Susan Haigney

Scaling up a drug manufacturing process is demanding under the best circumstances. The added pressure of meeting accelerated deadlines during a pandemic presents additional challenges for process development, materials supply, equipment acquisition and installation, and process validation.

Representatives from API and equipment manufacturers, as well as contract development and manufacturing organizations, shared with 

their perspectives on challenges and strategies for the scale up of different drug types under pressure.

 What kind of challenges occur when scaling up manufacturing within a short time deadline (e.g., when trying to meet demand for drug shortages)?

Sripathy Venkatraman, vice-president, Global Chemical Development, AMRI:

 When you need to scale-up quickly, several challenges to quality and safety come to mind, particularly inadequate data from small-scale experiments, especially around process safety. Another is poor understanding of the impurity profile and how that translates at scale. Shortened timelines can affect process development and understanding of the edge of failure, which is important for transfer. For example, not understanding the mass transfer and heat transfer can result in repeated rework of batches in order to meet specifications.

 I would say that all the normal scientific challenges we face, which chemists and engineers work to solve, are amplified under compressed timelines. For example, a common problem—if you don’t set the right specifications for scale up—is impurities. Setting specifications, whether for drug substance or drug product, is challenging and if not done properly can result in deviations or out-of-specs at scale up and regulatory delays. From a supply-chain perspective, getting all the raw materials for the product is challenging; you might not have enough batch history or know the vendors and their manufacturing record regarding quality.

Todd Stutzman, director of Pharmaceutical Development, Catalent, Kansas City:

 During scale up, it is common for scientists to have only limited quantities of API to use in process qualification. Experience of model design and in the identification of potential critical process parameters (CPPs) are crucial to the successful scale up of new chemical entities (NCEs). Process optimization has benefited from the use of a design-of-experiment (DoE) approach using fractional factorial software for decades, but recently, new approaches in modeling have allowed these experiments to be conducted whilst consuming significantly less API. This provides an opportunity to complete the development design space earlier and accelerate the introduction of NCEs.

Tim Gardner, director–Manufacturing and New Product Introduction, Vectura: 

For inhaled medicines, immediate challenges in the short term revolve around speed of supply due to increased demand for device components, as well as excipients and APIs, with potential pinch points around lead times that need to be overcome. The ability to be agile in balancing existing projects, and those that require urgent short time delivery, can be challenging. However, with the right team focus and clear equipment utilization and KPIs [key performance indicators] in place, demand can be met. The ability to repurpose or procure additional equipment and resources with speed is also key.

Ilan Avni, vice president, Business Development, Marketing & Intellectual Property at Wavelength Pharmaceuticals:

 When demand earlier in 2020 required that we triple and quadruple output of several urgently needed APIs for critical care of COVID-19 patients, we were well prepared for the challenge. That included having properly designed processes, a highly experienced team, and a robust supply chain. In-depth knowledge of process design, comprehensive process characterization, and control of critical parameters were essential to ensure scale up is successful the first time, both in terms of product quality and yield. Supply chains must secure sufficient supply of additional raw materials to meet expanded production.

Ralph Landau, head of Development, Drug Product at Cambrex:

 Our vast experience as a contract development and manufacturing organization (CDMO) has taught us that although the challenges that are faced during such situations vary from case to case, there are three common challenges: safety, supply chain resilience, and communication/transparency with customers.

Communication with customers is a crucial challenge to overcome. For instance, we have deployed Realwear technology from the start of COVID-19 lockdowns at Cambrex to help clients envision scale up manufacturing of their product(s).Realwear technology is one of the cutting edge mobile interactive video systems in which customers can see and communicate with the entire manufacturing facility as if they were walking through [it] themselves. They can safely observe the manufacturing process without physically being there.

Tania Pereira Chilima, deputy chief technology officer, Univercells Technologies:

 Technology selection is extremely important and will highly affect process scale-up. Manual technologies are typically easier to adopt as companies are rather familiar with these systems. However, these technologies are not scalable, which has a significant impact on COG [cost of goods], CAPEX [capital expenditure], and capacity given the footprint and skilled labor numbers required to support products with very high manual demands.

When it comes to bioreactors, achieving the same performance at large scale as in small scale under pressure can be very challenging and require significant expertise, and hence, companies selecting between manufacturing technologies must be aware of the trade-offs associated with them.

Byron Rees, senior manager, Process Development Services, Pall Biotech: 

While the principles of scale up are universal, each product comes with its own unique set of challenges. This is particularly true of therapies with less established platforms such as viral vectors used for gene therapy and any viral vector based therapeutic, or, most pertinent now, viral vaccines. Long cell-doubling times for mammalian systems slow down upstream process development (PD) and the ability to generate material for downstream PD to optimize for yield. Analytical cell-based assays with long turnaround times, low throughput, and product complexity may also present challenges, so efforts must be made to identify rapid surrogate assays that can be used for PD purposes. Many suppliers do provide small-scale PD devices that allow for high throughput and DoE experiments.

What is the best strategy for scaling up under a deadline? How can quality be ensured during scale up?

 Ultimately, the best strategy to ensure product quality during scale up is quality by design. When process design is done properly at lower scale, it inevitably paves the way to more efficient scale up—right first time. An experienced team will be well-practiced in identifying any process design gaps and will make sure to complete any missing data before moving to scale. Having the internal capability and experience to troubleshoot is also vital to keep such projects on track.

Quality by design is essential here, building quality into your processes. And teamwork is essential to that. You cannot anticipate all the challenges if, for example, you don’t involve the late-stage production staff early enough and ask, ‘Can you scale this process up?’ Well-staffed QA/QC [quality assurance/quality control] can ensure that process assays, cleaning method validations, and raw materials—and final product-release—happen on time. A robust, electronic QMS [quality management system]—not paper—brings efficiencies and quality enhancements. Lastly, it is important to accept only projects that fit the capabilities of the organization to avoid failure, especially in times of drug shortages.

 One strategy is running process development and analytical method development in parallel, versus sequentially. A common mistake, under tight timelines, is to push analytical method development to the very last stage. But to succeed in rapid scale-up, once a process is set, you must move quickly to understand the edge of failure for critical process parameters. Another strategy relates to availability of raw materials and identifying suppliers early on. You must qualify suppliers and set specifications for the materials. Understanding the quality tolerance of the materials sooner, and purging impurities, will help in consistently meeting the critical quality attributes.

 Time can be reduced by the approaches mentioned previously; however, there is a chronological order which must be followed in order to ensure that quality is built into the process. Process optimization test results and proper interpretation of the data must be completed prior to embarking on scale up/confirmation activities, and sufficient API quantities must be available for a minimum number of confirmation batches, and should include provisions for boundary batches, which are processed at a scale representative of commercial production. These batches establish the upper and lower limits defined in the master batch record, which is derived from the process optimization studies. The confirmation and boundary batches provide a complete picture of commercial manufacturing ranges and minimize risk to a successful pre-approval inspection (PAI).

 Every scale-up is under a deadline, so a plan becomes the critical pathway to quality. We use baseline engineering runs at full scale whenever possible to learn what to expect upon scale-up. This is confirmatory in nature and allows our team to collect as much info as possible to tweak the final process for registration scale-up batches. We allot for raw materials timings as part of our supply chain resilience, to avoid delays due to starting material hang ups.

 Scale up goes fastest when teams have deep knowledge and experience of both the product they are trying to scale up and the equipment that they are using. Of course, it is usually not practical for groups to have deep knowledge of their drug product or expertise with the manufacturing equipment: Therefore, some process development is essential for achieving a successful scale-up. 

Suppliers often have deep engineering knowledge and operational bioprocess experience of their equipment and how it performs in lots of different applications. Therefore, partnering with your equipment suppliers can often significantly accelerate process development.

 Strategic selection of cross functional, dedicated teams [is] need[ed] to manage the synergies required to scale up at speed. Streamlined protocols that ensure all CQAs [critical quality attributes] and CPPs are captured are preferential, to maximize the time spent gathering data for quality assurance and good practice (GxP) compliance purposes. Simplicity is paramount, and reduction of complex documentation is the key to meeting tight deadlines for demand when drug shortages are faced.

What are some best practices for streamlining scale up?

There are many, starting with superb project management—bringing the team together, with excellent coordination between chemists and engineers, to provide insights earlier in the process. You want team ownership of success, which requires seamless handoffs between early development and large-scale manufacturing teams. I’d add heightened supply chain control, from excellent vendor management to avoid issues with raw and starting materials not meeting specifications. Another would be having both the right equipment and personnel to study and evaluate scale-up parameters.

 Streamlining scale-up effectively is essentially a large planning exercise that considers all the moving parts of a process. Cutting-edge equipment and capacity are extremely critical, particularly for processes scaling into larger batches. We start with confirming the target scale-up equipment needs, from both a technical and staffing perspective, verifying that we have the right technologies that enable scale-up and the right people to operate the equipment. We plan for any points of changeover, and if there are disposables involved, ensure that all those resources have been ordered and are available to keep the process moving.

Each process is different, which means different potential problems. Development work should be well-documented, including any specific requirements for scaling of batches. And this work cannot ever be viewed as ‘complete’.

A focus on communications and continuous monitoring allows for threats to be identified early and dealt with before they cause disruption. Now more than ever, this also includes planning for capacity, with the availability to spread processes over multiple similarly equipped plants and conduct parallel manufacturing if/as required.

 Acknowledging the many different challenges of scale up is first. This translates to performing rigorous process design; using equipment and methods representative of commercial processes during scale up; and meticulously qualifying suppliers of raw materials to ensure a robust reliable supply chain. Wavelength continuously invests in our supply chain, carefully selecting our suppliers based on their quality processes and regulatory track record. We qualify at least two suppliers from different geographies for key starting material, keep sufficient stock on hand, and plan on a rolling 12-months-out so that we have a back-up in crisis situations. Another best practice is developing additional synthetic steps for manufacturing strategic products from simpler, more readily available starting materials. This paid off during the COVID-19 crisis, as we could apply these steps in-house or transfer the knowhow for quick implementation by an alternate supplier.

Pereira Chilima (Univercells Technologies): 

When it comes to technology selection, the best practices include using scale-down models that are representative of the target manufacturing scale. This will highly accelerate the scale-up process as well as reduce manufacturing costs as companies can identify optimal process designs at small scale and transfer these processes to the larger scale without significant adaption.

 Data-rich experiments can minimize or mitigate risk during scale-up. Because it is likely fewer experiments can be performed due to time constraints, they must produce maximum usable data. This requires advanced technologies that can capture data in one shot, speeding up process research without sacrificing quality. Also, a DoE approach, which is critical to understanding the design space, can give you an understanding of the space around the reaction that is very important. Modeling and simulations are also helpful in predicting and addressing issue that cannot be seen in small-scale experiments.

 Ensuring as much critical data can be captured, evaluated, and defined within the early-phase development is crucial. Early-phase development equipment and processes should be synergistic with those at the scale-up phase, thereby reducing required data capture for CPPs and CQAs. Involving late-phase manufacturing teams early in the development phases, to ‘debug’ any potential challenges early in the product lifecycle, really helps streamline scale up.

Recent advancements in compaction simulators can not only mimic tablet presses, but also roller compactors. Such simulators demonstrate how process parameters can now be established with a fraction of the API that would have been consumed using more traditional approaches. In addition to less API being required, simulation can also reduce the total time required to complete such activities. Although these new approaches reduce total API required in establishing the manufacturing design space, they do not preclude the necessity to confirm the results at commercial scale prior to product process qualification. Simulation minimizes API requirements and the risk associated with scale up activities, and confirmation batches solidify the target process parameters evaluated during the process optimization activities.


Volume 44, Number 10
October 2020
Pages: 38–41

When referring to this article, please cite it as S. Haigney, “Scaling Up Fast,” 

Articles

Industry experts discuss challenges and best practices for scaling up manufacturing under a short deadline.

Scaling Up Fast 

The COVID-19 pandemic has highlighted the challenges and complications of sourcing, tracking, and testing materials for pharmaceuticals. 

 spoke with Joe DiMartino, Luminata solution manager at ACD/Labs about the impact COVID-19 is having on the pharmaceutical supply chain and how companies can prepare for these challenges.

 The COVID-19 pandemic has highlighted potential gaps in the pharmaceutical supply chain. What changes must the pharma industry make in the short-term—and in the long-term—to ensure the quality of APIs, excipients, and final drug products?

Many stakeholders are traditionally challenged with accelerating clinical testing and commercialization timelines. This is especially pertinent today, when considering the aspirational goal of reducing the clinical trial and regulatory submission/approval timelines to support the COVID-19 infected patient’s needs.

Modern informatics technologies are needed to reduce both the reliance on document-driven decision making and human effort-dependent decision/approval points.

What steps should sponsor companies and contract manufacturers take to ensure they have a sufficient supply of API and raw materials to sustain production during a potential regional or global disruption to the supply chain?

 To ensure that the sponsor company and contract manufacturer are meeting sufficient supply, they need a communication plan. Particularly, with what has been completed and the ability to measure what they have done with the data-driven documentation. Things have arisen in the past where a contract manufacturer has changed a step in the sponsor’s process and this had global consequences to the supply chain. These issues could be prevented by using software that focuses on all analytical data associated with the batch material.

What measures should sponsor companies take to ensure an appropriate supply of materials during fluctuations in demand of certain types of drugs?

 Currently, there are supply chain systems that focus on production planning, demand planning, and location of batches. When we think of appropriate supply we shouldn’t be thinking only quantity of material but also quality. While the systems I mentioned earlier may help organizations with quantity, the way batch data [are] currently managed means there is a disconnect with the analytical data that can speak to quality of batches, which is equally important.

Manufacturers need to know if all batches are consistent in their content, and this becomes a crucial element when there are multiple contract manufacturing partners.

Do you foresee changes in global regulations of the supply chain to address complications that can be caused by a crisis similar to a pandemic?

 Global regulations already have measures in place for fast track, priority review, and accelerated approval. These digital systems capture all of the pertinent data used in preparing the human readable reports, which supports the QA [quality assurance] review-and-approval release step.

I do believe that storing and managing ‘structured’ datasets in persistent data management systems would help QA staff perform any type of follow up queries to create any further reports.

How does a company track the chain of materials from the original manufacturing site?

 There are systems that currently track the chain of materials from the original manufacturing site to the sponsor company site. Luminata offers a ‘manufacturing process-to-data’ association that is missing today. The ability to view the supply chain in one place, where not just meta data [are] associated to a batch, but also all analytical data [are] associated to prevent any issues from arising. For example, the genotoxic impurity that caused the recall of Valsartan.

Do virtual inspections of API, excipient, and materials suppliers impede the ability to ensure a safe, secure supply chain?

 It becomes quite difficult if the sponsor company is doing virtual inspections. They would need to have experienced group members and an informatics platform that they can easily access and identify if any batches have unexpected impurities in the supply chain.

The COVID-19 pandemic has highlighted the challenges and complications of sourcing, tracking, and testing materials for pharmaceuticals. Pharmaceutical Technology spoke with Joe DiMartino, Luminata solution manager at ACD/Labs about the impact COVID-19 is having on the pharmaceutical supply chain and how companies can prepare for these challenges.

Data and the Supply Chain

The supply of safe and effective medicines is crucial for the patients that rely on them. Drug shortages are an ongoing problem that regulators and industry work to address on a continuous basis. Drug shortages may arise from a variety of situations, including a lack of sufficient supply of APIs, raw materials, and excipients. And the reasons for material shortages can range from quality control issues at a particular facility to the complications caused by global crises, such as the COVID-19 pandemic.

For pharmaceutical companies, the COVID-19 pandemic has stressed the need to enhance supply chains, according to Ilan Avni, vice-president, business development at Wavelength Pharmaceuticals, a developer and manufacturer of APIs. “This includes prioritizing suppliers with a spotless regulatory compliance track record and uncompromising quality culture, who are continuously investing in improving and strengthening their own supply chain to assure uninterrupted supply,” says Avni. He recommends having at least two qualified suppliers from different geographical areas and having a sufficient amount of key raw materials in house.

To keep the supply of pharmaceutical materials safe, Andrew Badrot, CEO of C2 PHARMA, an API manufacturer, believes that global quality standards should be strengthened, and regulatory audits of foreign facilities should be performed without prior notice. “Still, mandates would need to be in place to avoid preferential treatment to local industry. For example, the recent announcement from China’s National Medical Products Administration (NMPA) suspending the import of Bristol Myers Squibb’s blockbuster drug Abraxane opened the door to two local Chinese manufacturers to fill the gap” (1), says Badrot.

In the short term, Sebastian Tomlin, logistics manager at Charles River, a contract research and development firm, says that time and investment in supply chain management and logistics operations are needed to expedite the movement of materials during this crisis. “Oftentimes there are multiple routes that can be considered from a transportation perspective, that are sometimes overlooked. It is even more critical to ensure the accuracy of documentation the first time around, so as not to jeopardize a time slot in an operation that may have reduced capacity,” he says.

Badrot stresses that pharma manufacturers and suppliers should have plans in place to ensure a healthy supply of ingredients so they are prepared for a crisis, should one happen. “It should not take an extreme event, such as this pandemic, to make this a priority,” says Badrot. In response to the COVID-19 pandemic, he says, being prepared and choosing good suppliers are becoming popular topics for pharma companies. “Reliability and redundancy of supply have become more than simple buzz words in procurement departments, and good suppliers of ingredients will be prioritized over less reliable ones,” Badrot explains. “By far, a cradle-to-grave supply chain with local starting materials, ingredients, and excipients for essential drug production will help to support resilient supply chains by removing the reliance on imports and driving new investments in green chemistry and Pharma 4.0 efforts.”

What can pharmaceutical companies do to ensure they have a sufficient supply of APIs and raw materials to meet their production demands? Maintaining a high safety stock of critical APIs and other materials is imperative, says Vincent Colicchio, vice-president and Head–Supply Chain and External Manufacturing for North America Generics at Dr. Reddy’s Laboratories. “Many pharma manufacturers and contract manufacturers maintain only two to three months of API supplies and other critical materials on hand.They need to consider increasing the inventory levels to four to six months. Even though the investment is higher, the ability to meet customer requirements is critical during any supply chain disruption. This will provide companies with a competitive advantage and allow the business to continue,” says Colicchio.

Having a stringent process for qualifying material suppliers is also important, according to Hamilton Lenox, senior vice-president, business development at LGM Pharma, an API sourcing and supply chain management company. “Ideally, to qualify manufacturers, you’d include an in-person visit or audit,” he says. Lenox also recommends having a dual-sourcing strategy for APIs and excipients. “If practical, we recommend having a second and third source identified and qualified; in the event something happened to your first one or two suppliers, you’re never left with just a single source.”

Understanding the supplier’s supply chain and looking for potential problems are key to de-risking the supply chain, says Lenox. “For example, if all your API suppliers are sourcing key raw materials from a single source or a single country or region, this is a risk. Diversification of the supply chain is critical. Another step is evaluating the safety stock of your suppliers; some maintain three to six months, while others order only on an as-needed basis; in a single-supplier situation with a disruption, even three to six months safety stock may not be enough. Check your suppliers’ safety stock system to ensure it meets your needs,” he says.

Lenox also recommends preparing for changes in demand by looking for flexibility in the commercial supply agreement. “If a single finished-dose supplier regularly runs at 90% capacity, maybe they can’t handle a surge, while one at 75% may have a short-term buffer to carry through a spike in demand,” he says.

Sponsor companies should take a long-term view when purchasing key starting materials (KSMs) and APIs sourced from countries such as China to be sure production can be sustained over months, says Colicchio. He suggests companies purchase additional volumes of key APIs in advance. “Taking a longer-term view of at least six months for key APIs will allow companies to remain competitive instead of staying with three months of supply of key APIs, for example,” Colicchio states.

Tomlin stresses that pharmaceutical companies must have more robust plans in place to establish supply alternatives. “It is important here to consider the depth of a sponsor company’s supplier network, and to look more closely at alternate procurement options for materials. This should take into consideration the normal lead time from order to availability, but also the geographical location of the origin as transportation and export/import regulatory compliance can have a negative impact on timelines for availability, particularly during unforeseen circumstances (such as the COVID-19 pandemic),” says Tomlin.

Broadening sourcing options and sourcing in different geographical areas reduces the risk of delayed materials, says Tomlin. “Reviewing a supplier’s disaster recovery plan in detail can help assess the level of risk associated with a supply chain.” Tomlin also states, “I think that having predetermined alternate options for sourcing in different geographical locations, and a plan to implement them, can help reduce the risk associated with supply from a single geographical location.”

Shailesh Vengurlekar, senior vice-president, quality and regulatory affairs at LGM Pharma, stresses not to get caught up in cost. “We evaluate what we call the Four Rs: Reputation, Resources, Reliability, and Regulatory History. Supply chain partners are business decisions and cannot be driven only by cost because lowest cost doesn’t factor in hidden costs,” Vengurlekar says.

Performing supplier inspections during a crisis

The COVID-19 pandemic has forced the industry to work in new ways, including performing virtual audits and inspections of facilities and materials suppliers. But how effective are these tasks when done virtually? “Virtual inspections can be useful as a supplement but can only be an intermittent or temporary measure. In no way can they replace physical inspections, nor should they become a regular occurrence. The reason is that there is no way for a virtual inspection to ensure/validate compliance to GMP if they are used for a prolonged period or as a stand-alone effort,” says Badrot.

Colicchio warns that identifying compliance problems is difficult with virtual-only inspections and missed problems could lead to supply disruptions. “Much can remain hidden, and virtual inspections will likely not be able to see all potential production, warehousing, and facility issues and gaps at the site.This could lead to an inadequate inspection of an API producer that in turn could lead to quality problems with the API in a finished drug product.The API and finished drug product suppliers are critical nodes in the supply chain,” he says.

While virtual inspections may work for already qualified suppliers, Vengurlekar says that when it comes to choosing new suppliers, virtual inspections may impede the process. “In-person inspections let you walk around the facility, see how it’s maintained, check its water source and environmental monitoring. You can see the equipment to evaluate for potential cross contamination, and check lab spaces, storage, and warehousing. You cannot get that picture with a virtual inspection. That said, virtual inspections are suitable for previously qualified vendors. If you’ve already been there, a virtual visit is appropriate as someone explains a new process, since you’re just sharing documents and reviewing data. But for an initial process or facility inspection, you should rely on in-person inspection,” he says.

The testing of APIs and raw materials is crucial for ensuring that pharmaceutical products are safe and effective. And establishing incoming testing control protocols is necessary to be GMP-compliant, says Badrot. “Each company is required to have its own incoming testing control protocols to be GMP-compliant, and this level of testing will be fully integrated into the manufacturer’s quality control processes. When we receive incoming raw materials, everything is tested and documented according to our DMFs [drug master files] and CEPs [certificates of suitability]. In some cases where we see the need for extra traceability, we will work to develop and validate our own analytical methods to increase accuracy and reliability of our tests,” he says.

Tomlin states that materials testing is dependent on the project and the customer. “From an import/export regulatory perspective, documentation required varies widely dependent upon the nature and final use of the material being imported. From a US viewpoint, for example, there are considerations to be made from a US Customs perspective, but also other regulatory agencies such as the United States Department of Agriculture (USDA), Centers for Disease Control and Prevention (CDC), FDA, and US Fish and Wildlife Service (FWS),” he says.

LGM Pharma has separate procedures for qualified suppliers and new suppliers. The company requires a certificate of analysis (CoA), all shipping documents, and the material safety data sheets from suppliers that have already been audited and qualified, according to Lenox.“With a new supplier or with any concerns, we advise our clients to do the release testing themselves. It can be very dependent on the product and the nature of the relationship with the vendor—their reputation, reliability, qualification status,” he says.

“If LGM Pharma had a lab to conduct testing, in addition to obtaining the CoA, I’d want to perform two tests—an identification test and an assay or potency test. These are valuable as part of testing received materials,” adds Vengurlekar.

The pharmaceutical industry’s reliance on offshore API and raw materials manufacturers has been a topic of interest for several years, especially when incidents such as the heparin contamination in 2008 cause injury and deaths to patients (2). And complications arising from the COVID-19 pandemic have once again put the idea of moving the manufacturing of pharmaceutical ingredients from foreign to domestic facilities.

In the United States, calls for bringing pharmaceutical ingredient manufacturing onshore have increased recently from some political circles. In May 2020, the Biomedical Advanced Research and Development Authority (BARDA), part of the US Department of Health and Human Services, awarded a contract to the newly-formed Phlow Corp. to produce pharmaceutical components and critical drug products in the US (3); other measures by the federal government to move production onshore have been met with mixed responses (4).

While the use of foreign API and raw materials suppliers creates concerns about quality and drug shortages during global crises, the dependence on foreign suppliers has potentially hurt the US pharmaceutical industry from a business perspective, as well, according to Lenox. “There is a strategic argument to be made that we in the US have collectively weakened our supply chain position. Most generic production, particularly of APIs, has moved offshore, putting us at risk. If COVID-19, and the potential for geopolitical disruption such as a trade war with China, has taught us anything, it’s that we cannot be entirely dependent on an overseas supply chain. And we are. Even generic drug and API production in India is dependent on Chinese raw materials and key intermediate supply. We need to move in the direction of reshoring a portion of the pharmaceutical supply chain. But it’s not going to happen overnight. Our domestic pharma business model cannot support it, as China and India have efficient models that keep costs low because they aren’t accountable to the same legal, insurance, and other impacts. Chinese industry also enjoys the support of its government,” he says.

So, how would moving raw material manufacturing onshore impact the supply chain? Having domestic manufacturing of materials and APIs would eliminate the reliance on imports and stabilize the supply chain, says Badrot. He warns it will increase costs, “but quality will also improve and most importantly, so will reliability and availability of supply in times of crisis. Everything has a cost, and that [is] one well worth paying for.”

Is moving production of materials onshore feasible? Colicchio warns that onshoring will increase costs and it would take time to build or modify production facilities in the US to fulfill demand. “The cost of onshoring finished drug products will increase at least 30–40% when including production of APIs and KSMs from US-based production facilities. The onshoring of API and KSM production presents several issues including: high capital costs to build an API manufacturing facility with sufficient long-term capacity for global supply; long lead times for permit approvals; the higher labor cost to produce APIs in the US versus China and India; and the higher capital investment for abatement systems to minimize environmental problems associated with API production,” says Colicchio.

There would also be some cost savings, according to LGM Pharma’s Vengurlekar. “China captured the US market by providing low cost. It could provide drug product manufacturing at less than half the cost of domestic production. But what Big Pharma didn’t anticipate, or even ignored, as it moved much of the supply chain to China and India, was issues with quality and intellectual property. They also didn’t consider potential hidden costs, such as the cost of monitoring overseas production. It’s a net positive to reduce our reliance on overseas production,” says Vengurlekar.

Badrot stresses that while price and quality are two factors that industry will take into consideration when discussing the move to onshore materials manufacturing, those factors are not enough to change how things are currently done. Government mandates will be necessary to create significant change, he believes.

“Comprehensive policies and government funded initiatives are needed to encourage the implementation of innovative and flexible manufacturing assets (which already exist) that will allow countries to quickly establish sustainable and independent manufacturing supply chains for essential APIs and drug products,” Badrot says. “At the same time, establishing economical barriers to imports, whether in the form of preferred access regulations, mandates for domestic supply, financial grants, or import duties would further these efforts. The approach could be similar to the mandates the defense industry has for using locally made components and domestic manufacturing. And though some argue this is too difficult or costly to implement, it is in fact the only responsible way forward for governments to establish effective policies that protect their citizens when the next pandemic hits.”

Lenox agrees that government intervention might be necessary to promote moving pharmaceutical material production onshore. “We believe government incentives of some form are needed to get companies to reshore production, more so of APIs and raw materials than finished dose forms,” he says.

“The US must recover from its loss of small-scale manufacturing. The US should encourage this manufacturing industry to flourish here, to bring back one-product manufacturers or those that do a handful of products really well,” says Vengurlekar.

The safety of the pharmaceutical supply chain is of utmost importance during “normal” times; the COVID-19 pandemic has illuminated potential pitfalls of the pharma industry’s heavy reliance on a global supply chain for critical ingredients and drug products. Increasing domestic production of APIs and other pharmaceutical materials is an option for boosting the supply and ensuring the quality of these materials. However, such a transition has a long timeline.

But what can be done in the meantime? Colicchio says another option is increasing the safety stock of these materials. “The way to accomplish this is to increase the amount of the national stockpile and require any manufacturer working with the government to carry at least six months of finished drug products in the US distribution centers.It is important to also conduct stability studies to extend the shelf life of the drug products to increase the expiration dating when maintaining higher safety stocks. This will yield a positive impact on the supply chain,” he says.

BeiGene, “BeiGene Announces Supply Update for ABRAXANE in China,” Press Release, March 25, 2020.

J. Wechsler, “Partnership Gets Millions to Supply US-Made Generics for Pandemic,” 

J. Wechsler, “Buy American Proposals Rile Manufacturers and Trading Partners,” 


Volume 44, Number 8
August 2020
Pages: 16–20

When referring to this article, please cite it as S. Haigney, "Ensuring a Safe and Robust Supply of Pharma Materials," 

The COVID-19 pandemic has raised several questions about the safety of the pharmaceutical materials supply chain. Is onshoring the answer?

Ensuring a Safe and Robust Supply of Pharma Materials

 spoke with Matthew Woodcock, director of LLamasoft, a supply chain analytics company that assists companies in their decision-making and supply chain challenges, about the impact the COVID-19 pandemic has had on the pharmaceutical supply chain.

 How can pharmaceutical companies and contractors prepare for a crisis, such as a pandemic, when it comes to protecting the pharmaceutical supply chain?

 COVID-19 has demonstrated that we live in a world of the ‘never normal’. That is to say that there will always be unforeseen disruptions to the supply chain, and companies must be prepared for any eventuality. The traditional remedy is to hold extra inventory, in order to bridge a supply gap or a change in demand. As significant world events only seem to be happening more and more frequently, companies need to consider what level of stockpile they will need to maintain a constant supply of critical drugs.

However, stockpiles are no good in the mid to long-term. If organizations are to ensure that their supply chain is more resolute moving forward, they need to incorporate comprehensive risk management strategies into their supply chain decision-making. This should include, but is not limited to, creating optionality for sources of supply in case of single points of failure.

What tools specifically can be used to ensure the transparency of the supply chain?

 To ensure transparency across the entirety of the supply chain, it is imperative for companies to invest in the capabilities of advanced analytics. Leveraging this technology, companies can build organizational capability to drive decisions which allow them to cope with sudden shifts, such as COVID-19.

Recent advancements in analytics, algorithmic intelligence, and cloud computing are allowing organizations to rapidly experiment and model supply chains. This allows them to react quickly and effectively to supply or demand side shocks. Meanwhile, digital twin technology could allow companies to digitally replicate and test its emergency strategies. This means that in the event of a crisis they could efficiently organize their supply chain to produce an optimum output.

 Has the COVID-19 pandemic impacted your services and/or the products you provide?

 COVID-19 has impacted almost every supply chain across the globe. For many companies, this has emphasized the ‘never normal’ nature of the global supply chain. Today the disruption is COVID-19, but tomorrow it could be Brexit, or trade wars. As a result, many companies are now seeking to manage risk within their supply chain more effectively. For example, one leading medical device company is now on a journey to enable a supply chain digital twin, allowing them to prepare for similar disruptions in the future. We anticipate that this moment in history will urge other companies to do the same.

Pharmaceutical Technology spoke with Matthew Woodcock, director of LLamasoft, a supply chain analytics company that assists companies in their decision-making and supply chain challenges, about the impact the COVID-19 pandemic has had on the pharmaceutical supply chain. 

Preparing for a Pandemic 

FDA warning letters often suggest that the pharmaceutical manufacturer receiving the letter hire a quality consultant to assist the company in fixing quality control problems at their facilities. What role can a quality consultant play in helping biopharmaceutical companies stay compliant? What measures should be taken to ensure the best match for the situation?

 spoke with experienced consultants—Aloka Srinivasan, principal and managing partner at RAAHA; Chris Moreton, PhD, partner with FinnBrit Consulting; Philip E. M. Crooker, J.D., vice president, Technical Regulatory & Access, Parexel; and Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates (RCA)—to gain insight on these questions.

What are the reasons a pharmaceutical manufacturer (sponsor or contractor) might hire a quality consultant?

 The reason for a pharmaceutical manufacturer or sponsor to hire a quality consultant may vary based on the size of the company, availability of in-house expertise, and the nature of the projects. In many cases, small companies prefer to use the service of quality consultants for their projects rather than hiring permanent staff. This gives them the flexibility of getting appropriate expertise based on the nature of the work, and can also be a better option, financially. However, mid-sized or bigger companies may also hire quality consultants when they are venturing into something new and the in-house expertise needs augmentation.

While in most cases the CMO/CDMO [contract manufacturing organization/contract development and manufacturing organization] may be hiring a quality consultant for the same reasons as the sponsor, there may be some areas where the CMO/CDMO’s reasons may be different. The CMO/CDMO may hire a quality consultant for a purpose which may be more specific.

Example, for a complex product, the CMO/CDMO may hire a consultant with a specific analytical skill related to a product that they are developing for better understanding the quality issues specific to the product or process. Overall, quality consultants are considered valuable by sponsor companies as well as CMO/CDMOs.

There are several reasons for sponsors to hire a quality consultant, but it all boils down to cost and head count. Many small biotechs do not have enough business to employ a full-time quality specialist and a consultant fits their model. For CDMOs, the reasons may be different. They may want to have someone review their quality systems and operations to point out any gaps ahead of a regulatory inspection. Or they may be moving into a new phase (e.g., from pre-clinical to clinical/commercial and need advice).

Start-ups and small companies may not have the resources to hire quality staff in-house and thus may seek experienced quality consultants to fulfill CGMP [current good manufacturing practice] regulations, which require a fit-for-purpose quality system and appropriate QA [quality assurance] functions at the manufacturer. Companies may need immediate access to deep skills in a highly specialized area (e.g., forensic investigation skills to examine data generated, collected, and reported during various stages of drug development, manufacturing, and regulatory submissions). Mock assessments and ‘pressure testing’ in between regular testing of quality systems helps manufacturers identify and mitigate gaps in advance of pre-approval inspections, post-approval audits, routine surveillance, and for-cause inspections after a product has been approved for marketing.

Health authorities may request, or require, the hiring of quality consultants to review a company’s quality systems and its remediation plans prior to or following enforcement action against a company, especially for serious or pervasive violations (e.g., when they enter into consent decrees or corporate integrity agreements with the US Department of Justice). Companies may seek quality consultants who were former regulators—such as field investigators, application reviewers, or compliance inspectors—to provide real-world insights about how a health authority would likely examine or respond to an issue.

 There are several reasons a pharmaceutical company might hire a quality consultant. In many cases the company may need expertise regarding special subjects that company personnel may not possess. For instance, a company may wish to upgrade their water system. They may wish to hire an outside consultant with significant experience in designing and installing water systems. A small start-up or virtual company may wish to hire consultants to help establish their quality systems and standard operating procedures because of the small staff that often plays multiple roles in the organization.

Companies might also hire consultants to help them work through significant compliance issues as a result of regulatory inspections. In some cases, the hiring of a consultant is in direct response to a warning letter recommending the firm hire outside expertise to assist the company in reestablishing compliant behavior and robust processes. The reasons for hiring consultants, whether you are a sponsor company or a CMO/CDMO, are consistent.

 What are the benefits or hiring a quality consultant? Are there any negatives to hiring a consultant?

Basically the advantages are head count and cost. The negatives are that the consultant may not be immediately available. In addition, a consultant may not be so intimately familiar with the activities of their client, and this can lead to misunderstandings.

There are several benefits to sponsor companies as well as CMO/CDMOs of hiring a quality consultant. The major benefit is that a sponsor or CMO/CDMO may be able to customize their engagement of a quality consultant to meet their specific needs. Several quality consultants with diverse expertise can be engaged at the same time to work on different projects. As the involvement of the consultants in most cases is for the duration of the projects, the process is advantage from the perspective of human resources management, as hiring several permanent employees for the same purpose may come with its own challenges. Also, based on the contracts between the sponsors/CMOs/CDMOs and the consultants, the timeliness of the deliverables can be assured, which in turn can help keep the projects in time and within budget.

There are a few downsides of depending fully on quality consultant. Hiring the right person for the right job can be challenging based on just the review of a CV or a brief interview of a consultant. Finding a good quality consultant can be difficult. Also, an external consultant, who is hired for a limited time may not feel the same ownership of a project that a permanent employee does. There may also be lack of quality in the deliverables, or lack of chemistry between the permanent staff and the consultant, which could cause unnecessary hindrance to the progress of the project. Finally, if the agreement with a consultant does not cover all aspects of the engagement, a consultant’s decision to discontinue with a project midway can inconvenience the company/CMO/CDMO significantly.

A specific skill or situation can be aligned with the consultant’s background and for the desired length of time needed to address the issue(s). Consultants who have experience in both private sector and a health authority confer a broader perspective and view manufacturing issues through a multi-faceted lens. A wide array of prior client engagements increases the consultant’s vantage point of possible gaps and thus their effectiveness in finding and remediating gaps in quality systems before they are identified by health authorities.

 The quality consultant typically has a number of years of experience and has seen a variety of issues that add depth to their understanding of issues. They also bring a third-party perspective, which allows them to view the organization with a fresh perspective and offer solutions that might be more effective in addressing issues facing the hiring company. Consultants usually have a broad base of experience and knowledge, and this allows them to view operations with a unique perspective. There are few negative issues when hiring a consultant provided the hiring company spends the time to review the qualifications of and interview the consultant to make sure they have the appropriate background, expertise, and demeanor for the project they are being consulted on.

What specific services can a quality consultant provide?

It depends; anything from advice on quality management systems and documentation to release of a batch of product. They can also advise on or undertake internal audits. Should it happen, they can also help in the remediation of FDA findings (483s and warning letters through to consent decrees)

 Quality consultants can provide a number of specific services to a company. They can assist in establishing a robust quality system, responding to regulatory inspections, performing supplier audits, helping implement new regulatory requirements, and advising on complex and challenging investigations.

They may help with development of quality assurance-related complex products, support with communications with regulatory authorities (483 responses, warning letter-related communications), train the staff related to various aspects of quality control, review regulatory materials, perform gap evaluations in the process, data acquisition and perform due diligence in mergers and acquisitions, perform audits, [and provide] support with solving numerous compliance related problems. Some of the quality consultants may have specific expertise in specific dosage forms [and/or] devices, which may be of great support to the sponsors/CMOs/CDMOs.

What to consider when hiring a consultant

 What are the steps for hiring a quality consultant?

 Companies identify quality consultants by surveying the marketplace (via websites, social media, online references), acting on recommendations, and using companies they’ve successfully engaged in the past. Once identified, consultants may be asked to submit a proposal to the company.

Based on the combination of the firm’s review of the consultant’s credentials and the response to the proposal, the firm can decide to move forward in the process and award the work to the consultant and reach a contractual agreement, negotiate further with the consultant or the consulting company, or continue their search without reaching an agreement. Manufacturers may have internal processes hosted by numerous functions—such as quality, technical operations, supply chain, and human resources—that they use to evaluate and select service providers.

There is no specific rule for hiring a consultant. There are several organizations that have pools of consultants with diverse skills and may be able to provide a company/sponsor/CMO/CDMO with a list of qualified consultants who have experience in the specific area. However, one should never hire a consultant based on just the qualification. It is imperative that the hiring manager, and possibly the other members of the department who are expected to work closely with the consultant, interview the consultant before hiring.

Certifications in specific areas may be helpful. There are also some certification programs like the [Regulatory Affairs Professionals Society] RAPs Certification. Again, the value added by these certifications are questionable. There may be excellent consultants who do not have any certification. More than certification, the qualification and interpersonal skills of the consultant and references should be the prerogatives in the selection process.

It is important for a hiring manager to select a few consultants who have the required skills and come highly recommended. The hiring manager should personally interview them to assess if the personality of the consultant aligns with that of the staff and the general culture of the company and select the best match.

 The first step for hiring a consultant is to write a scope of work for the job you are wanting the consultant’s help with. After that is finished, you can search for consultants/consulting firms that specialize in the area you are seeking expertise. It is important to screen the consultants to make sure you obtain the best consultant.

Some quality consultants may have certification, especially those consultants specializing in auditing. What’s more important than certification is experience and active involvement in the industry. Many consultants maintain their credentials and stay up to date by being members of trade organizations or writing books and articles. This experience is sometimes more important than a certification.

There is no set process. The prospective client should undertake a thorough due diligence and ask for references or cerifications such as [American Society for Quality] ASQ certification. However, there is no obligatory certification in the United States.

How does a quality consultant work with a company’s inhouse quality departments?

There may be various ways that a quality consultant works with a company’s in-house quality departments. The simplest one is ad hoc consulting. The consultant may be contracted based on need by the members of the specific department. Alternatively, a quality consultant is embedded in the department for an extended period. In this case, the consultant will need to undergo training based on the company SOPs [standard operating procedures] specific to the service he/she is providing and made aware of the working norms of the company. It is the responsibility of the hiring manager to make the consultant aware of his/her responsibilities and the company staff aware of the boundaries related to interaction with the quality consultants.

I think it is important to introduce the concept of a contract worker versus a quality consultant. Companies could have both of these consultant types working for them, but the roles and interactions will be different. Contract worker consultants are usually filling in and performing a specific job. They would interact with management just as a full time employee would interact. A quality consultant who’s role is to advise, guide, and teach should interact with management in a mentoring role. They should give management choices and options for achieving the assignment. These options and choices should be ranked from least risky to most risky with an assessment explaining why the options are ranked as they are. Their recommendations should also be supported by the regulations. The consultant should also provide implementation recommendations and potential improvements to be introduced over time to ensure continuous improvement.

 It depends on the nature of the consulting. There can be resentment and denial on the part of the client staff and senior management needs to explain the reasons for engaging a consultant, and obtain staff buy-in.

 Collaborations vary according to the nature of the concern, timing, severity of the issue, and the company’s preferred style or approach. The consultant could be embedded within the firm’s QA unit as a dedicated resource, as a temporary employee, or as a ‘person in the plant.’ The consultant could function semi-independently, simulating the role of health authority personnel conducting or evaluating an inspection where the involvement with the firm’s QA unit is at arm’s length. And then there are situations that synthesize elements from both approaches, where the consultant collaborates with the firm’s QA unit to review the results from gap analyses, assists the firm in implementing CAPA and strategic changes, or participates in responding to health authority inspection results.

How long should a quality consultant be retained? Should the consultant be a embedded service or only hired to help investigate and correct specific quality issues/problems (such as an FDA warning letter)?

 There really is no set timeline for how long a consultant should be retained. It will depend on the scope of the project and the time the company sets for completion. What is important is for management to make sure that the consultant remains independent and provides the third-party advice they were hired to provide. Consultants must guard against getting too comfortable with their client, so they can retain their independence and unbiased view of the operations they are working to improve.

I think that consultants can be either embedded or assigned to specific projects. There is a need for both of these service categories. The best way to manage the consultants in either role is to make sure the scope of the work you want them to perform is clearly defined to avoid scope creep and that they adhere to the specified project timeline unless there is an acceptable and understandable reason for a delay.

The length of time for which a consultant is retained depends on the nature of the work and the company. A consultant may work for an extended amount of time with a company, where they provide advice when needed. There are instances where a consultant has been involved with a company for years, advising the staff, when needed, on various quality issues. Alternatively, when resolution of quality issues is sought (FDA 483s, warning letters), the consultant may be retained till the problems are resolved. In some cases, quality consultants may be proactively hired to perform gap analysis of various quality system as well as evaluation of data integrity. However, an important part of hiring a consultant is to have a clear view of how long the service is required. If a consultant has been in a site for more than a year and it appears that he/she will need to be there for more time, it is possible that a permanent employee is needed for the role.

I know of quality consultants who were hired over several years at the same company, especially in the early days of start-ups as they transitioned into clinical trials, etc. However, most quality consultants are engaged for short periods, for fixed projects.

 Should a pharmaceutical manufacturer rely only on a quality consultant or still retain their own inhouse quality control and quality assurance departments?

From the perspective of the health authorities, it is expected that companies—regardless of their size or the type of organization—will have a fit-for-purpose QA function to meet CGMP regulations. The number and type of in-house quality personnel will vary across companies, but product owners and contract manufacturers cannot fully delegate CGMP compliance duties. They are responsible for the quality of the products they own and their manufacture. Thus, it is highly recommended that a firm—whether a product owner or contract manufacturer—hire the necessary in-house personnel who will own responsibility for the firm’s quality operations and decisions. These personnel can be supported by consultants, but it enhances the companies’ ability to comply with the CGMP regulations if they have established QA functions and processes in place as part of their organizations.

 From my perspective, it is better to retain an in-house quality control/quality assurance department because they will have day-to-day familiarity and knowledge of processes which can help in deviations and investigations. This knowledge is also valuable during audits because they can explain the operations to the auditor and potentially clear up any misunderstandings before they become observations. I think it is also important for companies to have a network of consultants they also rely on to help out when things start to go awry. I think the most successful organizations rely on their internal staffs and their trusted consultants to set the best culture for the company while maintaining compliance to the regulations.

If [the company is] undertaking routine clinical and/or commercial manufacture in-house, they should have their own full-time quality control and quality assurance groups. They can bring in consultants as advisors and for special projects.

 It is preferable that a pharmaceutical manufacturer has an in-house staff in all departments, especially in the quality control and quality assurance departments, who are supported by consultants as and when needed. The reason for this is the importance of ownership and responsibility related to quality of products and process. It is well known that quality-related matters can be critical for a pharmaceutical company, and having at least a limited number of internal staff in charge, supported by quality consultants, is a better option. In case it is necessary to assign the responsibility of quality control and quality assurance entirely to a consultant, selection of the consultant should be made judiciously to assure that he/she is responsible, qualified, and capable of understanding the seriousness of the assignment.

To conclude, a quality consultant can be an asset to pharmaceutical manufacturer/CMO/CDMO when appropriately engaged. However, the industry representatives should use good judgment in hiring the right person and work collaboratively with the consultant to assure the best results.


Supplement: Outsourcing Resources 2020 
Volume 44
August 2020
Pages: s29–s33

When referring to this article, please cite it as S. Haigney, "Consulting Quality," 

Hiring the right quality consultant can provide expertise and save costs.

Consulting Quality

 spoke with Bhroma Patel, head of product stability, and Baldev Jogi, lead scientist, both at Lonza; and Will Hatcher, senior manager, QC, and Rekha Patel, director, biologics analytical solutions, both at Catalent, about what steps companies need to take when setting up a current good manufacturing practice (CGMP)-compliant stability testing program for biologics.

 What are the first steps for setting up a CGMP-compliant stability program for biologics?

 The first step in setting up a CGMP-compliant stability program is to determine the analytical assays that are stability-indicating and to verify that the method qualification/validation has been performed appropriately to prove that these assays are indeed stability-indicating. After the analytical assays are determined, the next step is to set up the stability strategy, which will include long-term stability at the determined storage condition, short-term stability (accelerated and stressed), and possibly photostability or freeze/thaw studies. It is very important to be conservative with regards to timepoints within a stability study. If the appropriate amount of data [are] not gathered at the appropriate conditions, then it is possible that an entire study would need to be repeated, which becomes extremely time-consuming and costly, and could be detrimental to a regulatory filing timeline.

 An amendment agreement is required between the clients and outsourcing company to see what stages of work [are] required from start to end. This will include objective, activities (e.g., timepoints, temperatures, and intended storage temperature), test methods, and delivery of reports. In addition to this, methods and equipment require validation and specifications put in place prior to starting the stability study.

 What challenges should companies be aware of when setting up a CGMP stability program for biologics?

 The challenges companies must be aware of when setting up the GMP stability programs are that regulatory requirements, such as the ICH [International Council for Harmonization] guideline, are followed throughout the stability program, from pilot stability studies to drug product studies. Companies may require large facilities for laboratory capacity, storage, as well as stability chambers under different climatic conditions and relative humidity and freezers. In addition, companies are required to develop, validate, and evaluate testing methods and equipment to perform stability studies.

 Companies should ensure that they have redundancies in power, water, and air handling systems as well as appropriate alarm notification systems, to safeguard against possible impacts to the study. To ensure integrity of the study, sample traceability and inventory systems should also be in place. Having a sufficient volume of materials should not be overlooked. Study coordinators should ensure that they have enough materials to progress through the study as well as any investigations or extensions. If special studies are needed, such as freeze/thaw, in-use, forced degradation studies, photostability, etc., proper material amounts should be ensured as volume is often a challenge.

	Study coordinators should ensure that methods are proven to be stability-indicating during qualification/validation, are appropriately set up beforehand, and that orthogonal methods are available where appropriate. Analytical methods may change going from early to late phase (e.g., moving from ELISA [enzyme-linked immunosorbent assay]-based to cell-based), and investigators should plan for any bridging activities that may be needed. Appropriate planning also includes a thorough understanding of the study matrix and any special handling required. The timing of the study should be laid out to meet any critical regulatory filings. If planning to file globally, consider testing conditions specific to different regions in the same study, as this will provide sufficient data without the time and cost needed to conduct a separate study. 

 What are the specific regulatory requirements for a CGMP-compliant stability program?

 The specific regulatory requirement for stability programs for biologics are defined in ICH guidelines with reference to ICH Q1A (R2), 

Stability Testing of New Drug Substances and Products

, and EMA/CHMP/BWP/534898/2008 rev. 1 corrigendum, 

Guideline on the Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials

. For recommendations on how to establish shelf life or retest period based on stability studies, ICH Q1E, 

, is followed. In total there are six ICH basic guidelines for stability studies, Q1A to Q1F.

 The regulatory requirements for CGMP stability programs mainly come from ICH guidelines, specifically: Q7 11.5, Q1A (R2), Q1B, Q1C, Q1D, Q1E, Q5C. There are also regulations from the FDA (21 

211.166) and European Medicines Agency (EMA) (Guideline 3AB5a) that govern what should be contained in a stability strategy. In addition to these regulations, FDA provides guidance that can help determine an appropriate stability study strategy.

	With this bolus of information, it can be challenging to determine a clear stability strategy. However, as long as the assays performed are stability-indicating and the stability strategy includes long-term at storage condition, accelerated and stress stability studies, in most cases this can be enough for an initial filing. As a product moves through the clinical lifecycle, photostability and freeze/thaw studies will need to be performed. Additionally, depending on the properties of the product and the results of the stability studies, additional studies may be warranted.

Can you provide an example of how a company can ensure their stability program is following regulations?

 Companies can ensure [the] stability program is following regulations by [creating] standard operating procedures (SOPs) to help set up stability studies and protocol in compliance with regulatory expectations.

	[A] stability program should be described in the protocol to support the shelf life and storage condition and include:

		Objective/scope of the study (e.g., the stability study results may form part of submissions to the regulatory authorities to support the use of the product in toxicological studies and clinical trials).

		Storage conditions (e.g., intended, accelerated, and stress storage conditions)

		Sampling plan (e.g., samples to be tested at 0, 3, 6, 9, 12, 18, 24, and 36 months)

		Stability indicating parameters for testing of product characteristics, identity, potency, purity, and safety, which have been developed and validated

		Stability test methods (e.g., capillary electrophorsis sodium dodecyl sulfate [CE SDS], image capillary isoelectric focusing [icIEF], gel permeation chromatography [GPC], ELISA), which have been qualified for usage

		Acceptance criteria (e.g., limits for the test results)

		Reference standard to compare the sample against

		Approval process (e.g., approved by quality assurance [QA])

		Stability chambers are serviced, inspected, calibrated, and qualified regularly

		Out of specification and out of trend SOPs

		Evaluation of the acquired data to provide a shelf life

		Trained operators, which includes GMP training and data integrity training annual.

Industry experts discuss the challenges and regulations of setting up a CGMP-compliant stability testing program.