Compliance with FDA 21 CFR Part 11
How MES (Manufacturing Execution Systems) provide a new perspective on quality control
In pharmaceutical manufacturing, product quality is essential. Everything that pharmaceutical companies sell on the open market has to meet their own standards as well as the requirements of the protective authorities. Logically, quality assurance is the shared goal of regulated firms and FDA.
For this purpose, there are FDA and cGXP regulations that control the manufacturing process from product design up to final packaging. Due to more stringent regulations in recent years, FDA and cGXP compliance has increasingly become the focus of pharmaceutical production. And one of the most important criteria in this area is compliance with 21 CFR Part 11.
But how can pharmaceutical manufacturers guarantee uniform quality, given the variables of human and equipment performance, raw materials, and mechanical processing?
The answer lies in strictly controlled instructions and procedures, and even stricter documentation that details every step of the entire processing cycle. Computer system validation (CSV) is a primary goal in the verification of performance, quality and data integrity for any system that falls under regulatory requirements provided by the Code of Federal Regulations and is subject to 21 CFR Part 11 compliance. In this way, through a seamless documentation of what has taken place on the shop floor, assurance can be gained that all steps in the production process are in accordance with cGMP.
Manufacturing Execution Systems (MES) are software solutions which specify, execute and document all operations required in pharmaceutical production. Using different types of interfaces, they are integrated into an IT environment. The sustained purpose of MES products is to minimize error and optimize manufacturing processes. Traditionally, MES refer to a multitude of standard functions using a computer system to centrally control and manage all procedures in concert with the conditions of practice.
This quick overview of the modular component structure of a comprehensive MES mirrors the system's total capabilities:
• recipe/master batch record management
• electronic batch recording
• workplace operation
• production planning and scheduling
• weighing and dispensing
• packaging and filling
• machine integration and process data acquisition
• quality control
• material flow control
• work-in-progress tracking
• warehouse management
• performance management plus KPI calculation
• process monitoring and line control
• product evaluation
• regulatory compliance assurance
• system validation documentation
• and user administration.
The overall task of managing manufacturing procedures is an integral part of MES. In short, the system makes sure that all instructions are properly followed and that all steps are taken in the appropriate manner.
Central to the control of instructions for pharmaceutical processing is the MBR, or master batch record. This template, which details the recipe for a given drug or product, is typically written and approved in various steps, and may be changed from time to time. Since this is the one document that represents the official recipe for a drug, it is critical, therefore, to ensure that the proper recipe is used, even if the changes made are seemingly minor. This has the utmost relevance not only in regards to documentation, but as an instructional tool on the shop floor.
$ 1 Million in Losses Per Day
It is not uncommon for pharmaceutical manufacturers to have hundreds of different batch records, even thousands when packaging operations are factored in. Since these records are the first phase in the lifecycle of bringing a drug to market, it is critical that their instructions, or recipe, be consistently followed to the letter in order to assure ongoing quality as well as regulatory compliance.
Poor or incomplete record keeping and non-compliant computers or automated systems may potentially cause the issuance of a 483 Warning Letter. A large proportion of these letters result from documentation-related problems. Therefore, compliance is also necessary to avoid FDA intervention in the production or distribution of new or existing products.
According to PHRMA, the "missed-opportunity" costs of a new blockbuster drug missing its launch date due to FDA compliance violation is $1 million per day. With such high stakes, it is easy to understand why time-to-market and high-level quality of supplies are such key drivers in the industry.
In avoiding any compliance risk in production, the use of a comprehensive Manufacturing Execution System (MES) software suite delivers additional benefits. Pharmaceutical companies must manage large volumes of documents; this currently contributes to 10 - 15% of site operational costs (equal to $10 million for a medium-sized facility). Utilizing MES software will dramatically cut these costs.
Managing Electronic Records
MES simplifies and streamlines record-keeping, ensuring a fault-free trace of materials and manufacturing processes without any gaps. When proper documentation is maintained in an electronic manner, many of these checks can be performed up front by the software to make sure that the process begins with all its basic requirements in place.
In the 21 CFR Part 11 documentation, the FDA states: "FDA has concluded that regulations are necessary to establish uniform, enforceable, baseline standards for accepting electronic signatures and records." Part 11 regulations cover issues such as security, audit trails, electronic signatures, and copies for inspection. Therefore, it is vital that all systems will have to keep prior revisions of data and documents, including such information as who made a change, when was the change made, and what is the old and new data.
Typically, the kinds of questions that MES answers as part of its on-the-job operation include:
• whether or not the material has been officially released and is in the proper condition to be used
• does a given container have to be cleaned prior to its usage
• is a reactor still considered to be sterile
• can a given filter be combined with a certain granulator
• are the calculations correct for determining required amounts of API and compensating material.
These questions and many more are routinely anticipated and answered by MES. Simply explained, the system operates like an automatic watchdog, keeping track of the manufacturing process in terms of GMP guidelines and company policies. What's more, all of this information is instantly available without interrupting production.
One of the distinct advantages of electronic record keeping with MES is the fact that there are no missing signatures and, therefore, a drastic reduction in documentation errors. Since nearly half of all the incidents in a batch record are based on documentation errors, the use of MES can almost be justified alone on this basis. Yet MES does much more. It also eliminates paper waste and confusion, delivers true transparency to the manufacturing process, and tracks down all manufacturing errors.
Establishing New Record-Keeping Procedures
To achieve the goal of compliance the following procedures need to be established and they are substantial modules of a comprehensive MES program:
• validation of the system (CSV)
• the ability to generate accurate and complete copies of records both human readable and electronic forms
• protection of records to enable their accurate and ready retrieval throughout the records retention period
• limiting system access to authorized individuals and the use of authority checks to ensure that only authorized individuals can use the system
• use of secure, computer generated, time stamped audit trails to independently record the date and time of operator entries and actions without it being possible to manipulate these entries
• the use of device checks to determine, as appropriate, the validity of the source of data input or operational instructions; securing that the persons who develop, maintain, or use electronic records/signatures have the education, training and experience to perform their assigned tasks
• establishing of and adherence to written policies that hold individuals accountable and responsible for actions initiated under their electronic signatures in order to deter record and signature falsification
• use of appropriate controls over system documentation; and additional measures for open systems such as document encryption and digital signature standards to ensure record authenticity, integrity, and confidentiality.
Benefits of Electronic Records
There are significant benefits from using electronic records and electronic signatures. Chief among these are:
• increased speed of information exchange
• easy retrieval
• reduced need for storage space
• reduced number of human errors
• data integration
• KPI (product and process improvement)
• advanced searches of information through an automated database
• the ability to view information from multiple perspectives
• multiple person access to the document at the same time
• and avoiding initial and subsequent document misfiling.
In addition, there is no need to print documents for signing thus eliminating printer and paper management costs where documents are printed just "for signature". It is important to maintain each single record in an integrated control database, enabling users to access their individual authorized portion of the record. The system also will give the answer to multiple electronic review and sign-off by authorized individuals in the areas of controlled document review and approval, version management, and change control.
As compared to paper/manual processes, MES-supported processes provide:
paperless manufacturing recipes; paperless in-process control inputs; enforced process sequencing; electronic "go"/ "no go" decisions; the generation of electronic batch recording; and automated KPI data collection and calculation.
All operations relevant to manufacturing and quality are defined in MES and are made transparent, not only in the display and documentation of events, but also in their sustained and prompt processing, in order to evaluate and continuously improve the pharmaceutical manufacturing process and provide maximum possible safety and performance. MES also allows users to evaluate the overall production process in a way that facilitates the identification of any weak points in the manufacturing cycle. Conversely, it is easy to track any changes that are made to determine their impact on quality and lead times.
Saving Time and Costs
By using MES, the supply chain can be truly and completely integrated. The system is perfect for a total production environment, no matter what size, for one product or for any number of facilities. Providing quicker improvement of product quality, faster regulatory compliance, and information that is instantly available, MES offers benefits that all add up to savings in virtually every manufacturing department.
According to studies compiled by the Manufacturing Execution System Association, MES provides company-wide efficiencies in cost and time savings that can:
• reduce work in process (WIP) up to 20%
• reduce lead times up to 35%
• reduce cycle times up to 45%
• reduce paperwork by 55%
• reduce lost paperwork by 60%
• and reduce data entry by 75%.
Summary
The pharmaceutical industry is under increasing pressure to manage a large range of critical controlled documents - starting with the recipe - in an error-free manner. The inability of manual systems to meet this need is evident. Through the implementation of MES, companies can reduce compliance risks with one standard package.
MES for pharmaceutical applications should therefore strictly align with the requirements of pharmaceutical manufacturing processes. The substantial qualities that must be addressed are GMP compliant standard business procedures; 21 CFR Part 11 compliance; documentation of electronic records/electronic signatures; integrated audit trails; and validation capabilities.
Today's pharmaceutical industry demands safe, fast and cost-effective production. Compliance to quality standards and regulations and a reduction of production time and costs constitute essential factors for success. The Manufacturing Execution System (MES) can meet all these requirements. It ensures cGXP/FDA compliance, reduces costs, and increases productivity. And in so doing, it is setting new industry standards that benefit us all.
Werum America Inc.
Software & Systems
9 Campus Dr.
Parsippany, NJ, 07054
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