Aseptic filling and FDA

The Food and Drug Administration (FDA) is an American government agency for consumer protection. The aim of the FDA is to safeguard public health: FDA guarantees the safety and efficacy of medical products, biological products, medical instruments, food and beverages, cosmetics and materials that emit radiations. Since it is a regulatory body, the FDA adopts variable reference criteria on the basis of the field of application. Regarding beverages, "low acid shelf stable" beverages (low acid beverages distributed at room temperature) are regulated by the FDA in the United States. A bottler that wants to launch on the American market a beverage of this type must obtain from the FDA a "Letter of NonObjection" (LNO, or LONO) that declares that the technology used ensures the commercial sterility of the product (see 21 CFR 113.3 (e)). The letter of non-objection is therefore relative to a specific line, that produces for the United States market (not necessarily physically installed in the US) and it is the end bottler that has to request it from the FDA.

In order to facilitate the attainment of the LONO for their customers, some aseptic bottling line manufacturers first request a Master Filing review of their aseptic technology to the FDA. The FDA evaluates the technology proposed and, if acceptable, may release a LONO to an equipment supplier. The customers of said technology thereby may obtain in turn a LONO in a simpler and faster manner with future processor filings. The criteria adopted by FDA to validate a technology examines diverse aspects of its functioning; specifically, the system must guarantee commercial sterility also in the event of diverse critical conditions occurring simultaneously. Analysis of the project, verification of the materials, simple to clean testing and system sterilization, practical tests and verification of sterilizing efficiency with challenge tests are all part of the FDA certification procedures.

FDA Validation

As reported in the previous paragraph, to sell "low acid shelf stable" beverages in the United States it is necessary to get a "Letter of NonObjection" (LNO or LONO) from the FDA. To obtain it, an aseptic bottling plant has to be validated in a manner that proves that:

• All the applied sterilization processes are effective against relevant target microorganisms.
• All the applied sterilization processes are repeatable.
• The system when in production is able effectively to maintain the sterility.
• All the parameters that are critical to achieving and maintaining sterility, are properly monitored and any deviation is promptly identified and recorded. 

To get through the FDA process filing, a beverage manufacturer has to hire a process authority, a third party which will act as a consultant in front of the actual customer and as a sole spokesman in front of the FDA. The process authority is in fact in charge of:

• Evaluating the bottling plant features.
• Defining and conducting comprehensive validation trials.
• Organizing and submitting the trial data and other relevant documentation to the FDA.

The evaluation of the features is the stage on which the process authority "learns" about the bottling plant: where sterile area limits are, what sterilization processes are applied to achieve both plant and packaging sterility, how sterility is maintained during aseptic production, which monitoring devices are used and where they are installed and, most importantly, all the critical parameters of the system.

At the end of this stage, the process authority can revert with suggestions about system modifications or improvements. Once the evaluation phase is completed, it is the process authority’s task to prepare specific validation protocols and forms for challenging the system. These are normally related to:

• Installation Qualification (IQ) and Operational Qualification (OQ).
• Plant sterilization trials.
• Packaging sterilization trials.

It has to be noted that the FDA does not consider critical the cleaning operations of a plant and, as a consequence, none of the parameters of CIP/COP cycles are required to prove the plant capability to achieve and maintain sterility. However CIP/COP cycle trials, as well as production trials, are normally conducted, to collect preliminary or supplementary data to the filing process. Installation Qualification and Operational Qualification are two steps in which the plant is checked, to ensure it meets the Design Specifications and the Functional Specifications respectively. All the sterilization trials, as well as the CIP/COP and production trials, are part of the Performance Qualification step, in which the plant is challenged, to ensure it meets the User Requirements. Sterilization trials are the core of the Performance Qualification step. Since the aim of the FDA is to safeguard public health, each sterilization process must be effective against a specific pathogenic microorganism, that is identified considering:

• The danger to human beings
• Environmental distribution in general and on the items to be sterilized in particular
• Illness cases among human beings

The above mentioned criteria are also used to define the minimum required killing rate for the chosen microorganism.

Of course the plant sterilization trials cannot be performed using the pathogenic microorganism, for this reason a suitable non-pathogenic microorganism has to be identified and used as a surrogate. It has to be noted that the surrogate must have a resistance against the sterilization process to be tested, equal to or greater than the pathogenic microorganism. Once the surrogate has been identified, its minimum required killing rate must also be defined, according to the ratio: surrogate resistance/pathogenic microorganism resistance. Sterilization trials are conducted in the worst case scenario, with all the critical parameters set out of the required operating range (below the minimum value or above the maximum value, depending on which limit is critical) and carefully recorded. In this condition the sterilization process must achieve the desired killing rate and the related data has to be consistent. In case of failures (insufficient killing rate, inconsistent data or missing critical parameter values) root causes shall be identified, plant or process modifications may be implemented and the trials repeated.

Upon the successful conclusion of the sterilization trials, the final stage of the FDA process filing is the data and other relevant documentation submission to the agency, which will analyze all the material. In this stage the FDA may ask for clarification or further details for the process authority, regarding the plant features and sterilization processes. Once the analysis is concluded, and assuming a favorable outcome, the Letter of Non-Objection is released and the commercial production can start.

Electronic Validation

More and more often manufacturers receive requests to provide equipment with an overall line control system that covers the entire plant and not only each single machine.

This requirement has led manufacturers of beverage equipment to renew their design, building and certification processes, known as “Electronic Validation”. The methodology comes from the FDA environment and the pharmaceutical industry and is slowly extending to the whole Food and Beverage sector.

The Electronic Validation starts with a design based on the principles of GAMP 4 (EUROPEAN) and BULLETIN-43L (USA), these guidelines provide an effective tool to get clear specifications and certifiable software: essential to arrive at comprehensive reporting based on electronic recording and archiving of all relevant data (critical parameters, cycles, alarms and events).

The validation of the entire process of construction, installation and start-up of the machines allows paper records to be completely eliminated in favour of more powerful electronic recording.

The Electronic reports respond to the needs of the most demanding customers to have clear and detailed information on the production process with compliance to FDA 21 CFR Part 11 (Code of Federal Regulation regarding Electronic recording and Electronic Signature).

GAMP 4 Module

System Build

1. Machine building
2. Hardware and software development
3. System debug according to the functional and Setup specification
4. Possible updating of technical specification

System Validation

System Development

The basic steps of this system are perfectly expressed by the "V" model of the GAMP (Good Automation Manufactory Practice).

Paper Recording vs Electronic Recording

Guarantees must be maintained over time by using the certificate database (Microsoft SQL) and operating system level of password, with advanced encryption, automatic log out and requests to re-login for the most critical parameters.
The re-login is a common practice to increase the security of the system when someone tries to change parameters which are highly sensitive. It consists in an additional login request even if already logged into the system with the correct credentials.

In addition to the software controls the security extends to the hardware level through a server with all the main parts redundant (integrated UPS, double power supply, RAID disk, double Ethernet card and backup on CD-ROM or DAT).

Electronic CCH (Critical Control Handbook)

Having an electronic recording system, even the CCH needs to be electronic.
During the development and validation of the system one of the most important documents is the SETUP specification (created by the CCH electronic software system) that contains all of the critical parameters and related alarm values. The scope of the CCH system is to ensure the alignment of the configuration parameters in all of the main components of the plant (PLC’s, HMI’s, SERVER, documentations and reporting). 

The ELECTRONIC CCH is an application software used to:

• Define Machine Parameters
• Define Critical Control Point (CCP)
• Create the SETUP specification file
• Manage and Transfer all parameters to the SCADA and PLC
• Manage and Transfer all information to the server for the Batch Report (CFR21.part11)
  

Batch report

• Alarms
• Events
• CCP and related deviation in case of occurrence
• Trends of all critical process parameters

BACKUP rules

• Daily
• Weekly
• Every 4 weeks
• Every 26 weeks