The drivers for the development of new raw materials are, as always, changing customer needs. At the top of the list in today’s industry, according to Douglas Bowman, program manager for PharmaGrade raw materials at SAFC, is risk reduction. Beyond that, he says that customers are looking for effective ways to increase performance and output and optimize productivity. 


“The demand for supply chain security and transparency continues to grow and is the number one concern of many drug manufacturers as they navigate the new market,” asserts Bowman. In fact, many manufacturers are still working to respond to guidelines implemented in 2012 that require final end-users to have visibility of their raw-material supply chain. “Biopharmaceutical manufacturers are faced, now more than ever, with the reality of global events that have threatened and breached supply chain security,” adds Beth Ann McLane, SAFC’s product manager for enhanced quality. Global threats to the security of the raw-materials supply chain have caused a public outcry, and regulatory bodies have demanded higher levels of compliance. “Manufacturers are now being held fully responsible for the raw materials that go into their products and they simply do not have enough capacity to test for all of the possible contaminants that could find their way into the materials,” she comments. 

In response, the industry is moving towards risk assessment and risk mitigation of raw materials from the early stages of drug development. Manufacturers are looking to their raw-material suppliers to provide them with the support of a secure supply chain, according to McLane. “The more that biopharmaceutical manufacturers know about their suppliers and the raw-material supply chain, the more confident they can then be about the safety of those raw materials,” she says. Achieving this goal requires tracing these materials back to the manufacturer and demonstrating that there is a stringent change-control process in place. 


At the same time, the push to reduce risk has caused many manufacturers to move away from animal-derived materials that provide high performance in cell-culture manufacturing, such as serum, which is creating additional challenges in maintaining productivity and yields. The need to optimize productivity has, therefore, led to increased scrutiny of other raw materials in the media, as well as other bioreactor supplements. “There is a much greater focus today placed on isolating extraneous matter or impurities that could have a negative effect on the performance of raw materials,” Bowman observes. “Where, as a result, having a controlled source in combination with meaningful specification is optimal.”


In the past, according to Bowman, manufacturers typically asked only for the name of the source of a raw material from their supplier and considered this information to be ample identification of the “source”.  Much has changed since then, because customers realize the amount of risk such an approach involves, particularly given the requirements of increasingly stringent global regulations. “Manufacturers are now looking to source higher quality--GMP or similar quality level, such as SAFC’s Elite--across the board. It is no longer just a handful of raw materials receiving attention; any material being used in drug manufacturing is receiving a greater deal of attention,” he notes.  


The drive toward plant-based materials brings greater inherent variability to the table. “When something comes from the earth, there are many factors that cannot be controlled--factors that can change a material from lot to lot,” says Bowman. SAFC, as a raw-material supplier to the biopharmaceutical industry, has met this challenge by increasing its levels of testing and working to chemically define materials if possible. For those substances that cannot be chemically defined, and particularly in the case of plant-based raw materials, the company works to secure its sources and control what it can. “The rest of the process,” comments Bowman, “involves continuous learning built on research and testing of the materials that allows us to capture and analyze critical data points.” 

He does stress, though, that meeting these challenges is not as simple as it may seem. SAFC, despite the difficulty, has chosen to view the situation as an opportunity. “We have worked on expanding our PharmaGrade line of high-quality, controlled, and documented materials to remove some of the pressure on manufacturers, but the process is grueling. We must identify how/where the product is made, conduct audits, establish quality agreements, ensure there is a stable change-control process, and obtain full documentation for customers, and of course, conduct extensive testing.” Through this comprehensive process, the company believes it can gain an understanding of the types and levels of contaminants associated with raw materials and use that information to mitigate their biological impact at different levels. 


SAFC’s PharmaGrade portfolio was created in response to urgent demand from customers for products they can count on to be consistent and that are from a source where the production is controlled and changes are limited, according to McLane. “These types of customers are not only looking for a guaranteed level of quality; they also want to know what is happening with the raw materials and be notified if/when any changes occur,” she observes. To provide a higher level of documentation and support, SAFC has invested significant resources into the identification and qualification of products for the line and established a strong change-control notification system.

Each product has a complete dossier of information about it, including the site of manufacture and the quality systems associated with the product. New materials must also meet seven key criteria that were developed based on customer requests and include manufacture under GMP (or SAFC’s Elite) quality guidelines, supply-chain transparency, formal vendor qualification, quality assurance review and release of each lot, change-control notifications, quality documentation, and availability as catalog items. The PharmaGrade range includes amino acids, buffers, and specialty chemicals that are widely used in biopharmaceutical manufacturing.


SAFC has also been focused on a stringent raw-materials characterization program to improve product/media formulations that involves the identification of impurities that impact productivity and product quality. “The goal here is to test and gather enough data that we can automatically identify performance issues and correlate them to a specific raw material. We also believe that if we can fully understand the biological effects of contaminants, we can then work to identify specifications that will enable more efficient biopharmaceutical production for our customers,” Bowman explains. 

On the customer side, the company is also taking time to educate customers so that they receive the grade of material that they actually need. “Our PharmaGrade raw materials are often not required for early development projects, while research-grade materials are not appropriate for commercial applications and could have grave effects on the final drug product,” he says. “We are, therefore, focused on aligning with our customers to really learn their processes and help them identify the right materials that are fit for purpose and ultimately fit for manufacturing,” he continues.


Supply-chain security is an issue that the entire pharmaceutical industry is grappling with. Both biologics and small-molecule pharmaceutical manufacturers, contract manufacturers, and raw-material suppliers are facing the same challenge of ensuring the quality and safety of the products they purchase and/or sell meet the standards set for drug product manufacturing and formulation.

 “The industry is coming together over this issue because these challenges are not just for one manufacturer; they are challenges for all manufacturers. Finding appropriate resolutions creates great opportunity for everyone,” Bowman asserts. Groups such as Rx-360 and the Parenteral Drug Association are working to define and standardize methods for achieving supply-chain security and raw-material quality, as well as educate their members. “Such industry-wide challenges require industry-wide answers to ensure that drug manufacturers are meeting and exceeding quality standards,” Bowman says. In particular, he points to the efforts of Rx-360 to encourage the use of more effective, shared audits that would allow the industry to take a significant portion of the time spent auditing to focus on these greater challenges. On a more global scale, Bowman believes that the International Conference on Harmonization (ICH) Q3 guidelines for elemental impurities, which are under development and will update the analytical requirements for heavy metals and other contaminants, will likely result in significant changes in detection methods and limits that can help the industry streamline raw-material standards. 


In the end, raw-material development for the biopharmaceutical industry is no different than new product development in any industry with respect to the importance of determining what customers really need and then working to meet those needs with a clear, educated, scientific approach, according to Bowman. “To that end, at SAFC we have honed in on identifying product characteristics that impact the performance and consistency of the formulated products we develop. We also want to make it simple for customers by offering the most commonly used products at an exceptionally high-quality level right off the shelf in order to eliminate the need for customization,” he says.


Cynthia A. Challener is a contributing editor at Pharmaceutical Technology.

Articles

API Synthesis & Manufacturing

Customers are looking to reduce risk, increase performance, and optimize productivity.

Risk Reduction Top Driver for Biopharmaceutical Raw Material Development

Two years into the Generic Drug User Fee Act (GDUFA) program, enacted in July 2012, FDA officials are striving to meet goals and timelines for speeding new generic drugs to market. Agency reviewers have made some progress in eliminating the huge backlog in abbreviated new drug applications (ANDAs) pending in the Office of Generic Drugs (OGD), but not as quickly as manufacturers had anticipated. New guidance from FDA aims to help manufacturers meet standards and to streamline oversight. But a continual rise in submissions to the agency makes it hard for reviewers to get ahead, especially in the wake of a surge of 600 ANDAs filed in June to beat new stability testing requirements.

An efficient and comprehensive generic-drug review program is important for FDA to facilitate consumer access to high quality, low-cost generic drugs. Unfortunately, manufacturing problems with generics continue to precipitate recalls and shortages. FDA has blocked the import and sales of numerous generic products from leading manufacturers such as Wockhardt and Dr. Reddy’s Laboratories. And dissolution problems with beta blocker metoprolol have raised new concerns about the safety and efficacy of extended-release generic drugs. 

Quality lapses make it difficult for the generic-drug industry to challenge policies linked to enhanced drug safety and prescribing. An FDA proposal to require label updates when new safety issues arise has generic-drug makers up in arms. Brand manufacturers support the FDA policy as a way to reduce their liability for quality and safety issues involving generics. But generic-drug firms fear that differing labels on brands and generics will confuse and alarm patients and prescribers. A recent survey sponsored by the Generic Pharmaceutical Association (GPhA) indicates that physicians and pharmacists would be less willing to prescribe and dispense generics if the rule is adopted, and many members of Congress have voiced concerns over the FDA proposal (1).

Similar issues regarding the “sameness” of generic and brand-name drugs have ignited battles over the labeling and distribution of future biosimilars. Brands are fighting generic-drug manufacturers over whether follow-on biologics can use the same name of the reference product, while also seeking curbs on automatic dispensing of biosimilars by pharmacists. 


FDA officials have long maintained that generic drugs that meet its rigorous standards for bioequivalence, stability, dissolution, and quality are just as safe and effective as the original brand. But ongoing problems with generic-drug quality have spurred new efforts by the Center for Drug Evaluation and Research (CDER) to ensure drug quality throughout the product life cycle. CDER director Janet Woodcock’s strategy is to establish a new Office of Pharmaceutical Quality (OPQ) to implement a “one quality voice” approach. OPQ will feature review teams that assess the chemistry and controls aspects of a drug product from new drug application (NDA) through generic and over-the-counter versions. While seeking higher-level approval of the OPQ reorganization, CDER is piloting this approach, explained Woodcock at GPhA’s CMC workshop in June, noting that one team reviewing the reference drug and all later versions will avoid duplication. 

OGD also looks to a risk-based approach to its chemistry review program to focus efforts on products that raise more crucial issues. OGD is implementing risk-based quality assessment for solid oral-dosage forms, based on a “failure mode, effects and criticality analysis” algorithm that assigns a risk score to each product. This approach is being tested now, explained Susan Rosencrance, OGD acting deputy director for chemistry, with the intent of expanding it to immediate release solid orals and other dosage forms. 

OGD efforts to accelerate its review process have been hampered, though, by the steady rise in ANDAs and supplements. During GDUFA negotiations two years ago, industry and FDA estimated that approximately 700 new ANDAs would be filed each year, she noted. In fact, the volume exceeded 1000 last year and continues to climb, making it impossible for the agency to eliminate the backlog as fast as expected and creating concerns about how FDA will meet faster review goals that start to phase in next year. 

The solution, from FDA’s perspective, is for manufacturers to submit more complete and high quality applications in the first place. This step would reduce review cycles and the need for multiple amendments that extend the review time frame. OGD acting director Kathleen Uhl emphasized the importance of high quality submissions at the GPhA workshop. Just filing more data does not necessarily make for a quality application, Uhl noted. OGD wants submissions to clearly demonstrate an understanding of the product and process and to avoid “superfluous data” that tries to cover up problems. 

To this end, FDA issued draft guidance on ANDA content and format in June, identifying basic requirements for a complete, high-quality application (2). The guidance specifies the information to be provided in each section of an application, following the format of the Common Technical Document (CTD) developed under the International Conference on Harmonization (ICH). It also summarizes the statutory and regulatory requirements for ANDAs and provides references to other guidance documents. 

The content and format guidance builds on an advisory issued last year on what ANDAs should include to avoid rejection under the agency’s Refuse to Receive (RTR) policy. FDA’s draft RTR guidance indicates what can trigger an RTR, including faulty listing of active and inactive ingredients, poor packaging information, lack of dissolution studies, and inadequate stability data (3). Last year, FDA issued multiple RTR letters to companies that failed to pay GDUFA facility user fees on time, but recently revised its policy to limit RTRs to applications clearly in arrears on fees or with serious shortcomings.

FDA also is updating and clarifying stability testing and assessment requirements for generic drugs as key to minimizing queries, reducing stability failures, and enhancing generic-drug quality overall. A final stability guidance for ANDAs was published in June 2013 (4), and FDA sought to clarify policy specifics in a Question & Answer guidance issued in May (5). Rosencrance acknowledged that the new policy represents “a huge change for industry,” and manufacturers raised multiple questions at the GPhA workshop about how FDA will implement the many specific requirements. But FDA is hopeful that the revision will be beneficial over the long run. 

Despite these and other challenges, Uhl reported at the workshop that OGD has made progress in meeting key GDUFA goals. Some initial action has been taken on almost 50% of backlog applications, and she sees progress towards achieving parity in domestic and foreign plant inspections. OGD aims to finalize the RTR policy this year and to issue additional guidance on ANDA amendments and on manufacturing supplements. FDA is hiring more chemistry reviewers, as supported by GDUFA, and hopes to bring on board 140 new reviewers by fall. These efforts aim to help assure the high quality of generic medicines, which, said Uhl, is “imperative in assuring the American public that theproducts you make are of high quality.”  

 (2014), www.gphaonline.org/media/cms/GPhA_Report_v2_4_FINAL_2_.pdf, accessed July 10, 2014.
  2.	FDA, 

Draft Guidance, Content and Format of Abbreviated New Drug Applications

Draft Guidance, ANDA Refuse-to-Receive Standards

Final Guidance, Stability Testing of Drug Substances and Products

Final guidance: Stability Testing of Drug Substances and Products, Questions and Answers

’s Washington editor, tel. 301.656.4634, jwechsler@advanstar.com. Read Jill’s blogs at PharmTech.com/wechsler.

Regulatory Watch

FDA seeks high quality applications and products to facilitate approvals and reduce safety and supply problems.

Changes and Challenges for Generic Drugs

Contract manufacturing organizations (CMOs) should have the technical expertise to be considered by clients for partnerships. As results from BioPlan Associates’ 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (1) show, however, it’s no longer enough for CMOs to lay claim to technology, regulatory compliance, and IP protection expertise, as these increasingly become non-negotiable issues. 

Sponsors today are demanding high levels of professionalism, performance, and effectiveness in managerial areas to accompany CMOs’ technical expertise. Indeed, when BioPlan surveyed 238 industry decision-makers from around the world about the critical issues they consider when selecting a CMO, a leading 71% said it was ‘very important’ that they be able to establish a good working relationship--with another 27% indicating this to be important (see 

). In other words, virtually all decision-makers these days recognize the importance of a good working relationship. 

This consideration has been moving up the rankings over the years. Of the 19 factors assessed, it was the fourth-most important back in 2006, before moving to the second spot in 2010 and now the top position by a fair margin. The next-most recognized factor this year was sticking to a schedule, deemed at least important by almost 95% of survey respondents. While this would seem intuitively obvious, the fact that this issue continues to appear year-after-year, suggests little is being done within the industry to address the problems. 

Clearly, as this highly technical industry matures, customer service and establishing good client-vendor relationships are being perceived as more important attributes. But there are multiple factors that can jeopardize them. The CMO market--particularly for non-commercial scale manufacture--is competitive. CMOs are juggling multiple projects at the same time, and when clients select the lowest bidder, it’s not hard to understand that some CMO projects may not keep to schedule, despite everyone’s careful projections and planning. Add to this the uncertain nature of process development and problems that invariably arise, and it is easy to see how scheduling can be challenging. 

That doesn’t make scheduling any less important, of course. Even small-market biopharmaceuticals typically involve sales of at least $200 million/year, such that each delayed work day in getting a product to market can represent a loss hundreds of thousands of dollars in sales, if not millions. As a result, clients and CMOs want to plan ahead and reserve enough time for crucial methods and technology transfer activities, as these almost always take longer than expected. 


Selecting the right CMO is a labor-intensive process, and with good reason. As sponsor companies increasingly outsource high-value activities previously deemed core in-house ones, they must take greater pains to ensure that they pick the right partnerships. Clients are seeking an increasing volume of available information about CMOs before they begin their due diligence.  This type of vetting process allows for potential problem areas and questions to be identified at an early stage. As a result, it can take three or more months to build a rapport and start a project. And as the BioPlan study indicates, these first few months are crucial for both parties to build trust and a sound relationship. That relationship requires cooperation and flexibility, as well as the ability to understand the other side so as not to make unreasonable demands. 


CMOs themselves have something to say about all this as well. In past years, BioPlan has found widespread complaints from CMOs regarding excessive client demands such as

 “Clients don’t build in sufficient time for the project (unrealistic timeframes)”

“Clients want to contain cost by doing limited development runs, but still expect successful full-scale manufacturing”

“Clients expect us to resolve the most difficult scientific or technical problems.”

Last year, each of those complaints was cited by at least 9 in 10 CMOs as being a “very” or “somewhat common problem.” Each problem had also been cited by a larger share of respondents than in prior years. 

These are issues that can presumably be dealt with or even avoided if the contracting parties invest the effort to build solid relationships. But the data suggest that from the CMO perspective, clients have unrealistic expectations and simply may not be familiar with complexity of CMO operations--this suggests CMOs need to spend time upfront clarifying the overall project. The results also suggest that the majority of biomanufacturers, who are under increasing cost and time pressures, are pushing that stress onto their CMOs, potentially due to a lack of experienced staff dealing with CMOs and bioprocessing outsourcing.

Sponsors want CMOs to effectively handle tough issues

CMOs are being increasingly asked to quickly resolve tough problems, including cross-contamination issues. When BioPlan evaluated the changes over the years in how important clients/sponsors have considered various factors when selecting a CMO, we found a sizable increase in the share of respondents indicating that it’s “very important” that CMOs “effectively handle cross-contamination issues.” That consideration rose from 26.4% of respondents in 2006 to 60% this year, with that 33.6% point change the largest of any factor (see 

Close behind, “provide lead times to cover technology transfer” (+32% since 2006) and “protect intellectual property” (+31.7%) have also seen considerable increases in client concern, potentially due to heightened perception of these risks.

By contrast, factors that have become crucial to fewer respondents over the years include having production platforms relevant to the client’s product. This is likely due to most CMOs having probably worked with many of their own and clients’ production platforms, and should become less of an issue over time as production platforms continue to increase and become more standardized. Capacity-related concerns in the context of CMOs have also decreased, with this likely associated with the current lack of any industry-wide capacity shortages and with CMOs simply not seeking or taking on projects beyond their capacity. 


  Results from the BioPlan study show that clients continue to seek better relationships with CMOs, and that reliability is a key trait they look for in their partners. Technical considerations obviously are paramount, too--there should not be a big difference between results at small scale and large scale when a CMO has been engaged, and clients will always demand expertise and quality. 
But the trends in the data suggest that as the CMO market becomes more competitive and globalized, these sorts of qualities are being seen as prerequisites, and that questions of efficiency, timeliness, and reliability are coming to the fore. In essence, the technical expertise gets the CMO a seat at the table, but nowadays it’s the relationship that will seal the deal. 

11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production


Eric Langer is president of BioPlan Associates, tel. 301.921.5979, elanger@bioplanassociates.com, and a periodic contributor to Outsourcing Outlook.    

Outsourcing Outlook

Annual study shows CMO technical expertise is not enough.

Relationship-building at Top of Mind for Clients

 General Chapters <41> Balances and <1251> Weighing on an Analytical Balance became official on Dec. 1, 2013 (1, 2).  These revisions aim to ensure weighing accuracy and eliminate unnecessary overtesting for US pharmaceutical manufacturers and suppliers. The chapters attempt to simplify previous descriptions and reflect current state-of-the-art weighing practices. Revisions include modified balance test procedures, which focus on the determination of minimum weight, and the execution of routine testing.

The new requirements of General Chapter <41> are mandatory. The revised chapter now states that accurate weighing must be performed using a calibrated balance. It also details a relatively demanding balance assessment, describing accuracy and repeatability tests with new acceptance limits. This applies for balances used to weigh analytes for quantitative measures. 

For accuracy testing, use of a test weight of 5–100% of the balance capacity is now applicable. Accuracy, defined by 

 as the systematic error, must be determined at higher loads close to the balance capacity (i.e., largest systematic error), as it cannot be detected reliably below 5%. Hence, accuracy testing below 5% is no longer allowed (see 

In contrast, repeatability testing and minimum-weight determination should be carried out using a small weight below 5% of the balance capacity (see 

). In this lower range, the repeatability is the dominant source of error and is virtually independent of the test weight. With higher weights (i.e., above 5%), the repeatability is a weak function of the test weight and so the repeatability will increase, leading to higher minimum weight values.

For more information on balance testing, a video tutorial can be viewed at: www.mt.com/lab-usp-tutorial. 

Advisory Chapter <1251> provides additional clarification and extends the scope to any balance used for an analytical procedure. These major revisions focus on balance qualification and operation. Installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) recommendations are given. PQ, for example, should be carried out using a risk-based approach. 

For the first time, the term “minimum weight” is officially introduced in a pharmaceutical compendium. This requirement is clearly applied to the sample weight, not including the tare vessel. Every balance has an individual minimum weight, depending on the type and performance of the load cell, the location, and the environmental conditions. The minimum weight of every balance should be periodically assessed for conformance. During a webinar in December 2013, it was encouraging to note that the majority of balance users (75% of those surveyed) are already familiar with the term minimum weight (3). 

It is also important to note that USP recommends how to establish the minimum weight for applications outside of 

 <41>, with the phrase “If not subject to the requirements of General Chapter <41>, the minimum weight value may vary depending on the required weighing tolerance and the specific use of the balance” (1).

Chapter <1251> goes on to provide practical recommendations for the installation qualification and operation of balances. Amongst others, it describes several environmental factors that can influence the performance of a balance, such as air currents (drafts), temperature variations (e.g., direct sunlight), vibrations, and electrostatic effects. These factors can all affect the minimum weight of a balance at a specific time. 

Crucially, weighing net samples sufficiently above the minimum weight is recommended to take balance performance fluctuations into account. The implication is that a safety factor should be used when weighing, as shown in Figure 3. The use of a safety factor ensures that the smallest net weight is sufficiently larger than the minimum weight determined at a particular time by a particular person.

Applying a safety factor minimizes the risk of out-of-calibration, out-of- specification (OOS) or out-of-tolerance (OOT) results. The safety factor is the quotient of the smallest net weight and the experimentally determined minimum weight. It accounts for environmental influences and variations in operators, samples, and statistical factors. The safety factor applied should depend on the risk. It should be higher for more critical applications and unstable environments. 

Another consequence of the USP revisions is that a daily balance check, typical in the pharmaceutical industry, is no longer a requirement. Instead, the type and frequency of balance checks should be determined by the risk and process tolerance of the application. The more critical the impact of an incorrect result, the more testing should be carried out, to reduce the risk of OOS or OOT results. In any case, it should contain at least a regular calibration with determination of measurement uncertainty and periodic sensitivity and repeatability testing. Performing the right tests at the right intervals will ensure quality results. During a webinar in December 2013, a majority of balance users (77% of those surveyed) admitted to still carrying out balance checks daily or before every use (3). This result indicates that many companies could potentially benefit from eliminating unnecessary testing, which would bring significant time and cost savings. 

Common questions about the USP revisions 


Since the USP announced these revisions, some questions have arisen. 

Q: The USP chapters focus primarily on analytical balances. Are these revisions applicable to balances in a production or manufacturing environment?

A: The scope of USP is quality control of drugs. If the procedure referred to in a USP monograph requires materials to be ‘accurately’ weighed, a balance that weighs ‘accurately’ (meeting 0.10% requirements for repeatability and accuracy) is needed. If not, the balance repeatability and accuracy should meet other defined weighing tolerances commensurate with the requirements of the application. This aspect does not apply to production scales. However, production scales can also have a critical impact on the quality of drugs and thus need to meet GMP requirements. GMP requires scales to be consistently accurate and to be periodically calibrated and tested. Thus, the same scientific principles of managing weighing equipment--summarized in GWP (Good Weighing Practice, Mettler Toledo)--apply for production and quality control. The difference is that USP <41> explicitly requires a weighing tolerance of 0.10%, whereas the weighing tolerance in production can be chosen and defined based on specific quality and process requirements. Most pharmaceutical companies typically use a weighing tolerance limit between 0.1% and 2%.  

For all applications, weighing should be carried out using a calibrated balance that meets the requirements for repeatability and accuracy.

Q: What does USP mean when they say that balance checks with external weights can be replaced partially using automatic or manually triggered adjustment by means of built-in weights?

A: With some limitations, the internal test can be considered as an external sensitivity test. It detects systematic deviations and adjusts for it. However, since the internal weights are not traceable, an external, traceable weight must be used periodically. In practice, ‘partially’ means that if the internal test is performed on a daily basis, the external frequency can be extended to once a week or once a month, for example. It is recommended to activate the in-built automatic adjustment function using the internal weights and to program (or trigger manually) the balance for a daily adjustment. Depending on the risk of the application, further measures may be recommended. 

Q: Do we need to establish the minimum weight for each balance or can we just set a nominal minimum weight for all five-place balances?

A: Every balance has an individual minimum weight, depending on the type and performance of the load cell, the location and the environmental conditions. This means that 10 different balances of an identical model may have 10 different minimum weights. In theory, it is possible to set the smallest net weight to a relatively high threshold to cover a family of identical balances. However, this would eventually mean that weighing range is lost with those balances that perform better, and weighing more material could mean wasted sample and, therefore, higher costs. Nevertheless, if the smallest net weight for a series of instruments is set to 50 mg, for example, then the minimum weight of every balance must still be periodically assessed for conformance. 

Q: What is a safety factor and how is it determined?

) is the quotient of the smallest net weight and the determined minimum weight; it accounts for environmental influences and variations in operators, samples, and statistical factors. The safety factor depends on the risk. It should be higher for more critical applications and unstable environments. We would recommend measuring the current, actual safety factor through a GWP Verification and then defining it based on the results and the risk analysis. 

Commercially available programs, like Mettler Toledo’s Good Weighing Practice, can help pharmaceutical manufacturers and suppliers to comply with the new USP guidelines by putting the guidelines into practice in a structured and effective way. Services can, for example, perform risk assessments and provide test methods and frequencies based on specific risks. 

 <41>, “Balances,” Second supplement to 

(US Pharmacopeial Convention, Rockville, MD, June 1, 2013).
  2. 	

<1251>, “Weighing on an Analytical Balance,” Second supplement to 

 (US Pharmacopeial Convention, Rockville, MD, June 1, 2013). 
3.	G. Martin, M. Huber, and J. Ratcliff, “Ensuring USP Compliance with Revised Chapters on Weighing,” webinar (Dec. 3, 2013).


Joanne Ratcliff, PhD, is communications project manager for Laboratory & Weighing Technologies, Joanne.Ratcliff@mt.com, and Martin Huber, PhD, is head of the GWP competence center, Martin.Huber@mt.com, both at Mettler Toledo.

Troubleshooting

The latest revisions to the USP General Chapters <41> Balances and <1251> Weighing on an Analytical Balance aim to ensure weighing accuracy and eliminate unnecessary overtesting by simplifying previous descriptions and reflecting current state-of-the-art weighing practices.

Complying with Revised Weighing Guidelines

Numerous trends in the pharmaceutical industry, and particularly in the biopharmaceutical sector, are leading to the need for smaller-capacity production facilities, which in turn is affecting the types of investments being made by pharmaceutical manufacturers. First is the shift to biologic-based drugs, which has occurred along with a dramatic increase in the productivity, mainly in terms of much higher titers, of biopharmaceutical processes. “While demand has increased for biopharmaceuticals, it has not kept pace with the 10-fold increase in productivity,” states Günter Jagschies, senior director of strategic customer relations for BioProcess, GE Life Sciences. “As a consequence, there is an opportunity to scale down biologics manufacturing, and newer facilities are typically based on 2000-L or smaller reactors and are much less cash-intensive, which is a key factor for pharmaceutical companies today given the growing pressure for them to be more cash aware,” he adds.

The second factor is the shift to production in emerging markets, both because the middle class is increasing and demand for drugs is expected to grow significantly, and in response to individual government requirements, such as in Brazil and Russia, for western manufacturers that want to sell products--both large and small-molecule--in those countries to produce the drugs locally. “At present, however, demand for biopharmaceuticals in particular remains limited, generally due to affordability issues, so smaller production volumes are still required. In addition, domestic manufacturers are already serving these markets, which further reduces the required facility size,” Jagschies notes. In the biosimilar sector, the stiff competition will also keep volumes quite low, at least initially. There are approximately 100 companies worldwide looking to produce 5-7 of the most successful biologics that are coming off patent, and even if just 10 of them are successful, each will have a small share of the market, according to Jagschies. At the same time, many new drug candidates (i.e., antibody drug conjugates) have much higher potency and thus require much smaller doses, which also translates to lower production quantities. 

Increasing access to single-use technologies for biologics production is further enabling the scale-down of manufacturing facilities, because such systems provide flexibility and enable companies to quickly change their portfolios in response to market needs. For batch reactions in particular, Jagschies notes that the use of disposable technology can also help improve cash flow. The introduction of modular facilties is another enabling factor. “With modular facilities, companies can export the technology required for quality production to anywhere in the world, including areas where it would not be possible to construct such facilities otherwise,” says Jagschies. By their nature, modular facilities are smaller-scale.

“All of these trends together are driving interest in smaller facilities and smaller investments, particularly in the biopharmaceutical sector,” Jagschies concludes.

A summary of selected investments in both small- and large-molecule manufacturing facilities during the last year is presented as follows.

: Abbott signed an agreement in June 2014 to acquire Russian pharmaceutical manufacturer Veropharm for approximately $495 million, according to the company. Abbott will acquire Garden Hills, the holding company that currently owns more than 80% of Veropharm, but is expected to own more than 95% by the time the transaction closes. Veropharm’s portfolio includes products in the areas of women’s health, central nervous system disorders, cardiovascular disease, gastroenterology, and oncology. Veropharm is currently constructing a new manufacturing facility to expand its production capabilities, according to Abbott.

: AbbVie officially opened its newly expanded facility in Sligo, Ireland in June 2014 (announced in 2012), which provides manufacturing capacity to deliver on AbbVie’s existing portfolio of medicines and to support potential new therapies within its pipeline, according to the company, which invested €85 million ($115 million) in the project. AbbVie also announced in February 2014 that it will invest $320 million to build a facility in Singapore for the production of both small-molecule and biologic APIs. The facility will have 250 workers once it is operational in 2019, according to the company.

: Actavis is investing $48 million to reopen in Puerto Rico its solid dosage manufacturing and packing facility in Manati and expand hormone production at its site in Fajardo. The company expects to create 300 jobs by the time the facilities are operational in 2016.

: AstraZeneca announced in late 2013 that it is expanding its presence in Macclesfield, UK. The company is investing $190 million in a new plant to increase production of its blockbuster prostate cancer drug Zoladex (goserelin acetate). While no new jobs will be created, the decision does mean that the existing 300 jobs at the site will be retained.

: Bayer HealthCare is making several investments at home in Germany and abroad. The company will spend nearly $694 million at existing sites in Leverkusen and Wuppertal, Germany to expand production of its hemophilia drug Kogenate (antihemophilic factor), adding 500 workers by 2020. Bayer Healthcare is also investing $138 million to expand its packaging, logistics, and analytical capabilities at its facility in Beijing, China.

: After investing more than $350 million to improve manufacturing operations for injectable drugs at its Ben Venue Laboratories site in Bedford, OH, Boehringer Ingelheim announced that the plant would be closed because the cost and time required to overcome systemic problems was too high. Across the globe in China, the $95 million expansion of its plant in Shanghai that began two years ago and included the addition of manufacturing, packing, and distribution operations is now operational. Boehringer Ingelheim also indicated that it would make further investments at the site in 2014 to establish a development lab for biologic drugs.

: BMS is consolidating more than 575 jobs in information technology, marketing services, and financial services at its new North America Capability Center over the next three years. In 2013, the company also announced a $250 million expansion of its biologics plant in Devens, MA, adding R&D and clinical trial manufacturing capabilities. Over in Ireland, however, it is closing an API plant near Dublin and eliminating one manufacturing line at its API plant in Swords County. 

: The $450 million, 240,000-square-foot biologics facility in Kinsale, Ireland that Eli Lilly announced in 2012 is expected to be complete by the end of 2014, with the first production of GMP lots taking place in early 2016. In 2013, the company also announced nearly $1 billion in planned plant expansions for the production of its insulin products, including API and cartridge manufacturing capabilities: $245 million at its sites in Indianapolis, IN and Puerto Rico, $120 million in France, and $350 million in China. In addition, Lilly is spending $60 to $70 million on the construction of a 260,000-square-foot manufacturing facility in Nantong-Jiangsu, China with its Chinese partner Novast that will produce generic versions of several Lilly drugs. This plant is expected to be operational by the end of 2014.

: GSK and Novartis made big news in April 2014 when they announced a three-way swap of various businesses. GSK is selling its oncology business to Novartis and buying Novartis’ vaccines business (excluding influenza vaccines), and the two companies are combining their over-the-counter businesses.

In March 2014, GSK announced plans to invest as much as £130 million ($222 million) in five African manufacturing facilities and an R&D laboratory for non-communicable diseases over the next five years. Possible locations include Rwanda, Ghana, and Ethiopia. In the same month, the company announced that it is increasing production of several over-the-counter products at is Zebulon, NC plant. In September, 2013, GSK opened a $40 million plant in Cork, Ireland for the production of Gantrez, the adhesive used in the company’s Poligrip denture product.

Also in 2013, following its announcement in 2012 that it would invest more than $790 million upgrading two production sites in Scotland and construct a new plant in Ulverston, Cumbria, GSK indicated that it would invest a further $330 million on additional upgrades and a new technology center focused on continuous manufacturing, biocatalysis, nanotechnology, and supply-chain processes. The company also intends to use continuous processing for some of the manufacturing processes at the new facilities. 

In November 2013, GSK announced that it will invest approximately $136 million to build a new facility in India that will also use continuous processing. The facility is expected to be operational in 2017. The company is also constructing a $50 million facility in Singapore that will use continuous processing.

: Jannsen, a business unit of Johnson & Johnson, announced plans to construct a $200 to $300 million, 267,000-square-meter plant in Xi’an, Shaanxi province, China to replace a Janssen Pharmaceutical facility built by J&J and a Chinese partner in 1985. The new facility will serve as a supply-chain center for China and other Asian countries.
Merck KGaA: The company’s biopharmaceutical division Merck Serono will construct an €80 million ($108 million), 431,000-square-foot facility for the bulk production and packaging of drugs for the treatment of diabetes, cardiovascular disease, and thyroid disorders in Shanghai, China that is expected to be completed in 2016 and ready for production in 2017. In Europe, Merck Serono is spending $68 to $69 million (€50 million) to modernize its fill-finish plant in Bari, Italy. Merck’s Allergopharma unit, meanwhile, is constructing a $55 million (€40 million), 64,600-square-foot facility near Hamburg, Germany for the production of allergy medicines destined for China and other emerging markets. It is expected to be completed in 2016. 

: In addition to its purchase of GSK’s oncology business and sale to GSK of its vaccines operations (except influenza vaccines) in April 2014, Novartis also announced that the two companies would combine their over-the-counter businesses in a joint consumer-health venture.  At the same time, Novartis announced that it was selling its animal-health business to Eli Lilly. According to the company, it now has a more focused portfolio with depth in dermatology, heart failure, respiratory, cell therapy, and oncology in its pharmaceuticals business, a strong position in eye care through its Alcon unit, leadership in generics with its Sandoz business, and is well-positioned for innovation with Novartis Institutes for BioMedical Research (NIBR).

Also in April 2014, Alcon announced the opening of a S$200 million (US$160 million), 330,000-square-foot plant in Singapore for the production of products for the treatment of dry eye, allergies, bacterial infections, and glaucoma. In addition to the $500 million the company announced in 2012 that it would spend on a second facility for biologic drugs, Novartis indicated in February 2014 that it is expanding one of its existing plants in Singapore, adding a new GMP warehouse and raw material laboratory. 

Novartis is also working with African partners to expand research capacity in the region.  In 2013, Novartis conducted workshops in Kenya and Ghana to help African researchers construct safe and effective Phase I trial facilities for bioequivalence, and may hold additional workshops in other countries. NIBR and the University of Cape Town in South Africa also launched a collaboration in 2013 to expand research capabilities at the university’s Drug Discovery and Development Center.

In December 2013, Novartis announced the closure of an outdated Ciba Vision plant in Canada.

Novo Nordisk: Novo Nordisk is constructing a $100 million, 29,100-square-foot purification pilot plant at its new research and development facility in Denmark to expand its capacity for early-phase diabetes projects. The facility is being built to allow for a doubling of capacity if needed. The company is also constructing a plant in Denmark with R&D centers for diabetes and biologics, and recently announced plans to add 6000 positions in Denmark by 2022, half in R&D and half in production.

 Pfizer recently completed a $30 million expansion of its product technology lab in Ireland and is spending an additional $100 million to upgrade its biologics plant in the country. 

: In Ireland, Regeneron is spending $300 million to create a pharmaceutical plant at a former 400,000-square-foot Dell computer manufacturing site and expects to employ a total of 300 people by 2016. The company is also investing $70 million to complete the second phase of an expansion of its East Greenbush, NY facility, which will include the addition of two 10,000-liter bioreactors.

: Following its 2013 announcement to expand its biologics production capabilities at a cost of more than $880 million, Roche said in April 2014 that it will also be upgrading its small-molecule manufacturing operations, investing approximately $135 million to construct a new plant at is headquarters in Basel and improve other facilities for the production of both developmental and existing drug products. The new plant is expected to be onstream late in 2016.

The biologics investments include ~$210 million for a new ADC manufacturing plant in Basel, ~$286 million to expand production capacity at two sites in California, and nearly $385 million to upgrade its Penzberg, Germany plant.

Roche is also spending $105 million on a new packaging and logistics training center in Switzerland.

 Sanofi is investing in emerging markets. The company is not only increasing insulin production at its facility in Russia, it is investing $95 million in a new manufacturing plant in Algeria, which will have a capacity of 100 million units per year, and $75 million to construct its third facility in Vietnam, which will be operational in 2015. Meanwhile, Sanofi’s Genzyme business is investing $80 million at its recently approved facility in Framingham, MA, adding more downstream processing capabilities for Fabrazyme (agalsidase beta), its treatment for Fabry disease.

: Teva’s $2 billion cost-cutting efforts continue and will include the definite closure of 11 plants, and possibly an additional 16, which are under evaluation by the company. Plans to build an API plant in India have also been scrapped. In October 2013, however, Teva opened a $100 million plant in Croatia that produces tablets, capsules, and sterile formulations for the European and US markets. 


 Cynthia Challener is a contributing editor for 

Cover Story

Shrinking facility size, growth of biologics, and emerging market demand influence pharma investments.

Pharma Investments Reflect Key Industry Trends

In the complex and multi-dimensional environment of modern manufacturing operations, it is a challenge to identify the best manufacturing approach for a specific product, taking into account financial, product, and process related issues, including globalization of manufacturing, regulatory requirements, company-specific strategies and preferences, and a complex process development environment. The authors describe a method based on a techno-economic optimization procedure that supports process development by providing a systematic approach to investigating and comparatively evaluating various manufacturing approaches. The methodology can be applied to both traditional and innovative manufacturing technologies and to both existing and new products.

	Process development in the pharmaceutical manufacturing industry requires the identification and implementation of the best possible manufacturing approach for a specific product. Even more challenging, this task is typically performed in a complex and multidimensional environment with often contradictory technical and economic challenges. Additionally, in pharmaceutical manufacturing, a stringent regulatory framework regarding product quality and patient safety must be considered. Accordingly, new pharmaceutical products are commonly developed and manufactured using standardized recipes and an existing inventory of traditional unit operations. Innovative manufacturing technologies emerging in the process equipment market are often ignored or not considered for a lack of role models, equipment providers, or experience and fear of violating regulatory requirements. Although not all areas of pharmaceutical manufacturing are equally affected, it is certainly the case in the secondary manufacturing of pharmaceutical solid dosage forms. The methodology presented in this article, therefore, was initially developed for this area.

	Interest in innovative manufacturing approaches has grown for a number of reasons. First, cost pressure has been increased by generic-drug companies, the government health system, and the consumers of pharmaceutical treatments. Lean manufacturing concepts have been developed, and supply-chain management has begun to implement concepts, such as just-in-time manufacturing, deployed in other industries. Even more, innovative and continuous manufacturing equipment is gradually penetrating the process equipment market. In process development, concepts and technologies associated with process analytical technology and quality by design are becoming standard. Advanced conceptual approaches, such as real-time release, are slowly becoming a part of operations and appear to deliver their full potential when combined with advanced manufacturing approaches, rather than with traditional batch-based processes.

	In summary, pharmaceutical manufacturing is currently in a situation in which traditional approaches are increasingly questioned and new concepts and technologies are gradually finding their way into manufacturing operations. As such, a holistic evaluation of future manufacturing technologies becomes an increasingly important step in process development.

	The methodology presented here simultaneously considers economic and technological aspects and provides a flexible and holistic platform for the evaluation of pharmaceutical manufacturing processes. The goals were to provide:

		A financial justification of a specific manufacturing approach

		An evaluation of the economic and technological feasibility  of a specific manufacturing approach

		A basis for comparing manufacturing approaches and identifying the best one.

	The manufacturing process evaluation methodology can be applied in three areas, as depicted in 

: Identifying the best of the existing manufacturing approaches. Pharmaceutical products are often produced at different company sites or by different manufacturers. Not all of them may be using the same unit operations or manufacturing approach. For example, a product is manufactured via fluid-bed granulation at one site and high shear or dry granulation at another one. The methodology presented in this paper allows systematic investigation of the different manufacturing approaches to determine the best one among them. This is particularly useful for reducing the number of sites and for centralizing manufacturing.

: Identifying the best manufacturing approach for a new product. Manufacturing technologies are typically chosen at an early stage in product development. Often, the decision is based on the type of equipment used in the early development or the inventory of process equipment available in operations, rather than on a systematic search for the best manufacturing approach. By applying the proposed methodology, a rational selection of future manufacturing technologies can be made.

: Evaluating the feasibility of changing from a traditional to an innovative manufacturing approach. For pharmaceutical products that are already on the market, a periodic assessment of manufacturing approaches may help to identify cost-cutting potential or to increase competitiveness vis-à-vis generic-drug manufacturers after the product’s patent protection expires. In addition, a simple assessment of an existing manufacturing process can eliminate the existing shortcomings or limitations in terms of yield, product quality, or cost of goods by switching to a different manufacturing process. The methodology presented in this paper can help to identify the differences between established and innovative manufacturing technologies.

	Tools traditionally applied for financial analysis can generally be applied for techno-economic manufacturing process evaluation as well. The most relevant ones are briefly discussed as follows

. A cost-benefit analysis is a common technique to assist decision-making that aims at expressing benefits and costs of a project or investment in monetary terms, preferably as the net present value. The most desirable solution within a given set of options can thus be identified. A cost-benefit analysis, however, is ineffective when the benefits cannot be directly expressed in monetary terms, which is often the case in process engineering applications with complex and multidimensional product- and process-related evaluation criteria. Therefore, in process development, a cost-benefit analysis is primarily applied during the final decision-making steps and not in the early or conceptual phase

. A cost-effectiveness analysis relates the cost of a given option to a specific objective or optimization criterion. For example, if an objective were to reduce the overall manufacturing time in days, a cost-effectiveness analysis could be the first step in comparing the various options, followed by a cost-benefit analysis to produce monetary values for the decision-making process.

. A cost-utility analysis relates costs to a multidimensional measure of effectiveness, referred to as “utility” in economic analysis, as a representation of preferences. The utility value is a value assigned to a project or investment based on the anticipated performance. A cost-utility analysis can be used to measure the financial and technological dimensions of various options and generate a combined economic and technical efficiency.

	Because, from the start, a manufacturing process evaluation contains a number of economic and technical performance or compliance parameters, a cost-utility analysis is the tool of choice for an early or conceptual process evaluation. As process development progresses and risks and technical criteria become specified in more detail, a cost-benefit analysis can be applied if necessary.

	The evaluation methodology for a manufacturing process presented here is derived from classical cost-utility analysis and consists of the six consecutive steps described in

: Definition of ranking criteria and risk-profile elements. The first step is to define which ranking criteria to include in the process evaluation. This selection should be made by a team of technical and financial experts and will comprise cost-related and product- as well as process-related ranking criteria.

		Cost-related ranking criteria can include the following:

		Depreciation (e.g., of building, infrastructure, or process and analytical equipment)

		Direct material costs for primary manufacturing (e.g., raw materials) and secondary manufacturing (e.g., API and excipients, primary and secondary packing materials)

		Utility costs (e.g., energy, water, and HVAC)

		Costs of cleaning, preventive maintenance, and repairs

		Production area and factory overhead costs.

		Product-related ranking criteria can include the following:

		Compatibility with the existing dosage form and composition (regulatory product profile of the existing product, if available)

		Dosage form size, shape, and presentation

		Process-related ranking criteria can include the following:

		Commercial availability of process equipment

	If necessary, additional categories can be included in the evaluation procedure. Manufacturing in different countries, including the availability of trained personnel, wage levels, and energy prices, may be considered, for example.

	Risks are economic, technical, or other (e.g., regulatory) aspects not known at the time of the evaluation but potentially affecting the performance of the selected manufacturing approach. Because risks cannot be quantified, and, thus, cannot be directly incorporated into the process evaluation, each process evaluation includes an associated risk profile to indicate potentially critical unknowns that must be further investigated if the respective process option is ranked favorably.

		Risk profile elements may include the following:

		Changes in the solid state of the API vs. the desired state

		Residuals from chemical manufacturing in the product

		Problems with stability that reduce shelf life

		Technical concerns of the evaluation team.

: Definition of quantitative and qualitative ranking criteria. Each ranking criterion can be included in a quantitative or qualitative ranking procedure. If the former is applied, a direct numerical value is assigned as a measure of performance or compliance. Typical quantitative criteria would be available in monetary terms or in technical units (e.g., a footprint of the unit operation in square meters or the maximum output in doses per hour).

	If a quantitative figure cannot be obtained at the time of the evaluation, a qualitative ranking procedure can be used. Instead of actual numerical values, scores are applied to quantify the estimated magnitude of costs or the degree of technical compliance.

	Costs can be ranked qualitatively, for instance, by assigning the following five score levels:

		A score of 2 if a significant (>30%) cost reduction is expected

		A score of 1 if a minor cost (>10 and ≤30%) reduction is expected

Peer-Reviewed Research

A techno-economic profiling method supports pharmaceutical process development by helping identify the best manufacturing approach.

Comparing Manufacturing Process Options

Counterfeit drugs, which include cancer treatments, lifestyle drugs, and common prescriptions, such as painkillers and antibiotics, are an insidious, global public health threat (1, 2). “Counterfeiters come in where controls are weak and where they can find value,” notes Bill Fletcher, managing partner at 

. “Typically they produce counterfeit drugs and then exit before they are found; we only find out later from investigations. Brand owners, however, need to focus in on this problem now because it can have a huge cost. We’re one situation away from having a real backlash.” 

Various packaging technologies, such as tamper-evident closures and authenticity identifiers (e.g., holograms, taggants, security inks), are available to help combat counterfeiting 

). Packaging alone, however, doesn’t stop counterfeiters, says Fletcher, “Counterfeiters are adept at making authentic-looking packaging. Authentication technologies, such as holograms or marks on the package, are not effective at the consumer level because consumers typically don’t know what the authentic package or medicine should look like or if a change was made by the manufacturer.” 

Governments around the world have been stepping up to create legislation and systems designed to protect their drug supply chains. Most of these systems attach a serial number to a package and use a central database to verify that drugs being bought and sold match up. Serialization is already in effect in Turkey, Argentina, and for some drugs in China. In Brazil, new requirements begin in 2016. In the European Union (EU), the Falsified Medicines Directive was instituted to combat counterfeiting through various measures, including a requirement for pack serialization beginning in 2017.  

In the United States, the federal Drug Quality and Security Act (DQSA) and more specifically the Drug Supply Chain Security Act (DSCSA), referring to Title II of the law, was signed into law Nov. 27, 2013 (3). This federal law preempts a California state law, which would have required phase-in of a serialization and pedigree system for pharmaceutical packages in the state beginning in 2015. Under the DSCSA, companies in the supply chain will be required to have transaction records and verify that all trading partners are authorized distributors by Jan. 1, 2015. The law also provides specific requirements to quarantine and investigate suspect product based on packaging lot number or serial number. In June 2014, FDA released draft guidance on identifying and investigating suspect product (4). Serialization of saleable units and cases will be required by Nov. 27, 2017. A full pedigree system, which involves a unit-level track-and-trace system to document whenever a product changes ownership, must be implemented over the next 10 years, by Nov. 27, 2023. 

spoke with Fletcher about how companies should be preparing to meet the requirements of the DSCSA. 

: What do drug supply-chain companies need to understand about how the law applies to their activities? 

: The law defines manufacturer, exclusive distributor, wholesaler, and other supply-chain participants, and companies can fall into multiple categories with different responsibilities under the law. As a company develops a list of requirements and a solution for serialization, these categories should be considered. For example, wholesalers are defined as someone other than the manufacturer, but a company could be a manufacturer for one drug and a wholesaler for another.  There are a number of exemptions under the law for distributors, dispensers, and wholesalers, and companies need to understand what applies to them. 

: What do companies need to do now to comply with the DSCSA?
  

: Beginning Jan. 1, 2015, companies must verify that all trading partners are authorized distributors of record (ADR). Most companies already have a standard operating procedure for verification, but it may not meet the requirements of the new law. The verification process must include quarantine and investigation of suspect products, which may impact a company’s ability to effectively distribute goods. 
Also beginning Jan. 1, 2015, each entity in the supply chain must pass along a document that contains 10 transaction details for each item and packaging-lot number combination, the transaction history of the product, as well as seven statements related to the authenticity of the product (e.g., a statement acknowledging that you have not knowingly shipped suspect product). An exception to the transaction requirement is that the wholesaler, in certain situations, does not have to pass the original transaction history from the manufacturer but can start the history with their own data. All companies must capture, record, and maintain this information for six years, and companies must be able to readily provide data upon request from federal or state officials. Many companies already have transaction data but are not currently storing it in a manner that can be used later. The initial transaction from the manufacturer to the wholesaler is likely to come in the form of an electronic data interchange (EDI), and companies must be sure they are storing this EDI message in a useful way.  

Companies should work now towards building systems that can produce transaction statements and store data for use. The final FDA guidance detailing what the transaction statements should look like may not be released until as late as Nov. 27, 2014, but companies will need to comply by Jan. 1, 2015. 

: What are the serialization requirements under DSCSA?

: Serialization requirements will be phased in over several years, depending on where you fit in the supply chain, beginning Nov. 27, 2017. A unique identifier will be required on saleable units and cases. There is an exclusion for products that require a unique device identifier rather than the standardized numeric identifier (SNI) used for drug and biologic products; you need to make sure you understand which category your product falls into. The SNI for serialization under the DSCSA includes the national drug code (NDC), which encodes the manufacturer identity, drug identity, and package configuration into a 10- or 11-digit number. The law requires both a printed human-readable code and a two-dimensional data-matrix symbol containing the NDC and the serial number that can be scanned using a barcode reader. If desired, companies can also include other data, such as lot and expiration date, in the data-matrix symbol. Many companies have decided to follow the GS1 standard, and they are not precluded from this under the law; they can encode the NDC in a GS1 global trade item number. Companies are also looking at identifiers that can be used with other technologies, such as radio-frequency identification (RFID), which are already being used in some cold-chain solutions. Warehousing is often overlooked; companies should consider material handling requirements for serialized goods at the warehouse level.  

Companies are currently focused on these 2015 and 2017 deadlines. This year, they are preparing for transaction statement requirements. In 2015 and 2016, they will build serialization readiness and flush inventory so that by 2017, all inventory will be serialized. 

Within the next 10 years, FDA will work toward a true pedigree system, but companies realize that technology is changing too quickly to take action on 2023 requirements today. The way products are identified, perhaps with RFID or near-field tags, might be vastly different in 10 years. 

: What else should companies consider in developing a serialization solution?


: You need to include variability and flexibility into your solution. Laws can change. Companies were focused on upcoming California regulations, for example, then along came new regulations from Turkey, and they had to change their solution. There are variations in how packages are identified or coded around the world. China has unique requirements because it is a non-GS1 standard, and Brazil has a different spin on how they allocate serial numbers. These issues need to be considered during planning for a serialization program, whether you currently trade in these areas or not, because business leaders may decide to trade products there in the future.  Ensuring solutions support all world requirements is possible and has been accomplished by several companies.

Each person needs to align with a strategy so everyone knows what is going on and what their role is. Companies should put together a roadmap and clearly define their requirements specific to their business systems and practices. Each company, for example, has different versions of enterprise software (e.g., SAP), different packaging practices, and different warehouse practices. After defining this plan, a company can decide what vendor will meet their requirements.

Today, companies should establish work streams today for packaging serialization, warehouse handling, distribution and transaction documentation, and suspect product verification. 


  1.	World Health Organization, “Medicines: spurious/falsely-labelled/ falsified/counterfeit (SFFC) medicines,” Fact Sheet No. 275, May 2012.   
  2.	M. Kitamura, “ Fake Antibiotics Feed Growing Worldwide Superbugs Threat,”  accessed June 17, 2014.
  3.	FDA, “

,” accessed June 23, 2014.
  4.	FDA, “FDA issues draft guidance on identifying suspect drug products in the supply chain,” Press Release, June 10, 2014. PT

Supply-Chain Security

The US federal Drug Quality and Security Act (DQSA) and more specifically the Drug Supply Chain Security Act (DSCSA), referring to Title II of the law, requires phase-in of requirements to prevent counterfeiting. An expert discusses how companies should be preparing to meet the requirements of the DSCSA.

Pharmaceutical Technology-08-02-2014

Risk Reduction Top Driver for Biopharmaceutical Raw Material Development

Changes and Challenges for Generic Drugs

Relationship-building at Top of Mind for Clients

Complying with Revised Weighing Guidelines

Pharma Investments Reflect Key Industry Trends

Comparing Manufacturing Process Options

Implementing Supply-Chain Security

Bioavailability Enhancement with Lipid-Based Drug-Delivery Systems

Pharmaceutical Technology, August 2014 Issue (PDF)