Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

	FDA’s Lucinda Buhse has been spearheading the agency’s spectral library of excipients as a means to improving supply chain security of the pharma industry, particularly focused on raw materials entering US borders (there are 300 entry points in total). She and Philip Merrill of IPEC wrote about the library last summer in 

 and Bushe gave an update on the program at the IPEC ExcipientFest Americas conference in late April 2012..

	Hand-held instruments containing the libraries are being used at the borders to rapidly verify and authenticate materials via XRF, IMS, Raman, and NIR screening methods. Materials in question are then investigated at local FDA laboratories.

	FDA has been collecting samples from the industry to add to the library but only has about 20% of its most wanted materials (see Table I in the July 2011 PharmTech article) thus far. Incoming materials must match a Hit Quality Index of 0.95. Bushe pointed out that the supplier or site of material used for the library has not had a significant or statistical impact on the library index to date. Samples are therefore being collected from various industry players and from various sites.

	Looking ahead, FDA aims to fill its library with all the excipient samples it’s seeking and will work to finalize its classification and modeling strategies.

Articles

FDA’s Lucinda Buhse has been spearheading the agency’s spectral library of excipients as a means to improving supply chain security of the pharma industry, particularly focused on raw materials entering US borders (there are 300 entry points in total).

FDA Spectral Library and Border Patrol Work Under Way

The industry has seen growth in extended-release (ER) injectables in recent years. These complex, long-term delivery products aim to reduce the number of injections a patient needs, for example, moving from once-a-day to once-a-month or less frequently. ER injectables can also ease patient compliance and relapse. They are most often used to treat pain management, drug and alcohol addictions, psychological and behavioral conditions (e.g., schizophrenia and depression), fertility, diabetes, and certain cancers. 

Stockbyte/Stephen Smith/Getty Images; Compositing by Dan Ward			

One dominant type of an ER injectable product is polymer-based. This type includes microspheres, implants, and gels. These systems rely on diffusion through a polymer as well as erosion of that polymer to control release of the API. Another type involves conjugating a releasable chemical moiety to the active drug, thereby making a prodrug that is less soluble for slow uptake, or is slower to clear from the body. And another type would be insoluble salts.  

According to Heidi Mansour, PhD, an assistant professor in the College of Pharmacy at the University of Kentucky and editorial advisory board member of 

, these types of products are become more popular to manufacture because "scientific advances in polymer science and biomaterials have given rise to biocompatible and biodegradable polymers (e.g., various diblock and triblock copolymers) that offer a wide range in their temporal degradation profiles. As a result, there is a wide range in the temporal profiles of drug release for a wider range of drugs." In addition, she notes that, "there have been scientific and technological advances in particle engineering design methods, and in nanotechnology and tangible application to nanopharmaceuticals and nanomedicines."  

Extended-release injectables are considered to be complex dosage forms by the regulatory authorities. These products bring key challenges to the manufacturing process, including: sterility assurance, the number of unit operations required, as well as comparability and control strategy concerns. 

spoke to experts engaged in the development and manufacture of ER injectables to dig deeper into these challenges and to offer potential solutions.  

Participating in the article are: Paul Herbert, vice-president of process development at Alkermes; Andrew J. Thiel, PhD, an associate research fellow, and David M. Loffredo, PhD, a director, both in Pharmaceutical Research and Development at Hospira; Mary Stickelmeyer, a research fellow with Eli Lilly and Company; and Arthur J. Tipton, PhD, head of Birmingham Laboratories within Evonik's Healthcare Pharma Polymers product line.  

 ER injectables cannot be terminally sterilized. Why is this the case, and what types of sterilization should be used instead?  

 The challenge with terminal sterilization is that the physical and chemical stability of the materials used ER injectables—drug and polymers—do not generally withstand the temperatures required to effect terminal sterilization. Terminal sterilization utilizes high temperatures or radiation to make the product sterile. These conditions are likely to affect the API, creating some level of impurities. For polymer-based ER injectables, these high temperatures would melt the polymer, and radiation would typically decrease the molecular weight. 

Additional therapeutic areas for ER injectables			

Aseptic processing is therefore used to produce sterile product in temperature- and radiation-sensitive products. Process equipment is steam sterilized-in-place, and ingredients entering the process pass through sterilizing filters that remove any organisms that might be in the ingredients. The majority of the processing takes place in closed equipment to prevent human contact. Media simulations are conducted to demonstrate that sterile product can be made in the process equipment.  

 When terminal sterilization by autoclaving is not possible, the next default sterilization approach is sterile filtration followed by aseptic filling, as noted. However, some types of ER injectables are also unable to be filter-sterilized. For example, poly(lactic-co-glycolic acid) (PLGA) microparticle ER formulations cannot be filter-sterilized because the diameter of the PLGA microparticles exceeds the pore size of a sterilizing-grade filter (0.2 µg). These microparticle formulations require specialized manufacturing with sterile compounding and processing.  

 It is correct that terminal sterilization by heat, chemical agents, or radiation is not recommended. Typically, ER formulations containing polymers may be susceptible to degradation at elevated temperatures due to the low glass-transition temperature of the polymers, thus making heat sterilization difficult. Ready-to-use suspension formulations may be able to withstand an autoclave cycle; however, heat treatments of aqueous suspensions may accelerate hydrolysis reactions, flocculation, or Ostwald ripening and, thus, in many cases are not suitable. 

For chemical sterilization by gases, there are concerns about achieving adequate sterility and minimizing residual gas levels. Ionizing radiation may be feasible for solid particulate formulations (either gamma or electron beam) but may not be appropriate for biologics or for polymeric formulations because the radiation may affect polymer properties (e.g., cross-linking, degradation) that impact drug release.  

Development of electron-beam sterilization cycles that expose the product to a higher energy—yet shorter processing times—may minimize the impact on release properties and long-term chemical and physical stability. Lower irradiation doses based on bioburden level may also provide required sterility assurance while reducing impact on chemical and physical stability.  

Sterilizing filtration can be successfully applied to smaller particulate delivery systems but may not be feasible for larger particulate systems. In these cases, aseptic processing of sterile subsystems can be complex and increase risk. 

 The notion that ER injectables cannot be terminally sterilized is not universally true. If both the active and the excipients used in an ER formulation can withstand ionizing radiation independently—and combined in the dosage form—a terminal sterilization process can be developed and validated. However, many ER injectables are more complex and cannot handle radiation sterilization. This may be due to a complex active such as a protein that is susceptible to chain scission, oxidation degradation, disulfide bond rupture, or changes in conformation. Also, some of the formulation materials may be susceptible to radiation (i.e., they may undergo chain scission). In some cases, the formulation can be engineered to handle this decrease in polymer molecular weight. Finally, there may be complex interactions between formulation ingredients that can lead to instability.  

 Compared with a simple solution or lyophilized formulation, what additional unit operations are required for ER injectables and why? 

 Manufacture of ER injectables usually consists of a process to manufacture the ER injectable microspheres or crystals and then the more traditional process of filling into vials or syringes. The steps required to produce a polymer particulate-based ER injectable include: encapsulation, extraction of solvent from the particle, isolation of the particles—usually by filtration, drying of the particles to remove residual solvent and ensure physical stability of the particle, and filling of the particles and sealing in a sterile vial for storage prior to use. These steps are required in addition to compounding to avoid putting stability and drug-release characteristics at risk All steps must take place within a "sterile core" to ensure the product is in fact sterile, and each operation requires a sterile validation effort. The latter can be challenging when solid particles are being made and manipulated. 

 The additional unit operations depend on the type of ER formulation. In the case of PLGA microparticle formulations, these have traditionally been prepared using a double-emulsion technique. Briefly, the active ingredient is dissolved in an aqueous solution, and this solution is filter-sterilized. Separately, the PLGA polymer is dissolved in a water-immiscible organic solvent, and this solution is also filter-sterilized. The two phases are then combined with high-shear mixing or homogenization to prepare a water-in-oil (W/O) emulsion. This primary emulsion is diluted into a larger volume of another, outer aqueous phase with high-shear mixing to form the secondary emulsion (W/O/W).  

Then, there is a solvent-removal step to harden the newly-formed PLGA microspheres, and filtration (sieving) and rinsing steps to isolate PLGA microspheres of the desired size distribution while rinsing away everything else. Finally, the microspheres are dried (bulk lyophilization) and sterile powder filled. If this procedure is used, the additional unit operations compared with traditional parenteral manufacturing are the sterile emulsification, solvent removal, and particle-harvesting operations. Bulk drying and sterile powder filling are also specialized operations.  

There are other methods for preparing PLGA microparticles (e.g., spray drying), that would have entirely different unit operations. For 

 gel forming ER formulations, the manufacturing operations are more traditional, but may require specialized filling to handle viscous solutions. 

 Additional unit operations required are specific to the final dosage form. So for microspheres, commonly an emulsion step as well as a sieving and drying step are required. For liposomes, either an extrusion or homogenization step is added. If the product is a conjugate such as a PEGylated protein, an additional synthesis step is required. An implant will require a melt extrusion.  

Although these unit operations may be complex and add cost to individual products, they are the necessary steps to obtain the ER as compared with the conventional dose. The additional manufacturing cost is more than made up in the additional benefit and value of the resulting ER product.  

 What additional comparability concerns need to be addressed so that the release profile of these products is not affected?  

 Scale-up is associated with significant attention to comparability. Any changes in scale or unit operations are subject to significant regulatory oversight and require buy-in from the various regulatory bodies. Comparability becomes especially important when a change of manufacturing site is considered. Finally, having a good handle on the long-term stability of a product and its performance characteristics is a key component of comparability analysis over time. The key performance aspect, the extended release, is critically important because any loss of control or drift of release rate is potentially impactful: if, for example, the release rate increases over time on storage, such a change would be cause for concern about durability of efficacy and/or safety of the drug.  

 Ideally, during development of an ER injectable product, an appropriate

 assay can be developed that correlates with animal and human pharmacokinetic studies. In addition, consideration of orthogonal methods to characterize critical quality attributes such as particle size, for instance, is highly desirable to confirm that changes during development have not impacted the release profile.  

 In all cases of new formulations, stability data is needed. In some cases, the new dosage form may be more stable as compared with an immediate-release formulation. For example, a drug that has been supplied as a ready-to-inject solution may be more stable when formulated into a solid crystalline drug form in a microsphere. It is possible that the new formulation may present new stability issues. For example, perhaps an ingredient is a polymer with a low glass-transition temperature. So accelerated stability at elevated temperature may not be possible. Or, a novel formulation may be a suspension and additional data may need to be developed on the settling characteristics of that suspension. Also, items that may not have been important in the immediate-release formulation may be important in the ER formulation. For example, conventional syringes are lubricated with silicone oil. This small amount of silicone oil may interact with the formulation and result in unexpected properties, such as plasticizing a polymer used in the ER formulation. 

 What considerations do manufacturers need to keep in mind when developing and carrying out a control strategy for these products?  

 The technical risks encountered during development of complex, ER parenteral dosage forms can be addressed by incorporating a thorough understanding of the product quality attributes into the formulation and process design. This, in turn, will result in a robust manufacturing control strategy. For example, understanding the release mechanism (e.g., molecular weight of polymers, diffusive, and degradation properties) is critical to ensuring that there is no unintended or burst release. The use of orthogonal techniques during development to fully characterize the formulation and process design space should be considered to assess the impact of changes in formulation, primary packaging, process and/or devices. Data should be tied to clinical data to ensure that safety and efficacy are maintained.  

 tests may require nontraditional approaches such as a modified flow-through cell with low flow rates. With ER rates, the test may need to be performed over a long time period and thus include measures to minimize evaporation and assure stability of the active ingredient during the test period. Sufficient time points that characterize the release profile should be obtained. Multiple tests may need to be developed including a quality control test for release, an accelerated release to assess safety, and a test for assessing comparability for changes that reflects the actual release period.  

Finally, an understanding of inherent microbial activity of the formulation and the impact of processing and hold times should be assessed. Assessment of equipment and facilities for acceptable microbial and extrinsic particulate control should also be performed.  

 There will certainly be additional analytical methods required for an ER product. Most importantly, a method will be needed to confirm the extended release. A product that claims one-month duration, has to be tested to show that one-month delivery. A microsphere product will need a technique to confirm particle size. A liposome formulation likely will require a test for free lipid. In many cases, a test for free drug is desired. Depending on the technology used, additional testing for drug uniformity is likely. Finally, sterility testing may need to be adapted for a more complex formulation or geometry—for example, how to test that the inside of an implant is sterile. 

 Manufacturers need to identify the product's critical product attributes and process parameters. For example, for PLGA microspheres, the particle-size distribution might be a critical product attribute due to its potential impact on the release profile, and the batch size, volume ratio of oil and aqueous phases, temperature of these phases, type of mixer, mixing speed, and duration of mixing may be critical process parameters that could impact the resulting particle size distribution. The PLGA molecular weight (perhaps measured by intrinsic viscosity) may be another critical product attribute. 

 What regulatory challenges do ER injectables manufacturers face compared with more traditional injectable products?  

 As noted, ER injectable preparations, such as those based on biodegradable polymers, liposomal preparations, micellar preparations, or encapsulation, are considered to be complex dosage forms and as such, additional data (e.g., production scale data) may be required in the marketing authorization dossier. Unfortunately, specific regulatory guidances have been limited for these parenteral dosage forms. Typically, pharmaceutical scientists have applied the concepts used for modified oral products as a guide. More recently, industrial groups have collaborated with regulatory groups to address the challenges. 

 There may be a challenge with the development of an 

 correlation for some complex products. But in any case, one must have some data on how batch-to-batch performance is achieved for ER. The sterilization technique discussed above is an important regulatory aspect. Aseptic processes can be intricate, and therefore, a solid development history and validation will be required for product approval. Cleaning methods should be carefully reviewed as well. As the number of ingredients (polymers in particular) used increases, cleaning process equipment can be more difficult.  

In addition, filtration may not be a possible process step in many complex formulations, or may only be possible at an early stage in production, so extra care is required for foreign particulates as well as bioburden. Many of these efforts in process validation and product specification will be held in high regard by the regulatory reviewers. 

 In addition to comparability and mechanistic understanding, site-specific manufacturing is more complex for ER products than for other injectables. A site change may necessitate additional clinical studies for ER injectables, for example.  

In addition, the process development section of a company's common technical document submission tends to be longer and more multifaceted when filing for an ER product. In general, we have found that regulators understand the processes for ER products and are supportive of the technology.  

 What technological gaps exist for manufacturing ER injectables? What's needed going forward? 

 There are technological difficulties associated with the manufacture of very small particle-size ranges for nanoparticle formulations. Improvements in achieving narrower particle-size distribution for more consistent release and improved injectability are needed. Technology improvements for sterilization processes of fragile biological products and polymer systems are also desired. 

 In some cases, market needs only require modest production levels, so full economy of scale has not been realized. For products that require small-volume powder filling, there is a limited source of equipment. Isolation and drying of particles can require significant equipment and facility time increasing cost. There remains a relatively small number of suppliers for some critical raw materials, so backup sourcing can be a challenge in some cases. 

Of note, using a continuous processing method can help to maintain the same equipment for both smaller scale and larger scale production. 

 For polymer-based ER injectables, a polymer that is stable at room temperature and can withstand the temperatures associated with shipping and warehousing would be an important technological advancement. Most microsphere products use PLGA-based polymer, which requires cold-chain distribution. 

Sterilization and validation methods are also an area of near-term need. For example, the industry needs more refined ways of performing gamma-irradiation. Another opportunity is tailoring of molecular structure for intrinsic control of release. 

Industry experts working with extended-release injectables discuss challenges and solutions to formulating and manufacturing these complex products.

Meeting Manufacturing Challenges Tied to Extended-Release Injectables

Once again, Apple is doing something the rest of the world should be paying attention to. And this time it's not about the latest handheld wireless gadget or its unrivaled innovation strategy. It's about the company's approach to managing the global supply chain—even when things go wrong. 

In case you haven't been following the story, here's a brief summary. Steven Jobs' replacement as Apple's chief executive, Timothy Cook, has been visiting overseas sites where Apple products are made (I'll come back to the importance of this action later on). In late March, he stopped at a site in Zhengzhou, China, that is run by Foxconn—a multinational electronics manufacturer headquartered in Taiwan. Around the same time, the Fair Labor Association (FLA) published the results of a month-long investigation into Foxconn, including three of its China-based facilities which manufacture Apple products (Guanlan, Longhua, and Chengdu). The independent audit, agreed to by Apple after it joined FLA in January, cited 43 violations of Chinese laws and regulations, including communication gaps, excessive working hours, and dangerous conditions (1). Foxconn has been under fire for some time, including being tied to employee suicides as reported in various media outlets, including the 

(2). Foxconn and Apple have since agreed to improve conditions.  

While adherence to labor laws is a crucial aspect of managing any facility, this story has additional lessons to be learned. Supply-chain management and security have been hot topics of conversation among the pharmaceutical industry for the past several years. The increase of counterfeiting, economically motivated adulteration, and globalization throughout the pharma industry—much like that of the electronics or any other major industry—only adds to supply-chain complexity. And here is where due diligence comes into play.  

 visit their global sites. According to the 

 article mentioned above, two Apple employees pointed out that Jobs never visited the company's factories in China. It seems that Cook, in his new role, is aiming to change that practice by taking a first-hand look inside the facilities that are manufacturing Apple's products. And because he, like most chief executives, cannot spend every day visiting and auditing sites, he's asking a third party to help (i.e., FLA). The pharma industry has similar options through third-party auditing organizations and consortiums. No matter the time or cost, knowing what's going on inside your facilities is always going to be worth the effort. 

Second, companies need to keep their communication lines open. In one section of the FLA report about Foxconn, the association notes specifically that "communication is a two-way process…. The more workers participate in those processes, the more they are accepted, trusted and effective" (1). Some of Foxconn's problems are reportedly tied to top-down only communication. How many times have you heard someone in industry say that the Quality team doesn't communicate with the Development team, or that Senior Management doesn't communicate with the Technicians, and so on. Listening to employees—no matter their department—can only lead to improvement at all levels. 

Third, companies need to be transparent. Cook seems to be taking this seriously. A January 2012 Apple report included for the first time the names of companies that supply Apple with parts and services, something it had previously declined to do (3). Apple's site also notes that it  has audited every "final assembly factory in its supply chain each year since 2006" (4). The key phrase here is "final assembly." We know from recent unfortunate events, that the final manufacturer, distributor, or assembler is not necessarily where problems can occur. Quality must be sewn into and confirmed throughout every point in a product's supply chain. Regulators have enforced this message repeatedly. 

I believe these points are must-do's to help secure the industry's product supply chain. A statement by Apple to the 

 noted, "Our team has been working for years to … make Apple's supply chain a model for the industry.." (5). Clearly, the company still has some work to do—and so does pharma. But I think we're headed in the right direction. 

 1) FLA, Foxconn Invest. Report, Mar. 29, 2012.  2.) D. Barboza, 

, Apr. 1, 2012.  4) Apple Press Release, Feb. 13, 2012.  5) C. Duhigg, S. Greenhouse. 

Apple's experience with manufacturing facilities in China present opportunity for future best practice.

Some Supply Chain Lessons Can Go a Long Way towards Success

Once again, Apple is doing something the rest of the world should be paying attention to, only this time it's about the company's approach to managing the global supply chain—even when things go wrong. In case you haven't been following the story, here's a brief summary. Steven Jobs' replacement as Apple's chief executive, Timothy Cook, made a stop in late March at a site in China that is run by Foxconn—a multinational electronics manufacturer headquartered in Taiwan. Around the same time, the Fair Labor Association (FLA) published the results of a month-long investigation into Foxconn, including three of its China-based facilities. The independent audit, agreed to by Apple after it joined FLA in January, cited 43 violations of Chinese laws and regulations. 

While adherence to labour laws are crucial aspects of managing any facility, this story has additional lessons to be learned. For starters, companies must visit their global sites. According to a 

 article, two Apple employees pointed out that Jobs never visited the company's factories in China.  

Second, companies need to keep their communication lines open. Some of Foxconn's problems are reportedly tied to top-down only communication. How many times have you heard someone in industry say that the Quality team doesn't communicate with the Development team, or that Senior Management doesn't communicate with the Technicians? Listening to employees—no matter their department—can only lead to improvement at all levels. 

Third, companies need to be transparent. A January 2012 Apple report included for the first time the names of companies that supply Apple with parts and services, something it had previously declined to do. We know from recent unfortunate events, that the final manufacturer, distributor, or assembler is not necessarily where problems can occur. Quality must be sewn into and confirmed throughout every point in a product's supply chain. Regulators have enforced this message repeatedly. 

I believe these points are must-do's for securing the industry's supply chain.  

Once again, Apple is doing something the rest of the world should be paying attention to, only this time it's about the company's approach to managing the global supply chain-even when things go wrong.

Supply Chain Lessons

	Jim Miller of PharmSource gave a keynote talk this week at Interphex 2012 in New York City on the state of the industry’s outsourcing environment. Miller is also a member of the PharmTech Editorial Advisory Board. Below are a few highlights from his talk.

		Favorable tax provisions in the UK, Ireland, Hungary, and Singapore are leading to industry growth in those areas

		80% of outsourced clinical research goes to preferred providers

		Key growth areas and investment areas for Big Pharma are leaning towards niche/orphan products, biologics, and emerging markets

		The greatest threat to the outsourcing environment is not emerging markets, but rather new technologies and requirements

	Overall, he noted that the industry is slowly consolidating while CMOs  face new pressures and new business models. CMOs throughout the show confirmed that they are being asked more and more for quality based, risk based approaches, as well as for flexible facilities and processes. Visit PharmTech.com/PharmTechTV to see live videos from the show. You can also view Jim Miller’s full slide presentation 

		Industry is outsourcing mature technologies as well as specialized technologies, but keeping core foundational steps and knowledge in house

Jim Miller of PharmSource gave a keynote talk this week at Interphex 2012 in New York City on the state of the industry’s outsourcing environment.

Live from Intephex 2012: The State of the Outsourcing Industry

	PDA is hosting a few interesting workshops in the coming weeks on key topics facing the industry. PharmTech spoke to experts participating in the workshop plans and you can listen to the interview podcasts 

	The two events are: 1-PDA/FDA Virus and TSE Safety Conference (May 15-17, 2012, Bethesda, MD): Interview with Dayue Chen, a Research Advisor in Bioprocess Development at Eli Lilly and Company. The focus of the conference is on Proactive Approaches to Mitigate Virus & TSE Risk. 2-QbD and Vaccines: A PDA/FDA Workshop (May 14, Bethesda, MD): Interview with Sam Venugopal of Pricewaterhouse Coopers. The focus of the workshop is on Applying QbD Principles in Vaccine Development.

	Chen and Venugopal discuss why these topics were selected, current challenges within these areas, and key questions to be addressed at the meetings.

PDA is hosting a few interesting workshops in the coming weeks on key topics facing the industry.