Good Manufacturing Practices or GMP is a system that consists of processes, procedures, and documentation ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

GMP covers all aspects of production, from the starting materials, premises, and equipment to staff training and personal hygiene. Detailed written procedures are essential for each process that could affect the quality of the finished product. There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process – every time a product is made.

DEFINITION

Good Manufacturing Practices (GMP) are a set of regulations for manufacturers, processors, and packagers of drugs, medical devices, certain types of food, and blood to ensure the safety, purity, and effectiveness of these products. Without such GMP regulations, even well-designed drugs and medical devices may become ineffective and unsafe from defects, contamination, mislabelling, and other errors.

Why “Current” GMP?

Good Manufacturing Practices (GMP) and current Good Manufacturing Practices (cGMP) are, in most cases, interchangeable. GMP is the basic regulation promulgated by the US Food and Drug Administration (FDA) under the authority of the Federal Food, Drug, and Cosmetic Act to ensure that manufacturers are taking proactive steps to guarantee their products are safe and effective.

The “c” stands for “current,” reminding manufacturers that they must employ technologies and systems that are up to date to comply with the regulation. Systems and equipment used to prevent contamination, mix-ups, and errors, which may have been first-class a decade ago, maybe less than adequate by current standards.

It implies a constant commitment to the highest quality standards using up-to-date systems and technologies.

Why GMP is Important in Pharmaceuticals

Errors with a product can’t all be caught in a quality control laboratory. If there were no common GMP guidelines to follow at the manufacturing stage, there would be no way for regulators or manufacturers to know that every unit in a particular batch would be made to the same quality and same level of safety as whichever units were tested in the quality control laboratory.

So, GMP protects consumers/patients from the risk that they will purchase something with a dosage that is too high or contains a certain allergen that it’s not meant to. On the other hand, manufacturers following these best practices protect themselves from the potential liability of producing a faulty product that causes customer harm.

FDA inspects pharmaceutical manufacturing facilities worldwide for current Good Manufacturing Practice (cGMP) compliance, including facilities that manufacture active ingredients and the finished product. If a company is not complying with cGMP regulations, any drug it makes is considered “adulterated” under the law. This kind of adulteration means that the drug was not manufactured under conditions that comply with cGMP.

In the past few years, the FDA has issued numerous warning letters, import alerts, and seizures to manufacturers of finished products for violating the current good manufacturing practice regulations.

Trends In FDA FY2023 Inspection-Based Warning Letters

The U.S. FDA issued 180 warning letters to drug and biologics manufacturers in fiscal year 2023 (FY23).

Top Five Citations FY 2023

In FY2023, the FDA’s top five most frequently cited regulations in inspection-based warning letters were:

1. 21 CFR 211.100(a): Failure to establish adequate written procedures for production and process control, cited 38 times.
2. 21 CFR 211.22: Failure of quality control to ensure compliance with cGMP, cited 38 times.
3. 21 CFR 211.84: Failure to test and approve or reject components, containers, and closures, cited 37 times.
4. 21 CFR 211.192: Failure to thoroughly investigate discrepancies or failures, cited 30 times.
5. 21 CFR 211.165: Failure to test before release for distribution, cited 27 times.

These citations highlight recurring compliance challenges in the pharmaceutical industry, particularly regarding process control, quality assurance, and thorough investigations of discrepancies.

The “hit list” of the ten most common Good Manufacturing Practices (GMP) deficiencies remains consistent with previous years.

Analysis of Top 10 Most Common GMP Deficiencies

Analyzing the top 10 most common Good Manufacturing Practices (GMP) deficiencies reveals persistent challenges within the pharmaceutical industry. These deficiencies include quality control, documentation, laboratory practices, equipment maintenance, and personnel qualifications.

The high number of citations issued for violations related to the responsibilities of the quality control unit (21 CFR 211.22(d)), production record review (21 CFR 211.192), and laboratory controls establishment (21 CFR 211.160(b)) underscores the importance of robust quality management systems in ensuring the safety and efficacy of pharmaceutical products.

Furthermore, deficiencies in written procedures for production and process control (21 CFR 211.100(a)), stability testing programs (21 CFR 211.166(a)), and equipment cleaning and maintenance (21 CFR 211.67(b) and 21 CFR 211.67(a)) highlight gaps in manufacturing processes that can potentially compromise product quality and patient safety.

Good Manufacturing Practices (GMP) Case Studies

Quality System – Case Studies

Quality System – Case Study 1 – Contract Manufacturing

Background:

• A pharmaceutical manufacturing firm utilizes multiple contract manufacturers to make the products they market.
• Several of their contract manufacturers have received Warning Letters for cGMP problems.
• The review of material from contractors consists of checking only the Certificate of Analysis.

What Happened:

• FDA inspected the firm and investigated that products from contract manufacturers are not reviewed vs specifications.
• Multiple complaints and stability failures were inadequately investigated.
• FDA issues Warning Letter for cGMP deficiencies, including lack of oversight by the quality unit.

Takeaways:

• Firms that market their products are ultimately responsible for the quality of their products, regardless of who manufactures them.
• Manufacturers are responsible for the quality of their products and the reliability of associated test results regardless of who tests them.

Quality System – Case Study 2 – Microbiological Environmental Monitoring

Background:

A pharmaceutical manufacturer recently received a Warning Letter from USFDA due to issues with the topics of “test methods,” in particular, the sterility test and employee qualification; this Warning Letter focused on deficiencies in microbiological environmental monitoring. FDA Warning Letters refer to corresponding chapters of 21 CFR Part 211:

“Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv))

What Happened:

• The routine identification of all isolates found in the bottling environment was not performed.
• According to the SOP, the isolates were grouped according to their morphology and only one isolate from each group was routinely used for species identification.
• In the personnel monitoring programme, there were alarm and action limits of 3 and 4 CFU/plate respectively. The FDA expects that the employees there will remain free of contamination and the limits will be adjusted accordingly. Any growth in the number of people working within the ISO 5 range should always trigger an appropriate investigation.
• In response to the deficiencies, the firm stated that it was revising its microbial identification procedures to identify all “Grade A” and “Grade B” isolates. The grouping of isolates should be refined based on area, operational status, area classification, sampling, and morphology.
• FDA issued Warning Letter for cGMP deficiencies considering the answers to be insufficient. FDA lacked requirements for the identification of microorganisms at species or, if applicable, genus level. These identified microorganisms should have been entered into a database.

Takeaways:

• Comprehensive personnel and environmental monitoring programs must be established including sampling locations, sampling frequency, alarm and action limits, adequacy of sampling techniques, and trending programme to demonstrate robust aseptic filling environment conditions.
• Corrective and preventive actions (CAPA) must include a comprehensive, independent, and retrospective review of personnel and environmental monitoring data.

Quality System – Case Study 3 – Supplier Qualification

What Happened:

• Supplier Qualification and the respective contracts in outsourcing activities are always hot topics in inspections. USFDA issued a Warning Letter to pharmaceutical firms criticizing their quality and supplier oversight.

Background:

• The inspected firm “lacked a Quality Unit with appropriate oversight over the drug manufacturing and testing operations” which were conducted by their contracted facilities. The firm was not able to assure manufacturing records and test results were not adequately reviewed and approved, and it seemed that drug products batches were released without a complete “satisfactory product quality testing” by the contractor.
• Even worse, the contract manufacturer used was listed on the USFDA’s Import Alert. The firm was not aware of this and had to be informed during the inspection.
• In the Warning Letter, the FDA pointed out that “FDA regards contractors as extensions of the manufacturer” and recommends that the firm will “properly evaluate and qualify” all their suppliers and change the source of supply, where appropriate.

Takeaways:

• FDA regards contractors as extensions of the manufacturer; hence it is the manufacturer’s responsibility to qualify the GMP compliance of the supplier.

Quality System – Case Study 4 – Quality By Design

Background:

• Three pharmaceutical manufacturing companies: A, B, and C
• These firms manufactured prescription and OTC products under NDAs, ANDAs, and Monographs

Company A:

• For a coated tablet, operators visually determined the end point of the coating cycle.
• In two years, over 150 batches filed for dissolution, with a suspected root cause involving under and over-coating; firm utilized release testing to support partial lot releases of over 60 batches.

Company B:

• The company manufactures multiple tablet products with tablet coating, shape, color, impurities, and uniformity of finished product problems.
• The routine practice involved resorting to removing the non-conforming tablets they could find and releasing “conforming” products.

Company C:

• Found raw materials with high levels of impurities, problems with tablet shape, uniformity, etc., with up to 75% rejection rate.
• Complaints were received over the years.

What Happened:

• Warning Letter, Recalls
• Multimillion dollar fine
• Criminal Investigations
• Site shut down by parent firm
• Seizures
• Culminated in Permanent Injunction

Takeaways:

• “Quality cannot be tested into products; it should be built-in or should be by design.”

Quality System – Case Study 5 – Lack of Validation of the Aseptic Manufacturing Process

Background:

• A Biological Product manufacturer of human cellular and tissue-based preparations (umbilical cords, cord blood, amniotic fluid, etc.) was found to deviate from the regulations of current Good Tissue Practice(cGTP; 21 CFR 1271), but also the basic requirements of Good Manufacturing Practice (cGMP; 21 CFR 211).
• As the products of this firm all undergo aseptic manufacturing processes, the main risk is the occurrence of non-sterile batches. During their investigation, the inspectors found a high number of non-sterile batches – 152 in 8 months – which is not surprising given the lack of minimum GMP standards.

What Happened:

The Warning Letter describes the following GMP violations:

Validation of aseptic manufacturing processes (21 CFR 211.42; 211.100; 211.113)

The methods used to produce sterile preparations were not validated. There were no instructions for gowning and behaviour in the cleanroom nor there was adequate environmental monitoring.

Cleaning and maintenance (21 CFR 211.67)

Cleaning protocols for the sterile workplaces and their maintenance were not available, and the cleaning procedures were not validated.

Batch records (21 CFR 211.188)

Although there exists an SOP for the individual steps of the aseptic production process, documentation on these steps with details of times was missing.

Takeaways:

• Aseptic operations and processes must be validated for all sterile preparations.
• Proper cGMP instructions for gowning and behavior in the cleanroom must be followed.
• Cleaning activities and cleaning procedures must be validated.
• Each aseptic process step activity must be documented in the respective batch record.

Production System – Case Study

Production System – Case Study 1- Process Design

Background:

• A pharmaceutical manufacturing firm markets an extended-release tablet.
• Production includes the manufacturing of extended-release “beads,” which were blended with excipients before tablet compression.
• Operations have to pre-compress blend samples in the lab to determine operating parameters for tablet compression.
• Different blends require different settings, and the firm has no idea why.

What Happened:

• During routine FDA inspection, investigators observed the pre-compression practice.
• Investigators also found inadequate release testing, especially considering known process problems.
• Warning Letter was issued for lack of process validation.

Takeaways:

• Operational parameters should be selected using a risk-based, science-based approach.
• Process design/qualification must be completed and adequate before the distribution of the product.
• Knowledge gained during scale-up should be incorporated into process design/control strategy.
• Sampling plans for batch release should be scientifically sound.

Production System – Case Study 2 – Cross-Contamination

Background:

USFDA has recently issued a Warning Letter to a large pharmaceutical manufacturer following an inspection that revealed poor cleaning and later detected cross-contamination in manufactured tablets. Further, GMP violations, such as leaking HEPA filters and inadequate smoke studies in the sterile area, were detected.

What Happened:

Tablet Facility

Cross-contamination

• During the inspection, the FDA noticed insufficient cleaning of non-dedicated equipment in tablet production. Residues of what appeared to be different products inside the exhaust ducts were discovered.
• The analytical examination later revealed that these were indeed residues of various products. After the inspection, 7 of 268 batches of reserve samples were also found contaminated with another product.

Takeaways:

• A comprehensive Risk assessment is key to evaluating the probability of cross-contamination in a multi-product facility.
• A comprehensive cleaning validation program should be established to avoid cross-contamination in a multi-product facility.
• Exhaust ducts and other critical manufacturing equipment should be considered during the cleaning validation program.
• A comprehensive investigation and evaluation of cross-contamination and CAPA measures should be established to remedy the deficiencies.

Sterile Facility

HEPA Filters

• Another aspect of the Warning Letter concerns noticeable HEPA filters in the manufacturer’s sterile area. The majority of the HEPA filters had side leakages.
• The manufacturer had not sufficiently investigated this accumulation of filter integrity test failures. According to the manufacturer, gasket deterioration and lack of timely filter replacement were the most probable causes.
• In this context, the FDA noted that some filters had been installed many years earlier and that the manufacturer’s specified service life had long been exceeded. The FDA also lacked a retrospective view of which products/batches could be affected by the filter errors.

Takeaways:

• The integrity of HEPA filters is extremely important to ensure aseptic conditions.
• A comprehensive regular maintenance program should be established to assure the integrity of HEPA filters.
• A root cause analysis should be conducted to determine why so many adjacent HEPA filters failed in such a short period.

Smoke Studies

• The FDA also disapproved of the smoke studies, which are supposed to prove the correct unidirectional flow in the aseptic area.
• The data could not demonstrate that the protective airflow patterns are maintained during interventions, either because insufficient “smoke” was used or the camera angle was unfavorable.

Takeaways:

• Smoke studies should truly represent the unidirectional airflow during the aseptic operations.
• Smoke studies should be designed very carefully, considering the sufficient amount of smoke, the camera angles covering all the critical aseptic zones, critical aseptic operations, and actual interventions.
• Camera recordings of smoke studies must be kept for FDA Investigator review.

Production System – Case Study 3 – Process Design

Background:

• A pharmaceutical manufacturing firm manufactures a chewable tablet product.
• Routine stability testing found some tablets had three times the target of API.
• Release testing had not detected the problem.

What Happened:

• The firm immediately recalled all products.
• The firm determined that different particle sizes, densities, and flow properties caused the blend to desegregate during blender discharge.
• The firm worked to correct the problem by reducing “free fall.”
• The firm also implemented these corrections to other products with the same problem.

 Takeaways:

• For pre-compression blending, the firm should evaluate the uniformity of the material entering the press.
• An investigation should be extended to other batches, other products, and other points in the process.
• Release testing may not be a reliable method for catching process problems.

Production System – Case Study 4 – Deficiencies In Aseptic Production Media Fill

Background:

A pharmaceutical manufacturer recently received a Warning Letter from the USFDA due to issues with the media fill, inadequate “aseptic behavior,” and inadequate controls of materials used in the aseptic area.

Warning Letters of the FDA always refer to corresponding chapters of 21 CFR Part 211.

Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

What Happened:

• Integral units were removed from the media fill run and not incubated. The firm ordered the vials to be removed for a routine analytical test. From FDA’s point of view, this test could have been performed after incubation.
• The media fill did not sufficiently consider the risks of commercial production. In this case, a manual aseptic material transfer was not simulated.
• In the case of several employees, no activities were simulated for which they were responsible in production.

Takeaways:

• Media Fill studies should truly represent the actual interventions in aseptic production.
• Media Fill studies should be designed to represent the actual interventions very carefully.

Production System – Case Study 5 – Deficiencies In Media Fills And Smoke Studies

Background:

A pharmaceutical manufacturer was inspected by the USFDA recently. Serious deficiencies that had been noticed in the media fill and smoke studies were not sufficiently explained or remedied in the manufacturer’s response letter so a Warning Letter followed.

What Happened:

• The pharmaceutical manufacturer had carried out a media fill and received contaminated units. A specific, restricted part of the production line was suspected as a possible source of microbial contamination.
• USFDA complained that the manufacturer has not initiated any CAPA measures to remove the potential cause and performed a risk assessment for other batches that had been produced on the same line. On the contrary, the manufacturer had concluded that there was no influence on the product quality in this case and had, therefore, cited the passing results of subsequent media fill runs.
• The FDA also criticized the conduct of the Media Fills, stating that the interventions simulated in the Media Fill were not representative of the actual interventions in aseptic production.
• The FDA also considered the smoke studies in the aseptic production area to be insufficient. The manufacturer had not sufficiently simulated the actual interventions and processes in the smoke studies of its aseptic production area.
• According to the FDA, considerable manual intervention takes place with unprotected products and containers/closures. There is no unidirectional air flow, there is even heavy turbulence and the space around the critical area is very limited.
• In its response, the manufacturer said it had conducted additional smoke studies to prove the unidirectional airflow. This was not sufficient for the FDA because, on the one hand, no sufficient visualization of the flow conditions was shown. On the other hand, the smoke studies had not been performed under dynamic (real) conditions.

Takeaways:

• Appropriate CAPA and a thorough risk assessment are must in case of media fill failures.
• Media fill and smoke studies should be a true representation of the actual interventions in aseptic production.
• Smoke studies under dynamic (real) conditions representing the actual interventions are a must.
• Media Fill and smoke studies should be designed carefully to represent the interventions.

Production System – Case Study 6 – Cleanroom Behavior In The Aseptic Area

Background:

FDA issued a Warning Letter to a Pharmaceutical Company Limited following inspection issues with inadequate “aseptic behavior.”

Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

What Happened:

• Employees failed to disinfect gloved hands after touching surfaces (curtains/touch screens).
• Employees’ activities in the “sterile area” were carried out with fast movements instead of a slow aseptic movement technique.
• The firm’s response that it had trained its employees to behave adequately in an aseptic environment was insufficient for the FDA. Rather, the firm should extend this training to supervisory staff and generally demonstrate its effectiveness.

Takeaways:

• Proper cGMP instructions for gowning and behavior in the cleanroom must be followed.

• FDA expects that each person engaged in manufacturing, processing, packing, or holding a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.
• Training must be provided on the aseptic operations that the employee performs and on current good manufacturing practices as they relate to the employee’s functions.

For more case studies, check our course on Good Manufacturing Practices (GMP): FDA Citations and Warning Letters – Lessons Learned. For best practices on GMP, see the main components and principles below.

5 Main Components of Good Manufacturing Practice

It is paramount to the pharmaceutical manufacturing industry to regulate GMP in the workplace to ensure the consistent quality and safety of products. Focusing on the following 5 P’s of GMP helps comply with strict standards throughout the entire production process.

1. Personnel
   All personnel are expected to strictly adhere to manufacturing processes and regulations. A current GMP training must be undertaken by all employees to fully understand their roles and responsibilities. Assessing their performance helps boost their productivity, efficiency, and competency.
2. Products
   All products must undergo constant testing, comparison, and quality assurance before distributing to consumers or patients. Manufacturers should ensure that primary materials including raw products and other components have clear specifications at every phase of production. The standard method must be observed for packing, testing, and allocating sample products.
3. Processes
   Processes should be properly documented, clear, consistent, and distributed to all employees. Regular evaluation should be conducted to ensure all employees are complying with the current processes and are meeting the required standards of the organization.
4. Procedures
   A procedure is a set of guidelines for undertaking a critical process or part of a process to achieve a consistent result. It must be laid out to all employees and followed consistently. Any deviation from the standard procedure should be reported immediately and investigated.
5. Premises
   Premises should always promote cleanliness to avoid cross-contamination, accidents, or even fatalities. All equipment should be placed or stored properly and calibrated regularly to ensure they are fit for producing consistent results to prevent the risk of equipment failure.

The 10 Good Manufacturing Practice Principles

1. Create Standard Operating Procedures (SOPs)
2. Enforce / Implement SOPs and work instructions
3. Document procedures and processes
4. Validate the effectiveness of SOPs
5. Design and use working systems
6. Maintain systems, facilities, and equipment
7. Develop job competence of workers
8. Prevent contamination through cleanliness
9. Prioritize quality and integrate it into the workflow
10. Conduct GMP audits regularly