specific measures as one sees fit. For example, although “implementation plan established” is placed under “part implementation” in Table 53.4, one may choose to create that plan without an immediate intent to implement the part. Multi-sourcing can be effective if three conditions are met. (1) The material or component from a second source is fully interchangeable, with respect to all quality and performance attributes, with the original part. The proprietary nature of some raw material formulations complicates this effort. Such is the case with single-use films. Moreover, even though a material meets established specifications, it may not perform identically to the material it is intended to replace. Chromatography resins are an example, as they comprise complex biological materials with unique binding properties and purification profiles. Additionally, cell culture medium may have contaminants at micro levels, which adversely affect cell culture performance.
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TABLE 53.4 Risk Mitigation Steps Taken to Implement a Redundant or Alternate Raw Material or Product Step
Actions
Identification
Material specification Technical Assessment of material—proof of concept
Qualification
Sub-tier supplier approval Material qualification: critical quality attributes are met Risk assessment of the change to the new material
Implementation
Implementation plan established Supply agreement Quality agreement Qualification to verify process and product compatibility Operator training Procedural items (e.g., incoming inspection) Protocol revisions to reflect use of the new material Change notification executed (for suppliers) Regulatory notifications executed as needed (for manufacturers)
(2) The supply chain from two sub-tiered suppliers must be independent. For example, if two sub-tier suppliers share the same raw material suppliers, then the redundancy of the supply chain is directly compromised. (3) The supply chains from two redundant suppliers (e.g., finished products), must be independent. If the two suppliers share the same material sub-tier suppliers, then the redundancy of the supply chain is partially compromised. For example, multiple cell culture media suppliers were affected by a global shortage in folic acid in 2014 [5]. Full implementation of a second, redundant supplier, is a relatively aggressive risk mitigation strategy that should be used only after the costs and complexity to qualify, validate, and manage multiple sources are fully understood [6]. Table 53.5 provides common issues related to three product categories.
TABLE 53.5 Considerations for Multi-Sourcing Materials/Suppliers Consumable Category
Discussion
Single-use
• Chemical differences in functionally equivalent parts may require substantial qualification. • Forms of functionally equivalent parts may require training in the use of the redundant part. • Different plastics require fully redundant qualification work (processing conditions, shelf life, irradiation compatibility, extractables characterization). • Standard vs Custom: suppliers often have lists of standard materials, often chosen due to sub-tier detailed characterization, business stability, or purchasing power. Custom material runs the risk of lacking one of the above features. • If a material or part is IP protected, it can be challenging to negotiate transference during a time of crisis.
Cell culture media
• Proprietary or custom media platform formulations are often controlled by the supplier who won’t release exact details, requiring the drug manufacturer to start from the beginning in development. • Raw material chemical impurity profiles from different suppliers may also adversely effect product outcome. • Media format: suppliers produce media in different formats (e.g., powder or complex granulation) which are intrinsic to the manufacturing process.
Chromatography resin
• Complex raw material such as protein ligands and base matrix material need thorough characterization for confirmed interchangeability. • Regulatory hurdles to prove multi-sourced chromatography media have the same purification profile with unaltered effect on safety and efficacy of purified product. • Potential for increased variability, e.g., lot-to-lot variation on the end product. • Process complexity of validation/verification for two chromatography media sourced from the same supplier (two manufacturing facilities). • Cost/complexity of validation/verification concerns for sourcing two chromatography media from the different suppliers.
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Common drawbacks to multi-sourcing are as follows: ●
●
●
●
Sourcing a redundant supplier/material implies that they must be managed with the same attention as the primary source for critical products, and this requires resources. Sourcing a redundant supplier/material implies that they should be qualified for use. This implies the need for a risk assessment on the use of the redundant part, and the possible need to evaluate such resource-intensive issues as extractables and leachables testing, and drug substance/product stability. Often, this issue leads to multi-sourcing being implemented only when other risk mitigation strategies are deemed ineffective. Sourcing a redundant material/supplier may result in the need to set up two different processing steps to use the two different raw materials. For example, two different aseptic connectors, although viewed as functionally interchangeable, will require two dedicated instruction sets for use. It is difficult to engage in fruitful, collaborative relationships with suppliers when the sourcing volume is low. Difficulties can ensue with respect to quality or supply chain performance, such as with change notifications and predictability of delivery times.
53.4.3 Manufacturing Facility Risk Several elements of QMS work in tandem to keep manufacturing processes consistently delivering products to predetermined quality specifications. However, even the most well-run supplier manufacturing site is subject to events such as contamination, equipment failure, or force majeure events, which can lead to manufacturing interruption or shut-down. To manage this risk requires firstly an understanding of the manufacturing risk profile, followed by prioritization of high risk elements, and lastly, action plans that incorporate one or more risk-mitigation strategies. These steps are critical. Underestimating or ignoring the likelihood of disruptions exposes the supplier’s manufacturing facility to undue vulnerability, whereas overestimating risk can lead to undue time and resources spent on risk mitigation implementation. This chapter will focus on the considerations a drug manufacturer should make when evaluating an individual supplier’s manufacturing risk management. Three leading concepts for manufacturing risk management will be discussed: (1) multi-site considerations, (2) business continuity planning, and (3) safety stock.
Multi-Site Considerations Multi-site manufacturing is a strategy taken by a supplier to build redundant manufacturing capability. Although this is often driven by business needs such as capacity expansion or cost reduction (e.g., transportation, labor, and tariffs), it has the added effect of insulating both the supplier and drug manufacturers against disruptions in one of the supplier’s manufacturing sites. In this sense, multi-site manufacturing is analogous to multi-sourcing, but with certain intrinsic differences, benefits and liabilities (Table 53.6). The contrast between multi-site implementation by the supplier, and
TABLE 53.6 Considerations for Single Supplier Multi-Site and/or Multi-Supplier Approach Issue
Multi-Site
Multi-Suppliers
Supplier identity
Only one supplier to manage; two sites to be monitored
Two or more suppliers to manage and monitor.
Capacity
Transfer to the second site could lead to capacity limitations and delays, e.g., overseas shipping
Transfer of capacity to the second supplier could lead to capacity limitations.
Raw materials
Commonly the same raw materials are used, but this should be confirmed. If true, then redundancy is achieved
Many raw materials will differ, but this should be confirmed to document supply chain redundancy.
Product and Processes
Ideal state is that the processes should be identical, but critical to quality attributes should be evaluated to confirm identity
Considerable validation and regulatory requirements to treating the suppliers and “interchangeable.”
Business continuity
Based on minimal or no risk for the full manufacturing site to be incapacitated
A second supplier will provide “true” redundancy. This is based on the presumption the facilities are not affected by the same disruption or event.
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multi-sourcing implementation by the manufacturer, highlights that a given risk element may be more effectively managed by either the manufacturer or the supplier. This in turn reinforces the benefits of close communication between the two parties. A multi-site manufacturing strategy is often an integral part of the supplier’s business continuity plan where during a disruption, the second manufacturing site can be leveraged to supply the market demand until the primary facility is fully functional. Drug manufacturers may consider the risk to be reduced by knowing that their supplier has this capability. However, to fully benefit from this strategy it is prerequisite that (a) they have qualified or can qualify the second site, (b) the second site has complete, redundant manufacturing qualifications and capabilities, and (c) there is flexible capacity at the second manufacturing site to meet the demand. Unsurprisingly, due to process complexity or equipment costs, even though a secondary site is operational it may not have full capabilities to manufacture from start to finish. Therefore, when evaluating a supplier’s multi-site approach, it is important to enquire about the full breadth of capabilities to ensure no bottlenecks exist segregated the manufacturing chain. Most manufacturing disruptions or events are not catastrophic in nature and occur in isolated portions of the manufacturing facility. Considering this, a supplier may establish redundant manufacturing capabilities on the same site and take special precautions to keep the two manufacturing lines within from each other. The major benefit to this strategy as compared to having two separate manufacturing sites are that the same infrastructure is in place regarding water quality, air supply, organic solvent supply, quality management system, and trained and experienced operators. With these redundancies, the validation effort associated with manufacturing transfer within a site may be lesser than that associated with transfer between sites. The multi-site and multi-sourcing strategies may be contrasted as follows. In short, the consumables manufactured by multiple sites are intended by the supplier to be identical, whereas consumables sourced from two different suppliers are not identical. At best, they may be qualified by the drug manufacturer as being “interchangeable.” Suppliers undertake rigorous assessments to ensure likelihood and success in achieving consumable identity during a second site institution. From a drug manufacturer perspective, the level of supplier qualification and the level of validation and qualification efforts required in a multi-site sourcing strategy are often lower than that which is required in a multi-supplier sourcing strategy. However, a rigorous assessment of consumable criticality should be used to determine the effort required in second-site qualification. At times, one may need simply to process a supplier change notification through a risk assessment but without need for experimental work. In situations of high consumable process criticality, the qualification work could be extensive, and close to the effort required to source from a second supplier. Note that multi-site sourcing is not only a consideration for manufacturing, but also with service providers. Two common examples are providers of analytical chemistry and microbiology testing services, which can be a part of product release testing, and sterilization service providers, which are effectively a part of the manufacturing process for sterile products. While this chapter does not discuss these services in detail, they play an important role in the supply chain and merit attention when evaluating suppliers.
Business Continuity Planning The loss of a manufacturing facility can be devastating to a business and can have severe effects on its customers. Business continuity planning (BCP) is an ongoing and structured mechanism that “identifies an organization's exposure to internal and external threats and synthesizes hard and soft assets to provide effective prevention and recovery for the organization, while maintaining competitive advantage and value system integrity” [7]. Especially if they produce single- or sole-sourced materials, organizations should have a structured business continuity plan to ensure risks for supply and manufacturing interruptions are managed. BCPs consists of several complementary elements including communication, disaster recovery, business recovery, business resumption, and contingency planning. Organizational Business Continuity Management Systems (BCMS) practices can be developed at a corporate level holistically, but require tactical execution to be implemented locally based on the product and market needs. During an incident, a BCP is often executed by dedicated emergency response teams and crisis management teams to respond, recover, and ensure continuity. An ongoing part of BCP is to identify and evaluate risks to critical manufacturing assets and the anticipated impact to drug manufacturer and supplier. These plans seek to adopt preventive measures and to minimize damage if a disaster does occur. Additionally, plans are maintained, updated and tested as business processes change. Established industry standards serve as guidelines for BCPs, and often call for audits from certified external organizations. Historically, the framework is based upon the British Standard BS25999-1. In recent years, a more robust ISO 22301 certificate for business continuity management has been established.
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Safety stock The BCP often coincides with a safety-stock program. Safety stock programs mitigate risk by maintaining reserve inventory based on demand forecast. Stocking volumes are established on a case-by-case basis, and with inputs from supplier and drug manufacturer, considering: – – – –
Product impact and criticality to the drug manufacturer application or process Anticipated time to recover or replace the source Anticipated time for the drug manufacturer to qualify new materials or manufacturing site Forecasts of material utilization
Safety stock may be warehoused by the supplier or the drug manufacturer. In either case, safety stock programs can have a large financial impact, and they are naturally only considered for critical or high-risk materials and consumables. This financial impact, whether on supplier or drug manufacturer, may be warranted as a mechanism to assure uninterrupted supply of drug product to the patient population. In unusual circumstances, when supplier and drug manufacturer do not align on risk tolerance, one option is a supply agreement for a private safety stock service. When safety stocks are drawn upon, a controlled order intake and prioritization process governs which drug manufacturers will receive products and how much they will receive. These prioritization plans favor the immediate use in manufacturing processes for approved pharmaceuticals to prevent a lapse in patient treatment. Depending on the severity of the disaster, less critical operations such as research labs may experience shortages.
53.4.4 Supplier Agreements Drug manufacturers can minimize risk for quality- or supply-based interruptions through formal quality and supply agreements with suppliers. The quality agreements should stipulate items such as implemented quality management system, change controls, and information transfer between the organizations. For critical raw materials, commercial contracts should be executed. This is especially important in cases where the raw material is sole-sourced and there are no suitable alternatives. The commercial agreements can include safety stock agreements, last-time-buy options, stable forecasting processes, and process or technology transfer in the case of a disruption. Regardless of approach, the risk mitigation effectiveness will be enhanced with collaboration and shared vision between manufacturer and supplier.
53.5 COMMUNICATION Leaders in the biopharmaceutical industry have come to understand that risk mitigation of their supply chains, as described above, is best achieved when communication between companies is strong. Primarily, communication of critical information tends to flow from supplier to customer, a natural consequence of the drug manufacturer’s need for supplier information to feed risk assessments and to practice ongoing monitoring of the supply chain. This open flow of information to drug manufacturers has come to be termed “transparency” (e.g., Ref. [8]). Transparent communication has commonly involved the transfer of heretofore confidential information such as identity of suppliers, identity of raw material part numbers and specifications, and ranges of manufacturing process steps. Information such as this has come to be seen as important input into SoS (as well as initiatives to manage process variation). The general call for this kind of information has led to increased focus on supply chain mapping, which lends visibility, for example, to the geographical distribution of suppliers. Such visibility then allows one to monitor for disturbances worldwide and to alert one to the possibility that a supplier might be susceptible to a disruption. Presently, the biopharmaceutical industry is still developing best practices and the trust required to make this level of transparency the norm in the industry. Historically, drug manufacturers have had reservations about sharing process or forecast information, which is sometimes exacerbated by imperfect forecasting abilities or concerns about how suppliers may leverage the information. This hesitation to share information encourages a transactional relationship of order placement and order fulfillment with suppliers. Relying on this order fulfilment paradigm, suppliers’ forecasting, capacity planning, and future expansion plans hinge on their ability to anticipate demand with inadequate data. This in turn puts the drug manufacturer at risk, as suppliers are reticent to build capacity in the absence of demand for it. Recognizing this kind of dynamic, more advanced drug manufacturers are now practicing transparency, sharing proprietary information regarding business plans and manufacturing strategies with their key suppliers. The premise is that suppliers will be more willing to share information if they understand the need, and they will be more able to offer well-targeted support if they understand the problem. This is the essence of the benefit to engaging in a partnership with key suppliers.
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53.6 CONCLUSION Ushering modern SoS practices into biomanufacturing creates the opportunity for drug manufacturers and suppliers to work closely together long before and after materials and sub-tier suppliers have been selected, and manufacturing protocols and conditions have been defined. Their joint objectives should be to collaborate and communicate to deliver safe and efficacious therapies to the market. This partnership model enables true security of supply from raw material to drug manufacturing, allowing the drug manufacturer and regulatory bodies to develop trust and consider their primary suppliers both capable of and responsible for monitoring and managing the supply chain and risks. In conclusion, the diversity and complexity of supply chains and the risk profiles associated with the several consumable segments require drug manufacturers and suppliers to carefully plan and execute the various selection, sourcing, manufacturing, and risk mitigation strategies discussed in this chapter.
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