By Ken Falk, Industrial Business Area Market ManagerMETTLER TOLEDOThe standpoint of a regulator inspecting a pharmaceutical operation is likely to be “In god we trust – everyone else must show validated evidence.” This is particularly true when it comes to electronically controlled equipment, the use of which is increasing in all areas of industry.By setting such a marker by which systems need to be assessed, the “audited” may sometimes ask themselves, is this fair or indeed practical considering the ever-increasing capabilities of equipment, being controlled by hardware and software with greater built-in functionality. The disciplines required to monitor and control processes are becoming broader.
For those manufacturers producing product for the US market, their control must satisfy inspection by the Food and Drug Administration (FDA) regulators who have to include the task of auditing companies against the FDA regulation referenced 21CFR Part 11.This regulation outlines the rules for acceptability and use of electronic records and signatures in lieu of paper records and hand-written signatures.
From the perspective of regulators of pharmaceutical products, one of their prime goals is to take responsibility for the safety of products available in the medical world and ultimately, the general public. Consumers rely on their local regulatory bodies as an assurance that products available to them meet today ‘s standards.
US & European StandardsIn the US the FDA investigators and inspectors have the task of visiting facilities, seeing that products meet acceptable standards and are labeled truthfully. If a company is found violating any of the laws that FDA enforces, the company is initially encouraged to voluntarily correct the problem or to recall a faulty product from the market. Where a company cannot comply with the request, legal sanctions are available to the FDA. A company can be forced to stop selling a product and to have items already produced seized and destroyed.
In the Western world, the high standards set by the pharmaceutical companies combined with the continued monitoring by regulatory agencies of the relevant countries has meant that we now generally take the safety of medical products for granted. However, an incident in Haiti in 1988 acted as a reminder of the need for continued stringent control. It was found that locally manufactured acetaminophen syrup, used to reduce fever in children, was contaminated with diethylene glycol, resulting in kidney failure in 88 of the persons whom had taken the medicine. It was concluded that the process of manufacturing and regulation were not considered adequate by today ‘s global standards.
Supporting evidence & proceduresDevelopments in science continually add the request for the approval of new products for manufacture and release into the marketplace. The task of introducing and regulating such events is not a straightforward one, and therefore the requirement of evidence to support each stage of the processes involved is deemed essential. Concerning the manufacturing process itself, pharmaceutical companies have continued to provide evidence of control and traceability, not only to satisfy the regulators, but also as part of the overall industry’s, and individual company ‘s goal to provide the highest integrity of product.
The adoption of formal procedures for every aspect of manufacturing, whether it be from concept, design, installation, production, maintenance, upgrade or retirement will be in place, with continuous recording/challenging of each step. These formal procedures have historically taken the form of being recorded onto hard copy and been authorized by hand-written signatures. The advent of computerization is nothing new, but relatively recent developments have made an increase in the options available.
Information technologyHistorically, pharmaceutical companies had the resources to utilize larger computer systems from their early availability. The hardware, operating systems and application software tended to be the preserve of the few for the main company system. Typically, the early application software was apt for financial purposes, but did not lend itself well beyond this.
Later packages incorporated data related to the manufacturing process, but these systems were used to provide hard copy instructions to the manufacturing areas. Master records kept on hard copy would be the controlling document. Each process of manufacturing maintained control and traceability by manual control, with authorizing signatures for procedures. This method is the basis of many pharmaceutical operations today – planning being performed on the company main system, processes being performed, manual records taken, and data manually entered back to the application to complete the planning/resource function.
Where special manufacturing processes operated e.g.SQC and recipe systems, these tended to be with bespoke applications. These applications would perform specific functions, but were effectively self-contained systems and maintained individually. Relatively recent changes in information technology have meant that the options available to all companies have greatly increased. The most significant changes are that:
1. Hardware and software platforms have merged:
a) Microsoft has played a major role in determining an industry standard for operating systems with regard to data acquisition.
b) Manufacturing uses equipment controlled by PLC’s, that are now being supplied with the ability to exchange data with higher level systems.
2. The performance of IT equipment has increased: The ability to perform complex tasks within an acceptable timeframe is assured.
3. The price of the IT infrastructure has reduced: Uniformity of operating systems at PC level has made it commonplace within the business environment -this is now transferring to manufacturing.
4. The application software available has greater functionality and more packages are designed for manufacturing industry: Packages such as MS Excel, Word, Access are very powerful tools for storing and displaying data. The ability to merge/report data from differing databases has improved. SCADA packages for process control are modular in format, covering a wide range of industry applications. Software development tools such as Visual Basic plus Delphi improve the ability to produce good quality, reliable, application software.
Maintaining integrityIn the light of these changes, what steps have been taken to maintain an assurance that the integrity of the overall product can be shown?
During the early 1990 ‘s the pharmaceutical industry had recognized the need to improve the understanding of the use of automated systems, not just with regard to the regulations, but also to aid suppliers and define how such systems should be introduced. In the UK a Forum was set up, resulting in the Good Automated Manufacturing Practice (GAMP) Guide for validation of automated systems in pharmaceutical manufacture being produced. The guide focused on the concept of a ‘Life Cycle’ of an automated system covering specification, design, construction, testing, installation, acceptance testing, operation and maintenance. The principle of validation of a system and the responsibilities of both supplier and the pharmaceutical end user are given in the guide.
The validation of any system requires the supplier and user to work in partnership, with the supplier needing to understand the expected requirements as part of the validation process.
Following the original GAMP guide, further changes in automated systems have resulted in additional documents, covering classifications of types of system, in terms of risk. Guidance with specific regard to electronic records and signatures is also being considered.
The introduction of the FDA ruling on Electronic Records and Signatures effectively allows hand written signatures to be substituted by electronic alternatives, and the use of electronic batch recording. This ruling although difficult to interpret has been welcomed, as it provides a standard to which to work. The issue of demonstrating the overall integrity of products therefore continues to have frameworks in the form of guidelines and regulations that are readily available. Therefore, the ability to introduce new systems and remove the need for manual paper records should be considered where possible. This not only reduces the possibility of human error, but also the problems of long term storage and retrieval of manual records.
ConclusionIt is important that the equipment considered can be fully supported in the validation process by the supplier. Suppliers who understand the validation process and have prepared documentation to assist in the process can not only ease the burden on validation teams, but provide a quality solution to introduction of a system, bringing the system live in a reduced time.
Validation can sometimes be viewed as a difficult or complex task, but the key message from all the guides, however, is that the process of validation is no more than applying good practices to systems and procedures. A system that has been well planned, designed, constructed, tested, installed and maintained will not only satisfy the regulators, but also benefit the company operation.