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Several problematic issues are associated with the development and installation of automated drug manufacturing and testing processes. The author addresses how vendors can overcome these factors to deliver robust automation across multiple sites.
The use of robotic automation in pharmaceutical production processes continues to grow. Tighter control of manufacturing processes and increased regulatory testing requirements drive the need for automation. Well thought-out automation offers extensive benefits including high-throughput, robust, 24-hour manufacturing and testing; real-time process monitoring; reactive control; high-volume data gathering; and low data variability. In addition, automation gives pharmaceutical companies more information about the characteristics of its products, and its manufacturing and testing processes than ever before. As a consequence, a wealth of high-integrity data are available.
In a highly commercial market, any automation requires a solid business case to justify its implementation. The most common business justifications include cost benefits, increased data integrity, increased reliability, increased throughput, and harmonized manufacturing and testing benefits. The tried-and-tested approach of using cost benefits awarded by a reduction in headcount is not always enough to demonstrate the need for automation.
Instead, the soft benefits (e.g., data integrity and reliability) can hold the key. Increased data integrity results in reduced process variability and, therefore, avoids the need to reject or retest batches. Because the cost of typical pharmaceutical batches can be extremely expensive, only a small reduction in the number of reject batches can justify automation. Increased operation reliability and robustness also can decrease time to market and increase shelf life, which further justify the implementation of automation.
The need for harmonization
A broad look at the global pharmaceutical market indicates that automation is not only essential for the future success and growth of manufacturing and testing operations, but also for the harmonization of automation across manufacturing facilities worldwide. But, many pharmaceutical companies have encountered problems with ensuring consistent manufacturing and testing processes at sites worldwide because of variations in regional standards.
Good automation can help. Developing solutions suitable for global multisite implementation ensures that consistent, controlled methods are used during manufacturing and testing. The technology should function in an identical manner across all worldwide locations.
Figure 1: The steps required to develop an automation process include requirements gathering, user requirements specification development, concept design, and proof-of-concept activities.
Although this task sounds simple, many automation providers struggle to enforce the necessary development and commercial-build controls required to provide this assurance. Unlike many other industries, the pharmaceutical industry requires the development of novel, innovative technology followed by the quality-controlled supply of low-volume commercial roll-out units that are identical to the first. Thus, an ensured pedigree is required.
This requirement is atypical for many automation providers and thus, the needs of the pharmaceutical industry are not widely understood in this respect. Some suppliers focus on the one-off development of bespoke automation, whereas most others focus on large-volume product supply. Therefore, the pharmaceutical industry relies on a small number of specialist suppliers to meet its specific demands.
Developing a novel, innovative solution
The first step in the development of automated manufacturing and testing processes is to gather and analyze the requirements and needs of the pharmaceutical end user. Good automated manufacturing practice (GAMP) guidelines (1) provides clear information about the contents of the user requirements specification (URS).
Figure 2: Commercial roll-out objectives: first implementation performance assessment, enhancement program, design "lock down," and roll out.
Typically, the pharmaceutical end user provides the URS to the automation provider to define the detailed requirements for automation. Nonetheless, it is beneficial to involve the automation provider during the development of the URS. A good automation provider will help the pharmaceutical end user to document its objectives and needs, bring global sites together, and promote the detailed thinking necessary to ensure the resulting solutions meet the end user's needs for the future.
Once the URS is determined, the automation provider will begin the development of the automated solution. Because of the complex nature of drug manufacturing and testing, it is essential that the automation provider keeps the pharmaceutical end user fully involved during the early stages of the development lifecycle. The automation provider must avoid the temptation to jump into a detailed design too soon in the lifecycle. An early concept design exercise is essential.
Using modern three dimensional-modeling techniques, it is now possible to demonstrate in great detail how an automated solution will look and how it will operate in a short timescale. This tool can help explain the operating philosophy to nonengineering end users. Involving the pharmaceutical end user and soliciting the client's early comments on the proposed solution can greatly improve the long-term rewards.
Risk identification and mitigation
Novel, innovative designs often require the development of new techniques. Using formal project management techniques (e.g., Prince2, Projects Process Limited, Bucks, UK) encourages the automation provider to identify such areas during early risk assessment and to identify measures to mitigate the risk. Proof-of-concept (PoC) equipment is a good way of removing technical risk from a development project. It also provides the pharmaceutical end user with a technical assurance of success at a very early stage of the development lifecycle before significant spending occurs.
PoC equipment must be well thought out. Its purpose is risk reduction. It should demonstrate the success of core automation elements before full development and manufacture. Its success is heavily dependent on setting clear guidelines and targets for the PoC exercise. The purpose of testing, the acceptance criteria, and the contingency planning to correct any deficiencies encountered must be clearly defined before the PoC exercise commences.
It is essential that the automation provider keeps the pharmaceutical end user fully involved and aware of PoC equipment testing. The pharmaceutical end user must be comfortable with the PoC equipment and its performance before allowing the automation provider to develop and manufacture the solution. PoC equipment should be cost effective and designed for its intended purpose. It is for short-term use only.
The benefits of GAMP
ISPE's GAMP guidelines provide a useful model for the development of the first implementation. The guidelines ensure that requirements are traceable from the URS onwards. Traceability is demonstrated to the functional specification (FS), the factory acceptance test (FAT) documents, and site-acceptance test (SAT) documents. It is usually possible to ensure that the automation provider's documentation, particularly FAT and SAT documents, cover installation qualification (IQ) and operational qualification (OQ) requirements, thus simplifying and reducing the demands placed on the pharmaceutical end user (1).
Cost model for the early development of automation
It is useful to treat the cost model for the first implementation differently from that of repeat-build commercial units. During the development of the first implementation, the design is not fixed and it is likely that the automation provider may propose better ways of doing things or that the pharmaceutical end user may change its requirements. One common cause for a change in requirements is the parallel development of new drugs and drug delivery devices. Often, the drug development program will be evolving at the same time as the automated solution. A change in this program will directly affect the automated solution.
The pharmaceutical end user must preplan for this eventuality with effective finance planning. Otherwise, the quality and performance of the resulting automated solution may suffer. The timing and interaction between the development of drugs, drug delivery devices, and automated solutions hold the key to a successful automation program. An effective collaboration will allow automated solutions to form part of method registrations and pave the way for effective qualification.
Commercial roll-out objectives
The first implementation of robotic automation is typically installed at a lead site. At this location, the performance qualification (PQ) is completed and the benefits of the technology are measured over a defined time period. Often, a program of enhancements is implemented under change control to maximize the benefits of the automated solution. This is the pharmaceutical end user's first opportunity to use the robotic automation and measure its performance. The success of the first implementation and the benefits awarded is the usual trigger for commercial roll-out of technology to global sites. At this stage, the business case is clearly measurable against actual performance and funding is normally a simple process. Automation costs are clear and well-defined.
The commercial roll-out of technology to global sites realizes the benefits of automation on a large scale. The objectives of commercial roll-out are to implement a consistent, well-controlled means of product manufacturing and testing, independent of location. The drug product developed or tested at any location must meet an assured level of quality control.
Automation equivalence and longevity
Before committing to commercial roll-out, it is essential that the automation provider locks down the design of the automated solution. A thorough documentation package should be available upon the completion of the first implementation and should be used as the basis of lock down.
For example, the automation provider should review the design of the automated solution during the design of the first implementation considering factors such as component supply lifetimes, calibration techniques, set-up techniques, local standards, and regulatory requirements. When the first implementation is in place and operational, the provider should repeat the review exercise. Then, it would critically assess the design of the automated solution and ensure that, where possible, any roll-out issues and risks are eliminated. This process effectively "future proofs" the solution. Each commercial unit must have the necessary controls to set the performance to be equivalent to the first implementation. The benefits of global roll-outs are reduced significantly if equivalence cannot be achieved.
Commercial-build skill set
The skillset required to manufacture commercial-build units differs from that of novel, innovative design. In this case, quality control and consistency of manufacture are the keys. A dedicated team committed solely to commercial-build and roll-out offers an effective means to meet the increasing demands of pharmaceutical companies. Such a team would take over control of the automated solution and lock down the design and testing protocols once the first implementation is in place and operating effectively.
Harmonization challenges and regulatory standards
The quest for global harmonization of drug manufacturing and testing is complicated by the introduction of local standards and regulatory requirements. It is not unusual for a pharmaceutical company to have different operating procedures at various sites to comply with regional standards and regulatory requirements. It also is important to note the legal differences associated with the sale of equipment into different geographical regions.
Within Europe, the automation provider should operate to European directives supported by harmonized engineering standards. Equipment can be presumed to comply with the relevant directive if it is designed and manufactured in accordance with a harmonized standard. The result is the "CE mark" generally accepted across Europe. Typical directives relevant to robotic automation include the machinery directive, the low-voltage directive, the electromagnetic compatibility (EMC) directive, and the ATEX directive.
In the United States, the CE mark is not recognized and, in many municipalities, a UL assessment or "UL listing" is required. This requirement is met by submitting a product for testing and safety certification. The "field assessment" approach works best for robotic automation in which the inspection can take place at the end user's site. Using Europe and the United States as examples, it is clear that the automation provider must offer slightly modified equipment that accommodates different regional requirements. The automation provider must recognize the local requirements of the individual sites and the legal and regulatory standards imposed.
But, the automation provider must also ensure that these differences are transparent to the operation of the automated solution. The automated solution must function in the same manner and produce the same results, regardless of regional differences. Formal testing and qualification must demonstrate that these results are achieved. Focusing on the functional requirements of each component of the automated solution enables the automation provider to develop testing and qualification documentation that demonstrates equivalent operation of core components, regardless of the technical differences in implementation.
Harmonizing automated solutions across low- and high- volume sites
One common misconception blocking the introduction of harmonized automated solutions is that harmonized solutions cannot be implemented if the manufacturing or testing capacity of sites varies dramatically.
This is not the case. Automation providers can offer scalable solutions that allow lower-cost implementations to be delivered to low-volume sites. These solutions are achieved by identifying the core components that affect the manufacturing and testing process. Designing these core components to be scalable across platforms means that automation providers can offer a range of solutions that all operate according to harmonized standards.
For example, a typical dry-powder inhaler may require a consistent, harmonized means of actuation to release a controlled dose. The automation component that performs the actuation function can be delivered in either a low-throughput work-station solution in which the user loads a single inhaler one at a time or a high-throughput solution in which the user loads hundreds of inhalers at the same time and leaves the system to operate unattended. Through proper testing, the automation provider can prove that the robotics for handling the inhaler and placing it in the actuation unit do not alter the results data. Rather, data can be demonstrated to be the same as the low-throughput workstation. By making the core components scalable, the methods are identical and the manufacturing and testing are consistent, regardless of site capacity.
Finding the right automation partner
When identifying an automation provider, pharmaceutical companies should look for industry experience, coupled with ISO 9001 and TickIT accreditation. TickIT is an accredited quality system certification scheme and is extremely important given the complex nature of software development for real-time automated equipment. Regular audits conducted in accordance with GAMP guidelines also can offer a level of assurance to pharmaceutical companies embarking on automation projects. A good supplier will welcome the audit as a means of demonstrating its commitment to quality. The importance of data and data integrity means that the automation provider must have knowledge about and experience with 21 CFR Part 11 requirements. This guideline covers the use of electronic records and electronic signatures. Given the vast amounts of data that an automated solution can provide, using paper records is not a viable approach. The use of electronic records and signatures are necessary.
Maintenance and support
Automation providers will offer on-going support for the automated solutions they provide. Preventative maintenance is important to ensure continued reliable operation. Nonetheless, it is also necessary to consider "acceptable downtime" in case of equipment failure. This helps the automation provider to suggest the correct level of spares holding for the automated solution and the correct call-out response time.
Spares holding can be optimized to meet global multisite needs. It should not be necessary to hold a full set of spares at each local site. Instead, cost savings should be considered a result of the common technology used. It is an important strategic decision to know the proper level and location of spares.
A call-out response to equipment failure is another strategic decision. The cost of maintenance services is likely to increase exponentially as the requested call-out response time decreases. It may be worth investigating the possibility of local site staff to undertake simple maintenance tasks to remove the need for rapid call-out response. Local staff can be trained by the automation provider to perform basic maintenance functions.
Maintaining the harmonized state
Once commercial roll-out is completed and site operations are on-going, companies tend to allow local changes to be implemented. The automation provider often is contacted by individual sites to undertake enhancement work on a single site basis. Although this is a cost-effective means of meeting the needs of the single site, it destroys efforts to achieve the long-term harmonization that was needed in the first place. The automation provider will offer a means of change control for the client's global installations. But without the end user's support, the provider cannot prevent local changes. Changes must be controlled and rolled out to all sites. This process increases the cost of changes, but it also ensures the benefits of harmonization to be realized.
The pharmaceutical industry is keen to implement robust global automated solutions. There is a drive to operate to global standards, thus making it more achievable to develop harmonized automation solutions. Nonetheless, the cost benefits awarded by automation must be clear. The pharmaceutical market is highly competitive and harmonization must offer operating performance advantages. Without a sound business case, pharmaceutical end users are unlikely to embark on major automation projects. The business case can require careful consideration. It is often the soft benefits that offer high levels of payback.
Pharmaceutical companies must promote the harmonization of automated solutions from a corporate level. Often, individual sites are focused on their own localized performance and are unable to consider the broader company-wide benefits. Without drive from the corporate level, global automation programs can stall. If they do, they will inevitably cause the organization to be less effective in the future. In a competitive market, this loss of effectiveness can be catastrophic. Pharmaceutical companies that implement automation correctly will inevitably be future market leaders. They will deliver drugs to market in a more robust, reliable, and competitive manner than their competitors.
Chris Hansford is a founder and director of Astech Projects Ltd., Unit 15 Berkeley Court, Manor Park, Runcorn, Cheshire WA7 1TQ United Kingdom, tel. +44 1928 571797.
1. ISPE, GAMP 4, Guide for Validation of Automated Systems (Tampa, FL, ISPE).