Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	An example of a new cold chain temperature-controlled shipping technology is Cocoon, which was commercialized in November 2016 and designed for use with pallet-sized shippers. Cocoon, which eliminates the need for an external power source, was developed by World Courier’s Climate Optimization Research and Engineering (CORE) laboratories. Composed of vacuum-insulated panels in a honeycomb design, Cocoon weighs 15-30% less than comparable packaging products, covers European and US pallet sizes, and supports three temperature range requirements: -15 °C to - 25 °C , 2 °C  to 8 °C, and 15 °C to 25 °C .

	The vacuum-insulated panels, coupled with Cocoon’s phase-change materials, provide a high-level of thermal protection and stability for temperature-sensitive pharmaceutical products throughout long-distance deliveries. According to World Courier, Cocoon packaging solution maintained its internal temperature throughout a two-week delivery from Austria to Baghdad, Iraq, which included 10 days of storage in uncontrolled warehouse temperatures.


	Vol. 41, No. 2
	February 2017
	Page: 70

	When referring to this article, please cite it as A. Shanley, "Last-mile temperature control," sidebar to "Cold Chain: Zeroing In on the Last Mile," 

Articles

An example of a new cold chain temperature-controlled shipping technology is Cocoon, which was commercialized in November 2016 and designed for use with pallet-sized shippers.

Last-mile temperature control

	Ten years ago, installing quality management system (QMS) software was an intense process that could take years. Increased outsourcing of strategic manufacturing and development operations have only added to the potential complexity.

	More recently, a number of pharmaceutical companies, including Teva Pharmaceuticals and AP Pharma, have moved from traditional to Internet-based QMS programs. Even FDA, which began installing QMS in its Office of Pharmaceutical Science in 2009, added a Web-based QMS for additional divisions in 2014 (1).

	QMS vendors, including EtQ, Sparta Systems, and MasterControl, have adapted to changes in the pharma market by improving the user interface and making it less difficult for strategic contract partners to access documents. The newer approach does not require that companies buy additional licenses.

	These changes have made everything from corrective actions and preventive actions (CAPA) to root-cause analysis easier to do. However, sponsor companies must still have the correct approach to documentation and data and risk management if they don’t want to export the wrong processes to their business partners.

	Two of the biggest potential pitfalls that pharma companies face are “tribal data” approaches and “death by CAPA.” Matt Lowe, executive vice-president, and Patricia Santos-Serrao, director of clinical and regulatory solutions for the pharmaceutical industry, both with MasterControl, discussed issues and accomplishments with 

: Before a company invests in QMS software, especially if they are outsourcing to contract partners, what should they do to ensure the best results?

: One of the most important things to remember is that, if you plan on using a certain method or approach and it is part of the way that you manufacture products, you will need to document all of the procedures and all of the actions and activities that are required for this approach. Optimizing standard operating procedures (SOPs) becomes a cornerstone for this process.

	SOPs document how procedures are executed, what methods are used to execute them, what the related procedures are and how are they connected, for example, when one procedure refers to another. Regulators expect clarity and full documentation, but this is an area where some pharma company sponsors may still fall short. A surprising number of companies today still rely on tribal knowledge, or the ‘we just know that that’s what we’re supposed to do. It’s not really written down anywhere’ approach. That kind of approach cannot be audited or validated and it’s not repeatable. It’s word of mouth, and it’s not good enough.

	The industry is well aware that all of its processes must be documented, but questions often arise as to who should be responsible for it, and when and how often it should be done. SOPs provide the foundation for best practices.

	Once everything has been documented, the next question becomes one of training. Who will carry out which procedures, what training will they need, and what will their roles be?

	Our solutions focus on document management. We have solutions around good manufacturing, laboratory, and clinical practices (GMPs, GLPs, and GCPs), but SOPs form the foundation for each of them. Once you know which procedures are strategically important, you can develop training programs to align with them.

: What mistakes do pharma companies make with documentation and training?
	

: Some companies assume that a procedure is so basic that it needn’t be documented. When an auditor comes in, watches processes, and asks, ‘After this procedure, what does the operator do next?’, all too often, the SOP detailing that information just isn’t there.

: How about when you are outsourcing your R&D or manufacturing operations?
	

: Sponsors bear the responsibility for what their business partners do. Contract partners are just an extension of their organizations. One can outsource anything, down to the nittiest grittiest detail, but responsibility canot be outsourced.

: How are QMS systems being designed to allow better communication about quality with suppliers and contract partners?

: Over the past few years, we have broadened the ability to allow our customers to bring more collaboration to how they manage procedures, and push out more collaboration to partners. For instance, we have a GuestConnect feature that allows external users to access sponsors’ systems in a controlled way, to upload sponsor documents and to share theirs.

	Our license model is targeted to concurrent users. Partners can use a guest account. This approach encourages collaboration, without requiring additional licenses and cost. We’re creating supplier portals to allow companies that are working with contract partners to create work spaces for partners where they can collaborate.

	This approach allows for open-door communication and sharing tasks, and, eventually, the collaboration sustains and maintains itself. Sponsors and contract manufacturing organizations (CMOs) alike can share areas of risk and concern and suggestions on how to address them. Such portals will be critical to making partners an extension of the company. Partners can be treated like a department within an organization.

	Risk filtering to prevent ‘death by CAPA’

: CAPAs are an area where individual companies often fall short, as evidenced by 483s and warning letters. When collaborating with contract partners, there is even more potential for problems to fall between the cracks. Why is handling CAPA such a problem for companies, and what steps should they take before buying a QMS platform to ensure a successful approach?

: One of the biggest problems that we see is ‘death by CAPA.’ Some companies don’t reserve CAPAs for the significant issues that deserve that approach. Instead, they put anything and everything that goes wrong through their CAPA systems. As a result, they cannot identify the real problems that require a CAPA and can’t solve them all. Then they get written up in an audit as having 400 open CAPAs.

	Best practices require the use of an internal risk filter or risk gateway. The filter sifts through all the quality channels that feed into a CAPA system (e.g., nonconforming materials, deviation, variance).

	The filters are relatively simple. Typically, they are two-variable matrices using frequency and impact to ask ‘how often does this happen, and, when it does, what kind of impact does it have?’ That will set a risk profile so that, when a situation falls into a higher priority area, it triggers a CAPA.

	Another area where we see problems is around recurring CAPAs. A company opens a CAPA, does something about it, then closes it out, yet the problem comes back. This usually happens when root-cause investigation was inadequate and failed to get to the root cause of the problem the first time. We suggest asking who, what, where, when, why, and how to dive deeper and identify trends. For instance, are you always seeing these types of problems with specific healthcare customers?

: How do web-based programs help ensure more thorough investigations?
	

: Web-based enterprise QMS systems allow supply-chain partners to participate directly in the root cause analysis process and to add data in the CAPA. Trying to do this via email or passing paper back and forth can be extremely difficult, and, if a sponsor and a partner have very different IT systems, things can get very messy, very fast.

: How can sponsors ensure that they use QMS for CAPAs properly?

: It helps to have a system in place that will allow external collaborators to input data easily and to access documents from the sponsor efficiently. For any questions, they need to be able to reach the initiator. But the sponsor also needs to engage its partners in communications such as: ‘Here is a corrective action. Participate with us in the verification and validation process to ensure that we’ve addressed the problem and have put preventive actions in place to keep this from recurring in the future.’ Often, when you are dealing with the CAPA process, the outcome may be changes to documentation or recipe specifications. A system that allows those changes to be made seamlessly is crucial.

	Training is another issue. If a change occurs, how do you train partner companies on the change and record that they were changed? Having a system that has a mechanism to launch automatically when those changes occur is important.

: What changes have you made to help sponsors manage change?

: We recently completed a major overhaul of our user experience to make it much more friendly to the casual user, a term that will define most partners in the typical pharma sponsor’s supply chain. These users will be in a sponsor’s system once or twice a month. If it will take a major process to relearn what’s required every time, compliance will become an issue. You need to give them something simple that allows them to provide the information needed, but get out quickly.

	In addition to GuestConnect, we have added a quality event analyzer for CAPA that allows users to set up ‘analyzer agents,’ which look through the entire quality system to find trends and identify problems that might not yet be visible but are happening across a number of different channels. It is like having predictive analytics in place, and allows sponsors to take proactive measures to prevent things from getting worse.

	1. “MasterControl Continues Role as QMS Provider for FDA Office of Regulatory Affairs,” press release, mastercontrol.com, November 12, 2014.

Cloud-based information technology makes it easier for pharma companies and outsourcing partners to collaborate on quality, if risk-management steps are followed.

Connecting Contractors to a Pharma QMS

	Gelatin is commonly used for drug encapsulation. Jean-Philippe Talmon, chief procurement officer at Capsugel spoke to 

 about the critical quality attributes of gelatin as an excipient in capsule production, as well as measures that can be taken to ensure an uninterrupted supply of quality raw materials.

: What are the most important ‘critical-to-quality’ attributes for gelatin, for encapsulation?

: In today’s increasingly interconnected and highly regulated global pharmaceutical market, adherence to ‘critical-to-quality’ attributes is required to deliver best-in-class products.

	First, sourced gelatin must comply with the different pharmaceutical and food regulations in all the markets where the end product is sold. In global pharmacopeias, there are mandatory attributes to assure the quality, identity, and purity of the excipients used in the drug product. There are also non-mandatory attributes that provide information on control parameters for specific excipient use and include functionality-related characteristics. Various 

 monographs, for example, have listed relevant parameters specific to the intended use of the excipient, which can form part of the regulatory filing process. Manufacturers are increasingly expected to understand the functionality of excipients and their potential impact on the final drug product.

	Second, acquired gelatin must meet specific certification expectations and environment, health, and safety (EH&S) requirements. There are more than 15 regulatory references that form the basis of global gelatin purchasing specifications, including those from FDA, United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), Food Chemicals Codex (FCC), and World Organization for Animal Health (OIE).

	For example, there are specific regulations on the sourcing of bovine raw materials for excipient use. While Bovine Spongiform Encephalopathy (BSE) is well under control as a disease, the OIE is leading a global movement to standardize BSE regulations and establish a common guidance on prevention, control, and eradication of the disease. Global regulators base their regulatory framework on OIE guidance. In Europe, manufacturers of bovine material must provide certificates of suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM) to be incorporated into marketing authorization dossiers for applicable medicinal products. This is just one example of the types of certifications required.

	Third, sourced gelatin must maintain specified physical/chemical and microbiological requirements to provide appropriate encapsulation of individual APIs. These specifications cover a large number of criteria, including viscosity, pH level, loss on drying, and particle sizes, among others.

	Through adherence to these three critical-to-quality attributes, companies with capsule and encapsulation capabilities can help to minimize the business continuation risks associated with gelatin raw materials and gelatin production. For example, in 2013, when heavy levels of chromium were detected in gelatin capsules made in China, the 

) monograph for pharmaceutical-grade gelatin was revised to include testing for heavy metals. Some companies scrambled to comply with the new requirements, which then had a negative impact on their customers. However, companies whose gelatin purchase specifications included chromium restrictions could maintain product supply without delaying delivery of their customers’ products to market.

: What issues are entailed with the use of animal-sourced materials, as compared with synthetic or non-animal-derived materials?

: Animal- and non-animal sourced materials are used as excipients in pharmaceutical products. Each of these forms offers its own unique characteristics, specifications, opportunities, and challenges at various points in the development process. The positives and negatives associated with both forms must be well understood to ensure that any potential associated risks are identified in advance and controlled.

	Gelatin, which is made from the hydrolysis of collagen of bovine, porcine, or fish origin, is well-suited for the encapsulation of pharmaceutical ingredients because of its excellent gelling and film-forming characteristics that support the manufacturing process. These characteristics are the result of the unique property of the gelatin polymer, which exhibits a reversible temperature-based gelification, turning into liquid when heating and hardening in the cooling process.

	Hydroxypropyl methylcellulose (HPMC), which is made from plant/cellulose-based material, is an alternative to gelatin for drug encapsulation. Recent in-vivo and dissolution test results investigated the clinical performance of second-generation HPMC capsules compared to that of gelatin capsules, and found that the second-generation HPMC capsule performance was equivalent to that of gelatin capsules (1).

	The choice between gelatin and HPMC materials is based on numerous factors including, for instance, the targeted product profile, characteristics of the fill, and consumer lifestyle considerations (i.e., dietary restrictions based on religious practices, such as halal and kosher requirements, or on vegan or vegetarian diets). For example, while gelatin sets the benchmark for pH- and ionic strength-independent disintegration and product dissolution profiles, HPMC capsules maintain lower moisture absorption, more flexibility, resistance to chemical crosslinking, and a higher thermal stability than gelatin capsules, providing greater benefit for hygroscopic and moisture-sensitive ingredients.

: First, stringent raw material purchasing specifications and quality agreements are required that cover a large number of criteria. Second, a robust supplier qualification program is needed to provide a sound framework to guarantee that hard capsules meet the highest standards for quality, traceability, and integrity. At Capsugel, our multi-phase program requires that our critical raw material suppliers undergo an intensive, year-long selection process that includes 150 critical parameters for evaluation to verify they meet the most stringent regulatory and industry standards, the most important being unique specifications related to dissolution profiles and impurities. The process includes the following:

		Step 1: Supplier screening and investigation. A review of the quality system of the vendor, the state of their manufacturing technology, the scope of their product and service offerings, and a detailed understanding of their performance metrics, regulatory compliance, and raw material traceability. For example, more than 15 regulatory agency regulations inform the basis of our purchasing specs.

		Step 2: Quality evaluation. A review of supplier material quality compliance with the company’s specifications.

		Step 3: Manufacturing suitability evaluation. An analysis of small-scale production trials and R&D pilot, when relevant. This analysis ensures compatibility of materials with manufacturing processes and protocols and confirms both finished capsule product quality and manufacturing efficiency performance levels.

		Step 4: On-site supplier audit. A thorough traceability analysis, from raw material delivery to finished goods release, including a detailed review of quality systems. This audit also confirms compliance of production equipment and compliance to current good manufacturing practice (cGMP) requirements.

		Step 5: Scale-up and final approval. This step involves a full-scale manufacturing run of capsules to confirm that material consistently meets specifications and is continuously suitable to our full-scale production. This also requires an evaluation of the supplier’s ability to control product integrity and proper documentation across the entire supply chain.

	Third, it is important that long-term supplier partnerships are supported by a continuous supplier performance management program. This program includes an ongoing evaluation process designed to ensure supply-chain traceability and finished capsules that comply with the highest integrity standards. This program helps to maintain a global network of qualified suppliers with whom there are established long-term partnerships. Key components of this program are constant testing to the highest standards, updated with the most advanced instrumentation for contaminants tests, for example; regular in-depth onsite audits of suppliers; continuous monitoring at manufacturing facilities, including performing incoming quality control on each lot of raw material prior to its use; and follow up on supplier performance. Finally, a global sourcing strategy is needed to ensure consistent quality and security of supply.

: How do you prepare for potential disruptions in the supply chain?

: The key to preventing supply-chain disruptions is to develop long-term partnerships with suppliers across multiple production sites to ensure that alternative resources can be ramped quickly and effectively in the event of an unexpected issue. Companies must always look one step ahead of their current needs and the requirements of the regulatory environment and business market. This process includes continuously screening potential new suppliers, monitoring industry and governmental standards and trends, building and maintaining an extensive knowledge base of international regulatory requirements, and participating in membership associations and working groups. All of these efforts are aimed at anticipating and rapidly implementing changes to safeguard the integrity of supply chain and products.

: Supplier selection is guided by several core principles, including the quality of the suppliers’ products and services as well as their product traceability and integrity framework. Additionally, suppliers’ quality systems, certifications and cGMP, regulatory compliance, and EH&S compliance are important. Finally, it is critical to look for suppliers to maintain responsible sourcing initiatives and have viable business continuity plans. All of these attributes are central to ensuring that suppliers can consistently and reliably deliver.

: What are best practices for working with offshore suppliers?

: A robust framework is required to ensure that offshore suppliers meet the global expectations of companies and their customers. At Capsugel, we have a global production footprint, and our raw material sourcing efforts are globally coordinated and managed.

	We maintain supplier evaluation programs to secure identification of potential sourcing risks and development of appropriate mitigation plans in close collaboration with our suppliers. Supplier audit results, for example, are used to dictate the frequency, as well as the depth and breadth of the follow-up supplier audits we conduct.

	In parallel, we also maintain a thorough business continuity risk assessment program across our entire global supplier base. These assessments are conducted along six main dimensions, including supplier production capacity constraints; compliance to Capsugel quality expectations; compliance to regulatory requirements; single-sourcing risks; supplier financial health; and supplier intellectual property risk and third-party misappropriation.

Establishing a New Performance Standard for HPMC Capsules

Gelatin is widely used for encapsulation, and requires close attention to “critical-to-quality” attributes.

Ensuring Quality in Pharmaceutical Raw Materials

As more pharmaceutical manufacturers launch clinical research into cell- and tissue-based therapies, they must work more closely with contract research organizations (CROs) and contract development and manufacturing organizations (CDMOs) on logistics and cold-chain planning.  Andrea Zobel, senior director of product management, clinical trial supply, and logistics at PAREXEL International, reviews some of the key issues to consider.

	Differences with traditional cold chain planning

 How is planning for clinical trial logistics for niche innovative or novel/experimental treatments (e.g., immuno-oncological therapies, cell therapies, gene therapies, tissue therapies) different from the process involved for more traditional clinical-trial logistics for biopharmaceuticals or small-molecule drugs?

 The main differences involved in managing innovative therapies in clinical trials are:

		Time constraints (e.g., short shelf life or availability only at certain time points after manufacturing)

		The challenge of classifying the innovative product correctly in the dangerous goods class and tariff code.

	Very often, innovative therapies are developed to treat orphan diseases. Therefore, many countries and sites are required to find the necessary number of patients per protocol. But experienced investigators are also rare and patients may be too disabled or sick to visit the sites regularly, according to the protocol visit schedule.

	Early-stage development, an area where innovative companies are often focused, is one of the main challenges for clinical logistics trials. In early development stages, the product availability is limited and researchers must adapt from the research environment to a clinical research setting, which has regulatory, process, and quality requirements.

	Therefore, communication about the requirements of the clinical supply chain and the special requirements of the innovative product between the research company, clinical logistics experts, contract manufacturing organizations and CROs is very important. Scientists and logistics experts must find a common language in order to achieve success, and it is often helpful to have an expert with scientific and logistics background on both sides.

 How should sponsors and contract partners collaborate at the earliest planning stages? What information/processes should each party be responsible for?

 The collaboration should, ideally, start at a very early stage of the planning when the contract partners are selected. Selection should take into account the later requirements of the clinical supply chain based on location and capabilities of the contract partners. The whole process should be planned to enable upscaling to the product amounts and characteristics required for larger trials in Phase II to III, and to fulfill the quality requirements for the clinical-trial products.

	Formulation, primary and secondary packaging, a suitable product size, and labeling should be designed in a way that enables easy and correct usage at the clinical site, but also fits storage and distribution in the clinical supply chain. The sponsor is responsible for the product, but information about import requirements, especially for the European Union and other countries with similar standards, can be best provided by a contract partner. Finding the best contract partner for each development stage will help the sponsor avoid frequent changes due to requirements not considered in the beginning of the project. Based on the product specifications, the contract partners can develop the supply chain, select the shipping material, plan the process of product pick-up and delivery, identify the storage and shipment vendors in the supply chain, clarify import procedures, and plan the administration material, when that is required.

 What issues must be taken into account when managing cold-chain for clinical trials involving novel therapies, and how do those issues affect the choice of temperature-control and other technology, and overall planning?

 It is very important to provide stability data for the product that reflects the typical temperature conditions required for established shipping material and processes. Sometimes a product starts its development with a temperature range that is suited for a laboratory environment, but that range is not common in logistics.

	The clinical supply chain should be designed for the following temperature ranges: - 196 °C with liquid nitrogen, - 80 °C with dry ice, - 15 to - 25 °C for frozen conditions, 2 to 8 °C for refrigerated conditions and 15 to 25 °C for ambient controlled conditions. Stability data should be available for one of these ranges to start the clinical trials without delays.

	Maintaining the temperature of deep frozen products is a bottleneck in the clinical supply chain. Large hubs in the United States and Europe often have capabilities for storage and labeling, but it is challenging to find local depots in all countries that offer the required temperature capabilities in a GMP-compliant environment. An increasing demand for clinical research around innovative therapies may motivate depot vendors to establish -20 °C, -80 °C, and liquid nitrogen storage.

	As deep frozen material cannot be stored and prepared at each clinical site, but alternative procedures are possible. One example is a process to prepare stem cells and ship them during their shelf life of 48 hours to the clinical sites. In this example, the rate-limiting step is the time from pickup to delivery, but the logistics capabilities of premium couriers can be used, which are in place for time-critical shipments (e.g., blood products and transplants).

	Less time critical is the transportation of cells in liquid nitrogen and storage at the clinical site. But for this solution, the site must provide the storage capabilities and tissue culture to be able to thaw and propagate the cells. One possibility to overcome this restriction for the site selection is a patented method to prepare cells in a medium which allows usage immediately after thawing.

 How does the approach differ for autologous vs. non-autologous treatments?

 Whereas products for non-autologous treatments follow more or less the same processes used for ‘traditional’ clinical logistics, autologous therapies have additional restrictions and requirements. As the parent material for most products, cells or tissues are collected from an individual patient, and the inbound shipment to the manufacturing site is similar to a sample shipment for analytical or transplant purposes.

	The ‘dangerous goods’ classifications are applicable in most cases. After preparation of the therapeutic product using GMP-compliant procedures at a GMP-licensed manufacturer, the product must be sent back to the individual patient. Since the material is unique and not replaceable, this procedure requires a tracking system and processes which allow monitoring of the location and condition of the product in all stages of development, avoiding any risk of wrong allocation and damage. The process must be safe to guarantee that the patient who has delivered the cell material gets back the therapeutic product which had been generated out of their donated material.

	A very detailed time plan is required. It must take into account the cell donation at the patient’s hospital, the schedule of the manufacturing process at the current good manufacturing practice (cGMP) facility, and the treatment again with the autologous treatment product must be developed.

	In the case of the preparation of more than one treatment dosage out of a cell donation, an intermediate storage facility must be identified, with the required storage capabilities in a cGMP-compliant environment.

	Ideally a vendor is involved that knows both sides of the development journey, the sample collection chain with all the requirements and logistics challenges, and the clinical drug supply chain. With this combination, autologous therapies can be well supported.

	Global regulations covering new technologies

 What special temperature control, storage, and transportation options are required for these advanced therapies?

 The temperature-control requirements are not different from those of other clinical products, but other classifications could be applicable, depending on the nature of the product that is involved. For example, therapies using genetically modified organisms (GMOs) could require the respective dangerous goods classification (e.g., United Nations [UN] 3245 for air freight).

	Some countries requiring specific documents for import and storage locations could need a license for storage of these materials. At the moment, only one gene-therapy product is approved and only a small number of clinical trials are ongoing that use genetically modified organisms (GMOs). The majority of transported GMOs are for research and agriculture, so a mix-up of these products with investigational medicinal products containing a GMO must be avoided, and the correct classification according to the country regulations must be applied.

	Potential role for direct-to-patient logistics?

 Some clinical-trial materials are now delivered directly to patients’ homes. Do you see that approach being used in the future for these types of materials, and how would that complicate the overall process?

 There are two reasons why direct-to-patient home deliveries of advanced therapies could be required: the inability of the patient to regularly visit the clinical site; and the lack of clinical sites with experienced investigators for a rare disease in the proximity of the patients.

	Some research companies fly patients to the treatment sites for visits, but the alternative is applying the therapy at home. For home treatments, a nurse as well as home deliveries and pick-ups of samples and unused materials are required to provide the patient the appropriate treatment and diagnostics.

	One important challenge is the data privacy of the patient in a clinical trial. The logistics process should give the provider the patient’s home address, but the data must be kept separate from the clinical trial data that is available for the CRO and the sponsor.

	For these purposes, systems like Interactive Response Technology and Electronic Data Capture must be adapted and secure areas developed where the data could be collected and provided to the transportation vendor. All three parties, home care, the logistics vendor, and the patient need close cooperation and careful planning to schedule all deliveries and pick-ups.

	Another challenge is the delivery from the clinical site pharmacy or depot to the patients’ homes. Nearly all countries require a pharmacist for drug dispensing, but in some countries, a pharmacy license is not available for a depot. So mainly the clinical site pharmacies are the main partners for home deliveries.

	Also not all materials and treatments are possible at a patient’s home. Storage conditions could be critical. For these purposes, logistics providers offer special refrigerators to allow controlled and safe storage of temperature-critical products at the patient’s home. That approach could be more difficult, however, for other types of products (e.g., a GMO product that, for environmental reasons, requires the collection of contaminated material).


	Vol. 41, No. 2
	Supplement
	February 2017
	Pages: s8-s12

	When referring to this article, please cite it as A. Shanley, “Preparing an Approach to Cold Chain for Cell- and Tissue-Based Therapies," Supplement to 

Andrea Zobel, senior director of product management, clinical trial supply, and logistics at PAREXEL International, examines key issues and questions that sponsors and contract partners must address.

Preparing an Approach to Cold Chain for Cell- and Tissue-Based Therapies

	On December 13, 2016, during a webcast that is now 

, TraceLink released results of its first Global Drug Supply, Safety and Traceability Report, undertaken with the market research firm, Actionable Research.  The study surveyed 331 professionals from pharmaceutical manufacturers, wholesalers, pharmacies, and hospital pharmacies, to better understand issues and compliance trends at the lot level, in order to get a more realistic picture of gaps in readiness, and the challenges that face pharmaceutical companies, distributors and dispensers of all sizes in realizing full product traceability.

	Half of the pharmaceutical companies that responded to the survey expect to comply with electronic data transfer requirements within six months of the November 2017 deadline, and 54% describe themselves as well-prepared for serialization.  However, 19% of companies say they have not begun to address requirement, and only 24% say that their contract manufacturing organization (CMO) partners will be ready. 

	Respondents from pharmaceutical companies say that they underestimated the complexity of implementation, the total cost of IT upgrades required, and the overall impact that implementation can have on business.

	The question of product aggregation, considered the lynchpin to full traceability, shows different levels of sophistication among pharmaceutical manufacturers.  51% expect to have aggregation in place by November 2017, 28% say they haven’t made a decision about aggregation, 13% say they plan to focus on it after November 2017, and 8% don’t have any plans for it at all.    On the customer side, 26% of pharmaceutical distributors say they will require aggregated product, while 23% say they’d prefer to see aggregation, while the balance describe understanding that not all suppliers are ready yet.

	Moving down the supply chain, customers at the dispenser level complain that the documentation required for compliance is often missing from products that they buy directly from pharmaceutical manufacturers. In their dealings with drug distributors, dispensers fear that their electronic data, currently accessible via distributor portals, may not be available if they change distributors.

	In addition to shedding light on gaps in readiness, the survey offered an opportunity to test some common assumptions about the pharmaceutical distribution and supply chain, explained TraceLink CEO Shabbir Dahod.  He began to work in pharmaceutical traceability over 15 years ago, when the terms track and trace, pedigree and e-pedigree were first articulated, leveraging work done at MIT’s Auto ID lab to help the state of Florida improve the safety of its pharmaceutical supply.

	The “normal” linear view of the pharma supply chain so often seen on consultant PowerPoint slides, shows  90% of pharmaceutical products moving neatly from manufacturer to distributors (mainly the “Big Three”  McKesson, AmerisourceBergen Bergen and Cardinal Health) ) to dispensers. This is far from reality, Dahod said.  The true picture should include the practices of small players, and take into account a variety of business relationships and requirements, and models that include such practices as direct shipments, drop shipments and 340B distribution relationships.  Al“Lot-level serialization and traceability is not simple, because there is no ‘normal supply chain’,” Dahod said at the webcast.  These real-world conditions dictate the best way to manage data, in order to achieve compliance.

	A total of 331 people responded to the survey, 31% of them from pharmaceutical companies, where respondents were mainly managers or directors; 14% from wholesalers, 44% from hospital pharmacies, and 11% from retail pharmacies.

	Results showed that 25% of pharmaceutical manufacturers had more than 10,000 customers, while 31% had between 500 and 10,000.  In addition, 29% sell directly to hospitals and pharmacies.

	It’s not all about the “Big Three”

	Assumptions about the dominance of the “Big Three” distributors were also proven wrong by the survey, said Carter Holland, TraceLink’s chief marketing officer, who moderated the webcast.  Although between 80% and 90% of the market’s dollar value may go to the Big Three, that number does not match what happens on the transactional level.  In fact, the survey showed, respondents from pharmaceutical companies said that 43% of sales went to wholesalers other than the Big Three.

	Results suggest a highly fragmented distribution network. Of the distributors who responded to the survey, 58% said they have over 500 customers, and 35% of hospital pharmacies who responded to the survey say that they buy from 16 to 500 suppliers. In addition, 42% of hospital pharmacies and 19% of retail pharmacies resell products to other hospitals and pharmacies, the survey suggests.  

	Using TraceLink’s 2015 pharmaceutical customer base to illustrate the data exchange requirements for full lot-level traceability, Holland described 200 companies requiring 113,000 connections and 51,000 data exchange connections, an average of 143 files exchanged per transaction, 7.3 million files exchanged, over 60 million transaction histories recorded, and 46,000 unique National Ddrug Codes (NDC). Considering that this is only a slice of the full picture, the complexities become clear.

	And some of this complexity may be preventing some pharmaceutical companies, not only from achieving, but even from attempting to achieve compliance.  Although most respondents to the survey said that they found compliance to be “difficult but achievable,” a full 19% of pharmaceutical companies, 11% of wholesalers, and 9% of dispensers were not even addressing lot-level requirements, which took effect in 2016, at all.

	Some other highlights from the research:

		Roughly 37% of pharmaceutical companies bought a solution specifically designed to help with lot-level compliance, while 33% modified an existing third-party business system, 28% have implemented a manual process, and 20% have developed customized solutions.

		12% of T3 data (transaction statements and history as well as product information including lot number) are being handled via a portal, 30% on paper, and 58% electronically. 71% say that customers cannot handle electronic transaction types, but 21% say that they are not prepared to handle them.

		In cases where pharmaceutical manufacturers sell directly to dispensers, 27% of respondents from retail pharmacies and 5% of respondents from hospitals say that they do not receive any compliance documentation when they purchase directly from the manufacturer.

		31% of retail pharmacies and 27% of hospitals have been relying on wholesaler portals to access their “T3” data but they have no idea how long they’ll be able to access that data. They also worry about whether they will be able to access the data should they end their relationship with that distributor at some point in the future.

		54% of pharma company respondents said they were well prepared for the 

 (DSCA) serialization, but 10% said they were not prepared and 37% said they were unsure.

		83% of pharma company respondents say they understand all DSCA requirements, 70% say they can handle the scale and volume of data, and 67% say that responsibilities for serialization have been made clear within their companies.

		Where companies say they are not fully meeting requirements, 50% describe needing more dedicated resources, while 40% are concerned about customer connectivity.

		54% of pharmaceutical companies found that they had to modify systems to accommodate a customer request, but 16% reported being unable to make those changes in response to customer requests

		26% of pharmaceutical companies have experienced an increase in bad or incorrect data exceptions as a result of the compliance requirements. 53% have found that missing data and 47% have found that bad compliance documentation has resulted in product quarantine.

TraceLink’s first Drug Supply, Safety and Traceability Report suggests that 19% of pharma companies, 11% of distributors, and 9% of dispensers still haven’t begun to address lot-level serialization requirements. Only 20% say their CMOs will be ready for the November 2017 deadline.

Speed Bumps on the Way to Lot-Level Traceability

For the past few years, to help pharmaceutical manufacturers improve and sustain better product quality, FDA has been working with industry to define the metrics and key performance indicators that are most critical to product quality (1). This work actually began in 2008, with the release of the International Council for Harmonization of Technical Requirements of Pharmaceuticals for Human Use’s  (ICH) Q10 (2), which articulated the need for a systemic approach to quality that would get beyond the case-by-case approach of current good manufacturing practices (cGMPs) and final product testing.

	After FDA released initial guidance on quality metrics in 2015 (3), there were complaints about its broad scope. FDA had asked that manufacturers collect data for 10 metrics. In November 2016, FDA released a second version of the guidance (4), which focuses on the following three main metrics: Lot acceptance rate, or the number of accepted lots within a timeframe divided by the total number of lots started, for primary and secondary distribution and packaging, during a given timeframe. Included will be number of lots started, released, and rejected.

	Product quality complaint rate, or the number of complaints received divided by the total number of dosage units of that product distributed during that time frame.

	Invalidated out-of-specification (OOS) rate, or the number of OOS batch-release test results and long-term stability test results that were invalidated due to measurement process issues at the facility, divided by the total number of such tests performed at the facility during the time frame. Every OOS result will trigger an investigation, and the guidance specifies best practices.

	Long term, the agency’s goal is to furnish metrics that will help process operations and manufacturing teams, quality control departments, and regulators (especially plant inspectors) focus on key principles that determine product quality.  These principles should drive, not only day-to-day operations, but also investment in new technology. In addition, they should help regulators prioritize inspections to focus on facilities and companies that are at the highest risk of quality or compliance failure.

	In July 2016, FDA began to fund research that aims to analyze existing quality metrics, and to see whether new measurements that incorporate more of the language of the manufacturing plant floor and the principles of operational excellence might help achieve better results in the future (5).

	Working on this project is a team at the University of St. Gallen in Switzerland, led by Thomas Friedli, who has spent the past 15 years studying the application of continuous improvement techniques across different industries. Collaborating with Friedli is a team from the Dublin Institute of Technology, led by Nuala Calnan, and, based in the United States, pharmaceutical industry consultant Prabir Basu, who, for more than 10 years, was head of the National Institute for Pharmaceutical Technology and Education (NIPTE).

	Friedli’s team has been analyzing pharmaceutical manufacturing for well over a decade, based on the universal metrics used in automotive, aerospace, and other industries, which include “on-time delivery” and inventory levels.  St. Gallen’s surveys of pharmaceutical manufacturing operations look at such things as whether the facility or company uses total predictive maintenance, or how effectively the workforce is engaged in, or how strongly senior management supports, total quality improvement.

	Some pharmaceutical companies have been reluctant to embrace such universal manufacturing excellence metrics, with some insisting that “pharma is different,” due to the special requirements for product safety and testing. There has been debate over this topic for decades, and, even today, one sees uneven acceptance of such concepts as “process capability analysis” or process analytical technology (PAT) among drug manufacturers.

	At this point, FDA wants to see whether the language of operational excellence can further enrich the industry’s understanding of quality.  Research is still in a preliminary stage, and could not be discussed for this article, but Prabir Basu shared some of his thoughts on what the industry will need if it is to redefine, and transform, pharmaceutical quality control.

 Why is operational excellence (OpEx) so important to improving both pharmaceutical manufacturing and quality?

 Quality and operational excellence cannot be separated. Operational excellence metrics show how motivated people within a company are to improve overall performance, and quality with it.

	FDA has, in the past, taken an approach that has separated the two, as if quality were not a part of operations. The point is, that if a company is not investing in quality, that will show up in the operational excellence parameters, and they will have quality problems too.

	A great example is preventive maintenance. If you don’t have a corporate mandate and policy for this activity, you are very likely to have problems with product quality.

 Having links to existing OpEx quality parameters would be very helpful in ensuring that FDA can get pertinent information underlying deviations or batch rejections.
	Today, most manufacturing is taking place outside of the US, and FDA has limited ability to inspect all the facilities involved. Having indicators in place that are operations related and that suggest which facilities and companies might pose a higher risk of noncompliance or low quality will allow FDA to prioritize inspections. But it would be ideal if we could get to the stage where quality and operational excellence are considered as one. ICH Q10 gives us indications of how to get there.

	So, we are beginning a journey that has much potential, and we can get to this goal of a unified definition of quality, if we continue for the next three to five years.

	At this point, we are collecting data using benchmarking questionnaires, correlating between existing operational excellence measurements and quality metrics. We hope to expand the questionnaire to reflect on real quality information.

 In the past decade, we’ve heard more people in pharma talk about Deming’s approaches to excellence, yet concepts as basic as process capability don’t seem to have been widely embraced. Why is that?

 Some companies are working with the concept of process capability, but they tend to be the larger companies, such as Amgen and Pfizer. And even the larger companies don’t employ this approach for all products.

	We need to come up with metrics that will be attractive for all companies.

 That measure is too variable, because the cost of capital varies so dramatically depending on which country the facility or company is based in.

 How about the metrics that FDA is focusing on in its latest version of the draft guidance, including out of specification? Are these adequate?

 The metrics are okay but they aren’t yet tied to processes so they won’t necessarily reflect what is going on internally. For example, lot acceptance rate seems okay, but what happens if lots have to be reworked? Will the figure then be a true reflection of the facilities’ processes?

What are some concepts that might be more helpful?

 I think that Six Sigma value could provide a better indicator. In the early 2000s, a number of thinkers used to talk about doing this, but it hasn’t yet been fully accepted.

	Even if we were to use the lot acceptance rate as a quality metric, ideally some measure of accuracy could be factored in, for example, of the number of batches started, how many came out right the first time, without the need to rework them?

 What role should quality complaints play?

 This is an important metric, but first we need to define very clearly what the complaints are and where they are coming from. Are they coming from the warehouse? From distributors? From patients? From regulators?

	Some of the metrics that are currently being discussed may not adequately reflect internal processes. The beauty of operational excellence metrics is that they measure how well processes are performing, so they are much better reflections of the actual situation within a given facility or company.

	Some of the important operational excellence metrics to consider are on-time delivery and customer satisfaction. These measurements reflect internal processes.

	In addition, I believe that metrics must incorporate more of the spirit of ICH Q10, to determine the company’s quality culture, and such things as whether the firm has a continuous improvement program in place, whether its senior management is involved in quality, the degree of employee involvement, and how the company prioritizes projects for improvement (ie, whether it uses ICH Q9 and principles of risk assessment to help make those decisions).

	The most important question is whether the facility’s or company’s processes are in a state of control.  Here, key indicators are measures of variability of the critical process attributes. Even if process capability information is not available, at a minimum, trending of critical process variables and data on process drift such as shifting of the averages or changes in slopes of the trend, degree of implementation of ICH-Q9, etc. We need metrics to measure these areas, and also to identify facilities and companies that are at the greatest risk of quality and compliance failure.

	In the end, the number of rejected batches may be more important to screen than lot failures. In addition, relative numbers are more important than absolute numbers. For instance, the top 25% should have good systems in place, and the bottom 25% should receive more attention from FDA.

	It might be most beneficial to use the pillars that St. Gallen has been using to measure performance: total predictive maintenance, total quality management, and just-in-time inventory levels.

	Keeping a focus on process operations will ensure that companies and regulators are monitoring operational principles, looking at stabilizing systems, and developing frameworks for knowledge management and risk management. By definition, these efforts can only make any organization more focused on product quality. 

	1. Measuring Pharmaceutical Quality through Manufacturing Metrics and Risk-Based Assessment, 

, brookings.edu, May 2014. 
	2. ICH, ICH Q10, 

 (PQS), 2010, ich.org.
	3. M. Mezher, “

FDA Releases Long-Awaited Quality Metrics Guidance

,” raps.org., July, [2015], July 28, 2015.
	4. FDA, 

, Draft Guidance for Industry, November 29, 2016, FDA.gov, November, 2016.
	5. T. Friedli and P. Basu, “Measurement of Pharmaceutical Quality in an Operational Excellence Environment,” in CPhI Annual Industry Report, 2016, p. 15.

	When referring to this article, please cite it as A. Shanley, “Defining Quality: Joining the Quality Lab and the Plant Floor," 

As pharmaceutical quality metrics evolve, they will need to incorporate more of the principles of operational excellence, says consultant Prabir Basu.