Non-GMP in a GMP World: Does it Really Exist?
Specific strategies, when implemented, can permit “not for GMP” activities to co-exist within a GMP world
During routine operations of a pharmaceutical laboratory or formulation group, there are times when data generated or the product formulated is not intended for a regulatory purpose. Confusion sets in as to whether the use of qualified equipment or approved excipients is needed. The lines between compliance and non-compliance become blurred and many quality questions arise. Can non-GMP exist within a GMP world?
The focus of this article is to determine if there really is such a thing as non-GMP. Specific strategies and redefined terminology will be presented that, when implemented, can permit “not for GMP” activities to co-exist with that GMP world within your laboratories.
Batter up…
Ever attend a baseball game early enough to see the groundskeepers putting down the foul lines? They mark the baselines with great accuracy. Next comes the placement of the batter’s box, again perfectly aligned with the foul lines. The game starts and the first batter comes up, digs in, and begins to blur the lines immediately with their shoes expanding the batter’s box and removing all the precision—all part of the game. This analogy can be applied to the notion of current good manufacturing practice (cGMP) versus non-GMP. To some in industry, this terminology becomes the faint blurred lines or, “how can I make the box bigger?” But in practice, cGMP and non-GMP are conflicting terms, directly opposed from each other. Compliance versus a state of non-compliance. But is it really?
Say it isn’t so
You can hear the quality assurance folks out there gasping for air. In unison chanting, “Non-GMP, there’s no such thing, there’s no such thing.” I suggest it does exist but requires a better definition, some clarification, and examples. As a laboratory manager there are activities within your laboratories that might be considered “non-GMP”; however, I would suggest they are actually “Not to be used for cGMP” (NGMP). This becomes the basis of redefining this expanded terminology. As the former implies lack of compliance (non-GMP) and the latter (Not to be used for cGMP) defines the non-suitability of any data or product generated for use to support a GMP activity.
Routine analysis
If you’re the lab manager in a contract analytical business, you may be providing both “mom and pop” as well as GMP services. The mom and pop clients are usually just looking to determine chlorine in their pool water, maybe a simple ICP metals scan, or a researcher confirming if their chemical synthesis is within theory (e.g CHN analysis). Advantages are low cost, quick turn-around. A disadvantage is that analyses usually are performed with internal non-qualified methods. But there can be some hidden advantages if the equipment has been previously installed and qualified, SOPs created, analyses performed by qualified personnel, and the equipment is maintained and calibrated. Thus, your laboratory could use the same equipment for GMP or NGMP.
The important point is that non-regulated data was generated and reported on qualified equipment. Further advantages are that with qualified equipment, additional efforts for method development/qualification/validation may permit data to be used for submissions to regulatory agencies. These types of GMP services are usually provided to the client at a higher fee. Thus, the two worlds do not actually collide!
Formulations
If your operations provide pharmaceutical formulation or developmental services, the question always arises if it is necessary to use GMP materials in that process. Discussions with staff or quality are usually based on whether the use of qualified equipment or approved excipients was needed. Many times, confusion sets in. To clarify, let’s use the excipient lactose as an example. It might come as USP, NF, BP, JP, EP grades, different particle sizes, granulation, density, flow, and so forth. When developing a formulation, each of these characteristics may require evaluation and usually the same excipient is provided by multiple vendors. Under a quality management system, vendors must be pre-qualified prior to GMP use.
What about the time and cost to do that? Plus, evaluating hundreds of excipients for formulation can generate years of untracked inventory, undue compliance risks, and cause significant disposal issues.
If we look at this as NGMP, then as a laboratory manager, implementing a chemical inventory tracking system and proper labeling can provide better control and compliance. Consider how inventory management can track expiration dates, generate labels, assign unique identifiers, and provide data for any local, state, or federal hazardous waste recordkeeping. When multiple bottles of lactose appear, inventory tracking and assigning a unique identifier permit materials to easily move around the facility based on categorization of GMP or not for GMP.
Two concerns for consideration—the first being the need for spreadsheet validation and the second being the control of formulated product not intended for use in patients. As to spreadsheets, lab managers must determine if the tracking technique requires software verification or validation1, 2. This is based on workbook files access and determination of whether the workbook files are for single-user or multi-user applications.
As to experimental products, formulations should clearly be marked “Not intended for clinical use” and given an expiration date for destruction. For example, all Swedish-orange DB-AA capsules look the same. It becomes difficult to visually know clinical from non-clinical materials. Many labs have sample storage areas where clinical drug products are stored next to research samples. Identifying the status of formulation products is critical to maintain compliance. Otherwise, years of inventory of outdated formulation products just keep building.
Instrumentation/computerized systems
Bringing new equipment into any lab comes with challenges—finding bench space, making connections, miles of wires, documents, and procedures. But how do you just turn on that new toy and learn how to use it? In the GMP world, this would not appear possible. Since equipment is not qualified or validated, how is it possible to use it?
After installation and qualification, the intended application may not require GMP, but the equipment sits right in the middle of your GMP operations. Develop a system to identify the status or suitability of the equipment to perform certain GMP or NGMP tasks. Consider a visual identifier (e.g. color-coded tag) that indicates such categories as “Special purpose”, “Not to be used for cGMP” or even “Out of service”. This quickly identifies status and permits the system to be used until either: (1) the system is fully validated or (2) system is deemed not compliant for GMP use. Equipment can have multiple tags, indicating use for GMP and not for GMP activities based on acceptance criteria or ranges.
Suitability tags work within the framework of USP<1058> Analytical Instrument Qualification, where instrumentation is categorized into three distinct groups (e.g. A, B, C) and appropriate strategies for your lab’s metrology can be maintained. As lab manager, you can decide what level of compliance is needed based on expected use and can jump back and forth between GMP and NGMP.
Summary
This article has shown that being “non-GMP in a GMP world” is better defined as “Not to be used for GMP”. The concept of non-GMP is related only to non-compliance of regulations. However, during laboratory or formulation operations there are times when data or drug products are generated for use that is not needed to support a GMP activity. As lab managers, using the concepts provided based on the examples and suggested techniques, you can make this work in a GMP world. Of course, the downside is that it can become difficult to manage compliance and non-compliance events. Quality assurance and your analysts/formulators can become confused as to whether is this for GMP, not for GMP. With a good quality systems in place, even if that first batter or the next digs in and blurs the lines a bit, the two concepts can be managed and co-exist.