Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

The past decade has seen cell and gene therapies move from research concept to reality, as treatments such as Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel) have become full-fledged commercial products covered by patient insurance. As development continues to progress for allogeneic and autologous treatments, there is an urgent need for predictable and consistent manufacturing methods, and the means to measure them.

	In 2017, more than 600 clinical trials were in progress involving innovative therapies (1, 2), and, by 2018, FDA had received more than 700 investigational new drug (IND) applications for gene therapies (3). Growth in allogeneic treatments will require more efficient downstream separation and cell harvesting. Doses are expected to be in the billions-of-cells range, and batches made in quantities of up to 200 L (1).

	Separation becomes a different problem for innovative therapies, as compared with conventional biopharmaceutical processes, because irrelevant adherent cells disaggregated (2). Companies such as Novartis and Kite Pharmaceuticals have already refined processes that allow cells to be manufactured in two to three weeks, while work on other new manufacturing platforms is progressing. Biopharmaceutical consultant James Blackwell shared some insights into the challenges that these therapies entail with 

What are the biggest challenges with these therapies?

For commercialization, on the drug product delivery side, it’s much more challenging because the systems are much less well understood in terms of adsorption and potency, and you have related issues with scaling up.  Their behavior in a clinical setting needs to be understood. Also, scale considerations will determine how you deliver product to the patient in those settings.

	In order to achieve lower cost of goods sold (COGS) for autologous products, traditional batch area clearance concepts and the controls around them need to change. If you have a factory, a facility, or site that is manufacturing personalized medicines, you can’t be commercially viable if you have an individual processing suite for each patient.  

	Scaleup comes down to processing more single units, or doses, and the individual operations around the flows of a single product. These operations will occur in parallel. So, what’s really important is data integrity and the controls you have around the control space of that product lot on the production floor to prevent cross contamination or mix-ups and to provide validated documented evidence that none occurred. 

	You can use technology and advanced controls on the floor so you have an area around the lot that’s controlled, (e.g., by using barcode scanning and radio frequency identification [RFID]). Scaleup then becomes about operational excellence and achieving efficiencies on the operating floor and scaling those in parallel. The quality metric performance levels of the past won’t be acceptable any longer because failure won’t be an option for these types of operations. You will often be dealing with critical patients and materials will be needed for scheduled surgeries.

How will traditional definitions for established terms such as ‘batch’ and ‘lot’ change?

: The definitions will be the same, but their interpretations and implementation in a manufacturing setting will be novel. Adjustments will be required, both on the part of manufacturers and regulators.

	For example, we have a client that is developing a personalized therapy in a process that involves taking a sample from a patient, sending that sample to the lab for analysis, then, based on results, generating data to inform the manufacturing floor on various subunits, or lots, to be manufactured. These lots are combined to form a single batch that will be delivered to the patient.

How will the manufacturing plant floor need to be set up?

The floor must be set up in a way that is different from anything we’ve seen before because, with autologous therapies, personal patient data will be used to drive manufacturing and the necessary controls. We will also need to consider manufacturing in a hospital setting, in a situation where samples are taken right from patients, and the product is manufactured in equipment near that patient and delivered directly to his or her bedside. In this case, product could be considered as both a batch and a lot. Generally, anything that needs to be tracked individually would be viewed as a lot and would then go into a batch, which would be delivered to the patient. 

How will any adverse events that are tied to manufacturing be handled in this type of setting?

: The challenge stems from the fact that many of these therapies will need to be delivered just-in-time (JIT) to the patient. Existing technologies, manufacturing and supply chain practices, and testing methods haven’t caught up yet. Data and information need to be archived and accessible in a compliant manner in order to generate needed actions, and the reaction time will need to be instantaneous. Response rates will need to be in real time, so data access and integrity will be crucial.

Information technology (IT) and information sharing must be integrated holistically into a data sharing system. Controls will need to be rationalized and thought through so that there will be no cross-contamination or mix-ups. The quality system will then be able to release by exception and demonstrate that that all controls and procedures have been executed properly. 

What tweaks will be needed for allogeneic therapies to work within the traditional cGMP regulatory framework?

The cells will be the product, so tighter controls will be needed (e.g., more care and control of materials that go into the process and more control over the process itself). If there is an upset to the process, manufacturers will need to prove that it will not result in a change within the cells that could affect their efficacy and potency. Proactive control is the best way to avoid having these types of questions come up.

Are you seeing innovations in the equipment and IT designed for innovative therapies? 

For allogeneic therapies, the technologies are pretty much the same (i.e., single-use disposables). Most of the innovation is occurring in autologous product development, where we are seeing more self-contained units that prevent cells from being exposed to external environmental conditions. 

Will traditional quality metrics work for these therapies?  

When you think about it, these products, especially autologous therapies, will require use of right-first-time and JIT concepts, which pharma has lagged behind other industries in adopting. It won’t be business as usual. Lean thinking and concepts like it will be essential because, if the product doesn’t get to the patient on time, results can be catastrophic.  With personalized medicine, surgeries will be scheduled based on dosing. In addition, many of the patients for whom these treatments are being developed are seriously ill. 

	These limitations will present significant challenges for the biopharmaceutical industry. In the end, success will come back to focusing on data integrity, bringing data onto the manufacturing floor, and managing them flawlessly in the manufacturing execution system.

To be able to develop personalized medical treatments, will manufacturers be forced to digitalize data management? 

: It will become a prerequisite. Many of the clinics that are conducting clinical trials today are drowning in paper, and overall systems are burdensome and highly inefficient. You won’t be able to scale these processes with paper-based systems. Data systems need to be integrated as part of ‘Manufacturing 4.0’ process and quality systems. Some companies are already starting to adopt this type of thinking. Biogen Idec’s new facility in Switzerland provides an example of what is coming. Data integration will become easier over time. Smaller companies will need to work closely with partners who have expertise in this area.

	1. G. Pigeau et al., “Commercial-Scale Manufacturing of Allogeneic Cell Therapy,” 

5 (8), 233 (2018).
	2. W. Leong et al., “

Critical Role of Automation in the Manufacture of Cell and Gene Therapies


	Vol. 43, No. 3
	March 2019
	Pages: 48–50

	When referring to this article, please cite it as A. Shanley, “Reinterpreting Benchmarks for Innovative Therapies," 

Articles

While allogeneic therapies can use existing regulatory and quality frameworks, autologous treatments will require pharma’s adoption of true just-in-time and right-first-time concepts, says consultant James Blackwell.


Reinterpreting Benchmarks for Innovative Therapies

	The recent US government shutdown has been widely reported to have been the longest on record, and Standard & Poor’s Global Ratings estimates that it resulted in $6 billion in economic losses. On Jan. 25, 2019, the US President and Congress reached an agreement to fund US government offices for an additional three weeks. However, that will only take the government through February 15. Industry observers hope that the shutdown’s end will be permanent. 

	While legislators consider moves that could make government shutdowns illegal in the future, industry groups are reaffirming FDA’s importance to the health and safety of US citizens, and the health of the global economy. “As the gold-standard for regulatory review, it’s critical the FDA continue to fulfill its public health mission. As an innovative industry, our companies depend on certainty and predictability to bring tomorrow’s treatments and cures to patients. We support FDA using its existing authority to deploy user fee funds to continue to review applications,” said Andrew Powaleny, spokesperson for thePharmaceutical Research and Manufacturers of America (PhRMA). 

	Jim Nolan, CEO of the innovator company InClinica, believes that FDA should be added to the armed forces and other organizations on a list of agencies that would be exempted from the funding impact of government shutdowns. Nolan shared his views with 

on the morning of Jan. 25, 2019, the afternoon of which news of the shutdown’s temporary end was announced.

: What impact has the shutdown had so far, and what would be the most critical problems that a continued shutdown would have on the industry?

: The shutdown had and would have an impact that transcends our national borders. When FDA can no longer accept new drug applications and review them, that means delays, and not only [for] US-based innovators.  a lot of international companies in this space will be affected. This is a major short-term concern.

	But another question is what impact the shutdown would have on FDA’s adverse events (AE) reporting system. If you have a drug that has been accepted and you’re performing a clinical test and you get an AE, you have to follow a very detailed and elaborate protocol, in which you report that AE to FDA and explain whether or not you want to continue with your trial and why.  FDA reviews the facts and makes a decision.

	When a company’s drug gets an AE, the clinical trial for that drug stops until the firm receives a decision/explanation of what led to the adverse event. When you’re in the middle of a clinical trial, there’s a lot of momentum that builds up as you recruit patients and manage the trial.  A shutdown puts the entire process on hold. 

	I consider Scott Gottlieb a hero for reminding people that the shutdown could have resulting impacts on AE reporting and that this could affect patient safety. Imagine a drug company that had a drug approved six months ago and suddenly is dealing with AE reports for that drug from all over the world. People have to be in place at FDA to call that emergency. 

	And then, too, there are the technical difficulties presented by the science behind a drug. If you have been working with one FDA reviewer and the process shuts down for a few months, you will once again have to climb the learning curve and the process will slow down.

:  What could the economic impact of a resumed shutdown on the pharma industry? 

: Most discoveries today are coming out of biotech companies, and they have very limited finances. They budget to the penny; it’s no exaggeration. When you have a two-to-three-month delay, that is an enormous cost because the company must still carry expenses, dictated by its burn rate, and the cost of people and operations. 

	They must calculate how long the company can last based on its burn rate. Some small innovator biotech companies might have a burn rate of $20,000 a month, so a two-month delay would mean $40,000 that wasn’t in their budgets. That may be nothing for a company the size of Pfizer, but it’s enormous for a small innovator. In addition, they would lose the payments from investors that are tied to regulatory decisions (e.g., FDA green lighting a clinical trial).

: Reduced inspections would also be a problem. What would the impacts be there?

: Chemistry manufacturing and controls (CMC) is becoming the most important part of development-answering how the drug is made and proving that its ingredients are safe. It’s also very expensive. If you delay the CMC inspection process, you delay bringing an approved product to market.  Even if you want to make changes to improve cost efficiencies, those efforts are slowed down, so a shutdown would have ramifications across the board. There would be major issues related to proving safety and efficacy. For example, a company might conservatively decide to halt a clinical trial after AEs, when those AEs aren’t tied to the drug.

: What about the impact on a broader stage?

:  People at FDA use electricity, computer, and other services, and a shutdown has ripple effect on all these services companies, etc. If you require data and your computer goes down, you can’t recover it. In short, reverberations are enormous. You could also see an influx of counterfeit drugs because nobody would be available to follow up on inspection.

: What impact do you see shutdowns having on staffers at FDA?

: FDA has recruited top-level scientists and physicians. If they’re not going to get a paycheck, they might at some point be inclined to change positions. And policy experts and regulatory affairs experts are critical to innovator companies. When they are furloughed you have lost that knowledge base.

:  Should FDA be exempted from temporary spending cuts?

	Nolan: I think that we should exempt FDA from the funding impacts of US government shortages. After all, the US armed forces are exempt. FDA has a huge impact on patient safety, and they should be exempt as well. 

:  How do shutdowns affect compassionate use of an experimental drug for a dying patient?

: That whole process is then shut down, too. And also consider the synergies between FDA and the Centers for Disease Control. A shutdown takes all those connections down with it.

In January 2019, a temporary measure reopened the US government until Feb. 15, 2019, allowing FDA to resume full operations. Failure to find a permanent solution could have dangerous ripple effects on patient safety and innovation, says Jim Nolan, CEO of InClinica.

Resumption of the US Government Shutdown Could Have Drastic Effects

	Dr. Reddy’s Laboratories recently appointed Mark Kikuchi as CEO for its North American generic pharmaceuticals business, and the company has also been working on broad-based projects to modernize and improve manufacturing and quality. Radha Iyer, vice-president and head of Quality and Scientific Affairs, Global Developed Markets, shared some details with 

: Please discuss any new business initiatives underway at Dr. Reddy’s, as well as plans for R&D, manufacturing, and quality.  

: With our global philosophy of 'Good Health Can’t Wait,' our strategy continues to focus on building our pipeline of APIs, complex generics, biosimilars, and differentiated products. We will continue to tap on our internal capabilities but will also move into partnerships with external co-development or contract development/manufacturing partners to manage risks.

	Our strategy is a single global approach to developing products for key markets in the United States, India, European Union, Russia, and China.  To accomplish our strategy, we continue to build a local presence in these markets with a variety of approaches, ranging from plant expansions to building new facilities. We are also developing strong alliances with local and global partners while exploring various channels for market access. 

: Like other manufacturers around the world, Dr. Reddy’s has had its share of manufacturing and quality issues with regulators. Has the company changed the way it is approaching quality and compliance? Please discuss investments and initiatives, and overall short- and long-term plans in this area. 

: In support of our growth strategies, we have taken a closer look at our operations and have embarked on an organizational transformation journey. At the top of this list is process and quality improvement, and we are launching initiatives across our organization to help improve the bottom line. We believe it is even more critical for us to look ahead in terms of quality by creating a balance between the need to address the issues identified and improving quality as we continue to grow. 

	We have identified several foundational processes that we plan to use, such as developing value-stream maps across the product lifecycle, using process maps to see and close our gaps. In order to achieve our goals, we need to understand and plan at the organizational, regional, and local country levels, to ensure that we are taking cultures, values, local politics, and laws into account. We have embarked on significant efforts in the areas of quality improvement, change and process management, process integration, and product management, and have engaged experts to help us where necessary.

: How is the company using pharmaceutical quality-by-design (QbD) concepts?

: We have a process in place that drives QbD in our drug development efforts, which covers all the key elements of QbD, including critical quality attributes, target product profile, risk assessments, design space, and control strategy. To ensure the effectiveness of the design concepts, we plan to continue building on the process by providing guiding tools for product developers to make better decisions, while also giving them space to innovate, create, and plan. These tools help our drug development staff make better informed trade-offs during the execution of plans. 

:  What is the company doing in the area of optimizing data integrity? 

:  We have already implemented a number of remediation initiatives to assure data integrity and continue to build upon them using various preventive strategies. These include moving to electronic data and managing vendors for whom data integrity is a key component of quality agreements. In addition, we are using risk-based approaches, and providing behavioral training that includes data integrity in system selection and validation phases.

:  How is your company investing in and using new technology, e.g., IT, analytics, Industrial Internet of Things, artificial intelligence, and virtual or mixed reality?

: In support of our process and quality improvement initiatives, we are implementing digital programs in several of our operations. For example, to eliminate the significant efforts put in generating and maintaining batch records and logbooks, we have implemented OSI-Pi integration to manufacturing execution systems. This approach allows us to collect process data, alarms, events, and batch event data in some of our plants. 

	We are also working on proof-of-concepts projects in machine learning, and already have data in early stages of R&D to learn and implement these concepts. We have multi-year digitization plan and roadmap for investment into key value-added technologies. 

: Please comment on plans in biopharmaceuticals, precision medicine, and biosimilars.

: Given the significant growth in demand for innovative biological products, our strategy includes exploring opportunities in the biosimilar space. We are also looking to leverage the value of our current biological assets in oncology-which are already available in emerging markets-to the developed world, including the US. 

	In addition, we are building a new biosimilar portfolio of products for future growth that includes a global development strategy and external alliances and investments.

Radha Iyer, vice-president and head of Quality and Scientific Affairs, Global Developed Markets, Dr. Reddy’s Laboratories, discusses new initiatives at the company.

Dr. Reddy’s Embarks on New Quality Improvement Programs

Aseptic manufacturing, and particularly fill and finish operations, continue to challenge pharmaceutical manufacturers. Consultant and Editorial Board advisor Jim Agalloco discussed industry and technology trends and regulatory challenges with 

Have you seen any change in how the industry is using advanced aseptic manufacturing technology?

One trend that is moving very quickly is the use of robotics in isolators, eliminating the need for gloves, so that less human intervention is needed than there ever was. VanRx has taken this to an extreme with its gloveless isolators; other equipment manufacturers are moving in the same direction, including AST, IMA, Fedegari, and Aseptic Technologies. Currently, this robotic equipment runs at lower speeds than traditional equipment, but robots don’t take breaks or lunch so there is a lot of potential benefit. The essential first step was moving to closed systems, after that, vendors and end users can work on making them run faster.

	We are also seeing explosive growth, even faster than the growth of robotics, in the use of single-use disposables within aseptic manufacturing. The idea is to take away the stainless-steel piping and rigid lines, so that there is one connection from product supply all the way to the fill needle.

	Using disposables requires collaboration between single-use system vendors and equipment manufacturers, who must integrate single-use components into their filling controls and get them to work properly. This approach eliminates the need to clean and keep so many parts in inventory and reduces cost and contamination risk. Single-use systems are going into high-speed filling lines and into robotic closed systems.

Has there been any change in the scope of services that aseptic equipment vendors are offering pharma customers? 

We are seeing an alignment of supply chains so that vendors are doing much more of the upstream work that manufacturers used to have to do. For example, many equipment vendors are now providing pharmaceutical manufacturers with prewashed, presterilized, and predried glass, syringes, closures, and stoppers.

	This approach reduces the end user’s facility and personnel needs and puts more responsibility on suppliers. Vendors are taking the lead in this change. 

Are the mergers and acquisitions that have occurred in the contract manufacturing space over the past few years having any impact on aseptic operations within the industry?

Contract manufacturing organizations (CMOs) are getting larger. More pharmaceutical manufacturers want to work with one partner from small-scale to commercial manufacturing to reduce the number of hand offs. This trend also ensures that CMOs have sufficient resources. Poor performers are being weeded out.

CMOs are getting better and more players are getting into this space. However, major pharma companies continue to struggle and much of this is directly attributable to aging facilities. Anywhere you see an older plant you are likely to see problems. Generic injectables and vaccines sell with next to no profit, but modernizing manufacturing or replacing a facility could cost $200 million or more.

Is the emphasis on generic drugs creating this problem?

Drug shortages are merely the result of issues with cost control that came out of the approval of generic drugs. These issues have developed over 30 years as facilities have aged, and prices have fallen. Very simple drugs are in short supply because nobody invests in them when the margins are so thin. I am terrified about biosimilars, because now we are taking even more complex processes and making them cost competitive. 

Are you seeing greater acceptance of innovation in pharma? 

As far as adopting innovative technologies, pharma is still a laggard industry, especially on the sterile side. Even though the FDA’s Emerging Technology Team (ETT) has included advanced aseptic technology in its agenda, some equipment innovators struggle with a Catch-22: Regulators won’t review a new technology unless it is used in a drug submission, and no drug manufacturer will invest in the technology if no other drug manufacturer has previously used it and had a drug approved with it.

Do we need new guidances on aseptic manufacturing?

No. Guidances can become a barrier to improvement. FDA regulations work because they tell you ‘what to’ and not ‘how to’. The more regulators put ‘how tos’ into their expectations, the less innovative we become.

What are your thoughts on Annex 1 (1), the European Union (EU) draft guidance?

Annex 1 represents one of the EU’s first efforts to develop guidance in an open way with the industry, but they won’t get it right in one pass. Industry submitted thousands of critical comments, and my colleagues, James Akers and Russell Madsen, and I submitted over 170 comments (2).

What are the most glaring problems in the draft guidance? 

Apart from the way it is written and organized, my colleagues and I take issue with the fact that the draft presents a view that conflicts with existing and established global regulations, standards, and compendia (e.g., US and Japanese guidance on sterile manufacturing). For example, the document does not incorporate the requirements established by International Organization for Standardization (ISO) 14644, and perpetuates a myth that microbiological testing can improve sterility assurance (3). The document also uses an antiquated and arbitrary classification system, rather than ISO 5, 6, 7, and 8 categories.

	In addition, the draft does not incorporate the most modern and appropriate guidance for sterile product preparation, as outlined in 

Chapters 1211, 1228, and 1229 (4–6). Classification of controlled environments should be limited to non-viable particle monitoring as described in ISO 14644, and not based on microbial enumeration.

	Furthermore, the guidance presents an unscientific view of microbial monitoring. The limit of detection for microbial testing is much higher than one colony forming unit, as the document now states. As a result, it may overstate the value of environmental monitoring in manufacturing sterile medicinal products. Its language also conflicts with the European Medicines Agency’s (EMA’s) guidance, specifically its water for injection (WFI) Q&A paper (7), and 

Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products 

How does it cover cleanrooms and advanced technologies?

The document groups conventional cleanrooms, restricted access barrier systems (RABS), and isolators together, even though these technologies are demonstrably different in many ways. This approach diminishes the performance of isolators, inflates RABS capabilities, and fails to consider adequately the limitations of barrier-equipped manned cleanrooms. 

How does the document approach the topic of validation?

The draft guidance asks for testing of materials, containers, and surfaces, as if expecting testing alone to assure product quality. The core principle behind validation is to assure confidence in a process’ reliability and appropriateness in ways that testing alone cannot do. Misplaced emphasis takes us back in time.

	1. R. Madsen, J. Agalloco, and J. Akers, “Annex 1–Misses the Mark,” 

EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use,

Annex 1, Manufacture of Sterile Medicinal Products, December 2017.
	3. International Standards Organization, 

ISO 14644–Cleanrooms and Associated Controlled Environments-Part 1: Classification of Air Cleanliness by Particle Concentration

, 2015.
	4. USP, General Chapter <1211>, Sterilization and Sterility Assurance of Compendial Articles, 

(US Pharmacopeial Convention, Rockville, MD, 2017).
	5. USP, General Chapter <1228>, Depyrogenation, 

US Pharmacopeial Convention, Rockville, MD, 2017).
	6. USP, General Chapter <1229>, Sterilization of Compendial Articles, 

(US Pharmacopeial Convention, Rockville, MD, 2017).
	7. European Medicines Agency, EMA/INS/GMP/443117/2017, 

Questions and Answers on Production of Water for Injections by Non-Distillation Methods–Reverse Osmosis and Biofilms and Control Strategies

, August 2017.
	8. European Commission, 

EudraLex, Volume 4, EU Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products


	Vol. 43, No. 2
	February 2019
	Pages: 40, 42

	When referring to this article, please cite it as A. Shanley, "As Technology Advances, Annex 1 Falls Short," 

Robotic isolators and single-use technologies are gaining ground, according to aseptic processing consultant Jim Agalloco.

As Technology Advances, Annex 1 Falls Short

Analytical method transfer suffers from many of the same problems that plague technology transfer in general. All too often, a method may work well in the R&D lab as a characterization test, but fails when taken to a wider stage, where reproducibility is key. 

	In addition, incomplete information may be shared between the two organizations working on the transfer, and details on how to carry out standard operating procedures may be given short shrift. Partners may also fail to consider critical points (e.g., whether data interpretation software meets FDA regulations). As Berangere Tissot, general manager with SGS Life Sciences says, “The devil is in the details.” Tissot, a subject matter expert on protein and glycoprotein characterization and complex method validations, shared best practices with 

What mistakes do people typically make with regard to analytical method transfer for biologics?

The most common mistake people make is underestimating the complexity of analytical method transfer, particularly for biologics. The problem that will jeopardize any analytical method transfer, whether at very early or late stages, is the failure to convey the ‘knowhow’ in documentation that is sent to the transfer partner. Often, instructions are very detailed on some aspects of the method, yet key details are missing because they are not considered critically relevant. It’s important to remember that the manipulation of a biologic is very different from that of a small molecule.  For some assays, sample preparation is key to the  method, and more often than we would like to admit, it is the least described part of the methodology. Even in cases where it is well described, important elements are often missing. This can undermine the difficult challenge of reproducing an assay with consistency and robustness.  

	Another area where insufficient knowledge transfer typically occurs is when a company has to validate, or ask its contract development and manufacturing organization (CDMO) partner to validate, what was developed as an early phase characterization assay. In many cases, 50 –90% of the information that is needed in order to validate the method is simply not there. Not having the data on hand makes the next step, transferring that method from development to a quality control (QC) environment, a real challenge.

How and what kind of information must be conveyed, and what kind of mindset is needed to ensure that key issues are not left out?

Thinking in terms of developing what will later be validated allows one to have more control over the analytical development stage. When you develop an R&D method with the idea that it could be a QC test at some point in the future, you will do it differently than you would develop a characterization test that will remain an R&D characterization test.

	When you develop a method that will be transferred to QC or to another lab, you would want to focus on simplifying sample preparation and data acquisition. For example, you would not want to have a 60-step process for sample preparation. You may also consider, whenever possible, how to make the method unbiased to any specific type or brand of instrumentation.

  Do R&D scientists have to think like QC technicians?

  These two categories have different skillsets and mindsets. It does not mean the two are incompatible, but it requires some training to move from one to the other. When you work in QC, you have to deal with many restrictions on what you can change. 

	Scientists who are developing analytical methods in R&D typically do not have to consider these restrictions. However, if the method has any chance of ending up on a release panel, they at least need to know what these restrictions are in order to develop an assay that will take them into account. 

	For example, they shouldn’t specify the use of exotic enzymes, however more specific or appropriate they might be for the application. Such materials might pose availability and quality consistency problems that will affect the method’s continuity and robustness. For any enzyme that will be used in testing, consistency in quality and multiple sources of supply would be paramount.

	Early phase analytical teams are developing a new method because they are looking for new or more precise information. What will work best for moving the method along in R&D, however, is unlikely to work in the QC environment. Thus, it is very important to think about that translation at the beginning of assay development. 

	We always ask clients, when we are developing methods for them, whether they envision the method being used as a release assay at some point in the future, or whether they see it as having to be validated. Even if no one can be certain at that point, the mere possibility that it might is important for devising the most appropriate strategy around the method development.

But how can one know this at early R&D stages?

You don’t, at least not with absolute conviction. It is very difficult at that stage. Nevertheless, you may have some sense of whether this approach will be needed, and that sense needs to be communicated to whoever is working on developing the assay so that the method can be built on a solid basis with the appropriate mindset.

	This is the major difficulty with transferring analytical methods. Creativity is valued, and imagining the best possible way to approach the method is very important. However, analytical developers must also consider the most reliable way of performing the assay, if it is to be implemented in GMP environments and QC labs later on. Situations will come up where these two goals cannot be matched, and some compromises will be needed.

Should these considerations be a part of risk management?

It is essential to developing a good risk management strategy around the method itself and its lifecycle. Imagine you are working on the development of a characterization assay for N-glycan structure elucidation that will be used for a drug that has a very complex glycosylation (e.g., for a replacement enzyme, where you know that some form of derivatization or glycosylation will be key to the product’s functionality). In this situation, this method, which should normally belong to the characterization panel only, will likely end up being the best approach for monitoring and controlling a critical quality attribute (CQA) of the product.  

	For the purpose of the characterization assay, you are trying to understand, fully, the complexity of the N-glycan structures. In order to get detailed results, the method might be complex and convoluted. Repeatability or robustness will not be evaluated and rightly so, if this method is just a characterization one. The method efficiency will be as good as the scientist carrying out the assay, which is very common in R&D environment. 

	However, if you haven’t considered the future use of the assay and built some preliminary risk management (e.g., having some specificity, repeatability, and evaluation of the critical parameters to control in the sample preparation) done at the R&D phase, you will need to put a remediation plan in place. Then, a translation phase will need to be developed for that method, to demonstrate that the assay can be brought into QC, and to eliminate most of the risks that could be linked to a complex procedure.

Do you need to staff these projects in a special way? 

I would say that it depends on philosophy and size of the organization. In very small companies, there may not even be a QC or an R&D department. At many of the medium-size pharmaceutical companies, these groups may not be actively working together. However, a growing number of large companies now have groups in between R&D and QC that focus on bridging these two groups and assisting them with the transition of R&D methods in the QC environment. These ‘translation’ groups generally include people who are educated in QC and understand all the restrictions of QC work, yet who are well versed in R&D, to find that middle ground.

The trend began a few years ago, and it is likely to continue and to grow. Whether that group is involved during the transition or earlier in the analytical method development is a matter of choice for each organization. 

You mentioned the importance of describing all steps in detail. Why should that be necessary?

This is the key reason why these transfer or transition projects fail.  Let me describe one example when we received an R&D method to transfer in our lab and validate to cGMP. The protocol contained many details around the sample preparation, but failed to mention the fact that the protein of interest was adsorbed on plastic surfaces, and therefore was adsorbed on plastic microtubes. It took time to pin the difference observed in recovery to this very basic fact. However, nowhere in the protocol were glass containers mentioned, because it had been so engrained in the mind of the scientists who worked with this protein that ‘it went without saying.’

How do you ensure that clients communicate all this information? Do they or you use standardized templates?  How do you staff these projects and what backgrounds and experience are needed? 

We spend a lot of time talking with the client, the scientists who developed the assay, and reviewing the method before we even take the work in. We need to understand each of the steps of the method and evaluate how much of undisclosed details are at each of these steps. It may sound tedious, and we may ask questions that seem unimportant, but all of this is essential to understanding what is critical to the method and what is not.

	In general, the more we know upfront, the less we have to ask later. We need to be proactive about the transfer, and clients generally understand that a lot of preliminary work is required in order to maximize the efficiency of the transition and the chance of validating a robust and reliable assay.

Yes, it is a crucial factor. Compliance with US 21 

Part 11 requirements is not as critical for R&D methods as it is for cGMP methods. 

	For some high-end methods, it is still very possible that the software used to analyze data is not yet Part 11 compliant. When such a method needs to be validated, the risk management has also to account for the workarounds to be implemented around the data acquisition and interpretation. This is not trivial and requires close collaboration between the scientific staff, quality assurance, computerized system validation groups, and sometimes, the instrument manufacturer. This consideration must be more apparent to R&D scientists, with the understanding that the method might eventually have to be pushed to the QC lab.

Mostly by opening the communication and working around the language barrier between R&D and QC. Our first phase of evaluation is performed on our instrumentation, leveraging our ability to do R&D in a regulated environment. Based on that first evaluation, we define critical checkpoints (i.e., what may pose problem to specificity, repeatability, or any other critical validation requirement) and parameters that may require optimization or adjustments. We also evaluate critical reagents and work our way through defining multiple suppliers to briefly assess robustness, whenever necessary. The method is now in a ‘state’ where it can be evaluated more in depth for its applicability to release.

	What will be investigated next will depend on whether the assay will be used for an identity test, monitoring CQAs, or for quantitative residual testing. Each application will have a set of parameters for which specifications would need to be defined. Based on results, we will either optimize further or go straight to a pre-validation or pre-qualification study to see how the method fares and what could be the targeted acceptance criteria.

	Requirements will depend on the clinical phase for which the method needs to be validated. Stringency on acceptance criteria and extent of the study will be different whether the product is in Phase I or III. Once everything has been empirically assessed, we can put a validation protocol in place.

Have you ever had to ‘just say no’ to a project?

It is always difficult to say no because often it’s not impossible to work with the method. What can make a project impossible are the requirements that may come with the transfer. For example, when companies want to validate one of their R&D methods, but then ask for it to be validated within a week, they need to understand that this is not likely to be achievable. Rushing to such a critical step in analytical development will likely incur the risk of running into extensive and expensive remediation.

	Success requires a lot of homework and careful, educated evaluation of method from a preparation, analytical, and software/IT standpoint. The focus cannot be only on the instrument acquiring the data, but must also include the software analyzing those data and the way the data are being recorded. Everything must be considered.

How can you do the work and comply when the software isn’t Part 11 compliant?

This requires creativity and a good handle on regulatory requirements, but analytical instrument manufacturers are working on solutions. One can assume that there will be fewer of these gaps in the very near future.


	Vol. 43, No. 2
	February 2019
	Pages: 48, 50–51

	When referring to this article, please cite it as A. Shanley, “Analytical Method Transfer: Don’t Oversimplify," 

When transferring a method from R&D to quality control, success hinges on discovering where “the best” and “the most reliable” intersect.

Analytical Method Transfer: Don’t Oversimplify

Although the impact of the US federal government shutdown remains unclear (1), leaders within FDA say they are encouraged by the progress made within the agency and industry during 2018.

	According to reports published by the Regulatory Affairs Professionals Society (RAPS) (2), Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), singled out generic drugs as a key area where improvement was seen in 2018. She noted an increase in productivity in new molecular entity (NME) development and review at the FDA/Centers for Medicare and Medicaid Services Summit in Washington, D.C. on December 11, according to RAPS.  

	For 2019, the report said, Woodcock’s top manufacturing and quality-related priorities for CDER include:

		Establishing a framework for overseeing the safety and quality of compounded drugs

		Implementing new user fee goals and tracking the implementation of serialization legislation.

	FDA Commissioner Scott Gottlieb, speaking at the FDLI Enforcement Litigation and Compliance Conference on Dec. 12, 2018, emphasized the importance of risk-based inspection and efforts to ensure that the regulatory burden placed on drug manufacturers is aligned with public health priorities (3). Gottlieb also noted efforts to strengthen FDA’s Office of Regulatory Affairs (ORA) mentioning a program designed to integrate ORA and CDER more closely. He also spoke of global inspection harmonization, singling out the Mutual Reliance Agreement (MRA) with the European Union. An example of MRA in action that he pointed to is the International Active Pharmaceutical Ingredient Inspection Program, which was recently used to share information on valsartan API facility inspections.

	For manufacturers and quality specialists, what were the key regulatory achievements in 2018, and what issues promise to dominate this year? Susan Schniepp, executive vice-president of post-approval pharma and distinguished fellow at Regulatory Compliance Associates, shared some insights with 

: What key regulatory trends do you expect to take shape for 2019?

: Many of them will focus on quality. The fact that FDA is rethinking its quality metrics program, and that the agency asked for sites to volunteer to be inspected in 2018, was pretty significant. We don’t know what FDA’s final program is going to look like, but we did see signs in its data integrity guidances that FDA would be increasing its attention on how manufacturers approach the task of building a quality culture.

	This emphasis will bring FDA more in line with other global agencies, which did not jump on the quality metrics bandwagon but have been more interested in quality culture issues. 

Were there weaknesses in FDA’s original quality metrics plans?

The agency will continue to tie quality metrics to drug shortages, which will still be an issue in 2019.  This approach makes sense, since, once we see metrics, we can do surveillance to identify where problems are developing and how these problems can be deflected, diverted, and remediated before they develop into drug shortages.

	However, the metrics that FDA originally selected (e.g., corrective and preventive action [CAPA] turnaround time) were lagging rather than leading ones.  The industry would benefit more from metrics that indicate when facilities are heading into a problem (e.g., scrap rates, which signal manufacturing problems and tie in closely to the issue of aging facilities).

: Will aging facilities receive more attention from the industry and regulators in 2019?

This issue will continue to play out in 2019. At the Parenteral Drug Association (PDA), we’ve spent a lot of time working on post-approval changes, to allow manufacturers to get regulatory relief so that they can modernize facilities more easily. Until this process becomes easier, we will continue to see problems with aging facilities and a rise in scrap rates, reject rates, and aborted lots. These are the metrics that should be tracked. 

	There are also cost-vs-benefit questions [that tie into drug recalls and commodity drug shortages] and fit right into the aging facilities problem. For example, manufacturers may ask, 'Why modernize a sodium chloride line when it will not bring any profit?'

 PDA has been actively involved in a number of regulatory issues and in communicating with FDA. Where has PDA made the greatest progress in this regard in 2018?

 One important achievement was the development of best practices for laboratory data integrity, and PDA is now working on best practices for manufacturing data integrity, encompassing not only computerized and hybrid, but paper-based systems. It’s so interesting that data integrity keeps coming up as an issue for pharmaceutical manufacturers. Even though the industry went through this in the 1980s with the Barr decision, data integrity continues to rear its head.   

 What are the greatest challenges ahead and building a quality culture within the industry?

Investigations into CAPA, things that have gone wrong, and deviations, will continue to be significant problems. Another looming challenge is the fact that, as we move forward with individualized stem and gene therapies, quality risk-based decision making will also have to advance. 

	These issues will challenge the traditional quality professional. How will one release a lot, for example? And how will investigations into manufacturing problems proceed on site? How is quality going to integrate with manufacturing, so that we get out of our desk chairs and perform lab and site investigations in real time as problems happen, and ensure that the results are meaningful?

  Do you expect a framework analogous to current good manufacturing practices (CGMP) to be brought to bear on compounders?

It will be interesting to see how FDA manages compounding pharmacies in 2019. Remember, these facilities are essentially making uncontrolled drugs. They don’t have a new drug application (NDA) or filing associated with them, yet a number of large compounding companies are making large lots of product and sending it to hospitals, as permitted by 503b of the Drug Quality and Security Act.  

	Some of the guidelines that surround traditional aseptic processing are new to them (e.g., they are performing manual manipulations of product under a hood), yet they may not understand why they need to do a media fill or why a particle count is important. 

	They may also fail to understand how final product testing relates to production and what a certificate of analysis really means. Another question is how should they approach stability? Traditional manufacturers work on container closure issues, but compounders are manipulating closures, and often their product expires within 90 days.

Critical FDA Functions Continue as US Government Shutdown Hits the One-Week Mark

Woodcock Lays Out Top CDER Priorities for 2019

Remarks By Scott Gottlieb at the FDLI Enforcement Litigation and Compliance Conference


	Vol. 43, No. 1
	January 2019
	Pages: 46–47

	When referring to this article, please cite it as A. Shanley, "Data Integrity Topped 2018 Priorities," 

This year promises to bring more focus on risk management and building a quality culture, says consultant Susan Schniepp.