Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Platform technology is becoming a popular industry approach for bioprocessing, but just how are companies using it? 

talked to industry experts to gain insight: Morrey Atkinson, PhD, CSO and vice-president of R&D and Drug-Substance Manufacturing at Cook Pharmica; Peter Moesta, PhD, senior vice-president of Biologics Manufacturing and Process Development at Bristol-Myers Squibb; and Jim Powell, business development manager at Ashai Kasei Bioprocess.  

 (IMAGE: GREGOR SCHUSTER/PHOTOGRAPHER'S CHOICE RF/GETTY IMAGES) 

 How might platform technologies be applied to upstream and downstream processes? Is one easier than the other?    

 It is not easier to develop platforms for either upstream or downstream, it is just different. The main difference in developing platform processes for either is that, in most cases, one develops upstream processes for the cell line and the expression system, while downstream processes are tailored to the molecule itself. If the molecules are of a similar type, then the downstream process becomes easy to develop.  

In terms of difficulty, the cell lines and expression systems are inherently variable, and clone-to-clone variability adds to the complexity. Scale factors are also more difficult to control in cell culture and fermentation. In general, upstream therefore probably poses a slightly greater challenge, assuming that the molecules are in a given class or category. 

With today's level of know-how in molecular biology and expression, platform technologies are easier to develop for upstream processes. Identification of a preferred strain or cell line for microbial or mammalian expression, combined with a well-developed expression vector, is the first step in establishing a production platform. This step allows for the use of standardized fermentation or cell-culture conditions requiring limited media and feed optimization. The use of platform expression systems and upstream conditions allow for the generation of significant process experience and forms the basis for developing downstream platforms to the extent possible.  

It is easiest to develop a standardized process for initial downstream steps (e.g., centrifugation and depth filtration for cell-culture products). For monoclonal antibodies (mAbs), where the Fc protein domain–Protein A interaction can be exploited to capture the protein from clarified cell-culture broths, additional platform steps are possible (e.g.,  Protein A-based affinity chromatography and viral inactivation and filtration steps). The final purification steps (i.e., polishing) need to be tailored to the particular antibody at hand and usually require individual optimization.  For other proteins, downstream processing becomes less amenable to the platform approach. Individual process steps can be standardized, but will need to be pieced together and optimized on a case-by-case basis.  

BMS is developing molecules to which we apply platform-based approaches, including antibodies and adnectins. But even when dealing with well-defined classes of proteins, key challenges for establishing production platforms result from unique properties of individual proteins, such as charge heterogeneity, differences caused by post-translational modifications, and stability. These unique properties can impact both the cell's ability to express a correctly folded and stable protein as well as purification of a homogeneous drug substance. 

 Could a platform for purification accommodate variations between mAbs? Is it possible to develop a purification platform for various classes of products (e.g., mAbs and enzyme products)? 

 Platform purification processes must deal with both process- and product-related impurities. With antibody processes, the process-related impurities tend to dominate the development of the platform. Removal of host cell proteins (HCP), in particular, is usually a primary driver.  

For the product-related impurities, most antibody processes are usually dominated by the removal of higher-molecular weight aggregates, followed by clipped forms and other charge variants. This is why so many platforms use an affinity step, followed by some combination of ion-exchange and/or mixed-mode separation. 

It is important to note that a platform process for purifying antibodies must accommodate both charge and hydrophobicity variation between the molecules themselves. The constant regions of most immunoglobulins is consistent in physical and chemical behavior, but single amino acid changes in variable regions can drastically shift either the isoelectric point (pI) of the protein or the relative regional hydrophobicity. So the process must be able to remove a wide range of charge variants as well as various hydrophobic species (e.g., aggregates.) 

mAbs, Fc-fusion proteins and adnectins developed by Bristol-Myers Squibb have large conserved regions, resulting in physical properties that allow one to achieve the vast majority of purification using platform technology. Charge heterogeneity  in the variable region and post-translational modifications then require individually optimized polishing steps. For antibodies, this is usually a combination of an anion exchange step (either in flow-through or bind and elute mode) coupled with a second chromatography step. One must evaluate the remaining purification objective, select the best method, and optimize it. Viral inactivation and filtration steps, as well as diafiltration and concentration steps can be standardized and made to fit with a drug-product formulation platform if available. 

 Is it possible to develop a purification platform for various classes of products (e.g., mAbs and enzyme products)? 

 The challenge in developing platform processes that cover various classes grows as molecular diversity grows. Antibody and antibody-like fusion proteins can be treated as a broad class, but enzymes and other recombinant proteins will have very different molecular characteristics. So outside of broad platform generalities, such as no more than 3-4 columns, all aqueous processing with standard buffers and salts, standard viral filtration systems, and so forth, the platforms will otherwise most likely be quite divergent for different classes of proteins. 

Can purification platforms accommodate the rising titers that upstream processes are yielding?   

 The rising titers are both a blessing and a curse for downstream unit productivity. The capacity of most chromatography resins is basically sufficient for the increased titers, but the buffer consumption and the throughput become a challenge with very high titers. In this case, limiting the number of unit operations, for example, moving from a three-column antibody process to a two-column process becomes much more attractive. Engineering solutions, such as buffer blending and even possibly simulated-moving bed chromatography can also be considered to manage the increased productivity. 

Most downstream unit operations, with the exception of viral filtration, are inherently scalable to an industrial scale. I believe that the biggest downstream bottleneck for high-titer processes has become viral filtration. Most chromatography unit operations can scale effectively, but the need to use an expensive, low-throughput filter can create an inefficient bottleneck in the overall purification process for mammalian cell-derived products. 

Scale-up challenges include the high upfront cost for consumables (e.g. resins, bags, filters) as well as the challenges with liquid handling. Bulk volumes of liquid and intermediate holds are inherently inefficient. Engineering solutions for liquid transfer, mixing, and minimizing storage of liquids should be explored. 

 The technology available today can accomplish the manufacture of proteins up to the metric-ton scale. However, few products to date require this large scale of manufacture.  

Increasing demand for proteins, combined with higher titers in fermentation, can enable implementation of alternative technologies, such as protein precipitation and crystallization. These technologies provide a means to improve purification throughput while significantly reducing cost. Some examples include blood fractionation products and recombinant insulin.  

A key scale-up challenge is chromatography because there are physical limits based on resin-flow characteristics (e.g., back pressure and compression). The next step for industry is the use of simulated moving-bed technology, which can increase throughput.  

  Process engineers can accommodate rising titers using a combination of liquid handling systems and modern virus-removal filters. Because the ability to rapidly and reproducibly create accurate buffers in a minimal footprint is a common bottleneck during downstream processing, Asahi Kasei Bioprocess offers IBD inline buffer dilution systems to generate on-demand diluted buffers for capture, polishing, and virus-removal. Customized skids are easily integrated with existing equipment to improve purification efficiency.  

Additionally, next-generation virus-removal filters facilitate reliable processing at concentrations of up to 50 g/L. Before processing high titers, basic physics of production must be considered. Such factors include the viscosity of the feed material, mechanism of mass transfer, and filter efficiency. Purification becomes easier as the ratio of contaminants to product decreases yet caution must be used as high product levels often reduce cell viability.  

With regard to scale up, how do downstream process platforms perform? Are there limitations?  

Large plants, such as Bristol-Myers' Devens plant in Massachusetts, can have long piping runs between pieces of equipment with significant hold-up volumes. If appropriately designed, process piping either drains by gravity or can be blown out with compressed air, minimizing losses. Filter housings often require water flushes for adequate yield recovery. If properly optimized, large-scale process performance can meet or exceed that observed at smaller scale. 

 Scaling out, as opposed to up, is the preferred approach. During scale up, a facility transitions to larger diameter columns and filter housings before launching trains of production units in parallel. Besides reagent disposal, additional challenges include space as well as the use of water and buffer.  

Holding tanks may be required for byproducts that cannot be released directly into the environment. However, properly designed chromatography systems from Asahi Kasei Bioprocess can reduce the ratio between the hold-up volume and the filter or liquid chromatography (LC) column volume to minimize the waste burden and improve operational efficiency.  

Do these scale-up problems require customized solutions?  

Obstacles created by process scale up require customizes solutions to a certain extent, especially with  respect to automation. When a company moves forward with commercial production, a plant-wide distributed control systems have historically been the preferred method to control and gather data from each step in the process. But for smaller scale production. such as orphan drugs, "islands of automation" are still preferable.  

Finer, more accurate monitoring of this nature streamlines operations and enables tanks to open to skids at the proper time. Distributed control systems provide greater access to information in a manufacturing plant, thereby allowing euipment-related problems to be identified and addressed prior to impacting production. 

Looking ahead, how can platform technologies for analytical methods be improved? Can methods for detecting contaminating proteins, host-cell proteins, and protein level be standardized? What new technologies or methods could help? 

Analytical methods, by definition, should theoretically be amenable to platform standardization. As mentioned, the primary purpose is to detect process- and product-related impurities. The challenge for process-related impurities is that each upstream platform produces different impurities, such as type and amount of HCPs. Unfortunately 'generic' commercial kits are often poor substitutes for process-specific detection methods, but do serve a purpose when used consistently in a platform.  

For product-related impurities, the challenge is similar to that for downstream processing, and depends on specific molecular variants. In addition, the analytical technologies employed are not yet standardized. Charge variants, for instance, can be detected by at least four different methods, none of which effectively discriminate amongst several types of variants (e.g., sialic acid content, deamidation). 

If the platform methods are developed in parallel with the process, and used and controlled consistently, then they can be useful within the portfolio they are employed. Process-related impurities are better understood and controlled, and minor modifications can be made to address product-related impurities. However, the relative utility of the platform is lessened when applied more broadly across product portfolios. 

Ideal analytical methods would both separate and identify unique molecular species. A high-throughput, quality-control friendly functional equivalent to an LC–MS method would be desirable.  

Most straightforward analytical methods such as A280, capillary electrophoresis, polyacrylamide gel electrophoresis, isoelectric focusing, and size-exclusion high-performance liquid chromatography, are flexible and lend themselves for upstream and downstream analyses. More complex methodologies, particularly for unique post-translational modifications and potency, are not as easily standardized, particularly those requiring high-end analytical endpoints such as mass spectrometry (MS), nuclear magnetic resonance (NMR), surface plasmon resonance for binding kinetics, and cell-based bioassays.  

Once projects progress to the clinical-trial stage, it is advisable to take a closer look at standardized methods and optimize them for the molecule at hand. 

 The first requirement for being able to facilitate the use of an analytical platform is that the master cell line, expression vector, and upstream and downstream process steps are standardized as much as possible. The better characterized and standardized the process, a combination of anti-sera reactive against known impurities and HCPs can be created from premade anticontaminant libraries to provide sufficient coverage and sensitivity. Protein-A detection methods are relatively easy to platform while HCP methods tend to be the most challenging. 

Newer surface-plasmon resonance instrumentation is providing for significant improvement in the throughput and robustness required for ligand binding and binding kinetics assays. With particular molecule classes (e.g., mAbs), standardization of common reagents and capture approaches can improve and simplify the method development of specific binding activity method platforms.  

For cell-based bioassays (potency), the use of common cell-based systems, either off the shelf or specifically designed, and activity read-outs for classes of activities (e.g. cytokine production, cell migration, etc.), can significantly reduce the amount of 

 method development. Also, the standardization of read-outs such as chemiluminescence or enzyme-generated colorimetric measurements in a microtiter plate format can further improve throughput. 

Articles

The standardization of upstream and downstream bioprocessing is growing, but several kinks need to be ironed out.

Platform Technologies

Genotoxic impurities and how to identify them and control for them have been a concern for several years in the pharmaceutical manufacturing industry. In recent years, FDA has issued draft guidance on the subject, EMA has issued final guidance, and the International Conference on Harmonization (ICH) is putting together a related M7 guideline to complement its Q3A and Q3B guidelines on impurities (1–3). Still, challenges remain. 

spoke with Bo Shen, PhD, principal scientist at Amgen and chair of the American Association of Pharmaceutical Scientists (AAPS) Pharmaceutical Trace Impurities Focus Group, to gain insight on these challenges. 

Key challenges and regulatory requirements

What would you say are the key challenges facing drug manufacturers today regarding genotoxic impurities (GTIs)? Is there still concern over FDA and EMA requirements/threshold limits or approaches for controlling for these impurities? 

				The identification of GTIs in pharmaceutical products, assessment of a safe level of exposure to these impurities, and establishing the corresponding limits are the key challenges and concerns still facing drug manufacturers. 

Drug manufacturers have to identify GTIs early in process development, develop analytical methods, and demonstrate a control strategy to ensure patient safety. The assessment/identification phase involves a process by which the synthetic pathway is evaluated and through a combination of chemical reasoning and analytical testing, either known or potential genotoxic impurities (pGTIs) may be identified.  

To assess pGTIs, drug manufacturers use a combination of 

tools, evaluate scientific literature and public databases, and may conduct an Ames test to determine the mutagenic potential of chemical compounds. The result of an Ames test takes precedent over the predictions made by 

genotoxicity tests, the Ames test is the most reliable predictor of carcinogencity. Therefore, a compound that is positive in the Ames test is classified as genotoxic unless a substantial weight-of- evidence exists to conclude that the compound does not represent a genotoxic risk to patients.  

To build such weight-of evidence involves conducting additional 

 gentoxicity tests that require significant resources and can lead to program delays if the GTIs cannot be controlled to the threshold of toxicological concern (TTC) while additional studies are being conducted.  

Another challenge is that the Ames test may not be sensitive enough to detect GTIs when the impurity is assessed by testing the drug substance. The detection limit for many mutagens in the Ames test is 250 µg/plate, which represents a level far higher than is typically encountered for impurities in drug substances. Therefore, in many circumstances, the isolated impurity needs to be tested instead. Synthesis of an impurity in amounts and purity sufficient for Ames testing can provide a challenge to drug manufacturers.  

After identifying GTIs, to ensure patient safety, drug manufacturers have to establish a robust control strategy to prevent or limit GTIs in the final API. Control strategy approaches will vary by companies. Some companies may choose to alter synthetic routes to avoid using or generating GTIs altogether; whereas, other companies may consider this impractical, especially when multiple GTIs must be handled and making changes might only lead to new ones. 

The need of controlling several GTIs at the TTC level during analytical and process development further complicates the control strategy. Structural considerations can be complicated and numerous challenges can exist.  

With the regulatory guidance in this area evolving and the need to ensure drug product quality and patient safety, drug manufacturers are faced with the challenge of effectively establishing and implementing robust internal practices which balance time, cost, and risk.  

 From an analytical-chemistry perspective, to meet current requirements regarding genotoxic impurities, how does it change the level, extent, or type of analytical testing that needs to be performed for an analysis of a particular active ingredient or finished drug product? Is typical impurity testing sufficient, or what additional testing or approaches may be required?  

Consider the GTI control requirements, taking into account the TTC limit (1.5 µg/person/day) and the corresponding levels of the GTI in the drug substance, it can be calculated that for a daily dose of 1 g/person the limit for the GTI is 1.5 ppm and for a daily dose of 100 mg/person the corresponding limit is 15 ppm. This translates into target limits for GTI detection and quantification at levels of about 1 ppm, that is almost 500 times lower than those for classical impurity analysis (1 ppm versus 0.05%). Typical impurity testing is not suitable for GTI determination since their quantitation limit is generally 500 ppm (0.05%). Assessing multiple impurities in the low ppm range can be a significant analytical problem and challenge.  

Liquid chromatography (LC) with ultraviolet (UV) detection and gas chromatography (GC) with flame ionization detection are often adequate for the impurities at 100 ppm level. In the range of 1–10 ppm or lower, hyphenated mass spectrometry (MS) techniques such as LC–MS and GC–MS are by far the most appropriate techniques. These techniques, due to sensitivity and selectivity, have been widely used in GTI analysis. 

In addition to sensitivity and specificity, other challenges in GTI analysis may include:  					

Sample matrix interferences: techniques such as pre/post-treatment derivatization may be used to overcome these challenges. 

Analytes which are chemically reactive or unstable: special handling techniques may be required to overcome low recover or poor sensitivity. 

Analytes which are not suitable for common analytical detectors. 

 One of the FDA draft guidance recommendations on GTIs involves changing the synthetic or purification route to reduce or remove the impurity (1). Has this—or will this—become a challenge for drug manufacturers, particularly, if the synthesis of API involves intermediates or raw materials not internally produced and if these are be considered a source of the resulting impurity? If so, how is that addressed? 

Changing synthetic routes or using purification could effectively avoid generating GTIs during the synthesis. However, route selection takes into account both yields and manufacturability considerations. Because of their intrinsic high reactivity, reactants and intermediates used in manufacturing processes may be genotoxic substances and it may not be suitable to avoid their use.  

When changing synthetic routes is not feasible, pGTIs and GTIs are identified by a careful analysis of both the degradation products and the manufacturing process, taking into account reagents, intermediates and by-products. When the presence of a GTI is established, an explanation why no alternative to the use/formation of this impurity is possible (including alternate synthetic routes) should be provided as part of the pharmaceutical assessment. The technical effort aimed at reducing the GTI level according to ALARP, or as low as reasonably practical, should be documented. This latter part of the pharmaceutical assessment could give rise to some practical applicability issues.  

For the intermediates or raw materials not internally produced, most companies are conducting rigorous testing to control impurities, or even establish specifications. 

What has been the role of the AAPS Pharmaceutical Trace Impurities Focus Group for genotoxic impurities on this issue?  

The focus group provides benefits to pharmaceutical scientists by providing a single, broad forum to discuss technical and regulatory topics associated with the impurities, and to better understand at the grassroots level the practices, approaches, and trends used across the industry. Since its inception in 2010, the group has played an influential role on promoting scientific discussion for control and test strategy of genotoxic impurities. In the next few years, the group will continue to focus on highly sensitive analytical methodology development, process development, and genotoxicity tests for impurities/genotoxic impurities that are capable of controlling these impurities. 

The group will effectively communicate to establish dialogues among industry, academia, and regulatory groups to discuss technical advances, and understand and apply changes in regulatory viewpoint on impurities/genotoxic impurities. The group will aim to facilitate discussion around science/risk-based regulations and regulatory review practice, and will work to catalyze opportunities to expand targeted academic support and collaborations on topics involving impurities/genotoxic impurities. Overall,  the focus group offers a forum for discussion among researchers engaged in basic scientific work in analytical and  process chemistry as well as toxicology, and serves as an outlet to connect with members of other sections and focus groups with related interests in the field. 

The focus group routinely develops programming proposals in collaboration with other focus groups, such as the AAPS API Focus Group and other industry stakeholders, including the ICH M7 expert working group. For example, the focus group published the first industrial survey results about GTI and is in preparation and conducting a second industry survey on the methodology of the control of the GTIs. The AAPS focus group also organizes educational webinars and events.  

These activities reflect the goals of the AAPS focus group, which include to:  					

				 Establish a core group of interested scientists to explore diverse areas of genotoxic impurities and discuss technical and regulatory issues pertinent to genotoxic impurities 			

				 Define technical and regulatory genotoxic impurities issues related to development of pharmaceuticals 			

				 Provide a forum to discuss genotoxic impurities scientific issues and exchange ideas/best practices 			

				 Organize quality programs for the annual meeting and to conduct workshops on current ICH and FDA and international requirements 			

				 Provide an avenue for training of new guidance on impurities/genotoxic impurities topics 			

				 Act as a link among members of industry, academia, and regulators 			

Facilitate workshops/symposia and thereby share experiences and communicate key lessons learned with industry and regulators.  

We welcome scientists and regulators to participate in the activities organized by the AAPS Pharmaceutical Trace Impurities Focus Group.  

Bo Shen would like to specially thank Dr. Kurt Black, Dr. Ruth Lightfoot–Dunn, Dr. Jerry Murry, Dr. David Semin, and Dr. Sophie Wang for their review and input on this Q&A. 

Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches  

Guideline on the Limits of Genotoxic Impurities 

Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk,  

Genotoxic impurities and how to identify them and control for them have been a concern for several years in the pharmaceutical manufacturing industry. Pharmaceutical Technology spoke with Bo Shen, PhD, principal scientist at Amgen and chair of the AAPS Pharmaceutical Trace Impurities Focus Group, to gain insight on key challenges.

Genotoxic Impurities: A Q&A with Amgen's Bo Shen

Almost two years to the date after President Obama signed the Affordable Care Act, introducing a regulatory pathway for biosimilar approval in the United States, FDA has released draft guidance for industry about how to get such a product into the marketplace.  

Industry has been at a pivotal standstill since the Biologics Price Competition and Innovation Act (BPCI Act) was passed in 2010, as part of the government's overall healthcare act, but biologics developers and manufacturers seem ready to pounce. According to a press briefing given by FDA's Rachel Sherman in early February, there have been 35 pre-investigational new drug (IND) meeting requests for proposed biosimilars to 11 reference products, 21 pre-IND sponsor meetings held, and 9 INDs received. Sherman is the associate director for Medical Policy within FDA's Center for Drug Evaluation and Research. With the doors to FDA's biosimilar review desk widened, those numbers are likely to skyrocket in the coming months. 

The draft guidance—three documents to be exact—includes 

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

. FDA seems to have gone out of its way to anticipate and respond to key concerns in the documents, the first being whether animal and clinical data from a non-US licensed comparator drug can be used to demonstrate biosimilarity. The answer is yes, according to the 

 draft guidance, although justification and adequate bridging data to a US-licensed reference product will be required in these cases.  

Another question addressed is which studies a sponsor needs to perform and submit as part of its 351(k) application—the route to be taken for biosimilar approval. The BPCI Act set the stage for these requirements, and the draft 

 guidance states that companies must include "analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; animal studies (including the assessment of toxicity); and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product." 

Other items provided in the guidance documents are clear definitions for "protein" and "chemically synthesized polypeptides." These definitions are crucial because the pathway legislation added "protein" to the definition of a biological product for the first time. 

Also noted are pediatric assessments, which the draft guidance states are required for a biosimilar product that is not deemed "interchangeable." Pediatric study plans should therefore be part of IND applications.  

Overall, FDA is focusing on a step-wise approach for manufacturers and a "totality-of-the-evidence" approach for regulatory assessment for biosimilars. Essentially, the manufacturer needs to look at each step of biosimilarity demonstration, starting with extensive structural and functional characterization of both the proposed product and the reference product, to evaluate "the extent to which there is residual uncertainty about the biosimilarity of the proposed product" and then "identify next steps to try to address that uncertainty." For FDA's part, the agency will be reviewing the "totality of data and information submitted in the application...."    

Looking ahead, Sherman noted during the February press briefing that FDA still plans to address naming and tracking standards for biosimilars as well as additional exclusivity issues, which are addressed only briefly in the 

Also on the docket for the future: standards for "interchangeability." Once a product is proved to be biosimilar, a sponsor can work to demonstrate interchangeability, meaning that the biosimilar product produces the same clinical result as the reference product in any given patient, explained Sherman.  

Public comments on the draft guidance documents are due to FDA through the 

and will be used to shape the final guidance—hopefully sooner rather than later. The European Union has been ahead of the US in the biosimilar game for years, with approximately 14 approved products under its regional belt. It will be interesting to watch how the global market reacts to FDA's long-anticipated movement forward in this area. 

Has the long-awaited guidance answered all of the industry's questions?

FDA Guides the Way to Biosimilars in the US

FDA published in October 2011 the final guidance, 

Incorporation of Physical- Chemical Identifiers 

into Solid Oral Dosage Form Drug Products for Anticounterfeiting (1).

 The document was issued as a follow-up to the agency's 2004 Counterfeit Drug Task Force Report to facilitate the use of authentication technologies such as PCIDs, and is meant to provide guidance for industry on how using the technology would change the information expected to be provided in regulatory submission (2). The use of a PCID, defined in the guidance as "a substance or combination of substances possessing a unique physical or chemical property that unequivocally identifies and authenticates a drug product or dosage form," is voluntary. PCIDs include inks, pigments, flavors, and molecular taggants. 

In the guidance, FDA recommends that the PCID's ingredients be pharmacologically inactive so that they can be treated as excipients. To minimize toxicological risk, the agency recommends that drugmakers use permissible direct food additives, food substances that are generally recognized as safe (GRAS), or ingredients listed in the agency's Inactive Ingredient Guide (IIG) that have been used in solid oral dosage forms. 

To minimize the risk that a PCID will adversely affect the dosage form's identity, strength, quality, purity, potency, or bioavailability, FDA recommends that companies add a PCID to the product at the lowest level that will ensure the dosage unit's identification. PCIDs that are relatively inert also can minimize the potential for adverse interactions. In addition, the guidance states that manufacturers should examine the potential effect of a PCID on the product's quality, performance, and stability. 

In terms of documentation, the guidance includes recommendations for new drug and abbreviated new drug applicants proposing to incorporate PCIDs into new solid oral dosage forms. The guidance also describes the documentation recommended for applicants that want to incorporate PCIDs into solid oral dosage forms as a postapproval change. 

The amount of information to be provided for a PCID depends on its pharmacological characteristics, toxicological characteristics, and design, according to the guidance. Less information would be expected for a PCID that is a permissible direct food additive, a food substance that is GRAS, or an ingredient listed in the IIG than for a novel PCID. According to the guidance, the agency would expect to see information about items such as the PCID's chemical composition, the rationale for selecting the PCID, how the PCID is integrated into the product, the location of the PCID in the product, and the relevant physical–chemical attributes of the PCID. 

asked the agency a few follow-up questions about the guidance and plans going forward. The responses are provided by an FDA Spokesperson. 

 Location and presence of a PCID in a solid dosage form is crucial in order to avoid interaction with the drug substance. What are the key concerns that manufacturers must consider in this regard (e.g., release rate, drug substance interaction)? 

 The key concerns for the presence and location of a PCID in a solid oral dosage form are potential interactions with the drug substance and potential impact on the drug product release rate. Interactions with the drug substance could cause degradation. Interactions with rate-controlling exipients could impact the release rate of extended release or delayed release dosage forms. 

 It is recommended that industry use already approved direct food additives (e.g., those listed in GRAS or IIG) at the lowest specified levels to avoid adverse reactions. Does the agency have plans to create a list of specific PCIDs for the pharmaceutical industry to be used in the future? Will PCIDs that are not in the GRAS or IIG be considered by the agency if submitted by an applicant for use? 

 The agency does not have plans to create a list of specific PCIDs for the pharmaceutical industry. Proposals for the use of PCIDs that are not in the GRAS or IIG lists can be submitted by an applicant for evaluation by FDA.  

 According to the guidance, "There are various available means for presentation and detection of PCIDs (e.g., photolithography, holography, optical microscopy, laser scanning devices, excitation/fluorescence detection). Some identifying characteristics, such as pigments or flavors, could be easily observed by patients, healthcare practitioners, and pharmacists. Others could require the use of a detection instrument (e.g., a scanner, photometric detector, mass spectrometry)." What is the expectation in terms of who has responsibility—for example, healthcare providers or pharmacists—for determining and authenticating the presence of a PCID before patient distribution?  

 There is no intention by FDA to place a burden of responsibility on healthcare providers to authenticate drugs by determining the presence of a PCID before patient distribution. 

 Are there plans to extend the guidance beyond solid dosage forms? 

 There are no plans at this time to extend the guidance on PCIDs beyond solid oral dosage forms.  

  What other anticounterfeiting measures does FDA recommend for oral solid dosage forms in addition to PCIDs?  

 FDA encourages manufacturers to continue exploring promising technologies for use as anticounterfeiting measures. These may include radiofrequency identification (RFID), nanotechnology, encryption and other track-and-trace technologies. 

 Manufacturers can submit information about their intent to use a PCID in a solid oral dosage product in an NDA or ANDA or as a postappoval change. Some industry members have raised convern over confidentiality. Can you confirm that PCID information submitted in these documents is confidential and therefore protected from would-be counterfeiters?   

 FDA confirms that information on PCIDs submitted by applicants or master file holders is considered confidential. 

Guidance for Industry: Incorporation of Physical- Chemical Identifiers 

into Solid Oral Dosage Form Drug Products for Anticounterfeiting (Rockville, MD, October 2011).

 2.  FDA, Counterfeit Drug Task Force Report: "Combating Counterfeit Drugs" (Rockville, MD, February 2004). 

FDA answers key questions about the October 2011 guidance on using physical–chemical identifiers in solid oral dosage products to help prevent and avoid counterfeiting.

Physical-Chemical Identifiers: A Q&A with FDA on the Final Guidance

	Pfizer has proactively recalled 28 lots of birth control pills. An investigation by the company discovered that some blister packs may have mixed up the inert and active ingredient tablets. Watch the PharmaFaceoff 

 on YouTube to see what happened and why.

Pfizer has proactively recalled 28 lots of birth control pills. An investigation by the company discovered that some blister packs may have mixed up the inert and active ingredient tablets. Watch the PharmaFaceoff video blog on YouTube to see what happened and why.

Pfizer’s Birth Control Recall

Rachel Sherman, MD, Associate Director for Medical Policy, within FDA’s Center for Drug Evaluation and Research, gave a press briefing today. Below is a summary.

		In terms of background, the BPCI Act was passed in March 2010 as part of Affordable Care Act, and it creates an abbreviated licensure pathway for biological products shown to be biosimilar or interchangeable with an FDA-licensed reference product (section 351k of Public Health Service Act). FDA is eager to have an informational discussion on this topic because with the new pathway program, the agency is “essentially launching an entirely new regulatory paradigm” and public needs to understand this, said Sherman.

		The BPCI Act adds “protein” to the definition of a biological product which currently includes terms such as a virus, toxin, and blood. Historically, proteins have been approved as drugs under the FD&C Act (505) and under the PHS Act (351). Proteins (except for any chemically synthesized polypeptide) will be regulated going forward under PHS.

		FDA can rely on some existing information about the reference product when considering a proposed bisimilar product. Specifically, “biosimilar” means the product has the same mechanism of action as the reference product; the condition of use in proposed labeling has been previously approved for reference product; and has the same route of administration, dosage form, and strength as reference product.

		The agency has to decide whether the biosimilar product is highly similar to the reference product and ensure that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency. A doctor can provide product A or B, for example, and expect the same result. The doctor cannot go back and forth between Product A and B, however (see below), noted Sherman.

		The BPCI Act requires FDA to look at three buckets of information for the 351(k) pathway: analytical studies to show that the biosimilar is highly similar to the reference product; animal studies (including toxicity, and as needed); and clinical study(ies) to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed (including, among others, pharmacokinetics and immunogenicity).

		A common question: biosimilars are not identical to the reference product but are close-how close? As Sherman explained it, each study adds a piece of information to understand what the biosimilar product is and shows what more is needed to fully understand it. The method is similar to a fingerprint like approach to closely identify the product. There is no one size fits all assessment. Another approach FDA may take is to use the totality of evidence in assessing the biosimilar. Europe has a similar way of evaluating biosimilars. To provide the best advice on required animal and human studies to the biosimilar applicant, FDA should have competed a thorough review of data from structural and functional analyses.

		Interchangeability. This term means that the biosimilar product produces the same clinical result as the reference product in any given patient, AND for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater with repeated use of reference product without alternating or switching. An interchangeable biosimilar product may be substituted for reference product without authorization of a healthcare provider. NOTE: Biosimilarity is a prerequisite for interchangeability.

		Discussions happening at FDA: The agency is thinking about ways to consider non-US licensed comparator products; the definition of protein (including chemically synthesized polypeptides); standards for interchangeability; naming and tracking standards for biosimilars and interchangeable products; exclusivity issues; and pediatric assessment requirements.

		FDA will also be thinking about product class under the Act’s transition provisions. By 2020, every biological product will need to be approved under 351 of the PHS Act versus the FD&C Act.

		To date, there have been 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products. 21 PRE IND sponsor meetings held, and 9 INDs received

		As for the FDA guidance on biosimilars…. Sherman says it’s still in final stages. No details on timeline specifics.