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Pharmaceutical Technology March 2012 Solid Dosage Supplement (PDF)

Between September 2010 and December 2011, a joint committee organized by NSF International worked to complete a draft of  NSF 363, a new American National Standard for excipient GMP. The draft standard, Good Manufacturing Practices (GMP) for Pharmaceutical Excipients, has completed the public comment period and a final version is to be balloted shortly (1). The new standard aims to establish industry-wide GMP requirements for the manufacture of excipients. 

NSF 363 was developed based on the joint International Pharmaceutical Excipient Council and the Pharmaceutical Quality Group (IPEC–PQG) Good Manufacturing Practices Guide for Pharmaceutical Excipients (2). The suggestions expressed in the IPEC–PQG guide were reworked into requirements of the standard. Other IPEC guides are referenced in NSF 363 to clarify how industry can achieve conformance to the standard. 

Background and importance of an excipient GMP standard

NSF is an independent, not-for-profit, nongovernmental organization and an Accredited Standards Developer of the American National Standard Institute (ANSI). ANSI is a private, nonprofit organization that administers and coordinates the US voluntary standardization and conformity assessment systems. ANSI is the US representative to the International Organization for Standardization (ISO). American National Standards are developed in conformance with the ANSI Essential Requirements to ensure that standards are developed through participation by those directly and materially affected without financial or organizational membership barriers, a lack of dominance by a single interest category, individual, or organization, and a balance of interests (3). 

Of relevance to the industry is the fact that the National Technology Transfer and Advancement Act of 1996 requires that federal agencies adopt private-sector standards, particularly those developed by standards-developing organizations, wherever possible, in lieu of creating proprietary, nonconsensus standards. Further, the US Office of Management and Budget's Circular A119 provides for "Federal Participation in the Development and Use of Voluntary Consensus Standards and in Conformity Assessment Activities." As a result, FDA may adopt the ANSI standard GMP regulations for excipient ingredients manufactured for use in pharmaceutical dosage forms intended for US domestic markets. 

The NSF joint committee organized to prepare the excipient GMP standard, designated as NSF 363, is comprised of representatives of excipient manufacturers, pharmaceutical users, and the general interests of the industry, including FDA, academia, and public health organizations. The final draft of NSF 363 was completed in the fourth quarter 2011 and was made available for public comment at the end of the year. The 45-day public comment period ended in January 2012, and the NSF joint committee reviewed the comments to the draft standard. Revisions to NSF 363 are in progress with final approval of the standard is expected to occur in the second quarter of 2012. Following the joint committee's approval, the standard will be considered by NSF's Council of Public Health Consultants with final approval by ANSI's Board of Standards Review. If approved as expected, the standard will be published by the end of 2012. 

Excipients come from a broad range of the chemical- and food-ingredient industries. Inorganic excipients usually begin with the mining of minerals. Excipients whose starting material is grown on a farm or forest are often further processed into a derivative through chemical reaction or fermentation. Synthetic excipients can be produced at the manufacturing site from basic chemical starting materials, such as ethylene and acetylene. The one process common to all excipient manufacturing is purification of the material to meet the requirements of a pharmaceutical ingredient. A key challenge of the NSF joint committee, therefore, was to develop excipient GMPs that would be applicable to the diverse operational activities of the excipient industry. 

NSF 363 represents the evolution of the joint IPEC–PQG GMP for Pharmaceutical Excipients (2) into an American National Standard suitable for regulation by FDA. The most significant new requirement in NSF 363 not found in the joint IPEC–PQG guide involves the use of risk management to ensure consistent excipient quality. For the purpose of the article, quality is taken to mean consistent excipient composition and freedom from contamination. Risk assessment is defined in NSF 363 as "a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards" (1). (For details on conducting and documenting risk assessments as required by the standard, please see the article "Conducting Risk Assessment in Support of ANSI Excipient GMPs" in this issue.) The IPEC–PQG excipient GMP guide, as well as other IPEC guides, provide additional resources for risk assessment. The purpose of the many risk assessments stipulated in NSF 363 is to identify risks to excipient quality to assure control measures are commensurate with those risks (1). Several sections and clauses of the new standard are explained below. Note that the term "Section" as used in this article refers to requirements that also contain enumerated subordinate requirements referred to herein as "Clauses." 

The first clause in NSF 363 to refer to risk is 4.2.1 (Quality Management System/ Documentation Requirements/General) where the appropriate use of quality risk-management principles, defined as a systematic process for the assessment, control, communication, and review of risks to the quality of the excipient across its life cycle, are to be used to evaluate changes to the quality management system. Such changes include activities, operations, and processes that pose a risk to excipient quality. Also in this clause is the requirement to document a risk assessment that justifies those other clauses of the standard that do not apply to excipient manufacture and are thus not implemented. 

Section 4.3 on Quality Management System/Change Control requires the implementation of risk assessment as a tool to determine the impact of change involving the manufacture of the excipient. Here, IPEC–Americas has provided a guide as a basis for conducting the risk assessment. Any change that may impact the consistent composition or performance of the excipient should be considered potentially significant and the pharmaceutical customer should be notified as suggested in the IPEC guide for significant change reporting (4). 

Section 6 on Resource Management requires several risk assessments to identify the potential for contamination of the excipient. For example:  

Clause 6.2.3 (Human Resources/Hygienic Practices) describes risk assessment to identify the potential for contamination of the excipient by personnel and/or their activities. Where a risk to the excipient exists, the standard provides five measures that may be taken to minimize said risk. The proposed control measures will be familiar to manufacturers who have implemented excipient GMPs as noted in the IPEC–PQG guide (2).

Clause 6.3.1 (Infrastructure/Buildings and Facilities) requires risk assessment to evaluate the threat to excipient contamination posed by the buildings and facilities. This assessment is to consider the intended use of the excipient (i.e., oral, parenteral, topical applications, etc.). The five aspects presented for consideration are discussed in the IPEC–PQG guide (2). The provision to perform the risk assessment relative to the marketed intended use of the excipient links how the excipient is marketed to the tolerance for risk of contamination from the manufacturing facility. 

Clause 6.3.3 (Utilities) stipulates evaluation of contamination risk from utilities but does not require linkage to the intended use of the excipient.

Section 6.4 on Work Environment requires the assessment of contamination risk from exposure to the work environment. This risk assessment is linked to customer requirements and marketed use. The standard notes five control measures that are to be considered when conducting this assessment for risk. The clauses under 6.4 require documentation of conformance to the control measures implemented to address the risk to excipient quality noted in the assessment. However, Clause 6.4.4 (Pest Control) provides for a risk assessment to identify the elements needed in a pest control program.

Section 7 on Excipient Realization, further provides for risk assessments, as follows:  

Clause 7.4.1 (Purchasing/Purchasing Process) requires the identification of quality-critical materials and services through risk assessment. The requirements of this clause are applicable only to those materials and services identified as quality-critical, except for the general expectation to have an agreed specification from approved suppliers. While neither the standard nor the IPEC–PQG Excipient GMP guide provide criteria for the determination as to whether a material or service is quality-critical, the assessment should be based on the potential impact to excipient quality (2). The suppliers of quality critical raw materials should be expected to notify the manufacturer of a process change so that the excipient manufacturer can evaluate the change for the potential impact to the excipient.

Clause 7.5.5.1 (Production and Service Provision/Preservation of Product/Raw Material Packaging Systems) requires a risk assessment to assure the storage and handling of raw materials provides suitable protection against deterioration or contamination and that identification labels remain legible.

Clause 7.5.5.2 (Production and Service Provision/Preservation of Product/Excipient Packaging Systems) provides for a risk assessment only where reusable containers are returned for further use.

The only requirement for risk assessment in Section 8, Measurement, Analysis and Improvement, is in clause 8.3.2 (Control of Nonconforming Product/Reworking). Here, a risk assessment is required to assess the risk of the rework operation to excipient quality. 

In conclusion, the provisions for risk assessment in NSF 363 are new in that they are to be formally conducted and documented. Informal assessment of risk to excipient quality has always been an expectation in IPEC excipient GMP guides however. 

 Several other provisions in NSF 363 are either new to excipient GMP requirements or differ from that suggested in the IPEC–PQG Excipient GMP guide (2). In particular, the excipient manufacturer should be aware of the following differences. 

Clause 4.2.4 (Quality Management System/Documentation Requirements/Control of Records) requires that records be kept for 1 year beyond the excipient expiration date or first re-evaluation date. The standard further states that where the manufacturer does not stipulate a re-evaluation or expiration date, the records should be retained for five years. The IPEC-PQG Excipient GMP guide merely suggests keeping records for a defined period. 

Specified responsibilities of an independent Quality Unit are noted in Clause 5.5.1 (Management Responsibility/Responsibility, Authority, and Communication/Responsibility and Authority) with allowance to delegate some duties. While these responsibilities are also listed in the IPEC–PQG Excipient GMP guide as is allowance for delegation, the standard further notes that ultimate responsibility for oversight and approval remains with the Quality Unit. 

As noted, Clause 7.4.1 (Purchasing Process) requires the identification of quality-critical materials and services. However, unlike the IPEC–PQG Excipient GMP guide, the standard specifically includes packaging materials. Also where the guide notes that periodic audits may be required, the standard notes the assessments are to be ongoing. The expectation of the standard is for the manufacturer to continuously monitor the conformance of these suppliers to the purchasing agreement. 

Clause 7.4.3 (Purchasing/Verification of Purchased Product) adds several new requirements:  

Justification for not sampling any incoming material 

Verification of the measurements reported on the supplier Certificate of Analysis (COA)

Verification that the Certificate of Conformance for packaging components references the current agreed specification.

Section 7.5 on Production and Service Provision, also contains several new provisions:  

Requirements for equipment and utensil cleaning and sanitization are expanded under clause 7.5.1 (Control of Production and Service Provision). In addition to the expectations noted in the IPEC–PQG guide, the standard requires the establishment of criteria to confirm cleaning effectiveness, requires chronological records of cleaning activities and identification of the cleaning status of equipment.

There is a requirement to demonstrate ongoing evidence of process capability under Clause 7.5.2 (Validation of Processes for Production and Service Provision).

Clause 7.5.3 (Identification and Traceability) stipulates documentation that defines identification and traceability for raw materials in continuous processing. The IPEC-PQG guide suggests using the time material was processed for traceability. This clause also requires that labeling include the manufacturing address or a reference to the site of manufacture.

Under Section 7.5.5 on Preservation of Product, the manufacturer is expected to justify the handling and storage conditions for quality critical materials.

Where excipient is shipped in bulk, there is to be a list of restricted or allowed previous cargoes for non-dedicated bulk transport equipment according to Clause 7.5.5.3 (Excipient Delivery).

Section 7.6, Control of Monitoring and Measuring Equipment, describes the expectations for measuring and test devices used to make quality-critical measurements.  

There are several new expectations under Section 8.2.4, Monitoring and Measurement of Product:  

Clause 8.2.4.1.1 (Laboratory Controls) adds the requirement to provide documentation of sample preparation to show conformance with the test method. In addition there is a requirement to reference the test method. This documentation will facilitate the investigation of Out-of-Specification test results.

Clause 8.2.4.1.2 (Laboratory Procedures) notes that reagents and test solutions are to  have expiration or re-standardization dates.

Clause 8.2.4.5 (Certificate of Analysis) includes the provision noted in the IPEC–Americas COA guide to include the "manufacturer's name and site of manufacture or reference to the site of manufacture" (5).

Section 8.3 on Control of Nonconforming Product, adds a couple of requirements:  

Nonconformance is to be investigated to identify the root cause and potential impact to other batches or products.

Under Clause 8.3.2 (Reworking) customers are to be notified if they are provided with a reworked batch. Such material represents a potential significant change since routine processing was not followed.

The last addition of note is in Section 8.4 on Analysis of Data, which requires monitoring of nonconformance with this standard and of supplier nonconformance are new requirements. 

This article highlights the new requirements for excipient GMP as reflected in NSF 363. It expresses the opinion of the author as to what requirements in the draft ANSI excipient GMP standard differ from the IPEC–PQG Excipient GMP Guide. It is important to note that at the time this article was prepared, the public comment period for the standard had just been completed. Based upon input, requirements as described here may be modified. The reader is thus urged to review the requirements in the approved NSF 363 standard for applicability to their manufacturing operation. While certain new requirements are expressed in the standard, they either evolved from implied expectations in the excipient GMP guide or are enhancements resulting from the current business and regulatory climate. NSF 363 is organized in accordance with ISO 9001 but adds new clauses where appropriate. The organization of this American National Standard will facilitate submission of the standard to ISO for their adoption as a global standard. 

, is vice-president and chief operating officer at International Pharmaceutical Excipients Auditing, 1655 N. Fort Myer Drive, Suite 700, Arlington, VA 22209, tel. 703.351.5266. 

Draft Good Manufacturing Practices (GMP) for Pharmaceutical Excipients

Joint IPEC–PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 

Essential Requirements: Due Process Requirements for American National Standards. 

Significant Change Guide for Bulk Pharmaceutical Excipients

The author reviews significant changes to GMP for excipients in the forthcoming American National Standard, including a risk-based approach to excipient manufacture, why new requirements were proposed, and their potential impact to excipient manufacturers.

The American National Standard for Excipient GMP

The pharmaceutical industry, equipment and machinery companies, and academic researchers are investing to develop applications in continuous processing for drug production. Supported by quality-by-design principles, a regulatory environment that is encouraging the industry's move to continuous manufacturing, and lured by the promise of improved production economics and greater operating efficiencies, the industry is moving forward with select projects in continuous solid-dosage manufacturing. 

Although pharmaceutical production is a batch-processing operation, specific unit operations in solid-dosage manufacturing, such as milling or tablet compression, may be run in semicontinuous and continuous processing steps (1). The feasibility of developing continuous processes for specific unit operations requires advances in pharmaceutical equipment design and operation. For example, to make continuous mixing, granulation, and drying possible for small-scale operations, such as in the pharmaceutical industry, systems need to be developed with limited or no start-up and shutdown waste to enable reaching steady state in an extremely short time (2). A commercial example is GEA Pharma Systems' ConsiGma continuous granulation, and drying system. Designed in a modular way, the system consists of a patented twin-screw granulator, a segmented continuous fluid-bed dryer, and a granule-conditioning unit to prepare granules for a tablet press (2). 

One advantage of continuous operations is the elimination of scale-up, which may be difficult overall and in specific operations, such as granulation (1). As hot-melt extrusion is gaining popularity for solubilization of insoluble drugs, twin-screw extrusion also is gaining attention as a continuous alternative to traditional high-shear granulation. This continuous process enables faster throughput and easier scale-up. Ashland  Specialty Ingredients recently presented results on how hydroxypropylcellulose (Krucel), povidone (Plasdone), and hypromellose (Benecel) performed in continuous low-temperature extrusion granulation as compared with traditional wet granulation. The results showed twin-screw extrusion as a promising method for high-dose formulations and highlighted how tablets made by means of extrusion showed improved strength and low friability compared to traditional wet granulation, according to an Oct. 13, 2011, company press release.  

Researchers at Ghent University in Belgium and Complutense University in Madrid recently evaluated the strengths and weaknesses of several complementary process analytical technology (PAT) tools implemented in a continuous wet-granulation process, which was part of a fully continuous from powder-to-tablet production line (3). The use of Raman and near infrared spectroscopy and a particle-size distribution analyzer was evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline-lactose blend. The solid-state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the API. The researchers reported that a higher barrel temperature and a higher powder feed rate resulted in larger granules (3). 

Researchers at Pfizer and the University of Cincinnati recently reported on work regarding optimization for a continuous extrusion wet-granulation process (4). Three granulating binders in high drug-load acetaminophen blends were evaluated using high-shear granulation and extrusion granulation. The researchers reported that a polymethacrylate binder enhanced tablet tensile strength with rapid disintegration in simulated gastric fluid, and polyvinylpyrrolidone and hydroxypropyl cellulose binders produced less desirable tablets. Using the polymethacrylate binder, the extrusion granulation process was evaluated with respect to the effects of granulating liquid, injection rate, and screw speed on granule properties. Response variables considered in the study included extruder power consumption (screw loading), granule bulk/tapped density, particle-size distribution, tablet hardness, friability, disintegration time, and dissolution (4). 

Continuous manufacturing also is being advanced by industrial, public, and academic partnerships. For example, in October 2011, FDA awarded a $35-million, five-year grant to the National Institute for Pharmaceutical Technology and Education (NIPTE), a nonprofit research center focused on pharmaceutical product development and manufacturing, to improve drug manufacturing standards. NIPTE's goal is to increase science and engineering-based understanding, so technologies can be developed and science-based regulations can be implemented. The FDA grant will in part by used to promote continuous manufacturing as well as other issues, such as improving small-batch production, reducing the environmental impact of manufacturing pharmaceutical products, and rectifying other drug-development and manufacturing problems.  

NIPTE is partnered with 10 US universities involved in the pharmaceutical sciences and engineering. The member universities are Duquesne University, the Illinois Institute of Technology, Purdue University, Rutgers University, the University of Puerto Rico, the University of Connecticut, the University of Iowa, the University of Kentucky, the University of Maryland–Baltimore, and the University of Minnesota. 

In April 2011, the United Kingdom's Engineering and Physical Sciences Research Council (EPSRC) established the EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization. EPSRC is the main UK government agency for funding research and training in engineering and the physical sciences. The University of Strathclyde is leading the EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization, which also involves the Universities of Bath, Cambridge, Edinburgh, Glasgow, Heriot-Watt, and Loughborough. Industry partners include GlaxoSmithKline, Pfizer, AstraZeneca, Fujifilm, Croda, Genzyme (now part of Sanofi), NiTech Solutions, Phoenix Chemicals, Solid Form Solutions, and British Salt. 

The EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization has identified several key research challenges:   

Achieving precise control over manufacturing of solid particles using continuous-manufacturing technologies 

Understanding the control of nucleation and growth of particles by means of crystallization under continuous flow

Developing continuous crystallization platforms, process analysis tools, and strategies to manufacture particles for different applications

Delivering the tools to control crystal structure, particle shape, and particle-size distribution

Facilitating continuous manufacture of medicines and nanomaterials with kinetic, cocrystallization, and impurity control (5).

In 2007, Novartis formed a $65-million, 10-year research collaboration with the Massachusetts Institute of Technology (MIT) to launch and fund the Novartis–MIT Center for Continuous Manufacturing to develop new technologies to replace the pharmaceutical industry's conventional batch-based system with continuous manufacturing processes. 

The Engineering Research Center For Structure Organic Particulate Systems, a multi-university consortium consisting of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayagüez, is another academic-partnership involved in continuous processing. The center, which is funded by National Science Foundation and industrial partners, includes 35 pharmaceutical manufacturers and equipment producers involved in R&D for continuous processing (2). 

Researchers at Rutgers University recently reported on an enhanced model-based control of a continuous direct-compression pharmaceutical process. The control-loop performance was assessed 

 and results obtained will be incorporated into the pilot-plant facility of the continuous direct-compaction process at the National Science Foundation's Engineering Research Center at Rutgers University. The models used in the study were obtained by means of a system identification from a combination of first principles-based dynamic models, experimental data, and/or literature data. The purpose of the study was to formulate an effective control strategy at the basic/regulatory level for the integrated continuous operation of the direct-compaction process and to maintain the process at the desired set-points, taking into account the multivariable process interactions and disturbances (6). 

 3. M. Fonteyne et al., "Real-time Assessment of Critical Quality Attributes of a Continuous Granulation Process," 

., online, DOI 10.3109/10837450.2011.627869, Oct. 24. 2011.  

 5. EPSRC, "EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization," 

www.epsrc.ac.uk/funding/centres/innovativemanufacturing/Pages/imrccontinuousmanufacturing.aspx

The article examines some recent developments for this process step and for continuous manufacturing overall.

Advancing Unit Operations for Continuous Processing in Solid-Dosage Manufacturing

The forthcoming American National Standard for GMP for pharmaceutical excipients, NSF 363, utilizes quality risk-management principles to ensure that the implementation of this standard provides appropriate controls in manufacturing to produce excipients that are safe, of appropriate quality, and of consistent composition (1). (See "The American National Standard for Excipient GMP" in this issue for background details). The need to apply risk-management principles to excipient manufacture and use was born out of the challenge of defining a clear and auditable standard that can be applied across the vast diversity of excipient manufacturing processes, their raw-material sources, their chemical and physical properties, and their many end users in different types of drug products. Attempts to define requirements in such areas as personnel hygiene, infrastructure, or work environment, inevitably lead to clauses that may be appropriate for one excipient but not for others (e.g., indoor operations versus outdoor multiacre facilities, multiuse facilities versus dedicated production lines).  

The Joint International Pharmaceutical Excipient Council and Pharmaceutical Quality Group (IPEC–PQG) GMP Guide for Pharmaceutical Excipients was used to develop NSF 363 (2). The standard addresses the aforementioned industry differences by discussing various points for consideration during excipient manufacture as well as calling for a risk assessment. The American National Standard Institute (ANSI) is expected to review and approve NSF 363 this year. This article provides guidance for industry on how to comply with NSF 363 upon its pending approval, with a focus on risk assessment as part of excipient GMP. 

Table I: NSF 363 sections requiring a risk assessment (Ref 1).			

NSF 363 requires risk assessments to support decisions and implement controls (see Tables I–IV). For example, Section 4.2.1 on Documentation requires incorporating quality risk-management principles into changes to the quality-management system (1). The International Conference on Harmonization (ICH) Q9 

guideline, a reference document for NSF 363, gives two primary principles: "The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient" and "the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk" (3). 

Table II: NSF 363 sections requiring justification (Ref. 1).			

These principles can help to frame a company's thought process when conducting and documenting risk assessment by focusing the activity on the overall goal of protecting the patient. The principles direct the industry to use science when determining the significance "of the probability of occurrence of harm and the severity of that harm" (1). It is also pointed out that not all risks are equal, and therefore, each documented risk assessment may or may not provide the same level of detail or supporting data. 

Table III: NSF 363 sections requiring decisions based on risk assessment (Ref. 1).			

NSF 363 adopts the same definition for risk assessment as found in ICH Q9, namely: "a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards" (3). In Q9, a hazard is a potential source of harm and harm is "damage to health, including the damage that can occur from loss of product quality or availability" (3). This definition highlights the difference between risk assessment for excipients and hazard analysis for food ingredients. In Hazard Analysis and Critical Control Points (HACCP) plans used throughout the food industry, the focus lies on preventing microbiological, chemical, or physical contamination that is reasonably likely to cause illness or injury. No consideration is given to consistency of composition or functionality of the ingredient. Excipient manufacturers must assess the impact of a change to excipient composition on its functionality and performance in the drug product, but only the user of the excipient can adequately make this assessment. The excipient manufacturer understands the range of variability, in chemical composition and physical properties, of its product and may communicate this to the user during qualification. The excipient manufacturer is expected to use risk assessment to prevent deviations in the stated range of variability. For this reason, the excipient manufacturer's documentation of its product's composition and variability provides crucial information for conducting an adequate risk assessment. This information is also a requirement of NSF 363 Section 8.2.4.6 on Excipient Composition (1). 

Table IV: NSF 363 sections requiring risk controls as a result of risk assessment (Ref. 1).			

Risk assessment consists of risk identification, risk analysis, and risk evaluation with the output forming the basis for determining appropriate risk control. The sections of NSF 363 requiring risk assessment preload the process by defining the scope or risk question, providing the nature of hazards to be considered, and pointing to risk controls that should be implemented. The documentation necessary to demonstrate conformance to the standard should facilitate assessment of the results in terms of the risks to be controlled, the reasoning and facts leading to the conclusions, understanding the risks that were considered, and provides evidence that competent people equipped with adequate information followed a process that ensured a complete assessment. The actual process for conducting a risk assessment may vary depending on the scope of the exercise but the documentation, except where risk are either obvious or cannot possibly exist, should include (4):  					

Team members and their supporting qualifications (e.g., technical expertise and/or training in conducting risk assessment)

Description, diagram, or flow chart of what was included

Supporting references and information relating to the assessment, including policies and procedures

Data, assumptions, and their sources and validation

Limitations, assumptions, and justification of hypotheses

Critical assumptions and other factors which need to be monitored

Conclusions and recommendations or reference to resulting controls.

As with all records, this documentation should be maintained and be available for audit as well as for use in periodic review of the assessment to ensure its continuing validity and suitability in the presence of new information. Including a summary and reference to the risk assessment reports in the quality manual helps describe the quality management system and aids in understanding the basis for controls included as part of the GMPs. To prevent the loss of a company's knowledge base, training and familiarization with the content of the risk-assessment documents should be included as part of succession planning, personnel development or job descriptions for key positions where appropriate. 

Conducting and documenting a risk assessment of the manufacturing process as directed in the NSF 363 Section 6 6.2.3 on Hygienic Practices, 6.3.1 on Buildings and Facilities, 6.3.3 on Utilities, and 6.4 on Work Environment can be combined into a common exercise and risk-assessment report. The report may begin with a summary of the risk-assessment results and supporting arguments. The common supporting documentation would be included in the body or an appendix. Supporting documentation includes items such as a description of the product with background information such as: 									

Susceptibility for growth of microorganism and other characteristics 

Description of the process and a flow diagram showing all unit operations, inputs, and recycle streams 

List of team members participating in the risk assessment with a description of their qualifications to perform such a task. 

A clear statement supporting the excipients unique chemical and physical characteristics and any unique processing conditions or equipment will help justify the exclusion or inclusion of potential hazards. For example, a low pH can be used to justify the absence for specific controls to prevent microbiological contamination.  

Documentation should demonstrate that the risk assessments required in NSF 363 Section 6 were performed for all unit operations. A matrix table can be included documenting the process flow, unit operations, and production and storage areas in rows with columns listing potential hazards and the justification for suitable controls (or controls being unnecessary) to protect against such risks as: contamination from personnel and/or their activities; contamination or mix-ups due to deficiencies in buildings or facilities; deterioration of excipient quality from contact with utilities; and contamination from exposure to the work environment. Reference to the supporting documentation (including a statement of how the process flow was verified for accuracy and inclusion of all operations) should accompany the table. 

The risk-assessment process for determining significant change as a part of change control is discussed in the IPEC–Americas Significant Change Guide (5). A key point from this guide is that, "Any change by the manufacturer of an excipient that [may] alter an excipient physical or chemical property outside the limits of normal variability, or that is likely to alter the excipient performance in the dosage form is considered significant." The level of significance depends on the type of change and is evaluated according to seven criteria: 

1. Will there be a change in the chemical properties of the excipient as a result of the change? 

2. Will there be a change in the physical properties of the excipient as a result of the change? 

3. Will there be a change in the impurity (composition) profile for the excipient as a result of the change? 

4. Will there be a change in the functionality of the excipient as a result of the change? 

5. Where applicable, will the moisture level changed? 

6. Where applicable, will the bioburden changed? 

7. Will there be a change in the origin of any raw materials or contact packaging? 

These criteria can be used in a change-control program and should be referenced in the documentation to comply with NSF 363 Section 4.3 on Change Control.  

The requirements to perform documented risk assessments in support of GMP controls are not entirely new. Section 8.3.2 of the IPEC–PQG GMP guide states (2): "An activity that is not a normal part of the manufacturing process (reworking) should only be conducted following a documented review of risk to excipient quality and approval by the quality unit. As appropriate, when performing the risk assessment, consideration should be given to....." 

The procedures and controls associated with the IPEC–PQG GMPs have always been the output of risk- assessment exercises. NSF 363 takes this concept further to justify the thought process used to support and document controls are. Such documentation facilitates better understanding of GMP controls across excipient manufacture. 

 is chair of the International Pharmaceutical Excipient Council of the Americas (IPEC–Americas). 

Draft Good Manufacturing Practices (GMP) for Pharmaceutical Excipients 

 Joint IPEC–QG Good Manufacturing Practices Guide for Pharmaceutical Excipients

This article provides guidance for industry on how to comply with the pending American National Standard on excipient GMP, with a focus on risk assessment.

Standardized Excipient GMP

In tablets, the active pharmaceutical ingredient (API) is often only a tiny proportion of the finished product. The steps that precede the tablet press are designed to incorporate the API within a blend that processes efficiently to produce tablets of the required quality. Excipients include fillers, as well as components that play a more active role in processing, such as glidants to improve powder flow and lubricants that reduce ejection force and prevent adherence to the press. 

These raw ingredients may be screened, granulated, dried, milled, classified and blended, often in a number of steps, to produce feed for the tablet press. Batch processing, in which a defined amount of material is processed and then tested to confirm its suitability for the next step, is common.  

Each ingredient and unit operation is a potential source of variability arising from any number of factors including:  

Human intervention (especially if the plant is manually controlled)

Sampling and analytical test method variability

Process equipment capabilities and calibration limits (1).

Materials are tested after each processing step with the aim of quantifying variability, which raises the question of how to characterize "in-process" materials to ensure success. Because the tablet press is at the end of the line, any sources of variability along the way will tend to act cumulatively at the tablet press. 

Effective management of variability relies first on being able to detect a problem. This means that a specification used to define acceptability—in a feed or after a processing step— must reliably identify a material that will fail to process as required in a subsequent step or that will go on to produce a substandard product. Such specifications must be based on properties that closely correlate with the aspects of performance that are critical to success. This approach relies on identifying and measuring powder properties that have a defining influence on the efficiency of the operation and the quality of the final product. 

Powder behavior is influenced by an array of different variables, including primary parameters such as particle size and shape, as well as system factors such as extent of consolidation and aeration. This complexity makes it difficult to predict behavior. To develop a secure basis for process optimization, it is necessary to select powder property characterization techniques that simulate the process environment, because it is difficult to reliably infer performance from test data acquired under conditions that are not representative of those applied during processing. 

Manufacturing tablets from a blend tends to be a single integrated process. However, closer analysis reveals four distinct stages, particularly in terms of the conditions applied to the powder. These are:  

Tablet manufacture begins with discharge of the blend from the hopper, ideally at a consistent, controlled flow rate. Material flows under gravity, at relatively low flow rates, into the feed frame. In the hopper itself, moderate stress is imposed by the weight of the stored powder. The resulting consolidation may inhibit flow, either because of interactions between the vessel and powder or as the result of powder-powder interactions. Shear strength and wall friction are therefore highly relevant powder properties. 

The hopper discharge is routed to the feed frame via enclosed pipe work that provides containment. The ease with which the blend flows under gravity is important here, but so too is the permeability of the powder (2). A blend with low permeability that resists the backflow of air necessary for smooth flow will tend to pulse or 'slug' into the feed frame (see Figure 1). This can result in erratic pressure that varies at a relatively high frequency. The tablet press weight control system cannot adequately compensate, which results in variable tablet weight. In contrast, more permeable blends tend to exhibit more consistent flow, ultimately delivering a more uniform density to the feed frame and a more consistent final product. 

 Figure 1: More permeable  powders tend to flow consistently from a hopper, while those that are less permeable can give rise to a low rate, ’pulsing’ flow that is detrimental to process efficiency and product quality. 

From the feed frame, powder is swept into the dies to ensure a complete fill. Here the blend is moderately to loosely packed, but sheared at relatively high speeds as the paddles of the frame rotate. Agglomeration and attrition are both potential problems, exacerbated by the need to recycle powder around this part of the process. Both can lead to segregation of the blend, giving rise to non-uniformity in the finished tablet. Attrition additionally gives rise to dusting, creating fines that can compromise processing efficiency and the properties of the finished tablet. 

In the feed frame, the powder flows under gravity but, depending on the design of the paddles, there may also be a significant element of "forced flow." Angling the sweeping paddles can help to force the powder down into the dies to improve filling efficiency. While optimizing the flow regime in the feed frame improves consistency and the rate of die filling, doing so relies on understanding how the powder flows under different conditions and, in particular, the material's response to forcing conditions. 

In addition, the response of the powder to air is critical for consistent die filling. A permeable blend that quickly releases entrained air will settle rapidly and efficiently fill the die. Simultaneously, air can provide lubrication and promote flow in the feed frame. Therefore, a material that releases air too easily may not flow consistently. Understanding exactly how the powder responds to air can be critical in optimizing die filling. 

During the final compression step, the powder plug is subject to high stress. Here, the compressibility of the powder is relevant because it quantifies how the movement of the punches will impact the powder. In addition, adhesivity indicates how likely it is that material will stick to the tablet press tooling.  

Choosing the best powder characterization techniques

Successful processing requires a powder that is compatible with all stages of the process. Because it is important to understand how the powder will behave under many different conditions, applying a single powder testing technique may not give adequate information. Historically, the pharmaceutical industry has relied on parameters such as Hausner Ratio and Carr's Index, which are both derived from tapped density techniques. More recently, the industry has begun to use shear testing.  

These approaches do have some relevance when trying to access information to support optimization of the press.  Shear testing, for example, was developed, and remains widely used, for the design and troubleshooting of hoppers. This test provides valuable shear strength data that is relevant to design and operation of the feed hopper and to the compression stage, in which applied stresses are even higher. However, shear testing may not be the best technique for generating data to support other parts of the tablet manufacturing process, in which applied stresses are far lower. 

For example, the shear data presented in Figure 2a for vanillin and ethylvanillin classifies them as closely similar. However, as shown in Figure 2b, the dynamic flow energy measurements tell a different story, suggesting that the materials can behave differently in certain circumstances. Flow energies are generated by measuring the axial and rotational forces acting on a paddle as it rotates through a powder sample (3). Downward rotation of the paddle imposes a forcing, bulldozing action while an upward traverse measures a flow energy more closely associated with gravity induced flow. The data suggests that while these two materials may behave similarly in the hopper, and in terms of how they cohere in the finished tablet, they will behave very differently in the feed frame. The ease with which the materials flow into the feed frame, and subsequently into the die, as well as their response to a range of blade designs, are all likely to be different. 

Figure 2: Shear data classifies these two excipients as closely similar while flow energy measurements show that in certain circumstances they can behave quite differently. 

Similarly, tapped density measurements can differ from flow energy measurements. Although tapped density measurements do detect changes that indicate differences in powder properties, they are far less sensitive than dynamic techniques in specifically measuring flow properties (see Figure 3).  Variability in a material, which could go on to impact flow behaviour in the tablet press, might be undetected by tapped density measurements.  

Figure 3: For this system, tapped density data are less sensitive than flow energy measurements in detecting changes in powder flowability. 

Looking across the tablet-making process in its entirety highlights the properties that could be measured to optimize performance at each step. These include:  

—for the design, operation, and troubleshooting of hoppers 

Bulk properties such as permeability and compressibility

—to assess the response of the powder to air, the ease with which displaced air will be dispersed, and how the blend will be impacted by compression

Dynamic properties that directly quantify flowability under different conditions

—for optimizing flow through the feed frame, assessing the impact of different paddle designs, investigating the effect of air on powder flowability, and quantifying de-aeration behaviour.

Dynamic testing can also be used to assess powder stability and is therefore a useful tool for investigating the likelihood of attrition, segregation, and/or agglomeration. 

Together these measurements form a database of properties that can be used to tightly define an optimal blend specification. Furthermore, such data would support investigation into which parameters in upstream processes ultimately dictate performance in the press and the quality of the final product. Such strategies are highly beneficial in pushing towards more efficient manufacture on the basis of secure knowledge. 

Within the pharmaceutical industry there is increasing emphasis on processing efficiency and more effectively controlled manufacture. In production, it is impossible to eliminate all the possible sources of variability, but it is feasible to compensate for them and control their impact. This relies on identifying, measuring, and controlling those parameters that define processing efficiency and the quality of the finished product.  

In solid-dosage manufacture, achieving this goal requires a relevant and sensitive powder testing toolkit capable of reliably generating parameters that can be directly correlated with process performance. Key to this is the ability of a technique to effectively simulate the specific processing environment, which, as an analysis of tableting reveals, can vary considerably. Instruments that combine established techniques, such as shear and bulk property testing, with newer methodologies, such as dynamic testing, can be valuable. The user can then tailor testing to the specific application, and access the most complete information for process design, optimization, and control.  

is operations manager at Freeman Technology, 1 Miller Court, Severn Drive, Tewkesbury, Gloucestershire, GL20 8DN, United Kingdom, tel. +44(0)1684.851.551, fax. +44(0)1684.851.552, 

*To whom all correspondence should be addressed. 

 1. M. Glodek et al., "Process Robustness: PQRI White Paper," online,  

  2.  G. Carlson and B. Hancock, AAPS Annual Meeting and Exposition (Atlanta, GA, 2008). 

This article considers the different conditions to which the powder is subjected in the tableting process, and discusses which powder properties should be measured to accurately reflect likely powder behavior in the process.

Powder Testing Techniques for Tablet Manufacture

The solubility of an API plays a crucial role in drug disposition because the main pathway for drug absorption is a function of permeability and solubility. Poor aqueous solubility is caused by two main factors: high hydrophobicity and highly crystalline structures. The aqueous solubility of a compound plays a role in its success or failure as a drug candidate. Better solubility results in better absorption in the gastrointestinal tract, reduced dosage-level requirements, and better bioavailability. In the development phase, poor solubility can lead to inadequate exposure in efficacy and toxicity studies. Higher dosages required to compensate for poor solubility can lead to side effects, food effects, and intersubject variability. It may drive up overall costs for drug development and production and lead to poor patient compliance because of the higher doses required to achieve a therapeutic effect (1). As pharmaceutical companies attempt to resolve these issues, contract-service providers and excipient suppliers are seeking to meet these challenges through targeted offerings. 

Both physical and chemical methods can be used to improve drug solubility, Chemical methods to improve solubility include developing more soluble prodrugs or improving solubility through salt formation. Physical methods include micronization or nanosizing, producing a polymorph, changing the crystal habit, complexation, solubilization through self-microemulsifying drug-delivery systems, and solid dispersions (1). 

 define related compositions in which at least one active ingredient is dispersed in an inert matrix. In solid dispersions, separate regions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solutions, refers to the case in which drug–polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutical polymers are used to create this matrix. Polymer selection is based on many factors, including physicochemical (e.g., drug–polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints (1, 2). 

Solid dispersions may be made through mechanical activation (i.e., cogrinding), coprecipitation, freeze drying, spray drying, melt extrusion, and KinetiSol technology (DisperSol Technologies), a fusion-processing technology. The solid-dispersion components consist of the API, the polymer, plasticizers, stabilizers, and other agents. Various polymers may be used in solid dispersions. These include methylacrylate polymers, polyvinyl acetate, polyvinylpyrrolidone, copovidone, poly-(ethylene-vinylacetate-vinylcaprolatam), and cellulose derivatives (e.g., hypromellose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and methyl cellulose) (1). 

Hot-melt extrusion is used to disperse APIs in a matrix at the molecular level to form solid solutions and is used as a method to improve solubility of poorly water-soluble drugs (3). Evonik has developed a system, Melt Extrusion Modeling and Formulation Information System (MEMFIS), as a predictive modeling tool in developing hot-melt extrusion formulations. MEMFIS helps in selecting initial formulations with no API consumption, using mathematical models and algorithms based on solubility parameter theories (i.e., hydrogen bonding and polar and dispersive forces). MEMFIS uses chemical structures, solubility parameters, physicochemical properties, and a myriad of processing conditions to suggest initial formulation components and process settings for a hot-melt extrusion formulation (1). 

In terms of miscibility estimation, for example, MEMFIS evaluates which excipients have higher potential to form a solid solution by assessing the drug miscibility of a given excipient in comparison to other excipients. The qualitative method, (i.e., which excludes hydrogen-bonding capability in the evaluation) considers the drug miscibility with an excipient in comparison to other excipients to make the determination of whether one excipient is more or less miscible. Only dispersive interactions are considered. Qualitative-only methods may lead to the exclusion of valuable excipients from the screening studies that could potentially form strong hydrogen bonds with the APIs (1). 

In the quantitative evaluation in the MEMFIS, which is a deeper analysis, in addition to polar and dispersive interactions, the specific possible hydrogen-bonding interactions are investigated at a molecular level to derive a quantitative expectation in terms of drug–excipient miscibility in a binary system. In this quantitative assessment, additional specific hydrogen-bonding capability is considered. This involves considering polymers from a monomer perspective (i.e., meaning the composition of the polymer) and specifying the type of hydrogen bonding that could be involved and its impact on the solubility parameters. Solubility-parameter estimation and molecular-interaction considerations are important tools in estimating first formulations in solid-dispersion product. High-throughput screening is accomplished based upon molecular structure, intra- and inter-molecular bonding, and their impact on solubility parameters (1). In addition to MEMFIS, Evonik is positioned in solid-dispersions through its methylacrylate polymers (Eudragit). Several late-stage products have been developed with these excipients in solid-solution formulations. Evonik has both hot-melt extrusion and spray-drying capabilities. 

Other companies are advancing their hot-melt extrusion capabilities. In October 2011, Ashland Specialty Ingredients, which acquired International Specialty Products (ISP) in 2011, announced it was adding a GMP hot-melt extruder at its Columbia, Maryland, R&D center to better serve pharmaceutical companies working with poorly soluble drug compounds. The 180-mm Leistritz extruder allows companies that seek to commercialize drugs, which are made more soluble with dispersions from Ashland, to scale up to GMP clinical and commercial quantities produced by hot-melt extrusion. Ashland planned to finish installing and testing the equipment in the fourth quarter of 2011 and to begin a full-service offering early in 2012. The company has an existing extruder at its Wilmington, Delaware Research Center. With the addition of the extruder, Ashland is able to conduct kinetic-solubility and polymer-screening tests using both spray drying and hot-melt extrusion techniques to determine the best solubility solution in clinical trials. In October 2009, ISP launched a drug-solubility initiative that focused on solubilization technologies that involved excipients, formulation, and related processing services, which included solid-dispersion technology, both hot-melt extrusion and spray drying. In 2009, ISP partnered with the equipment manufacturer Coperion for advancing hot-melt extrusion technology. 

Thin-film technology advances as a specialized oral dosage form			

In February 2012, the CDMO Bend Research formed a licensing agreement with Eli Lilly under which Lilly gains access to Bend's proprietary spray-dried dispersion technology, which is designed to improve the bioavailability of compounds with low aqueous solubility. In addition, as part of an already existing agreement with Lilly, Bend Research will continue to provide formulation, development, analytical, engineering, and manufacturing services to Lilly to support its preclinical and clinical development programs. In August 2011. Bend Research also formed a collaboration with the CDMO Xcelience for oral solid-solubilization formulation solutions and clinical-supply manufacture. 

In July 2011, the CDMO Pharmaceutics International (Pii) added hot-melt extrusion to its formulation and process-development solutions capabilites. The company purchased a 16-mm and an 18-mm Leistritz twin-screw extruders. This investment enables Pii to carry out feasibility studies to pilot-scale cGMP productionfor Phase I and II clinical-trial materials using hot-melt extrusion. 

Emerging technologies: oral peptide delivery			

In 2009, BASF launched its polymeric solubilizer, Soluplus, which is used in hot-melt extrusion applications. In 2010, the company partnered with GEA Niro to allow BASF to make cGMP spray-drying tests and pilot productions of APIs at GEA's test station in Copenhagen. Dow Wolf Cellulosics offers several expicients for hot-melt extrusion applications, including poly (ethylene) oxide resins (e.g., Polyox) and cellulosic derivatives [e.g., Ethocel (ethylcellulose ethers)] and Methocel (cellulose ethers).  

In April 2011, the CDMO Pharmatek Laboratories added spray drying to its drug formulation and manufacturing capabilities. The company purchased a Buchi B-290 Mini Spray Dryer for formulation feasibility studies and small-scale clinical manufacture.  

Researchers at Purdue University recently reported on an  extrusion-based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin, and spironolactone) was improved through solid crystal suspensions. The drug and mannitol were coprocessed in a hot-melt extrusion operation. The resulting product was a mixture of the crystalline drug and

crystalline excipient, with up to 50% (w/w) drug load. The 

 drug release from the obtained solid crystalline suspensions was more than two orders of magnitude faster than that of the pure drug. The researchers reported that because the resulting product was crystalline, the accelerated dissolution rate did have the physical stability concerns as with amorphous formulations. The researchers reported this approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug (4).  

Pharmaceutical companies, equipment providers, contract-service providers, and excipient manufacturers apply various approaches for improving solubility. The article examines some recent developments.

Meeting Solubility Challenges

Taste-masking of solid dosage and liquid drugs is a challenge for pharmaceutical manufacturers. Most APIs are unpleasant or harsh tasting leading to patient noncompliance. This challenge affects all age groups, but is specifically problematic for pediatric patients. The global market for pediatric drugs and vaccines is forecast to reach $85 billion by year 2017, according to data from Global Industry Analysts. The US is the largest market for pediatric drugs followed by Western Europe. Implementing taste-masking programs into the drug-manufacturing process is crucial to avoid losses due to noncompliance. Pharmaceutical manufacturers are faced with challenges in life-cycle management, cost control, global regulations, and patent protection.  

 examined formulation-development strategies in product life-cycle management, including specialized formulations such as pediatric formulations, and the specific technical issues that may evolve in excipient selection and functionality, including taste-masking and moisture protection, to develop an orally palatable product.  

Participating in the webcast were: Avinash Thombre, PhD, research fellow, pharmaceutical sciences with Pfizer Global Research and Development, who discussed life-cycle management and new dosage form options; Karen C. Thompson, PhD, distinguished senior investigator, pharmaceutical sciences at Merck & Co., who discussed insight into pediatric formulations and related dosage forms; and Nigel Langley, PhD, MBA, head of North American technical sales, Pharma Ingredients & Services, BASF, who discussed novel taste-masking excipient solutions. The webcast may be found at 

Taste-masking in Formulation Development.

In 2011, BASF launched Kollicoat Smartseal 30 D, an aqueous  disperson of a film-forming polymer with taste-masking and moisture-barrier applications. The excipient is highly impermeable to water vapor, which helps preserve the potency of sensitive active ingredients, according to the company.  The polymer is stable in saliva and specifically soluble in gastric juice. These properties allow for effective protection from unpleasant taste in the patient's mouth and rapid release and onset of active ingredient action in the stomach. 

In October 2011, BASF and Colorcon announced a collaboration for the development of future film-coating systems using BASF's Kollicoat Smartseal 30 D and a new Colorcon preformulated additive. Colorcon developed the preformulated additive system for use with Kollicoat Smartseal 30 D to enable efficient preparation and application of this polymer in taste-masking applications. The preformulated additive lowers the number of materials to be dispensed by 50% and reduces the preparation time by almost 40%, according to an Oct. 21, 2011, BASF press release.  

"We have chosen Kollicoat Smartseal 30 D because it is the best-in-class reverse enteric polymer for taste masking", said Kamlesh Oza, general manager, film coating at Colorcon, in the BASF press release. "Kollicoat Smartseal 30 D is the first water-based dispersion having both taste-masking and moisture-barrier properties. It was developed to simplify and accelerate aqueous film coating operations and opens new doors for formulating tablet, pellet, and particle coatings. Our collaboration to develop the additive will bring batch-to-batch color consistency, performance, speed, and simplicity, enabling easy reconstituting of the film former in pharmaceutical coating operations while maintaining functionality," he said.  

Kollicoat Smartseal 30 D is part of BASF's existing tablet coatings portfolio. Under the Kollicoat brand, BASF markets a range of coating polymers and copolymers that are used to coat tablets, capsules, and pellets and to control the release of drugs from solid-dosage forms. The Kollicoat family includes: Kollicoat IR and Kollicoat Protect instant-release coatings, Kollicoat IR Color Coating Systems, Kollicoat MAE enteric coatings, Kollicoat SR 30 D sustained-release coatings, and the new Kollicoat Smartseal 30 D protective coatings. 

Taste-masking is an important consideration to ensure patient compliance.

Advances in Taste-masking

Solid dosage forms are the most popular method of drug delivery and although tablets are widely established throughout the pharmaceutical industry, this doesn't mean it is an unmoving area. According to a recent 

poll, manufacturers are seeking to reformulate or reinvent their currently marketed solid-dose products to both renew patents and improve efficacy (see Figure 1). 

One possible way to achieve these goals is to reformulate tablets into more exotic forms such as multilayer tablets, fixed-dose combinations, and other innovative dosages.   

 brought together experts in solid dosage for a special roundtable on the formulation and manufacture of multilayer tablets. We also spoke to researchers about fixed-dose combinations, an area that has raised controversy, regarding adverse effects. Participants in the roundtable include: Marcus Behrens, sales director at IMA Kilian; James Calvin, Elizabeth Companies; Doug Kirsch, Technical Service Manager at Natoli Engineering Company; and LakshmiDevi Ethirajan, Manager, Formulation Development at Tedor Pharma. 

Figure 1: Demand for reformulation (PharmTech poll).

How has demand for multilayer tablets altered in recent years? What factors have influenced this trend?  

Fixed-dose combination drugs are becoming increasingly popular, particularly as life-cycle management strategies seek to extend intellectual property and minimize generic exposure by creating an innovative dosage form. The multilayer tablet is a viable way to combine different actives for a synergic therapeutic effect, or different formulations of the same active in order to achieve a specific release profile. Furthermore, multilayer tablets can help avoid interactions between different drugs and optimize each formulation in terms of pharmacokinetics and manufacturability. 

From left to right: Marcus Behrens (IMA Kilian), James Calvin (Elizabeth Companies), Doug Kirsch (Natoli); LakshmiDevi Ethirajan (Tedor Pharma) is not shown.  

 The growth of high-potency and combination drug products over the last decade has made multilayer and tablet in tablet (core tablet) hot topics in the pharma industry. These novel delivery systems have been essential not only in formulating new products, but also in helping pharmaceutical companies to extend patents.  

Among other advantages, triple-combination therapy in a single-dosage form is being used to promote better treatment adherence by providing a convenient single tablet. As well as increasing patient compliance, multilayer tablets can help to reduce the cost of medication.  

Considering the split drivers of compliance and patent extension, do you think multilayer tablets will continue to be successful in the future?  

 If we think of fixed-dose combination drugs as a way to treat two closely related diseases, or to improve compliance and thus efficacy of prescribed medicines, we believe that this trend will continue. However, multilayer tablets could be a less frequent option if, in the future, the drugs are designed to be mixed into a unique powder that can be processed in a standard tablet press. 

Experts in solid dosage discuss the formulation and manufacture of multilayer tablets.

Pharmaceutical Technology-03-01-2012