The pharmacy cleanroom recommendations herein are for educational and discussion purposes. Each cleanroom and its applications have unique cleaning requirements. At no time should this guidance replace existing documents and procedures established by the pharmacy facility unless written permission is obtained from the facility manager. Consult your cleanroom standard operating procedures for protocols specific to your critical environment.
Current Good Manufacturing Practices (cGMP) are a large set of complex regulations, directives, and guidelines with a simple goal: total quality management of the manufacturing process to ensure products are produced with consistency and carefully controlled to quality standards that are relevant for their intended use.
cGMP applies to FDA-governed manufacturing in areas such as food, cosmetics, medical device, and pharmaceuticals. For pharma manufacturing in the US, the FDA 21 CFR parts 210 & 211 are a central focus of the minimum requirements for the guidelines. 210 deals with the manufacturing process and 211 with the Quality Control lab that is paramount to effective pharmaceutical production and control ensuring cGMP is followed and any incidences are investigated, and learning incorporated into the facility’s procedures.
Implementing and rigorously updating and following written procedures for your facility’s cGMP compliance reduce the inherent risks of drug and other medical-related production.
Various international and national guidelines influence cGMP for pharmaceutical products. The codes, guidelines, and directives tend to complement one another. As an example, to clarify its cGMP requirements, the FDA adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.
The FDA has produced 34 different, but supporting, final guidance documents for cGMP in the pharmaceutical industry. Each of these addresses various areas such as process validation, quality metrics, and data integrity.
Pharma facilities should adopt standards that are related to where the facility is located and where product is sold. It is important to note that implementation of cGMP is not about rigid procedures though written standard operating procedures that are consistently followed are of utmost importance. But rather, the guidelines should be used to implement an approach of total quality management (TQM). As regulations and processes change, checklists and procedures must change but within a framework of quality management.
This brings up one point of confusion for many: the differences between ISO and GMP.
GMP deeply addresses pharmaceutical product quality because it is specifically written for the industry. ISO, being a standard for all types of industries, is general by nature, but stronger than GMP in addressing high-level management responsibilities for quality systems, continual process improvement, and targeting important aspects of internal customers and external customers. ISO helps organizations monitor, evaluate, and drive improvements in all areas.
To further explain, ISO 9001 requires measurement of the quality systems’ effectiveness and of customer satisfaction. FDA 21 CFR Parts 210 and 211 have a focus to ensure that the products are safe, pure, and effective. GMPs center on safety and efficacy. ISO 9001 has a focus on the effectiveness of a quality management system in meeting customer requirements.
The importance is to recognize that GMP and ISO are not at odds but are symbiotic. A facility’s quality system benefits from the depth and specifics of cGMP and the ISO’s influence to improve and evolve. The standards very much support one another with similar focuses on written procedures, records management, application of good statistical practices, personnel training, equipment maintenance, product identification, etc.
There is a big difference between GMP and ISO in that manufacturing facilities of pharmaceutical products sold or distributed in the US are legally required to comply with GMP. There are no US legal requirements for any organization to comply with the ISO 9001 standard.
Why the small “c”? Use of “current” to qualify the FDA’s good manufacturing practices is to ensure that manufacturers fully acknowledged that the GMP is not a static checklist. Facilities must utilize processes, technology, and systems that comply with the regulations as they are today. Implementation of a facilities standard operating procedures that comply with GMP can be best kept current utilizing concepts such as ISO’s total quality management.
cGMP focuses on quality in various areas to reduce risks of cross-contamination and mistakes (such as incorrect labeling):
- Operating Procedures
- Raw Materials
- Management Systems
- Detecting Deviations
- Investigating Deviations
- Reliable Testing.
If cGMP regulations are followed, organizations can avoid many of the most common causes of quality failure which threaten patient safety, such as drug contamination, deviations, or mix-ups.
These historical cases illustrate what can happen when cGMP is not followed resulting in a failure in product quality:
- 5 deaths occurred in Devonport, UK, when dextrose intravenous solutions became contaminated and consumers became infected. An undocumented change to autoclave operation that was only orally communicated among staff produced products that were not uniformly sterile.
- The U.S. Centers for Diseases Control and Prevention reports 751 patients in 20 states contracted fungal meningitis infections after receiving steroid injections produced by Michigan-based New England Compounding Center in 2012. 64 died.
As in these examples, any number of events can be the issue such as inadequate maintenance, equipment malfunctions, lack of training or inadequate understanding, or failure to follow SOP. The cGMP is the framework that helps pharmaceutical manufacturers protect the ultimate customer, the consumer.
The FDA utilizes inspections and enforcement to ensure the consumer is best protected. The enforcement activity generally matches the infraction and history of infractions. The least punitive is a letter requesting correction of the violation with more serious violations being addressed actions such as seizure of violating products, court injunction to prevent further violations, up to criminal prosecution of the individuals or the company. Prosecution may result in imprisonment of up to a year for each offense and/or fines.
Misdemeanor fines governed by the Criminal Fine Enforcement Act of 1994 provide for fines are applicable for each convicted misdemeanor offense:
- Up to $100,000 for an individual’s offense that does not result in death.
- Up to $200,000 for a corporation’s offense that does not result in death.
- Up to $250,000 for an individual’s offense that results in death, or for a felony.
- Up to $500,000 for a corporation’s offense that results in death, or for a felony.
Being compliant with GMP regulations not only helps you avoid prosecution, but it is also good for your company’s business. Following GMP reduces materials waste and other expenses of batch recalls and keeps its reputation intact by avoiding bad news in the headlines. But even more importantly, it is good for consumers as GMP decreases the number of people who have adverse reactions.
Each facility must address key areas to ensure that GMP is fully implemented and effective:
Create and maintain a quality team – personnel focused on compliance and improving quality. Select a well-trained and experienced member from each department such as operations, validation and testing, storage, maintenance, and distribution to build a diverse quality team capable of analyzing and identifying root causes of problems.
Implement a Quality Assessment process – once the quality team identifies a problem’s root cause, they determine if it has the potential to deter the GMP compliance. They develop improvement measures to prevent future problems or errors.
Implement validation processes throughout – GMP requires an ongoing documented validation process focusing on the following aspects:
- Process validation
- Cleaning and sanitation validation
- Computer system validation
- Analytical method validation.
Conduct regular surprise audits – unexpected audits in every department gives a clear view of the level of GMP compliance and points to sources of non-compliance. Frequent internal audits prevent systems from breaking down further over time and prepare your facility for formal FDA inspections. You may find the following FDA GMP audit preparation checklists useful in conducting your internal audits:
Provide your staff GMP compliance training – The most effective means of compliance is personnel education. All staff in your facility before beginning work, should receive training on record-keeping, equipment handling, labeling, specific facility procedures, etc. Guidelines, manuals, instructions, and principles are of no use if staff are unaware of their content and importance. In some key areas that are persistent issues in FDA audits such as good GMP aseptic technique when working under a clean bench, more frequent training and audits can produce much-improved results for the company and the consumers of its products.
Now that you have a deeper understanding of cGMP’s purpose, meaning, and importance, we will address the area that Cleanroom Connection can help you with directly. Proper cleaning of a pharmaceutical manufacturing cleanroom to meet GMP requirements is often a point of failure.
Pharmacy managers are responsible for their cleanrooms’ hygiene, but frequently are not well-versed with cleanroom technology. Our cleanroom-trained consultants are often asked what the most effective and/or economical ways there are to clean and disinfect each zone of their pharmacy cleanroom.
Having well-trained cleanroom staff regularly performed written cleanroom cleaning procedures to remove dirt, grime, oils, and micro-organisms as well as to disinfect is essential for safe operation of pharmacy cleanrooms. And are required and influenced by USP guidelines. Key points from regulations including ISO 14644-1 (2), VDI 2083 (3), and GMP that should be included in your overall cleaning procedures are:
- Risk assessment process with corrective measures
- Validation of cleaning and disinfection processes and their documentation (SOP)
- Regular monitoring for effectiveness of cleaning and operational procedures
- Use of apparel and equipment (mops, wipes, etc.) suitable for the cleanroom’s applications
- Effective disinfectant plan that assures compatibility with all products used in sterilization.
All cleanroom cleaning and disinfection products in a pharmacy’s GMP A/B areas must be sterile. We recommend purchasing sterile consumables to eliminate the need for on-site autoclaving. Following autoclaving procedures can be a point of failure in pharmacy cleanrooms so procuring sterile cleanroom cleaners, mops, wipes, and apparel is the best choice.
Cleaning equipment as with all items introduced into your sterile cleanroom should be disinfected the first time it is brought into a cleanroom. Regular disinfection, usually with sporicide, also, is necessary.
Another often overlooked attribute of cleanroom cleaning equipment is ergonomics. Well-designed equipment is good for work safety and worker morale. Consider telescopic handles, touch-free cleaning devices, extendable handles, lightweight construction, and other features that make cleaning faster, easier, and more efficient. The better the ergonomics, the more likely cleanroom cleaning procedures are followed to the letter.
One of our most recommended products for pharmacy cleanrooms is Hydroflex PurMop disposable mop with 2.0 ERGO touchless mopping system. The mop not only emits a low level of particles and fibers as is called for in the guidelines but are durable and have excellent ergonomics One of the best attributes is that it is disposable reducing risk of contamination spreading from an improperly sanitized mop or through abraded, worn-out materials used over time. Especially in the manufacture of cytotoxic chemotherapy, reusable mops cannot be guaranteed to be completely free of residues after washing.
Include procedures in your cleaning processes that define when the disposable mop should be discarded, and a new unused mop used for the next area.
Another important area of concern is that equipment such as trolleys, mop handles, and frames be constructed from compatible materials that will not rust, pit, or otherwise degrade with the use of the assigned cleaners and sterilants. We recommend stainless steel, which has a higher resistance to disinfectants, autoclaving cycles, and wear from general use.
Choose your cleaning system based on cleanroom size and areas which determine the number of mops required. For most pharmacies and small cleanroom areas, smaller cleaning solutions that require less space are recommended. For example, trolley use can be eliminated by choosing to use ready-to-use presaturated mops.
Our cleanroom consultants can help you select the right cleanroom wipes for your cleanroom applications and cleaning needs to eliminate contamination (particulate or microbial).
Nonwoven wipes made from polyester/cellulose, polyester microfiber, or polypropylene are not washed so their use can be a significant source of contamination. Nonwoven wipes should not be used near the pharma product such as in workbenches or isolators.
Knitted wipes made from 100% polyester knit, polyester microfiber knit, or blends offer an exceedingly high purity with low linting and particulate emissions as they are meticulously laundered and dried with ultra-pure air inside a cleanroom facility. The washing process removes most residues. Knitted wipes are designed for use on critical surfaces such as GMP A/B areas.
Additionally, wipes should be matched to their purpose:
- Microfiber for cleaning
- Presaturated wipes for liquid release
- Dry, absorbent wipes for absorption.
Presaturated cleanroom wipes offer many benefits including saving of time and effort, avoiding overspray, using the correct amounts of solution, and higher efficiency). Proper soaking levels with solution are vital for proper disinfection. Wipes that are too dry will not disinfect effectively; too wet, results in costs of wasted solution and additional drying or wiping time.
Convenient presaturated wipes are available in combination with various biocides and sporicides.
The GMP stipulates use of several disinfectants with different spectrum of efficacy including one that eliminates spores. Note that effective sporicidal disinfectants are oxidizing agents making them aggressive and harmful to staff health and are a frequent cause of equipment finish damage. Sporicides should be used as often as necessary, but as little as possible. A common cycle for sporicidal disinfection in pharmacies is once per week for A/B areas and once a month in C/D areas.
To select the best disinfectant protocol, designate one disinfectant in each category then adjust, if needed, after performing an internal risk analysis and completing a validation. Depending on the cleanroom requirement and product application, surface type, along with the risk assessment, disinfectants and sterilants are selected with corresponding application frequencies (daily / weekly / monthly) set in the cleanroom hygiene portion of the SOP.
Typical for disinfection of surfaces of any kind are alcohol based, residue-free disinfectants such as isopropanol 70 / 30. Mostly other types of disinfectants that create residues are used only for floors. An additional cleaning step must be specified to remove residues.
We recommend pre-mixed, ready-to-use disinfectants, especially in small rooms such as in pharmacies where the mixed fluid often must be disposed of because it cannot be completely used in one cleaning session. Pre-mixed solutions also eliminate the risk of dosing errors and the need for additional solutions such as WFI quality purified water.
Disinfection by wiping is superior in effectiveness over spray disinfection. Presaturated mops and wipes offer significant advantages in handling, time-savings, and safety. And the additional cost of presaturated consumables is not as high as you might think when you consider waste, time, and potential for safety lapses due to errors.
What: Production areas such as laminar air-flow workbenches and barrier isolators
When: Disinfect before and after the manufacturing process and, in most cases, during the shift.
Sterile isolator cleaning tools that are basically small mop pads should be used for side and rear panels to prevent cleaning staff from having to lean in over the manufacturing area. Presaturated is recommended for proper dosing and convenience.
- Optimal disinfecting cleaning solution is sterile isopropanol 70 % with WFI quality water 30%.
- Periodic sporicidal disinfection should be a part of the cleaning procedure.
In some cases, the additional safety of an alkaline cleaning step to inactivate proteins and cytostatics is helpful.
- After disinfection using proper biocide hold times defined in your standard operating procedure, a rinse step may be recommended by the biocide manufacturer. If so, use purified water with lint-free wipes or mops to remove the residues and to prevent corrosion of equipment and material.
What: Materials, equipment, furniture, and supplies brought into the cleanroom, especially non-sterile items
When: Disinfect before bringing into critical environment
Airlocks make it possible to disinfect using VHP (Vaporized Hydrogen Peroxide, H2O2).
Alternatively, manual wiping or an autoclave cycle can be used to disinfect.
- IPA 70/30 for manual disinfection
- A sporicidal agent is also recommended.
Our cleanroom experts can help you ensure your cleaning and disinfecting chemicals are compatible with your cleaning tools and are appropriate for your application. We make product selection and ordering simple with free samples on all our cleanroom supplies and apparel. And all our cleanroom supplies prices are guaranteed to be the lowest.