The comprehensive guide emphasizes risk-based evaluation for complying with FDA cGMP regulations.
ISPE, the International Society for Pharmaceutical Engineering, has released new guidance on design, construction, commissioning, and qualification of packaging, labeling, and warehousing (PACLAW) facilities.
In presenting the first comprehensive guidance for PACLAW facilities for meeting FDA cGMP requirements, “ISPE Good Practice Guide: Packaging Labeling, and Warehousing Facilities” addresses Quality by Design, with directions on how to comply with FDA’s systems-based approach with a risk-based inspection model.
The guide uses a risk-based approach as described in ICH Q9 “Quality Risk Management,” and in ASTM E2500-7 Standard Guide For Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment—guides that apply the concepts introduced by FDA’s “Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach.”
A guide for a risk-based approach to automated equipment following GAMP 5 (Good Automated Manufacturing Practice) is referenced. A collaboration between JETT (Joint Equipment Transition Team), a consortium of healthcare industry equipment users, suppliers, and consultants, and ISPE’s Risk Management special interest group on GAMP 5, the Practical Application of Risk Management Process guide defines the key process steps involved in risk assessment preparation and testing. [See chart below]
“What is really valuable about GAMP 5 and the risk-based approach is you concentrate and test on those areas that are quality critical to the product. This can save a huge amount of time in validation,” says Mel Bahr, founder of MGS Machine Corp, and a team leader on the “JETT Risk-Based Approach to Automated Equipment” guide.
“We are not seeing as many pharmaceutical companies as we expected embracing the risk-based approach [for packaging operations]. It is difficult for the large companies to change,” Bahr says.
“We have held training sessions in the last year with some generic manufacturers to help get them started using this approach for secondary packaging,” Bahr adds.
The risk-based inspection model has gained the most traction on the drug manufacturing side, agrees Nancy St. Laurent, chairman of the ISPE group that developed the PACLAW guide.
“When it comes to the ICH Q9 risk-based approach, packaging is usually a step child. All the thought and planning for QbD seems to surround the upstream manufacturing operations,” St. Laurent says.
“This is a guide on how to design and build and operate the packaging, labeling, and warehousing operations. We are asking people to think through each step along the way—from ground-up design to validation. That is a manifestation of QbD,” St. Laurent adds.
St. Laurent and her PACLAW team commenced the Guide process in 2004. The Packaging Machinery Manufacturers Institute (PMMI), Weiler Engineering, and Omori Machinery Co., besides MGS Machine, represented equipment manufacturers. Pharmaceutical companies and consultants assisted in the guide’s development. FDA provided review and technical guidance on each chapter, St. Laurent says.
Areas covered include architecture, utilities, temperature mapping, and flow of people, materials, equipment, and product.
“Pharma manufacturers often don’t have the space to adequately segregate materials. The most common FDA recalls have continued to involve labeling issues. The guide describes what the spacial and physical arrangements should be for the different operations to prevent cross-contamination and avoid these mix ups,” St. Laurent says.
MONITORING AND CONTROL
Control and monitoring is addressed for both packaging equipment automation and building management systems. In packaging operations there will be two types of controls: machine controls and SOPs.
“Assuming the appropriate SOPs are in place, a risk-based approach to the design of the controls and verification systems on machines is the best strategy to eliminate mix ups, Bahr says.
“Automation—with such devices as vision systems (for print verification) and bar code scanners integrated with properly designed controls—can virtually eliminate product mix up
problems. Control systems have to be fail safe as part of a verified system—if a problem is detected, the line should shut down automatically,” Bahr says.
Adds St. Laurent: “The implementation of systems with controls for sequential bar coding should help improve control on packaging and labeling processes where you have total control of printed label material.”
The guide covers good commissioning and verification practices with specific monitoring strategies—such as Process Analytical Technology (PAT)—applied to critical parameters and processes.
A key concept in facility design and related to QbD and risk evaluation is cGMP critical parameters. “The cGMP critical parameters can be prioritized through a risk-based evaluation. For example, where hygroscopic, light-sensitive, or temperature-sensitive materials are being packaged, the product sensitivities will define critical design parameters that will need adequate control in order to maintain product quality,” the guide reads.
A systematic process where individual hazards are identified, analyzed, and evaluated, risk assessment is a continual/ongoing process throughout the life cycle of an automation solution, as described in the “JETT Risk-Based Approach to Automated Equipment.”
The amount of effort invested in risk management should be commensurate with the level of risks of the function(s) being automated, as incremental iterations of risk management activities are performed throughout the system life, the JETT guide says.
Various methods are available for risk management, depending on the risk category, the JETT guide describes. FMEA (Failure Mode and Effects Analysis) is used in the pharma industry to assess machine component meantime between failures.
Other methods include HAZOP (Hazard and Operability Analysis) for analysis of continuously operating equipment where there is a single operating state, and OHA (Operating Hazard Analysis), which looks at each step in the production process and is useful for analyzing batch processes for potential hazards, the guide states.
FTA (Fault Tree Analysis) provides a graphical depiction of all causal chains of failure of a system or subsystem.
“It is recognized that while these methods are well known throughout all sectors of industry, practical application of these methods within the life science industry is not well developed,” the guide says.
Using the “JETT Risk-Based Approach to Automated Equipment” in the risk assessment process, you apply a structured analysis to the system to determine what business processes, system activities, and human control activities need to be assessed. The JETT guidance then provides a step-by-step example of a risk assessment process. Items requiring rigorous testing are then subjected to a FMEA-type approach.
“For machinery manufacturers, validation requirements can vary widely. [With a risk-based approach] you decide what is critical to quality and focus on that,” says Bahr.
“Without using a risk-based approach, as much attention was given to an annunciator sensor (indicating a low magazine on a cartoner) as to test a bar code scanner that verifies you have the right carton and right bottle going in the carton.
“I also like to promote an output-based approach. For example, [take]a cartoner after the product is loaded and the carton is to be printed with the lot and date code, which needs verification. The vision system is rigorously tested, the print unit need not be subjected to the same rigor. The printing system is commissioned, the vision system is validated,” Bahr says.
In a trial with a pharmaceutical customer, MGS Machine assisted in slashing the validation time with the risk-based approach.
“After the FAT process, the equipment was put under change control at our plant. The documentation was rolled over and the line was validated after two weeks in their plant and turned over in four. They would typically allow 12 to 14 weeks after delivery of equipment to finalize validation and turn over to production.”
The ISPE Good Practice Guide is described as an approach to satisfying cGMPs, while providing realistic solutions to business and operational concerns.
“PACLAW facilities are very different from other types of pharmaceutical facilities, and up to this point, there has been no consistent guidance available to help companies ensure compliance,” says Guide author Nick Davies.
“With this (Guide) the industry finally has tools to ensure their PACLAW processes are efficient, compare their processes to established best practices, and demonstrate compliance to regulatory agencies.”