Desmond G. Hunt is principal scientific liaison, USP Department of Science, General Chapters.

Desmond G. Hunt

	Particulates have become a major quality and safety issues, especially in 

Control and Determination of Visible and Sub-visible Particulate Matter in Biologics

was held at The United States Pharmacopeial Convention (USP) headquarters in Rockville, Maryland, on June 26-27, 2017. The first USP workshop to focus specifically on particulates in biologic drugs, the program addressed many issues and challenges unique to biologics-including protein aggregation and immunogenicity-as they relate to particulate control and determination.

	The workshop's goal was to provide a forum for stakeholders to come together, share information, and discuss key issues. This article summarizes highlights from the event. 

	Particulate matter in biologic drugs comes in many sizes, shapes, and materials. Generally, particles may be categorized as intrinsic, extrinsic, or inherent. Intrinsic particles are generated within the manufacturing process and may include silicone oil, rubber, glass, or stainless steel. Extrinsic particles come from outside the process and could include metal, human hair and skin, or dust.

	Inherent particles, such as protein aggregates, are naturally present in protein therapeutics and may be acceptable with the appropriate control strategy. However, just because the particles are inherent does not mean they should be ignored or assumed to be safe. The safety aspects of inherent particles should be assessed throughout a product’s life cycle. Overall, it is important to distinguish between inherent particles and intrinsic or extrinsic particles

	Another way to conceptualize particulate matter is to divide it into two categories: visible and subvisible. Detection of visible particulates (greater than 100–150 microns in diameter) depends on multiple factors such as the lighting, magnification, and container characteristics, as well as the technician’s training and visual acuity.

	Subvisible particles are usually defined as particles that are 1–100 microns in size. In the area of subvisible particulates, there is increased focus on distinguishing between silicone oil and non-silicone oil particles.

	Flow imaging can be used to visualize and count subvisible particles, which involves determining the aspect ratio to classify them. However, aspect ratio is not always reliable and it frequently misclassifies particles. Thus, a method is needed that will recognize patterns in the images.

	Some companies are investing in the use of artificial intelligence to analyze thousands of particle images and categorize them. These algorithms, and equipment using them, scan images from a training set and “learn” to distinguish between the various particle types.

	During the visual inspection process, when a particle is observed in a product, that unit is pulled and either discarded or set aside for further analysis. Several presenters at the workshop emphasized that it is important to have standard operating procedures (SOPs) in place for defects that have been identified during inspection, along with alert and action levels. Taking time to analyze rejected units can reveal clues that will allow manufacturers to prevent similar problems from happening in the future. More importantly, the same problem may be occurring in other lots or even other products, and the analysis may help improve these other materials too.

	Particulates in drug products can form at any stage in the manufacturing process or during storage. Various environmental stress conditions (heat, shock, or vibration) can lead to particle formation. Thus, when developing or refining a formulation, stress conditions should be applied to learn about the formulation’s propensity to form particulates.

	Presenters suggested that, in order to optimize the process and minimize particulate formation, it is best to follow a continuous improvement approach. Continuous improvement can be applied to formulation development, component compatibility, manufacturing procedures, and other processes.  All personnel involved should align on best practices and should also share accountability for the end product.

	Protein aggregation in biologics can compromise the safety and efficacy of the product, noted an FDA presenter. Many triggers for aggregation have been identified, including oxidation, mechanical stress, impurities, pH shifts, and temperature changes. 

	With blood products, another concern is platelet-derived extracellular vesicles (PEVs), which have a 50- to 100-fold higher pro-coagulant activity than resting platelets. Release of PEVs can be associated with the donor’s lifestyle, the collection procedure, and storage conditions. PEVs have a broad size distribution and are associated with adverse events including transfusion-related acute lung injury (TRALI). 

	The gold standard methods for detecting protein aggregates and PEVs in biologics are flow cytometry and light obscuration; however, there is no regulatory guidance available on PEVs. It is always important to use orthogonal methods because these processes are very complex, and each method has limitations, according to the presenter.

	Particles can have adverse effects on the drug product and/or the patient who ultimately receives it. The focus should be on the patient, presenters agreed. For example, if a relatively large number of subvisible particles is detected, one should characterize them and perform a clinical risk assessment. This assessment can reveal information about the impact of particles on the drug product’s clinical performance.

	Important clinical factors to consider include the route of administration, which is often intravenous, and the intended patient population. The most vulnerable patient populations include neonates, young children, seriously ill patients, and the elderly. Protein aggregates and other particulate matter can be immunogenic and can also alter the drug’s efficacy.

	In the worst-case scenario, the patient may develop an autoimmune response. This reaction is sometimes missed because the patient’s illness can mask the adverse effects of the therapeutic product.  It is unclear whether all aggregate types are potentially immunogenic, but there is growing evidence that the size of the aggregates has an effect. For example, vaccine components  are purposely aggregated to increase the immune response to a vaccine.

	FDA speakers recommended that orthogonal techniques based on different separation and detection principles should be used to both enumerate and characterize particles. Presenters from the National Institute of Standards & Technology (NIST) described a standard they developed that is optically similar to protein particles. It mimics the fibrous nature of proteins and is made of abraded ethylene tetrafluoride (ETFE). Unlike particle sets for instrumentation that are spherical and do not resemble proteinaceous material, the ETFE standard is made of a more stable material than protein and also can be easily counted. The NIST study showed that abraded ETFE looked more like protein than did polystyrene beads.

	Another concern raised was that during the final steps before a biologic drug is administered to a patient, particles can form if the drug is mishandled. Thus, it is critical to provide clear, explicit instructions on the administration of drug products. The instructions should describe how these drugs must be handled to protect their potency and efficacy.

	One of the most important and challenging questions raised at the workshop was what is acceptable-how many particles are allowed?  There is no simple answer, said an FDA presenter, adding that FDA looks at the whole profile and cannot specify a limit that will be appropriate for every product. FDA’s evaluation is product specific and is done on a case-by-case basis.

	However, FDA does tell sponsors to collect and provide as much information as possible about their product.  In general, there is no clear evidence regarding a threshold of criticality or cutoff point. How does one justify that a specific level of exposure to particulates is acceptable? In each case, it depends on the product and the patient.

	Assessing drug products for particulates can be challenging for a variety of reasons. Often, reference to the “safety” of a product is connected to particulates, but every product has a risk–benefit profile. To further complicate matters, different patients react differently to the same product.

	One might assume that visible particulates pose a greater risk than subvisible ones, particularly with injectable medications, simply because the visible ones are larger. However, visible particles typically do not fit through the lumen of a needle and thus they do not get injected. For example, 100 microns is about the size of a 36-gauge needle. In contrast, the subvisible particles are very likely to be injected and thus could pose a greater risk.

	In some clinical settings, in-line filters are used to catch any remaining particulates during infusion of the drug to the patient. This approach may sound promising as a final measure for protecting the patient, but in-line filters can be problematic because they can produce particles as well. In addition, hospital personnel might use incompatible filters, unless the appropriate filter is supplied with the medication. Hospitals generally take the position that the drug manufacturer needs to qualify and supply the filter if a filter should be used.

	Some presenters said that in-line filters should only be used if there is a sound, clinically based reason to do so. In some cases, the use of a filter is the only option for a medically necessary drug, where no alternatives are available. However, the in-line filter for a product needs to be qualified as capable of reducing visible and subvisible particles.

	A related issue is the potential for particulates to enter the drug product from the administration set, which is not a filter but rather the standard equipment used to infuse intravenous medications. Administration sets may be loaded with particles, negating the impact of any and all controls and tests designed to prevent particulate contamination.

	If a patient does receive particulates, this has potential clinical implications. In many cases, there is no clinically discernable effect, but this does not mean that no effect has occurred. Particulates can be vaso-occlusive, blocking pulmonary capillaries, or they can act as irritants, leading to soft-tissue granulomas. The composition of the product in terms of organic and inorganic leachates can also be affected.

	When evaluating the intended patient population for a new medication, the factors to consider may include: patient age, comorbid conditions, presence of ischemic tissue, altered immune status, and volume of drug product to be given over a certain time period. If any adverse events occur, finding the root cause and linking clinical effects with particle counts can be very challenging.

	Cell therapy products differ from other types of drug products in several important ways.They may be grouped into the following categories:

		Minimally manipulated-not requiring a biologics license application (BLA)

		More than minimally manipulated-requiring a BLA

		Autologous-coming from and going back to the same patient; because the amount available is limited, destructive testing cannot be done

		Allogenic-coming from a single source and, typically, going to many patients.

	During manufacturing, cell therapy products cannot be purified or filtered using the standard approaches to remove particulate matter from drug products. In addition, these products are often opaque rather than clear, limiting the effectiveness of subvisible and visual particle detection methods. 

	Differentiating between contaminants and the product itself, which typically contains particulates too, is often complicated, noted one of the FDA attendees. There are many challenges involved in monitoring particulate matter, therefore emphasis should be placed on limiting introduction of particulate matter that may be in raw materials or introduced by the manufacturing process.

	Particulates that affect cell therapy and gene therapy products do not come from one single source. Instead, particulates are generated by many sources, often with no consistency. Particles can come from the original biological components, such as solid tissue or bone marrow. Other sources are tubing, bags, vials, and stoppers that come in contact with the materials and could also contain and release particulates. Other sources for particulates include the environment, personnel, instruments, and excipients.

	Although FDA recommends using orthogonal methods to evaluate and analyze biologic drug products, this is not always possible. In some cases, there is no orthogonal method available. In the area of cell therapy, there are no established industry-specific standards for particles.

	In one presentation about cell therapy and gene therapy, the speaker emphasized the growing challenge of controlling particulates in cell/gene therapy products, and the need for new detection methods. More scientists and their companies are starting to admit that they are encountering problems and challenges with particulate control and determination. However, there is still a lack of data on this issue, and manufacturers are searching for solutions to various problems.

	Control of particulates is as important as developing methods to reduce them. FDA presenters advised cell therapy manufacturers to first determine the number, size, and type of particles, and then try to control and/or reduce particles. The next step is identifying the likely contributing sources, then developing mitigation strategies such as:

		switching to better-quality source material

		evaluating and improving cleaning practices

		finding ways to reduce the number of handling steps

Inspecting products for visible particles

	As one member of USP’s visual inspection expert panel mentioned, before 2010, there were few standards for performing particulates inspection. Now, it appears, people are taking some consistent and similar approaches.

	Today, performing a robust 100% inspection of the finished drug product is a must, according to members of the expert panel. The goal is to use a statistical approach to inspection to achieve a product that is essentially free of visible particulates. The concepts involved were defined in 

USP general chapter <790> “Visible Particulates in Injections.” 

	However, striving for zero defects seems unrealistic, according to workshop attendees, because visual inspection is such a probabilistic process.

	Another dilemma is knowing when to stop looking for particulates. USP inspection conditions have been defined and are now harmonized with the 

; they apply to extrinsic and intrinsic particles. In fact, as a number of workshop participants noted, the three major pharmacopeias are now 

(i.e., USP chapter <790> versus EP 2.9.20 and JP 6.06), which is a big step forward.

	Another aspect of inspection is the “difficult to inspect parenterals (DIPs).” A product may be a DIP due to the container type, even if the solution itself is clear. With DIPs, there is a diminished capacity for 100% visual inspection; the actual rate is more like 70%–80%, according to a presenter on this topic.  Stakeholders need to develop and use testing and controls that can detect particles and statistically significant changes throughout the lifecycle of a product.

Themes and concepts discussed in the workshop

		Particle control involves many factors and should be characterized and monitored throughout the product lifecycle.

		Even though FDA does not recommend specific orthogonal methods to detect particles, the consensus is that they are important, as is quality by design (QbD), which requires evaluating each step in a procedure.

		More rigorous particle characterization is necessary. In particular, silicone oil poses many concerns because it can interact with products and be immunogenic.

	Based on the issues raised during this workshop, USP will consider suitable revisions to the existing chapters or the creation of new standards for certain classes of biologics. 

Articles

The workshop focused on topics specific to biologics, including particulate control and determination, becoming the first workshop of its kind for the organization.

USP Workshop Focuses on Biologics

Today, it is common for pharmaceutical products to be sourced in a complex maze of processing and handling throughout the course of manufacturing, storage, and distribution--all against a global supply-chain backdrop. Before a product even reaches the patient, it is likely that multiple ingredient manufacturers, suppliers, and distributors from different parts of the world have had a hand in making, storing, and handling the finished drug product. Multiply this complex chain of events by the number of available drugs and countries involved in both producing and consuming medicines and the vulnerable areas within the global pharmaceutical supply chain become quite evident. In response to the rapid transformations taking place in the global pharmaceutical supply chain, the United States Pharmacopeial Convention (USP) is developing and revising standards to aid manufacturers, transportation providers, and other stakeholders to deal with many of these complex issues.

  To help protect product quality, USP is developing a series of informational general chapters on good distribution practices that will appear in the 

United States Pharmacopeia--National Formulary (USP-NF),

 USP’s compendia of public quality standards. Detailed in a stimuli article published in the July-August 2013 issue of 

--USP’s free, online journal for posting and receiving public comments to developing standards--the chapters are being developed in a collaborative effort involving four USP Expert Committees: Compounding; Monographs--Excipients; Packaging, Storage, and Distribution; and Physical Analysis.

The general chapters will address four key areas, highlighting key principles as well as practices related to good distribution: 
  • Quality management system. Topics will include documentation control and resources management; nonconformances, complaints, and corrective actions; and the role of continuous improvements.
  • Good importation and exportation practices. Topics will include audits and supply agreements; container seals, cargo inspection, customers, and brokers; and verifying product and firm compliance with regulations.
  • Supply-chain integrity and security. Topics will include adulteration and counterfeiting; diversion and theft; and product recall procedures.
  • Environmental control management. Topics will include building/facility (storage), transportation vehicles (shipping), and controlled-temperature environments.


  For its proposed general chapter on environmental control management, USP’s Expert Committees are placing a strong emphasis on understanding the environmental impacts to which a product may be exposed during distribution. By framing the chapter in terms of management of environmental controls, USP encourages manufacturers to look at external factors that could affect product quality whether in cold-temperature, ambient, or extreme heat conditions.

This chapter also addresses cold-chain products, for which many well-established robust temperature monitoring systems are available. Measures such as packaging systems with dry ice and containers with active cooling systems are often employed to help ensure product quality throughout the course of distribution and many regulations currently exist that specifically address shipment of cold-chain products. 

Aligned with its current thinking about the role that environmental control management plays in product quality, USP is also proposing a change in its definition of “controlled-room temperature.” USP’s current temperature range for a usual and customary working environment is 20 to 25 °C. In a 

 article in the November-December 2013 issue of PF, USP proposes the expansion of this range to 8 to 30 °C. In part, the motivation for this change is to encourage companies to put broader temperature ranges on product labels, allowing for greater flexibility in how products are distributed. The appropriateness of expanding the temperature range for a product is based on stability data that have been generated on the product. 

Public comments on USP proposed standards

 article on USP’s definition of “controlled-room temperature” will be received until Jan. 31, 2014. USP’s proposed suite of general chapters on good distribution practices is scheduled to publish in 

in early 2014. For more information or comments on these standards, please direct all communications to Desmond Hunt at dgh@usp.org.

Desmond Hunt, PhD, is senior scientific liaison, General Chapters, US Pharmacopeial Convention, dgh@usp.org.

USP is developing and revising distribution standards in response to changes in the global supply chain.

USP Plans Standards on Good Distribution Practices

Prefilled syringes, parenteral drugs, and many therapeutic biologics delivered through infusions are contained in plastic packaging systems. Packaging systems must protect and be compatible with the drug product and not compromise the stability, efficacy, or safety of the drug product. In turn, the ingredients of a drug product should not be absorbed onto the surface or migrate into the body of the plastic packaging system. 

The US Pharmacopoeial Convention (USP) is currently revising its existing quality standards and developing new standards for plastic packaging systems. Because these standards will have a significant impact on drug manufacturers and packaging-material suppliers, USP is actively seeking feedback from drug manufacturers, packaging manufacturers, and suppliers as well as other stakeholders who may be affected by the new standards.


  Plastic-packaging systems can include not only the container that holds the drug product, but also gaskets, rubber stoppers, tubing, and other components that may be a part of the overall system that delivers the drug to the patient. For the manufacturer, understanding and mitigating risks associated with extractable and leachable aspects (unintended migration into or out of packages) is an important part of ensuring the quality and safety of the medicine delivered to patients.

Extractables are chemical compounds that can be extracted from a material under laboratory conditions, which can include the use of solvents and/or extreme temperatures. Leachables are extractables that may migrate into the drug product over the course of a drug product’s shelf life. Drug-product leachables can affect the stability and efficacy of the product, and in some extreme cases, pose significant patient safety risks

Plastic materials are used in a variety of ways within the pharmaceutical sector, from packaging systems and medical devices to tubing and single-use components used in the manufacturing process. A question faced by the manufacturer is, “What ultimate impact does a plastic material or component have on the drug product?” Because the makeup of most packaging materials is proprietary, drug manufacturers must rely on their own testing for extractables and leachables to determine if a material is suitable. With a robust compendial standard, knowledge of a material can be obtained that will provide the manufacturer with an ability to make more informed decisions about materials during the drug-development process, which ultimately saves time and effort. USP introduced a biocompatability standard for plastic materials in 1965 and physiochemical standards in 1970. Improvements in analytical techniques in recent years have prompted pharmaceutical manufacturers to take a closer look at potential risks associated with plastic materials used to package pharmaceutical products, and therefore, a need to update the standards. 
  



  Plastics used in packaging systems are composed of polymers with a range of molecular weights and contain additives such as antioxidants, stabilizers, lubricants, colorants, and other additives. The nature and amount of additives for packaging systems are dictated by the type of polymer used, its application, and the process used to convert that polymer into components, containers, or packaging systems.
  
  As drug products are manufactured, packaged, stored, and administered, these drug products come into direct contact with packaging systems and their plastic materials of construction. Because such contact may result in an interaction between the product and its packaging system, it is important that both the drug product and the packaging materials are not adversely affected by such interactions. The use of well-characterized plastic materials of construction in components, containers, and packaging systems and the appropriate testing of packaging systems help to determine if such adverse interactions are taking place and whether the packaging material of choice is suitable for its intended use.
  USP’s new and revised standards for plastic packaging systems have been proposed as a suite of interconnected chapters in the 
  United States Pharmacopeia--National Formulary (USP-NF):  

General Chapter <661> Plastic Packaging Systems and their Materials of Construction          

<661.1> Plastic Materials of Construction

<661.2> Plastic Packaging Systems for Pharmaceutical Use

General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems

General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems                  

<1664.1> Orally Inhaled and Nasal Drug Products

General Chapter <661> Containers--Plastics is being revised and will be titled Plastic Packaging Systems and Their Materials of Construction. The chapter will provide the testing rationale for plastic materials of construction and packaging systems used for the pharmaceutical industry. USP recognizes that the use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suited for its intended use as the properties and characteristics of the materials can be matched to the performance requirements of the packaging system. 

New General Chapter <661.1> Plastic Materials of Construction will help determine whether a material is deemed well characterized by establishing its identity, biocompatibility (biological reactivity), general physicochemical properties, additives, and extractable metals. The objective of <661.1> is to provide tests, procedures, and acceptance criteria for plastic materials of construction used in pharmaceutical packaging systems, because proper characterization of these materials facilitates the identification and use of appropriate materials in pharmaceutical systems. 

The testing of packaging systems to establish that they are suitable for their intended use is addressed in new General Chapter <661.2> Plastic Packaging Systems for Pharmaceutical Use. The applicant who seeks regulatory approval of a packaging system or packaged pharmaceutical product is responsible for establishing that the product’s packaging system meets the expectations of <661.2>. This chapter establishes what is meant by “appropriately tested,” which includes the requirement that the packaging system has been established to be safe by way of appropriate chemical testing, which could include extractables testing, leachables testing, and appropriate toxicological assessments.

Screening the materials used in a packaging system and its components for ingredients that are probable extractables and possible leachables is an important step for establishing suitability. New General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems presents and describes best-demonstrated scientific practices for accomplishing an extractables assessment. New General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems outlines a framework for the design, justification, and implementation of assessments for drug-product leachables derived from pharmaceutical packaging and delivery systems. Accompanying <1664> is General Chapter <1664.1>, which addresses specific considerations for leachables in metered dose inhalers, nasal sprays, dry powder inhalers and inhalation solutions, suspension, and sprays. General Chapter <1664.1> is intended to incorporate into USP’s chapters specific best practice recommendations of the Product Quality Research Institute (PQRI) related to leachables in orally inhaled and nasal drug products, including the first safety-based thresholds for leachables characterization and safety qualification.


Revised General Chapter <661> and the suite of related new chapters have been published for comment in the September-October 2013 issue of Pharmacopeial Forum (PF), USP’s free-access, online publication for posting proposals and receiving public comments to its developing standards. A 90-day comment period for receiving feedback to these chapters as they appear in PF will end on Nov. 30, 2013. Once finalized, the general chapters will be published in USP-NF. However, USP’s Packaging, Storage, and Distribution Expert Committee will carefully review the comments received through PF during this period and further revisions to the chapters may result. 

Like USP, the PQRI Extractables and Leachables Working Group is also working to develop guidelines, specifically for packaging systems used for parenteral and ophthalmic drug products. On Dec. 9-10, 2013, USP and PQRI will co-host a workshop, “Suitability and Compatibility for Packaging and Delivery Systems: Extractables and Leachables.” The workshop will take place at USP’s headquarters in Rockville, Maryland, and both organizations invite stakeholders to provide input on each organization’s developing work related to plastics packaging systems.

For more detailed information on the December workshop and to access USP’s suite of proposed general chapter changes, visit 

Desmond Hunt, PhD, is senior scientific liaison, General Chapters, US Pharmacopeial Convention 

USP seeks input from stakeholders on new and revised standards to mitigate extractables and leachables in plastic packaging systems.

USP Seeks Input on Standards for Plastic Packaging Systems

A key factor in maintaining the quality of a pharmaceutical product throughout its shelf life is the integrity of its packaging. Preventing moisture from permeating through the packaging is an important function of the container-closure system used for medicines. Today, moisture uptake is a common cause of product package failures in the pharmaceutical industry—and a topic that the US Pharmacopeial Convention (USP) is addressing with an upcoming revision to 

United States Pharmacopeia–National Formulary (USP–NF) General Chapter  <671> Containers—Performance Testing for Plastic Containers

Initially developed in the 1970s primarily for use by pharmacists dispensing medications into the familiar amber vial, General Chapter <671> has become heavily relied upon over the years by pharmaceutical manufacturers, packagers, repackagers, and FDA because it is referenced in the agency’s 

Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics

. However, the general chapter has had only minor edits and additions in intervening years. Because it is being used beyond its original scope and utilizes an older permeation test, modifications to the general chapter have become necessary. This effort is supported by industry, and the newly proposed standard builds on method development work completed over the past decade by the Product Quality Research Institute (PQRI). PQRI is a nonprofit consortium of organizations that conducts research to generate specific scientific information on issues of interest to FDA and to standards-setting organizations such as USP.

One of the key ways the general chapter is being updated is through the proposal for a new moisture vapor transmission rate test method for solid oral-dosage forms. The current test method is a gravimetric method that is not very robust, which can lead to variation in test results. The proposed new method is also gravimetric, but is more reproducible and uses more rigorous environmental test conditions. Both the older and newly proposed methods measure weight gain over time. However, the information yielded by the new method will give end-users a more accurate assessment of how much protection their packaging is affording to the final product. 

The proposed general chapter, including the new method for calculating moisture vapor transition rate, aligns with the recently released ASTM International standard: “ASTM D7709–12 Standard Test Methods for Measuring Water Vapor Transmission Rate (WVTR) of Pharmaceutical Bottles and Blisters.” ASTM sets international voluntary consensus standards. The revised USP general chapter is included in Pharmacopeial Forum 39(2) March–April 2013, and USP invites comment on the proposal at www.usp.org/usp-nf/pharmacopeial-forum.

An underlying issue relevant to this activity is the USP classification system for packaging. At present, USP specifies the categories of “well-closed” and “tight” in its classification, with the latter used much more frequently. Certain medications, however, require packaging beyond “tight”—requiring no moisture permeation. While no change to the classification system was included in the new proposal, USP would like to open a dialogue with regulators, manufacturers, contract packagers and repackagers, and other stakeholders about whether, and how, this classification system could be expanded. The classification system—along with applications of the new  <671> method, manufacturer case studies, current regulatory thinking from FDA, and other areas affected by the new method (e.g., desiccant choice, which is particularly important with the method change)—will be among the important areas of discussion at a May 20–21, 2013 workshop cosponsored by USP and PQRI in Rockville, MD. 

USP is proposing a new performance testing standard for moisture permeation of pharmaceutical packaging.

Moisture Permeation of Pharmaceutical Packaging

During the past two years, the growing problem of glass particles in injectable medications has led to a number of product recalls. The crux of the problem is the durability of glass containers. Specifically, the inner surfaces of some glass containers are less durable and thus more susceptible to delamination (i.e., the shedding of glass flakes from the vial's interior walls) than others. Numerous factors may affect glass durability. Although the impact of glass delamination on patient safety remains a point of debate, the presence of these particles is at the very least a serious quality problem that must be addressed.  

In a March 2011 FDA advisory to drug manufacturers on the formation of "glass lamellae" in certain injectable drugs, the agency noted that, although no adverse events had been reported at that time, there is the potential for drugs administered intravenously that contain these fragments to cause embolic, thrombotic, and other vascular events; and when administered subcutaneously, to lead to development of foreign body granuloma, local injection site reactions, and increased immunogenicity. Several conditions have been associated with a higher incidence of lamellae formation, including glass vials manufactured by the tubing process (and thus produced under higher heat); drug solutions formulated with certain buffers; drugs formulated at high pH; and drug products that undergo terminal sterilization. Based on the sudden increase in this occurrence and subsequent recalls, the US Pharmacopeial Convention (USP) Packaging, Storage, and Distribution Expert Committee developed a new general chapter that recommends approaches to predict potential formation of glass particles and delamination. The new informational chapter, General Chapter <1660> 

Evaluation of the Inner Surface Durability of Glass Containers,

 will be proposed in the July–August 2012 

 and was posted in advance of its publication on the USP website in May 2012.  

For the purposes of pharmaceutical packaging, three types of glass are defined by USP General Chapter <660> 

. Type I (borosilicate glass) is suitable for most products for injectable and noninjectable use. Type II is treated soda-lime glass, and Type III is soda-lime glass on the basis of the hydrolytic resistance of the glass. Glass, in the form of ampuls, bottles, cartridges, vials and prefillable syringes, is the container material of choice for injectable products, particularly biopharmaceuticals.  

Recent recalls underscore the fact that not all Type I glass is equal in terms of quality. Glass delamination, which ultimately results in the appearance of lamellae, is a lagging indicator of structural instability of a container. Although delamination is the most obvious visual indicator of instability, it represents the final stage of a seriously weakened glass surface structure, and can be observed only at a point where prevention is no longer an option. As such, proper evaluation of the quality of glass containers is crucial. 

Among the areas covered by USP's new informational chapter are: 									

Good Glass Supply-Chain Practices: The chapter recommends steps for manufacturers in selecting a glass container vendor, including auditing the supplier, obtaining glass formulation from the supplier, designating formulation of Type 1 glass (33 glass or 51 glass), determining tubing glass source(s), and determining whether the containers have been treated with ammonium sulfate, among others.

Glass Surface Chemistry: This section discusses use of the aqueous chemistry of surface glass to decide on the potential drug product formulation and treatment steps that could increase glass stability. 

Factors that Influence Inner Surface Durability: This section offers information on factors that have the potential to influence the durability of the inner surface of glass containers. These factors include glass composition, the conditions under which the containers were formed, subsequent handling and treatments, and the drug product in the container. The section notes that not all factors influence surface durability to the same extent, and their effects can be additive. 

The draft general chapter also details screening methods to evaluate inner surface durability. These build upon General Chapter <660>. At present, each lot of Type I glass containers received by a pharmaceutical manufacturer must comply with the Surface Glass Test detailed in General Chapter <660>. Although this test provides an indication of the durability of the surface, it does not provide a direct correlation with the susceptibility to form glass particles or to delaminate. The most important variable that affects surface durability is the drug product itself (i.e., the interaction between the product and the container). The Surface Glass Test does not take the drug product into consideration. Therefore, as USP states in the general chapter, this test represents only the first step in quality control of surface durability, and additional screening methods should be employed. 

Predictive screening methods help evaluate glass containers from different vendors, glass formulations, and post-formation treatments. The general chapter addresses the three key parameters that screening methods should employ as well as commonly used analytical methods for evaluating the three parameters. It notes that predictive tests should look for precursors that lead to delamination rather than flakes themselves, and should be able to quickly provide predicative indication of surface durability. The general chapter also details other testing that may be useful, particularly in evaluating interaction with specific drug products.  

Formation of glass particles in injectable drug products represents a growing challenge. USP's new informational general chapter is intended to augment its current glass standards via recommended approaches for predicting the potential for this disintegration to occur. This may serve as a resource for manufacturers, and the organization is seeking input on its proposal. To read the full general chapter, and to learn how to provide comments, please visit 

www.usp.org/usp-nf/notices/evaluation-inner-surface-durability-glass-containers-posted-comment

 is senior vice-president of compendial science, and 

is senior scientific liaison, both with the US Pharmacopeial Convention (USP).			

US Pharmacopeia documents best supply-chain practices and seeks broad input on proposal.

Inside USP: US Pharmacopeia Proposes New Standard on Glass Quality

Listen to USP officials speak about supply chain integrity as part of a video series. Go to PharmTech.com/PharmTechTV and click on the "USP" tab.

One of the most daunting challenges facing pharmaceutical companies is securing the long and complex supply chains that are typical in today's global industry. From the sourcing of raw materials to final delivery to the pharmacy, practitioner or patient, the number of nodes in the global supply chain for a medicine is astounding, with each link presenting an opportunity for the insertion of risk or harm. Although most companies have highly sophisticated, multifaceted approaches to addressing this challenge, approaches vary. 

In addition, there can be huge differences in approach not only between large and small or medium pharmaceutical manufacturers, but also among raw-materials suppliers, logistics providers, and the plethora of other companies involved in the production, distribution, and delivery  of medicines to patients.  

For example, many companies involved in the chain do not handle pharmaceuticals as their primary business. Despite the good work and due diligence that a pharmaceutical company, wholesale distributor, or other supply-chain stakeholder may employ, the effort can be rendered useless at the seemingly smallest breach. Wherever the breach occurs, someone may be there to take advantage. In the pharmaceutical supply chain, therefore, every step is important, and a company truly is only as strong as the weakest link. 

To address this issue, the US Pharmacopeia (USP) recently published a proposed set of recommended best practices on supply-chain integrity, for which it is seeking broad input. If followed, these best practices will help ensure that medicines can be traced back to their original manufacturer, are not adulterated or counterfeited, and are transported to their intended destination with quality intact.  

 General Chapter <1083> "Good Distribution Practices—Supply Chain Integrity," which is published in the March–April 

Once in its final form, the general chapter will document what is envisioned to be a universal approach for helping to achieve supply-chain integrity. The general chapter is informational (i.e., nonmandatory), but USP hopes that the chapter can be a resource for companies that need to be brought up to speed on supply-chain issues and that it can serve as mechanism for building consensus across different industries. 

The USP Packaging, Storage and Distribution Expert Committee, which is responsible for the new general chapter, has been interested in this topic for several years and sees the new proposal as one of an eventual suite of distribution chapters, following on the widely used General Chapter <1079> "Good Storage and Shipping Practices." Supply-chain integrity—which involves minimizing risks that arise anywhere along the supply chain—may be too broad for just one general chapter, however. That is one of the key questions USP has for industry and other stakeholders as it asks for feedback on the new chapter's contents. 

 USP expects the general chapter to evolve significantly from its draft, and hopes the public vetting will result in a strong final product that will be valuable to all relevant parties, including manufacturers; transportation companies involved in automobile, truck, rail, sea and air services; third-party logistics providers, freight forwarders and consolidators; brokers, importers and exporters; packaging and repackaging operations; wholesalers and distributors; retail, mail-order, hospital, nursing home and other pharmacies; and mail distributors, including the US Postal Service and other expedited shipping services. 

The general chapter <1083> provides recommendations on how to minimize risk in international supply chains through effective partnerships and manufacturing quality systems. As it is written, the chapter covers four main areas:  

Importation, which details three primary initiatives importers should undertake to help prevent and detect potential risks (i.e., supply-chain risk management, development of effective supplier partnerships, and building a supply-chain quality system).

Counterfeit Drugs and Medical Devices, which documents types of counterfeit drugs, medical consequences, and distribution and extent of counterfeit drugs and devices.

Best Practices to Combat Counterfeit Drugs and Medical Devices, which covers packaging technologies (e.g., tamper-evident designs, authentication technologies and serialization); drug pedigrees; machine-readable data carriers (e.g., two-dimensional [2D] barcodes and radiofrequency identification [RFID] tags); repackaging guidance; information retention and security; best anticounterfeiting practices, and more.

Diversion and Theft, which addresses factors that raise the risk of theft of drug products and components; security systems, devices, and procedures that should be implemented to reduce risk; and critical information to be gathered after a theft. 

The practices included in the general chapter are top-level, and are purposefully nonprescriptive so as not to box companies in to one way of doing something. The general chapter intends to set a framework; companies can use the best approaches for them within that framework. When discussing track-and-trace technology, for instance, USP points to the two most widely recognized options: RFID and 2D barcodes. It is not, however, USP's role to decide on the actual technology to be implemented.  

There has been much discussion in the industry regarding the challenges posed by a global supply chain, and yet, there are no overarching, comprehensive industry-wide practices to date. What does exist is piecemeal, with pockets of information available through FDA guidance, trade organizations, and other sources. USP believes it can provide value as a convener of different stakeholders. The organization can bring disparate views together and help organize the prevailing thoughts, finding commonalities among all players. In addition, through its inclusion in 

—compendia widely recognized both domestically and internationally—recommendations put forth in a general chapter can have more weight than, for example, a technical report.  

in a continuous state of revision, a mechanism exists for consistently updating the recommendations to reflect current realities. Because change is constant, USP's Expert Committee will be charged with monitoring whether there is a need for adapting the general chapter, thereby providing all parties with one central place for up-to-date  information.  

Given the complexity of this topic, USP is seeking extensive input from all the parties that have an interest in the new general chapter <1083>. Although the expert committee responsible for the chapter represents a diverse group of manufacturers, pharmacists, and other experts, USP is seeking additional perspectives to assist in providing a strong final product. The draft general chapter being published this spring may be deemed too broad or too specific, or may evolve into multiple chapters, for instance.  

USP will evaluate all of these considerations based on feedback received from the diverse stakeholder community. In addition to comments obtained 

, USP is planning a Supply Chain Integrity Workshop at its headquarters in Rockville, MD, on May 22-23, 2012, to further solicit input. The workshop will seek to clarify USP's role in supply-chain integrity and address key topics such as related regulation and technology, and the roles and responsibilities of all parties in the supply chain. The workshop will have a strong international component as well. 

 is vice-president of general chapters, and 

is a senior scientific liaison, both at the US Pharmacopeial Convention (USP). 