The Difference Between Product and Process Controls
It’s been thirty days, and the eagerly awaited letter from the agency is expected today. Despite the usual last minute preparations, the submission went in on time and complete. All of the pre-clinical studies looked good, so it should be approved without comment. When the letter finally arrives, the Regulatory Affairs associate tears open the envelope and a list of questions fall out. What was the problem? There were insufficient controls to guarantee patient safety.
Unfortunately, scenes like this are all too common. Failures to establish the proper controls are one of the major reasons why submissions are rejected. While it is not the responsibility of Regulatory Affairs (RA) to ensure the product is manufactured correctly, RA is often the only quality guidance on a new product development team comprised of engineers, scientists, physicians, and managers. The focus of this article will be to identify the major components of process and product control quality systems so that RA professionals can better understand the requirements.
Product Controls
Quality systems that focus on sorting and isolating defective product are generally called product controls. Because the process generates defective product, efforts are made to identify, sort, and segregate the defective product. Often, the defects are made throughout the process but only culled at the end. For example, a manufacturer sells a sterile original equipment manufactured (OEM) part. The part is made from a metal press, where it is etched with a lot number, cleaned, packaged, and steam sterilized. Prior to shipment, samples of the sealed product are inspected. If the metal press caused hairline cracks to form in the part, then this may be detected only at the very end of the process. All of the cleaning, labeling, packaging, and sterilization are wasted on essentially defective product. Because defective product is definitely present, product controls require 100% inspection or multiple 100% inspections to guarantee product quality. Statistical sampling plans are not useful because they presume an acceptable defect level of a few percent, which is generally not acceptable for Food and Drug Administration (FDA) regulated products.
Management also must be prepared to accept the greater costs that come with a quality system founded on product controls. Management issues are important to understand in that frequently these choices are made without consideration until a decision is required. It is at that time that RA is asked to change submissions, approve altered specifications, or release deviated product, a compliance nightmare that most want to avoid. Higher inventories are required to accommodate all of the inspection steps. Likewise, with a proportion of all production being scrapped, manufacturing will need to buffer that with higher production levels as well. Greater waste will be generated as value is added to defective product. Management must be willing to tolerate the loss of entire lots of product, as some errors will be unrecoverable. In the example above of a metal stamped part with a hairline crack, it would be impossible to determine the extent of the nonconformity, and presumably it would affect all parts stamped with that die. In that case, all of that lot and every lot manufactured since would have to be scrapped or substantially reworked.
In order to have quality system based on controlling product, robust systems for material control, calibration, maintenance, and rework (as applicable) are required. The process starts with material control. Segregated areas for material hold pending inspection, hold pending rework, hold after rework, rejected materials, and released materials are recommended as a minimum. If there are multiple inspections, further areas are advisable to prevent the product from bypassing an inspection step. Regardless of the nature of the material control, the FDA will be most concerned with assuring no mix-ups occur between any of the areas, ensuring all of the product goes through every inspection step, and that unreleased product does not leave the facility. Will the product be adequately labeled indicating inspection status? What happens if a single unit is found outside of the hold areas? Is it scrapped or does a cost conscious operator mistakenly put it in the released area?
Keeping the equipment calibrated and maintained will be even more critical in a product control quality system since it is really the only evidence that the product meets requirements. Any problems or shortcomings of the equipment can have disastrous consequences (i.e. recall). All measurement equipment used to verify the product meets the requirements will have to be calibrated and maintained in accordance with approved procedures. The measurement procedures will have to be shown to be accurate and precise with respect to the application. For example, a syringe will have a specification for diameter. The organization may choose to use pin gauges to verify the diameter is within the specification. In order to do this, the gauges will have to be kept calibrated, free from dirt, grease, and corrosion, and approved procedures on how to execute the measurement developed. Are inspectors suppose to use every pin gauge to get the exact measurement of the diameter or can they just use the gauges corresponding to the specification limits to verify the diameter is within specification? Agency concerns will be ensuring that the calibrated equipment is used and not substituted for another, all of the procedures are followed as directed, the measurement procedures are validated, and if the equipment is subsequently found out of calibration, how was product quality assured. This will drive calibration frequency, as well. If a measurement is made with a piece of equipment calibrated quarterly, what happens if it is found out of tolerance? All of the product released over the last three months is now in question, and in a product control quality system, there is little to fall back on to ensure the product is within specification.
If rework is possible, then this will be an area of great concern to the agency. In a product control environment, routine rework and the redress of nonconforming product will be closely scrutinized. The rework procedures must be very precise as to which kind of defects they apply to, which product stages they apply to, and how the rework will be verified as effective. It goes without saying that the rework procedures will have to be validated. Additional attention must be paid to ensure that the non-conforming product has been completely redressed to bring it to the level of regular product.
Process Controls
Process controls are quality systems based on preventing defects by controlling and monitoring manufacturing processes. Because no defective product is produced, these processes can achieve much higher quality levels than a system based on product controls. Processes must be rigorously characterized, understood, and controlled for this system to be effective. For example, a pharmaceutical manufacturer typically combines a number of drug components into a heated batch reactor, mixes them thoroughly, dries them in a granulator, and compresses them into tablets. Process controls for this operation would include specifications on batch size, mixing speed, drying temperature, mixing temperature, drying time, mixing time, and speed at which pellets are compressed. These are distinct from product specifications in that they will be different depending on the equipment used.
While process controls are less focused on final product inspection, they can be difficult to implement with the increased requirements on documentation, calibration, and measurement equipment. Since the manufacturing process must be well understood, quality systems based on process controls tend to have more procedures. Specifications increase greatly as the focus shifts from product to process. A single product requirement, like the tensile strength of a catheter, could be translated into several extrusion process controls. Cooling bath temperature, screw speed, extruder temperature, and air temperature could all be defined in the process specifications. Furthermore, these additional controls must be measured with calibrated instrumentation. In some cases, instrumentation will have to be developed or improvised. If a chemist makes a batch in a beaker on a combination magnetic stirrer / hot plate, he or she may have no idea of the exact volume, mixing speed, and average temperature. Beakers are not that accurate, stirrers typically have a knob from 1 to 10, and hot plates do not evenly heat. In order to implement process controls, a method for measuring the temperature, stir speed, and volume would have to be developed. While a calibrated thermometer and tachometer would do for part, detailed procedures on how much material is added would be required to ensure constant volume.
Management expectations must also be aligned with the realities of process controlled operations. With the increase in specifications, the organization must be very disciplined about following procedures. While some claim this stifles innovation, in truth it reduces variation permitting a better understanding of cause and effect. Management also must come to terms that process specifications will be just as important as product specifications, and they are an accept/reject criterion. It is one thing to scrap a lot of product that is clearly nonconforming, but it is something else to trash a lot of product because an abstract parameter was out of tolerance. For example, if a plastic coating process leaves uncoated segments of wire, it is clearly defective and can be scrapped without too much fuss. Alternatively, if the same plastic coating process ran at a line speed beyond the tolerance and studies have shown that this will lead to thin spots in the plastic, but they are not observable, some managers will balk at rejecting this product. Management must also be willing to tolerate the increased costs associated with calibration and hiring statistically literate personnel. Process controls often require statistics to determine optimum set points and monitoring frequencies.
The two most important quality systems in a process control environment are process validation and change control. Because the process specifications will be used to release product in lieu of product inspections, the process validations will be more numerous and rigorous. Validations for assembly, packaging, cleaning, software, utilities, and general manufacturing are all common to process control environments. Each process should be shown to be statistically capable with process capability indices in excess of 1.33. Change control must also be thoroughly implemented. This includes changes to equipment, software, hardware, and gauges used in validated processes. Often these changes are presented as like-for-like, but often process controls are equipment specific and the response of a motor, gauge, or sensor may be different depending on the supplier. A change that would be easily approved in a product control environment can require complete revalidation in a process control environment.
The FDA generally looks favorably upon process controls since they lead to higher quality product. Be assured they will closely examine equipment validation files, change controls, and product release records to ensure they are all in alignment. It is important that all of the process parameters identified during validation are reflected in the ongoing inspection records for the production lot. This can also be audited by a physical walk-through to ensure that all of the gauges specified in the batch records are present and working.
Conclusions
Which system is better? Product controls are usually quicker and easier to implement with more variability permitted in the processes. Oftentimes, the higher margins associated with FDA regulated products cushion the economic impact of running a product control operation. Process controls are definitely more compliant than product controls and have less overall cost. Unfortunately, many organizations are unable to achieve process controls because of the discipline required. A hybrid operation is then implemented incorporating some of the elements of process controls, but relying on a final product inspection as a final check of the process.