Committee E55 – an update

Since its creation in December 2003, ASTM International Committee E55 on Manufacture of Pharmaceutical Products has grown in size as well as global relevance. Recent liaison relationships have been established with the ISPE and the European Compliance Academy (ECA) regarding their internal distribution of E55 draft standards for the purpose of gathering member feedback and, in September 2006, several E55 officers addressed the European Medicines Agency (EMEA) with the goal of creating a similar relationship.

The committee’s membership has steadily increased (it now stands at 297 individuals and organisations), as has its work program (16 registered work items). Also, the conditions surrounding the understanding of Process Analytical Technology (PAT) as a tool relevant to the manufacture of pharmaceutical products have continued to evolve. This evolution has caused Committee E55 to closely examine itself, to ensure that it is still positioned to effectively serve the industry it represents. This article provides an introduction detailing the need for standards, a discussion of ASTM International and its relevance as a global standards developer and an overview of the evolution of Committee E55.

Standards impact bottom line

Far from a purely academic exercise, standards are essential for the evolution of any industry and contribute directly to the bottom line. Conversely, the lack of standards can cost industry revenue, as well as hinder future growth into new and potentially lucrative markets. Adoption of business critical standards enables an industry to meet its challenges head-on and enjoy the benefits of efficiency, cost savings and the capability to leverage assets and create new products.

About ASTM International

ASTM, a not-for-profit corporation established in 1898, is a management system for the development of standards and related technical information for materials, products, systems and services. It provides a legal, administrative and publications forum where producers, users, ultimate consumers and representatives of government and academia can meet on a common ground to develop industry standards.

ASTM’s technical committee structure is made up of main committees, subcommittees and task groups. The task groups initiate draft standards, followed by review from sub and main committee membership in conformance with the consensus procedures described in the Regulations Governing ASTM Technical Committees. The ASTM procedures are based on due process, openness and transparency; principles in place to ensure that the standards produced are technically sound and rest on a solid legal foundation, with appropriate concern for issues such as restraint of trade and volunteer liability. The multi-tiered balloting process is web-based and ensures that feedback is gathered efficiently.

In this process, any interested party has both the ability to participate on an ASTM committee and the opportunity for an equal seat at the standards development table. Relative to Committee E55, this means that the regulator, the regulated, the academic community and all other relevant stakeholders hold the same degree of access to the standards development process.

ASTM committees and standards are dynamic structures capable of modification to mirror the evolution of their respective industries. This is how ASTM standards remain relevant. This development system employs a multiple-path approach driving the course of standards development through the marketplace, rather than a standards developing organisation or political entity.

Evolution of Committee: title, scope, structure

The E55 Executive Subcommittee (comprised of a combination of elected and appointed officers and charged with the overall leadership of the main committee) has continued to review and evaluate E55’s direction and objectives during the past year. 2005 saw the definition of the E55 building blocks (see E55 homepage), the addition of subcommittee E55.03 on General Pharmaceutical Standards and the approval of a series of work items under its jurisdiction.

Since the addition of Subcommittee E55.03, the original title and scope of the E55 main committee was reviewed; it was determined that E55 should update the original language in view of the current understanding of the PAT Guidance. As the understanding of the intent of the Guidance document increases, it is clear that the term PAT has a much wider intent than the straightforward application of measurement systems to existing process technology. The Guidance requires a much higher level of understanding of manufacturing science; consequently, the Committee title and scope must give E55 the flexibility to address issues in this area. It was also clear that there is a need to continue to strengthen the communication in this area to allow the complete E55 membership to fully understand the direction of their committee.

Furthermore, as noted by Ms. Helen Winkle (US FDA) in her remarks during the May 2006 E55 workshop in Toronto, PAT is one of an important collection of tools available to ensure that pharmaceuticals are well manufactured and packaged (see E55 homepage for complete remarks). Hence, the E55 Executive Committee proposed to make the scope of the Committee more inclusive of all the tools, instrumentation and sciences that might be used by the industry in the management of their manufacturing processes.

To accomplish this, a ballot was issued on September 16, 2006 that proposed the following update to the original title and scope of E55:Title: Committee E55 on Manufacture of Pharmaceutical Products.

Scope: The scope of the Committee shall be development of standardised nomenclature and definitions of terms, recommended practices, guides, test methods, specifications and performance standards for the manufacture of pharmaceutical products. The Committee will encourage research in this field and sponsor symposia, workshops and publications to facilitate the development of such standards. The Committee will promote liaison with other ASTM committees and other organisations with mutual interests.

This ballot closed on October 24, 2006 and as the percent affirmative for the ballot exceeded the requirement contained in the E55 Bylaws, the charge to the title and scope was approved.

Work items – Subcommittee E55.01

WK5930 New Standard Practice for Risk Management as it Impacts the Design and Development of Processes for Pharmaceutical Manufacture

Initiated on 23 September 2004, this standard describes risk assessment and mitigation as it impacts the design and development of pharmaceutical manufacturing processes. Risk management is a key component in the design and development of pharmaceutical processes. This standard is necessary to provide a focus on risk management, as it relates to process understanding in the pharmaceutical industry.

WK5935 New Standard Practice for Process Understanding Related to Pharmaceutical Manufacture and Control

Initiated on 23 September2004, this standard describes Process Understanding, as it applies to processes for pharmaceutical manufacture and control. Historically, process understanding has been function related within the pharmaceutical industry. This document is necessary to provide a wholistic approach to process understanding, and build on the concepts set forth in the FDA’s PAT guidance.

WK9192 New Standard Guide for the Application of Continuous Processing Technology to the Manufacture of Pharmaceutical Products

Initiated on 4 October 2005, the aim of this standard is to generate a guideline document that identifies the principles of continuous processing for manufacture of pharmaceutical products; shows how continuous processing is both consistent with and supportive of the GMP principles set out in the FDA publications regarding GMPs for the 21st Century and PAT; and reviews current regulatory requirements and identifies specific potential regulatory concerns that may need to be solved by virtue of the following:

• Explanation or amplification of the intent of the current regulatory requirements
• New regulatory principles approach specific to continuous processing
• Recognition of improvements in currently available technology
• Generation of improvements in technology to address current shortfalls

The document will also give guidelines for the traceability of pharmaceutical products made continuously

The production of pharmaceutical drug products has traditionally used batch based processes and techniques which are essentially scaled up versions of the methods used in the laboratory during the development of the product.

Unlike the chemical and food industry, in-process measurement and control has been limited by both the availability of suitable sensors, but also by a significant lack of understanding of the relationship between the process conditions and/or in-process material characteristics and the quality of the final product.

Control of product quality by virtue of process validation is based on repeating processes using conditions that have been previously shown to give a satisfactory result assuming that all other inputs to the process, typically physical properties of input materials, or environmental conditions remain unchanged or do not influence the process.

In general terms, product quality control strategies could be characterised as mixed recipes, with no in-process feedback as opposed to closed loop control strategies used in other industries which maintain output product quality by adjusting key process conditions on the basis of in process measurements.

Recent FDA guidance on PAT and Risk based GMPs has highlighted the need for better understanding of process dynamics and the implementation of measurements and closed loop control strategies which actively control key process parameters in order to maintain product quality.

However, implementation of closed loop control strategies is significantly easier in continuous, time invariant processes (particularly those with low entrained process mass) where the relationship between process disturbances and corrective control actions is much more visible against the background of normal steady state process conditions, rather than having to be decoupled or extracted from the more complex time variant data produced by the natural progression of a batch (non steady state) process.

However, concerns over process stability and on ensuring that any off specification product could be fully isolated (without risk of cross contamination) have previously caused the industry to shy away from continuous processes for production of drug products.

The goal of this guidance document is to identify the potential concerns associated with the transition between batch processing and continuous processing and to assist in the preparation of regulatory submission, which demonstrated that the issues have been addressed in a suitable manner such that the replacement of batch processes with continuous processing actually reduces the risk of off spec., which requires subsequent reprocessing or scrapping.

WK9645 New Standard Guide for Application of Process Capability

Initiated on 30 November 2005, this standard is being developed to facilitate the uniform application of process capability as an objective means for the routine evaluation process performance and driving continuous process improvement. No such document exists.

WK12892 New Standard Practice for Process Sampling

Initiated on 3 October 2006, the scope of this standard is general sampling considerations for PAT, including sampling interface, amount of sample being interrogated, data collection and processing and risk. Scope excludes detailed/technology specific considerations identified as key area for guidance from E55. Sampling is a very important component/consideration for the successful application of PAT.

Work items – Subcommittee E55.02

WK4185 New Test Method for the Measurement of Thermal Effusivity of Raw and Process Materials

Initiated on 12 February 2004, this test method describes a general procedure for rapid, quantitative, non-destructive determination of thermal effusivity of samples using the modified transient hot wire technique.

Effusivity in general can be used to monitor blending, drying, wet granulation and segregation in the tablet press hopper. It has been shown to monitor over lubrication as well. All of these are on and off line applications. ASTM plays a strong educational role and, at this point, we would like consistency in the understanding of the tool in general.

WK4694 New Guide to Assure Fitness-for-Use of a Measurement System to Determine or Control Process or Product Quality Attributes

Initiated 15 April 2004, the practices specified in this guide are intended to assure fitness-for-use of a measurement system, regardless of the specific technology, to determine or control pharmaceutical manufacturing process or product quality attributes. A measurement system consists of an analyser, instrumentation, or sensor, either alone, or networked, including but not limited to those with software or firmware, that generates analytical measurements of pharmaceutical process or product quality attributes. Assurance of measurement system fitness-for-use requires measurements of process or product quality attributes of pharmaceutical manufacturing processes or products specified by the user. The measurement system should not be implemented until its fitness-for-use has been assured.

No such document exists – it is anticipated that the standard will adopted and/or referenced by the US FDA.

WK5015 New Practice for Pharmaceutical Process Design

Initiated 30 May 2004, this standard encompasses the following:

• Define for pharma what ‘pharmaceutical process design’ means in context with PAT for assessing and controlling variability / risk
• Describe the process for ‘pharmaceutical process design’. List and describe aspects, items and activities that should be considered for ‘pharmaceutical process design’ in a PAT context
• Propose an ASTM guidance document for approval of E55 / E55.02. Reference existing documents (not necessarily specific to pharmaceutical application) where appropriate

‘Pharmaceutical Process Design’ encompasses (based on transformations of materials at each step of a process):

• Assessment of process understanding as a function of risk management / mitigation
• Process measurements and controls
• Best practices for pharmaceutical manufacturing

WK5931 New Standard Practice for PAT Data Management

Initiated 22 September 2004, this document will discuss data transfer from instruments, data transfer to and from software applications, and the evaluation of necessary computing requirements.

This document will satisfy the requirement for a structured approach to the management of data generated as a result of a PAT implementation.

PAT applications may generate a large amount of electronic information, execute complicated analyses where performance (timeliness and accuracy) is critical, and have architectures which are simple or complex.

In all such cases, data operations must occur in real time. In order to achieve this in an efficient and effective manner, a high degree of interoperability and transparency is required.

WK9182 New Standard Practice for Qualification of PAT Systems

Initiated 3 October 2005, the scope of this document is to define the necessary and sufficient qualification principles and practices for systems designed for the development and manufacture of pharmaceutical products using PAT principles. This standard provides a framework for undertaking the qualification of systems, covered by the FDA document Guidance for Industry. PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, which are designed for the manufacture of pharmaceutical products.

It establishes the core principles that are used in the qualification of such systems and provides more detail of some of the crucial components of such a process.

The application of Process Analytical Technology, PAT, to the processes used in pharmaceutical manufacturing results in a number of significant changes in one or more of the areas of equipment design, process measurement, instrumentation, process control and process change and development. These changes require a major revision of the methods used to qualify current manufacturing processes. It is the purpose of this document to provide clear guidance on the form and extent of qualification required when operating under the PAT paradigm. It is recognised that the major changes in manufacturing processes will require equally major changes in the methods and mechanisms of qualification.

WK9191 New Standard Practices for Multivariate Analysis Related to Process Analytical Technology

Initiated on 4 October 2005, these practices cover a guide for multivariate analysis (MVA) related to process analytical technology (PAT) in the pharmaceutical industry. These practices are applicable to all stages of model creation and use and post-process data mining from process parameters. These practices provide a procedural outline for the validation and implementation of MVA models, including quantitative and qualitative models. No such standard presently exists.

Work items – Subcommittee E55.03

WK9864 New Standard Guide to a Science and Risk-Based Approach to Qualification of Biopharmaceutical and Pharmaceutical Manufacturing Systems

Initiated on 20 December 2005, this guide provides a science and risk based life cycle approach for the qualification of manufacturing systems that are subject to current Good Manufacturing Practices (cGMP) regulations. This guide covers all activities throughout a project life cycle that contribute to the Qualification of the system. The system life cycle begins with the definition of product user requirements, and includes qualification to demonstrate that the delivered manufacturing system meets product and process specific user requirements and that they have been verified as acceptable by the quality unit. The life cycle is completed upon retirement of the system.

This guide is applicable to manufacturing facilities, process equipment, process control and automation systems, support equipment and utilities. This standard does not purport to address pure information technology systems that directly support the manufacturing operation such as laboratory information systems, material management systems and maintenance management systems. In some cases, there is not a clear delineation between these two types of systems; the user of this standard may selectively use this and other industry guidance documents or standards as appropriate to control the specification, design, delivery and validation of such systems.

This guide does not address process validation (PV) methodologies.

This guide may also be adapted for use with laboratories supporting GMP manufacturing and to facilities subject to Good Laboratory Practice (GLP) and Good Clinical Practice (GCP) regulations.

Process Validation is essentially an international regulatory requirement. The purpose of Process Validation is to provide a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. In order to accomplish this requirement, based on science and risk, manufacturing equipment, facilities, utilities, process control and information systems must undergo qualification activities to assure system elements critical to quality and compliance function as specified and support the process needs. In the early stages of qualification in the pharmaceutical industry, the manufacturers – not knowing how to optimally accomplish the qualification goal – took the approach to leave no stone unturned and chose to validate all project activities including the good engineering practices. Although the results achieved the goal that was desired, it was an unacceptably inefficient process that developed reams of paper, many frustrations and unnecessary investigations. As part of 21st Century Quality Initiatives, the industry and regulators determined it was time to get back to the basics and develop an efficient, streamlined qualification process that focuses on the original intention of the regulations to assure product quality. This ASTM standard proposal provides a robust approach to system qualification that delivers a systematic science and risk based approach to assure the product quality related elements of systems are properly designed, installed and verified so that the associated process will consistently produce a product that meets its specifications and quality attributes.

WK9935 New Standard Guide for the Application of Continuous Quality Verification to Pharmaceutical Manufacturing

Initiated on 5 January 2006, this guide provides a science and risk-based Continuous Quality Verification (CQV) quality assurance approach for pharmaceutical manufacturing processes that may be applied to drug product, active pharmaceutical ingredient (API) and biopharmaceutical manufacturing processes.

The purpose of this guide is to address the application of Continuous Quality Verification to those manufacturing processes that employ modern quality management systems often supplemented with modern process analytical chemistry systems and controls.

This guide conceptualises the principles of Process Understanding, Risk Assessment, Process Capability, Continuous Improvement and Process Design as depicted in the ASTM E55 Building Blocks for PAT.

Process Validation is essentially an international regulatory requirement. The purpose of Process Validation is to provide a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications, quality attributes and performance.

This proposed ASTM Standard Guide provides an alternative science and risk-based approach to process validation. The current conventional process validation approaches can be enhanced with a move from the current testing to document quality paradigm to a Continuous Quality Verification paradigm that can improve our ability to ensure that quality was built-in or was by design.

Process understanding and control will allow us to use product based Process Capability (Cpk) metrics of the critical quality attributes and process parameters to indicate the capability of our processes. This will deliver a number of benefits and will be the foundation on which industry changes the current operating paradigm and will address both compliance and operational goals.

From a compliance perspective, Continuous Quality Verification will achieve the following:

1. Enable us to demonstrate our science based understanding of our manufacturing processes, by assessing our capability with respect to agreed critical quality attributes and process parameters
2. Extend a science based risk management system throughout the lifecycle of the product
3. Provide a means of developing data driven rationale for negotiating changes to our measurement/control or specification requirements for each product
4. Provide the framework for systematic process improvement with the corresponding reduction or elimination of process deviations and reduction of costs (reworks, resample, retest)
5. Focus on what is critical to quality with the more effective utilisation of resources
6. Provide the evidence to allow regulators to assign a low risk assessment to operations, with the potential benefit of modifying inspection schedules and allowing an increased degree of self regulation
7. Provide a level of process understanding and confidence that will enable the quality release of product as soon as it reaches the demonstration or scale-up stage of manufacture
8. Provide an opportunity to rationalise formal validation documentation. The basic quality system requirement would be fulfilled by an initial evaluation of process performance and formal conclusion that the new process is operating acceptably

From an operational perspective, Continuous Quality Verification will achieve the following:

1. Enable us to transition from being reactive to issues and evolve to a proactive continual improvement mindset
2. Enhance the process by which we prioritise deployment of PAT applications
3. Provide a common basis whereby sites manufacturing the same product can collaborate to establish the optimal process
4. Enhance the understanding and communication of concerns with product transfers
5. Establish a basis on which to evaluate contractor performance as they manufacture products
6. Drive our processes to be effective (high capability)

There will be some manufacturing processes for which continuous quality verification approaches will not be readily applicable and for which the traditional process validation approach will still apply.

WK9936 New Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus

Initiated 12 January 2006, this procedure will cover the set up and calibration of the paddle and basket dissolution apparatuses. Dissolution testing is used as an in vitro surrogate in formulation development and bioequivalence. Dissolution tests are also used as quality control measures for most solid dosage form drugs. Dissolution failures have long accounted for >10 per cent of drug recalls. The variability inherent in this test method and not product performance may be contributing to these out of specification results. Strict set up and mechanical calibration of the instrumentation can reduce variability and hence the risk of failure.

WK11898 New Standard Practice for On-line Total Organic Carbon (TOC) Method Validation in Pharmaceutical Waters

Initiated on 29 June 2006, this standard describes the scientific and risk-based method validation of on-line TOC analysers to ensure suitability for use in pharmaceutical manufacturing applications.

The justification for this standard follows. TOC monitoring is required for pharmaceutical water release as defined by USP <643> and EP 2.2.44 and is commonly used for cleaning validation. Laboratory TOC measurements are currently relied upon to fulfill these needs. Laboratory TOC methodologies have been validated through ASTM, EPA and other groups for use in drinking and wastewater analysis. Transitioning from laboratory to on-line TOC is a common focus for pharmaceutical companies implementing PAT initiatives due to the significant potential for improving both quality and manufacturing efficiencies. Inhibiting this transformation is the lack of a common scientifically based approach for online TOC method validation.

The standard will provide the industry with a validation procedure applicable to online instrumentation that will allow pharmaceutical manufacturers to critically evaluate the performance of various technologies so that they can make an informed decision about which technology meets their needs. The gap that exists today, that this standard plans to address, is that although the elements of a scientifically-based validation protocol currently exist (e.g., ICH Q2B), there is no guidance for the industry as to how to apply it to online technologies.

TOC monitoring is required for pharmaceutical water release as defined by USP <643> and EP 2.2.44 and is commonly used for cleaning validation. Laboratory TOC measurements are currently relied upon to fulfill these needs. Laboratory TOC methodologies have been validated through ASTM, EPA and other groups for use in drinking and wastewater analysis. Transitioning from laboratory to on-line TOC is a common focus for pharmaceutical companies implementing PAT initiatives due to the significant potential for improving both quality and manufacturing efficiencies. Inhibiting this transformation is the lack of a common scientifically based approach for online TOC method validation.

The standard will provide the industry with a validation procedure applicable to online instrumentation that will allow pharmaceutical manufacturers to critically evaluate the performance of various technologies so that they can make an informed decision about which technology meets their needs. The gap that exists today, that this standard plans to address, is that although the elements of a scientifically-based validation protocol currently exist (e.g. ICH Q2B), there is no guidance for the industry as to how to apply it to online technologies.

Work items – Subcommittee E55.91

Active standard: E2363-06a Standard Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry

Initiated on 19 February 2004.

1.1 This terminology covers process analytical technology in the pharmaceutical industry. Terms are defined as they are used relative to the PAT framework in the pharmaceutical industry. Terms that are generally understood and in common usage or adequately defined in other readily available references are not included except where particular delineation to process analytical technology may be more clearly stated.

1.2 This terminology is therefore intended to be selective of terms used generally in process analytical technology as it is applied in the pharmaceutical industry and published in a number of documents, such as those listed in the succeeding sections. The listing is also intended to define terms that appear prominently within other related ASTM standards and do not appear elsewhere.

1.3 The definitions are substantially identical to those published by the U.S. Food and Drug Administration and other authoritative bodies, such as ISO, IEC, ITU, and national standards organisations.

1.4 This terminology supplements current documents on terminology that concentrate on process analytical technology as it is applied in the pharmaceutical industry.

1.5 An increasing number of product designations and designations for chemical, physical, mechanical, analytical, and statistical tests and standards are coming into common usage in the literature, regulatory environment and commerce associated with process analytical technology in the pharmaceutical industry. Section lists those documents referenced in this terminology.

Committee E55 addresses issues related to process control, design and performance, as well as quality acceptance/assurance tests for the pharmaceutical manufacturing industry. Stakeholders include manufacturers of pharmaceuticals and pharmaceutical equipment, federal agencies, design professionals, professional societies, trade associations, financial organisations and academia. At present, 297 members are involved in this multinational initiative, with 17 countries represented on the E55 roster (Argentina, Australia, Belgium, Canada, Denmark, Germany, Ireland, Israel, Italy, Japan, Korea, Mexico, Netherlands, Portugal, Sweden, United Kingdom, United States).

The current work program for E55 is available on the E55 homepage: http://www.astm.org/COMMIT/COMMITTEE/E55.htm – this information represents the documents currently under development and should not be viewed inclusively.

Conclusion

The pharmaceutical manufacturing community has recognised that full consensus standards are the bedrock it currently lacks, a foundation on which its future operations must be anchored. ASTM International Committee E55 will serve as a catalyst through which the widely diverse interests of this community (including manufacturers, users, regulators, trade associations, consultants and academia) will be focused to produce industry driven, market relevant, full consensus standards.