Equipment Logbooks Compliance

GMP equipment logbooks are essential for ensuring the quality and safety of pharmaceutical products throughout the manufacturing process. They provide a chronological record of equipment maintenance, calibration, cleaning, and other critical activities that can impact product integrity. By documenting these activities, logbooks help to:

1. Maintain Equipment Functionality: Logbooks serve as a reference for when and how equipment maintenance and calibration was performed. This information is crucial for ensuring that equipment is operating within its specifications and not introducing any contaminants or variability into the manufacturing process.
2. Traceability of Product History: Logbooks provide a link between equipment usage and the production of specific batches of pharmaceutical products. This traceability is essential for investigating potential quality issues or recalls, as it allows investigators to identify the equipment that may have contributed to the problem.
3. Compliance with GMP Regulations: GMP regulations mandate the maintenance and documentation of equipment records. By maintaining comprehensive logbooks, pharmaceutical companies demonstrate their commitment to GMP compliance and reduce the risk of regulatory scrutiny.
4. Preventive Maintenance and Predictive Maintenance: Logbook entries can be used to identify patterns in equipment performance that may indicate the need for preventive maintenance or predictive maintenance activities. This proactive approach can help to prevent equipment breakdowns and production downtime.
5. Training and Competency Verification: Logbooks can serve as a training record for operators who are responsible for maintaining, calibrating, and cleaning equipment. By reviewing logbook entries, supervisors can ensure that operators are properly trained and competent in their duties.
6. Root Cause Analysis: When quality issues arise, logbooks can provide valuable information for conducting root cause analysis investigations. By examining the timing and nature of equipment maintenance, calibration, and cleaning activities, investigators can identify potential contributing factors and implement corrective actions.

Content of GMP Equipment Logbooks

A comprehensive GMP equipment logbook should include the following information:

1. Equipment Details: The type of equipment, serial number, and manufacturer should be clearly identified.
2. Maintenance Schedule: A list of scheduled maintenance activities, including dates, frequencies, and responsible personnel.
3. Calibration Records: Documentation of calibration activities, including calibration dates, parameters calibrated, and calibration certificates.
4. Cleaning Schedule: A list of cleaning activities, including dates, frequency, and cleaning agents used.
5. Deviations and Nonconformities: Records of any deviations from the planned maintenance, calibration, or cleaning schedule, along with corrective actions taken.
6. Logbook Review Signatures: Signatures of authorized personnel verifying the accuracy and completeness of logbook entries.
7. Storage and Archiving: Logbooks should be stored securely in a designated location and archived for the required period, typically several years.

Accepting the GMP Out-of-Specification Test Results?

The term Out-of-specification is used so often in pharmaceutical industry, but many of us are still unaware of its meaning. Well, when a drug undergoes stability testing or release testing and the tests results aren’t within the limits of pre-defined specifications, it is said to be Out-of-Specification result that may trigger an OOS investigation.

Laboratories sometimes follow a practice called ‘testing into compliance’ where they respond to an OOS outcome only by performing additional tests until they somehow obtain the passing results. FDA’s response to such activities is:

“This practice of retesting without proper investigation is completely unscientific and objectionable under the cGMP  regulations. The OOS results may sometimes legitimately reflect the batch quality.”

But the real question is – when should an OOS result be reported? What should be the acceptance criteria for triggering the OOS investigation?

What is Reportable Value to Trigger a GMP OOS Investigation?

In pharmaceutical laboratories, the results are generally arrived at by averaging the replicates of the same preparation. For example, let’s say the results of HPLC assay are determined by averaging the four consecutive responses of the same preparation. If the acceptance criterion for HPLC assay is ≥99.00%, and the individual values obtained by a validated method are  - 99.70, 99.36, 99.83, 98.89%. Should it be considered an Out-of-specification result? According to FDA guidance, since all the values are close to one another and only one value is slightly below the acceptance criterion, the results are acceptable and there is no need to warrant an investigation.

However, when the variations are much greater than the expected variation for that method, it should trigger an investigation. For example,  if the acceptance criterion for a test is 95%, and the two results are 98% and 87.4%, there is no meaning in averaging the values. An instant investigation should be initiated in such cases.

How to Establish Acceptance Criteria that Doesn’t Lead to Unwarranted GMP OOS Results?

Determining the acceptance criteria poses a big challenge as it must ensure the safety of patients. The residual solvents, impurities and degraded compounds should be limited in the product to a level that doesn’t harm patients in any circumstances.

Another thing worth considering is the efficacy of products. Impurities are acceptable to a level that doesn’t affect the effectiveness of drug. You should evaluate all the statistical figures, procedures, development history and clinical trials when deciding upon the acceptance criteria.

How Else Can You Limit the GMP Out-of-Specification Results

Qualification of the laboratory equipments and quality analysts is one of the most important factors that can limit unnecessary OOS results. A trained analyst better knows the critical calibration requirements for the instruments to perform tests. Well, think who can more effectively conduct a laboratory analysis – an analyst who has received training on general HPLC or the one who has received specific training on each of the individual HPLC techniques?

Qualifying a New GMP Pharmaceutical Products Manufacturing Facility

In pharmaceutical production, a GMP (Good Manufacturing Practices) facility stands as a testament to stringent quality control and precision. Serving as the cornerstone for producing safe and effective pharmaceutical products, these GMP-certified facilities encompass a range of specialized areas, each playing a critical role in the manufacturing process.

New GMP Compliant Facility: Brief Overview

Establishing a new GMP facility involves a deep understanding of its foundational elements and operational intricacies. After all, in pharmaceutical manufacturing, every detail matters – from the architectural design to the subtleties of maintaining quality assurance throughout the production process.

First, we’ll delve into the essential components of a GMP facility, exploring the critical aspects of construction, design, GMP cleanrooms, and equipment qualification. After that, we’ll focus on pitfalls and best practices.

What is a GMP Facility?

A GMP (Good Manufacturing Practices) Facility is dedicated to the production of pharmaceutical products. It houses manufacturing spaces, storage areas for raw and finished products, and supportive laboratory zones.

Ensuring these activities are error-free is paramount, as manufacturing mistakes can result in contamination or inconsistencies in the end product. In the realm of GMP, the role of quality assurance (QA) cannot be overstated.

Note: GMP facilities operate under the guidelines established by the CFR (Code of Federal Regulations) Title 21, Parts 225 (Current Good Manufacturing for Medicated Feeds – Subpart B), and Part 226 (Current Good Manufacturing Practice for Type A Medicated Articles – Subpart B).

Construction and Design of New GMP Facilities

A new GMP facility begins with the construction of its foundation, the main building, and the integral cleanrooms.

Both during and post-construction, the essential facility utilities are installed as per a pre-determined design for their intended purpose. This includes HVAC, city water, gases (LN2, O2, CO2), piping, drainage, and other supply systems, all of which adhere to industry-standard quality specifications.

GMP Cleanrooms

GMP facilities and GMP cleanrooms are mandatory in various sectors of the pharma, biotechnology, and drug manufacturing industries to ensure high product quality. A cleanroom’s objective is to create an environment with minimized contaminants, suitable for drug-related production.

Equipment Qualification

Following the facility and utilities setup, the equipment qualification phase commences. This process can involve anything from simple apparatuses to intricate systems.

As illustrated in Figure 1, equipment qualification adheres to specific GxP guidelines, such as GAMP5, ISPE, and ISO standards. Customized or more complex systems undergo factory acceptance testing (FAT) and/or site acceptance testing (SAT) during the commissioning phase.

These pivotal tests, when thoroughly conducted and documented, can mitigate errors in the subsequent qualification stage. An efficient qualification not only streamlines the process but also alleviates project-end pressures.

Thorough documentation of GMP processes and outcomes is vital for GMP compliance. The validation process essentially documents that the instruments, processes, and activities at the facility consistently produce expected results. GMP mandates process validation, cleaning and sanitation validation, computer system validation, and analytical method validation.

New GMP Facility: Pitfalls & Best Practices

In the intricate journey of GMP facility qualification, no path is without its challenges. From planning to team collaboration, this section explores the pitfalls we’ve navigated and the insights we’ve garnered, ensuring (your?) future endeavors are even more streamlined and efficient.

Plan Adaptively

From our experience in qualifying new GMP facilities, we’ve amassed a wealth of lessons. We’ve navigated pitfalls concerning planning, budgeting, and other factors. Yet, we creatively overcame these obstacles to ensure quality deliverables.

As mentioned earlier, everything stems from a predefined design. This encompasses the tasks to be done, the timeline for completion, and the personnel required to achieve the objectives. Proper planning integrates all this information. Ideally, such planning should already account for potential project delays, be they in construction, equipment delivery, or installation issues. While we cannot predict every turn of events, we must be prepared to adapt when unforeseen challenges arise.

One significant pitfall is the temptation to delay activities, particularly early in the project. While no approach is flawless, it’s vital to establish clear agreements from the outset about how to handle such shifts. Postponing tasks can risk overshooting the budget and missing deadlines. 

It’s advisable to only delay activities when the installation hasn’t been scheduled or when it doesn’t affect other operations. If not, consider rearranging activities in your plan. When one task gets postponed due to unforeseen delays, another can be expedited.

Set Realistic Timelines & Budgeting

To ensure a smooth process without unnecessary adjustments, it’s essential to establish a realistic timeline from the onset. A deep understanding of the activities involved is crucial for accurate timeline estimation.

This necessitates a multidisciplinary team equipped with insights into construction, the impact of installations, qualification, validation, and a clear understanding of the resources required for each activity, both in terms of time and budget.

Beyond just the resources needed for the main tasks, supporting departments such as production, maintenance, calibration, and especially QA play vital roles in providing input, conducting reviews, and approving expected deliverables.

As previously emphasized regarding planning, building in flexibility is essential when setting up a new GMP-compliant facility. This allows for adjustments in response to unforeseen delays. Avoid setting rigid milestones, where feasible, to prevent creating a high-pressure, stressful working environment.

Set and Celebrate Achievable (!) Milestones

We’ve addressed planning and timelines. To mark progress and foster a sense of achievement, it’s vital to set realistic milestones throughout the project. These can signal the onset of a new project phase or the qualification and release of the first cleanroom for use. Achieving these milestones boosts team morale and drives motivation.

However, it’s crucial that these milestones are attainable. Setting unachievable targets can lead to feelings of defeat, dampening the team’s overall spirit. Beginning a project with the mindset of “we know it’s nearly impossible, but you must achieve it” is not the ideal approach, especially for high-pressure projects.

Communicate and Cooperate Effectively

A project isn’t a one-man show. Achieving a qualified GMP facility requires the collective expertise of many, spanning technical know-how, GMP qualification, quality assurance, procurement, finance, and other resources. Effective communication from the outset ensures all departments align their goals, intentions, and understanding of each other’s expertise.

In projects with strict timelines, appointing a SPOC (single point of contact) for each team is essential to facilitate seamless two-way communication. Such a step fosters appreciation and respect.

When concerns arise, it’s crucial to address them rather than dismiss them; unattended issues might escalate as the project progresses. Prevention is always preferable to resolution.

Pharmacovigilance (PV) Audits: Importance, Process, and Challenges

In healthcare, safeguarding patient safety and upholding the integrity of pharmaceutical interventions are paramount. Enter pharmacovigilance (PV), a scientific discipline dedicated to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related issue.

The essence of pharmacovigilance is to recognize the balance it seeks to maintain between the benefits and risks of medication use. While clinical trials offer a controlled peek into a drug’s safety profile, the real test begins once the drug enters the market.

The diverse and uncontrolled real-world environment exposes the drug to a broader demographic, including pregnant women and the elderly, highlighting the indispensable role of pharmacovigilance in the lifecycle of a drug.

This is where Pharmacovigilance (PV) Audits step into the spotlight.

What Are Pharmacovigilance (PV) Audits?

The implementation of the new 2012 PV regulation implied the legal obligation to carry out PV audits by the competent authorities of the member states, the EMA, and the MAHs. These audits aim to assess and verify the adequacy and effectiveness of the PV systems, their implementation, and execution, including the quality system for PV activities.

The PV audit aims to obtain and evaluate evidence to determine whether the required criteria are met through a systematic, disciplined, and documented process. These criteria, in the context of PV, should reflect the requirements of the PV system, including the associated quality system.

The risk-based approach in PV audits intends to determine the probability of an event occurring that will have an impact on the achievement of objectives, taking account of the severity of its outcome and/or the likelihood of non-detection by other methods, or, in other words, a risk. These risks can be assessed through different stages:

• Strategic level audit planning – high-level statement of how the audit activities will be delivered over a period of time (usually 2-5 years)

• Tactical level audit planning – set of one or more audits planned for a specific timeframe, normally for a year
• Operational level audit planning – audit plan for individual audit engagements, prioritizing audit tasks based on risk and utilizing risk-based sampling and testing approaches, and reporting of audit findings in line with their relative risk level and audit recommendations in line with the suggested grading system

Why Are Pharmacovigilance (PV) Audits Important?

At their core, Pharmacovigilance Audits are not merely regulatory hurdles; they are vital cogs in the machinery of public health.

They serve a dual purpose:

• ensuring that pharmaceutical entities continually monitor the safety of their products
• and validating that these companies fulfil their regulatory responsibilities.

Through rigorous examination of safety data in real-world conditions, these audits are instrumental in maintaining a delicate balance between drug efficacy and patient safety.

Legal and Regulatory Framework of Pharmacovigilance (PV) Audits

The guidelines on the Pharmacovigilance Audits are the subject of Module IV of the GVP (Good Pharmacovigilance Practices). The minimum requirements of the pharmacovigilance systems and the quality system are set out in the Commission Implementing Regulation (EU) No 520/2012 (IR) on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC.

The PV Audit Process: 3 Important Stages

1. Audit Planning and Preparation

Before conducting a PV audit, pre-meetings can take place to understand and determine audit objectives, scope, and roles/responsibilities.

With these features defined, a list of the necessary documentation to be reviewed must be determined – at this point, the audited organization will receive a notification regarding the future audit, including a list of the requested documentation. The final agenda can now be set and shared with the audited organization.

2. Audit Conduct

Before the actual interviews with the corresponding personnel, a “kick-off” meeting should take place as a way to introduce the involved people and also serve as an opening.

Following the previously prepared agenda, the actual audit can now take place, and the interviews can start, including document reviews, demonstration of activities and processes, and showing archiving and storage processes (physically in the company or informatic archives).

After the reviews, the conclusions and a preview of the general results are presented, and the audit interviews are concluded.

3. Post-Audit Activities

The data obtained during the audit interviews will be the basis for the elaboration of an audit report, in which, after summarizing and presenting the scope of the audit, the auditors describe what was observed and list the findings, classified as Minor, Major, or Critical, according to the defined guidelines. Some suggestions for improvement are also included. The audited organization shall ensure that mechanisms are in place to address the audit issues appropriately.

Upon receipt of the audit report, following the findings identified and after clarification of any issues, a CAPA plan must be prepared – for each finding, determine:

• a root cause,
• the impact analysis,
• the associated corrective and preventive actions,
• the deadlines by which they should be completed,
• and who is responsible for them.

Evidence of actions taken to address each finding should be kept on file, and there should be periodic follow-ups to ensure that all CAPAs are closed. The learning and experience gained from the audit will serve to promote a culture of continuous improvement in the company’s PV processes.

Challenges in Pharmacovigilance (PV) Audits

Specialized Training and Solid Experience

The ability to carry out quality audits implies the need to invest in the human resources required to do so. One of the challenges this presents is that auditors need to have specialized training and solid experience in PV audits, to know how pharmacovigilance systems work, and to be able to adapt to different clients, in different contexts.

Countries with less-developed pharmacovigilance systems

That said, a very particular challenge that auditors occasionally encounter is conducting PV audits in countries where pharmacovigilance, and their systems, are yet less developed, have significant gaps, or are compromised by unique events (such as a war in the country in question). Experience and adaptability are particularly important in these cases.

Ensuring the PV auditor’s independence

On the other hand, conducting audits within small organizations is also a challenge in terms of ensuring the auditor’s independence, which may be affected by limited resources and/or the accumulation of functions.

Mastering Cleanroom Qualification: navigating the latest regulatory updates 

Discover the latest key changes in cleanroom qualification regulations, exploring the impact of the different test phases (qualification, classification, requalification, monitoring) with a focus on risk assessment.

In 2022, significant updates were made to the main standards that impact the qualification of cleanrooms. These updates include:

EU GMP Annex 1: Manufacture of Sterile Medicinal products: This document outlines specific requirements for the manufacture of sterile medicinal products, complementing the EC-GMP Guide.

• ISO 14644-4:2022 Cleanrooms and associated controlled environments – Part 4: Design, construction and start-up: This document provides a comprehensive process for creating cleanrooms, covering everything from initial requirements to design, construction, and start-up.

What is a cleanroom?

According to the normative reference ISO 14644-1:2015, a cleanroom is a controlled environment where the concentration of airborne particles is managed and classified. It is designed, constructed, and operated in a way that effectively controls the introduction, generation, and retention of particles within the room. Additionally, other important parameters such as temperature, humidity, and pressure are controlled as required.

What is cleanroom qualification?

As per the guidelines outlined in EU-GMP, premises should be strategically located, designed, constructed, adapted, and maintained to align with the intended operations. The layout and design should prioritize minimizing the risk of errors and facilitating effective cleaning and maintenance processes to prevent cross-contamination, accumulation of dust or dirt, and any potential negative impact on product quality.

Furthermore, the EU GMP Annex 1 specifically mandates that cleanrooms and clean air equipment must undergo qualification procedures following the methodology outlined in Annex 15. It emphasizes the importance of clearly distinguishing cleanroom qualification, including classification, from operational environmental monitoring.

Cleanroom qualification activities

So, qualification activities of cleanrooms should consider all stages from the initial development of the user requirements specification through to the end of the use of the facility.

The main stages and some suggested criteria (although this depends on individual project circumstances and may be different) which could be included in each stage are indicated (Annex 15):  

• User requirements specification (URS),  
• Initial Risk Assessment  
• Design qualification (DQ),  
• Factory acceptance testing (FAT) /Site acceptance testing (SAT),
• Component Criticality Assessment.
• System Impact Assessment
• Requirement Traceability Matrix
• Functional Risk Assessment
• Installation qualification (IQ),  
• Operational qualification (OQ),  
• Performance qualification (PQ). 

User requirements specification (URS)

The first step in the qualification process is the definition of User requirements specification (URS). For that, an analysis of the need for a cleanroom and its justification shall be performed. This analysis shall address, but is not limited to:

• contamination risk to products, processes, people, and environment;
• statutory requirements;
• relevant regulations;
• business-related aspects (financial viability and resource capability);
• and future needs.

Design qualification (DQ)

The output of the requirements (URS) is the input for the design. The design of the cleanroom shall consider an effective contamination control strategy for all aspects of its construction, testing, operation, maintenance, and life cycle.

There are typically three stages in the overall design process: conceptual design, basic design, and detailed design (ISO 14644-4:2022). Depending on the nature and scale of the project, these stages can be executed in one or more steps with appropriate design iterations and reviews.

At the end of each design stage, an agreed design document(s) shall be produced.

Factory acceptance testing (FAT) /Site acceptance testing (SAT)

The installation shall be constructed in accordance with the agreed detailed design and specifications and the construction plan and the quality plan. As proposed by ISO 14644-4:2022, a clean-built protocol can support the construction phase to limit the sources of contamination.

Upon completion of the construction of an installation, the start-up period commences with commissioning to confirm that the installation is complete and performs as specified.

A series of verifications shall be carried out to demonstrate that all the performance parameters are in accordance with the agreed specification and to determine that all parts of the installation operate together to achieve the designed conditions.

For a cleanroom, this shall at least include a classification test in accordance with ISO 14644-1. Other parameters may be evaluated such as viable particulate contamination, chemical contamination, and… Rationale shall be documented for the scope of verification. Under certain conditions, these tests can be leveraged in the next qualification phases (IQ and OQ).

Installation qualification (IQ)

This step could be considered as an “As-Built Testing phase”. An As-built cleanroom refers to a cleanroom that’s functional and ready for operation but doesn’t have any equipment and personnel inside yet. As-built testing is an initial cleanroom qualification step, which reflects the supply air quality. In a non-exhaustive manner, the following tests can be carried out : HVAC calibration, P&ID loop verification, HEPA filter integrity test data review, critical equipment calibration status, …

In this stage, the microbial contamination for airborne and surface should be also measured to determinate the initial (baseline) recovery of microorganisms.

Operational qualification (OQ)

This step could be considered an “At-Rest Testing” phase. The At-rest cleanrooms are complete, functional, and ready to use. The equipment is in place but not the staff. Performing clean room testing at rest allows for thorough smoke testing of surfaces of equipment that is installed but not yet operating.

The OQ protocol should address, at least the following tests:

• Installed filter system leakage and integrity testing,
• Airflow tests – volume and velocity,
• Air pressure difference test,
• Airflow direction test and visualization,
• Microbial airborne and surface contamination,
• Temperature measurement test,
• Relative humidity test,
• Recovery test,
• Containment leak test.

In this stage, the cleanroom classification “at-rest” can be done. The minimum number of sampling locations and their positioning can be found in ISO 14644-1.

As requested by Annex 1, cleanroom classification is part of the cleanroom qualification and is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration.

For the aseptic processing area and the background environment (the grade A and grade B areas, respectively), additional sample locations should be considered and all critical processing areas such as the point of fill and container closure feeder bowls should be evaluated. Critical processing locations should be determined by documented risk assessment and knowledge of the process and operations to be performed in the area.

The microbial contamination for airborne and surface must be also measured both “at-rest”. The number and location of sampling points should be based on a documented risk assessment.

Therefore, according to Annex 1, two types of risk assessment are required, one for the particulate and one for the microbial contamination.

Performance qualification (PQ)

This step could be considered an “In-Operation Testing” phase. This phase is performed when all equipment and personnel are in operation inside a cleanroom. This final testing aims to prove that the cleanroom has all the required operational performance in place for a safe cleanroom application.

The cleanroom classification at “In-Operation” state can be done. For cleanroom classification, the total of particles equal to or greater than 0.5 and 5 μm should be measured in accordance with the limits specified in Table 1 in Annex 1.

The microbial contamination level of the cleanrooms should be also determined “in operation” states. The number of sampling locations should be based on a documented risk assessment and the results obtained from the previous tests (room classification, air visualization studies) and knowledge of the process and operations to be performed in the area. The maximum limits for microbial contamination during qualification for each grade are given in Table 2 of Annex 1.

Release of cleanroom

The acceptance and release phase should be done when all the previous testing phase are completed and all discrepancies successfully closed. The acceptance and release process is completed through a summary report. A traceability matrix may be also used as a tool to identify the critical aspect and includes references to the tested documents in link to the requirements.

Cleanroom monitoring

After their release, the cleanrooms should be monitored. Annex 1  specifies that operational environmental monitoring should be clearly differentiated from cleanroom qualification (including classification).

The program of operational environmental monitoring should, according to the guidance, contain the following elements:

• Environmental monitoring (total particle),
• Environmental and personnel monitoring (viable particle),
• Temperature, Relative humidity, and other specific characteristics,
• Aseptic process simulation (for aseptically manufactured products only).

It explains what factors should be assessed in your risk assessment. These include sampling locations, frequency of monitoring, monitoring methods used, and incubation conditions.

Information from the environmental monitoring program should be used for the release of products, but also for ongoing assessment of the conditions of the cleanrooms, and during investigations.

The risk assessments must be based on knowledge of the processes, as well as historical monitoring data, qualification monitoring data, and the facility itself.

Requalification

The requalification of cleanrooms should be carried out periodically following defined procedures. The requalification should include at a minimum the following tests:

• cleanroom classification (total particle concentration),
• integrity test of final filters,
• airflow volume measurement,
• verification of air pressure difference between rooms,
• and air velocity test.

Appropriate requalification should also be carried out after any change through the change management process.

Conclusion

Make sure that your cleanroom qualification complies with the new version of standards EU GMP Annex 1 and ISO 14644-4:2022 and that your risk assessment is sufficiently justified.

The revisions of both regulations made it possible to clarify certain notions such as the layout of the different test phases (qualification, classification, requalification, monitoring) and especially emphasized the notion of risk. So, the new version of standards requires that each test and test plan be justified by a risk assessment

Qualification of laboratory equipment: key considerations and challenges

The introduction of a new product into your company’s portfolio may require expanding your existing laboratories or even building a new laboratory to support additional testing requirements for process controls and batch release.

When analyzing and testing products produced in a GMP environment, qualification of laboratory equipment is a mandatory aspect to comply with regulations (e.g. FDA, EMA). Laboratories need many different types of laboratory equipment to perform their basic QC activities, and therefore qualification of this equipment can seem like a daunting task.

It is best to specify a qualification strategy for the use of all types of equipment to avoid unnecessary qualification activities: a risk-based qualification approach to determine what qualification activities are required for each piece of laboratory equipment.

Defining the necessary qualification effort: risk-based approach

Risk-based qualification of simple laboratory equipment

The required qualification effort depends on the complexity of the laboratory equipment. “Simple” laboratory equipment (e.g., vortex, water bath) might only need installation and calibration.

In this case, a User Specification Requirement (URS) might not be necessary since it is simple off-the-shelve equipment. (The User Requirement Specification (URS) documents all user-specific requirements for the equipment.)

Risk-based qualification of complex laboratory equipment

On the other hand, complex lab equipment (e.g., HPLC, plate reader, plate washer), which uses firmware and/or software, likely needs a full qualification including URS and Installation, Operation, and Performance qualification (IOPQ).

Because this type of equipment is a computerized system, it is recommended that the ISPE GAMP 5 guideline be used for the qualification of the software, as the complexity of the software can make qualification and compliance with regulatory requirements challenging.

Also, when using firmware and/or software, data integrity must be assessed in compliance with, for example, EMA Eudralex Volume 4 Annex 11 and FDA 21 CFR part 11.

Using the (right) Pharmacopoeia

After determining an appropriate qualification approach, it is important to consider the various requirements in the pharmacopeia. The pharmacopeia describe:

• qualitative and quantitative composition of medicines
• the tests to be carried out on medicines
• the raw materials used in the production of medicines
• the intermediates of synthesis

As mentioned, the User Requirement Specification (URS) documents all user-specific requirements for the equipment. This includes installation, operation and performance requirements, as well as documentation requirements (e.g., Standard Operating Procedures, Work Instructions). As part of the qualification, pharmacopoeia requirements must be listed in the URS.

Depending on the exporting country, different pharmacopoeias may apply to laboratory equipment. The different pharmacopoeias that may apply are (not an exhaustive list):

European Pharmacopoeia (Ph. Eur.)

• US Pharmacopoeia (USP)
• Japanese Pharmacopoeia (JP)
• Pharmacopoeia of the People’s Republic of China (PPRC)

For example, the test requirements for pH measurements are described in USP <791> and Ph. Eur. 2.2.3. This means that these requirements must be taken into account when qualifying a pH meter and demonstrated during qualification.

Conclusion

When introducing new laboratory equipment for analytical testing of GMP products, qualification is mandatory to comply with various regulations (e.g. FDA, EMA). To avoid unnecessary qualification of simple laboratory equipment, a risk-based qualification approach should be followed.

When qualifying computerized lab equipment, ISPE GAMP 5 might be a good guideline to follow since complex firmware and/or software needs to be qualified. Also, a data integrity assessment should be performed to comply with EMA Eudralex Volume 4 Annex 11 and FDA 21 CFR part 11.

Certain analytical tests must meet different pharmacopoeia requirements depending on the export area (e.g., Europe, the U.S., Japan, and China). These requirements must be taken into account when qualifying laboratory equipment.

Essential Components of a GMP-compliant Stability Protocol

Batches and Selection Criteria

Batches form the foundation of your stability study. A stability protocol must specify the number and selection criteria of batches, ensuring a representative analysis of the product. Typically, this involves selecting batches from different production runs to capture variability in the manufacturing process.

Container Closure System

The Container Closure System plays a crucial role in maintaining the product’s integrity. The protocol should detail the type of packaging used, mirroring the final market product to predict real-world stability outcomes. From aluminum strips to HDPE bottles, understanding the interaction between the product and its packaging is crucial.

Orientation of the Containers

The Orientation of the Containers during storage can impact the product’s stability. Whether stored upright, sideways, or inverted, each position provides insights into how the product interacts with its container, affecting stability outcomes.

Time Points and Study Design

Time Points are critical for assessing the stability profile of the medicinal product. A well-structured timeline, informed by ICH guidelines, outlines when and how frequently tests are conducted. Employing both full and reduced study designs allows for comprehensive data collection without unnecessary redundancy.

Storage Conditions

Storage Conditions must be tailored to the climatic zones of the target markets. Adhering to recommendations from the ICH, CPMP, and WHO ensures that products are tested under conditions they will face post-market.

Testing Methodology

The Testing Method is the backbone of the GMP-compliant stability study. Prior approval of methods, coupled with rigorous validation, ensures that analytical procedures are fit for purpose. Stability-indicating methods, developed through stress testing, are essential for accurate predictions of product shelf life.

Acceptance Criteria

Finally, Acceptance Criteria must be explicitly defined, covering chemical, physical, biological, and microbiological attributes. This upfront clarity is crucial for determining the study’s success and ensuring regulatory compliance.

EU GMP Annex 1’s Revision: overview and insights

Scope, Principle, and Glossary

The scope of the EU GMP Annex 1 has been expanded to include additional areas beyond sterile products, such as:

• contamination control strategy,
• design of premises,
• cleanroom classification,
• qualification,
• validation,
• monitoring,
• and personnel gowning.

The revised “Scope” and “Principle” sections now clearly reference the importance of applying the principles of Quality Risk Management (QRM).

In addition, key areas and special requirements for sterile products are now more clearly listed and divided into 3 categories. Laslty, a glossary has been added to provide guidance on specific terminology, avoiding ambiguity and inconsistencies.

Pharmaceutical Quality System (PQS)

A new concept brought into EU GMP Annex 1 is the Pharmaceutical Quality System (PQS) for sterile product manufacture. This section – related to ICH Q10 Quality Management System – lists the specific requirements for sterile product manufacture and takes generic approaches into scope:

• risk management,
• sufficient knowledge and process understanding,
• proper non-conformity and CAPA management,
• MGMT responsibility,
• access to information for certain responsibilities,

The importance of non-conformity investigation related to sterility or microbiological load is emphasized.

Premises

The revised “Premises” chapter now clearly uses the term “cleanrooms” and outlines the different classes and requirements for classification.

The importance of both “at rest” and “operational” is emphasized, and requirements for total particle concentration and allowable microbial contamination have been slightly changed.

Specific reference is made to the need for periodic re-qualification of cleanrooms and clean air equipment. The use of Restricted Access Barrier Systems (RABS) in addition to isolators as a barrier technology is introduced.

This section also contains a comprehensive description of the design and use of airlocks, along with clear specifications for airflow patterns and air pressure requirements.

Finally, a new requirement is added, namely the need to be able to observe Class A and B areas from the outside.

Equipment

The revised “Equipment” chapter outlines the need for an equipment design description, and precautions related to equipment design and installation are outlined in more detail. Finally, the need for a cleaning and sterilization process (if applicable) of the equipment has been added.

1. Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control|PDA TR 1
2. Validation of Dry Heat Processes used for Depyrogenation and Sterilization|PDA TR 3| Revised
3. Sterile Pharmaceutical Packaging: Compatability and Stability| PDA TR 5
4. Fundamentals of an Environmental Monitoring Program| PDA TR 13-2022 (Revised)
5. Validation of Tangential Flow Filtration in Biopharmaceutical Applications|PDA TR 15
6. Process Simulation for Aseptically Filled Product| PDA TR 22
7. Sterilizing Filtration of Liquids| PDA TR 26
8. Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals| PDA TR 28
9. Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products| PDA TR 34
10. Current Practices in the Validation of Aseptic Processing| PDA TR 36
11. Sterilizing Filtration of Gases| PDA TR 40
12. Process Validation of Protein Manufacturing|PDA TR 42
13. Quality Risk Management for Aseptic Processes| PDA TR 44
14. Moist Heat Sterilizer Systems: Design, Commissioning, Operation, Qualification and Maintenance/PDA TR 48
15. Points to Consider for Biotechnology Cleaning Validation| PDA TR 49
16. Biological Indicators for Gas and Vapor-Phase Decontamination Processes: Specification, Manufacture, Control and Use| PDA TR 51
17. Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations| PDA TR 54
18. Process Validation: A Lifecycle Approach| PDA TR 60
19. Steam In Place: PDA TR 61
20. Pharmaceutical Technology Transfer| PDA TR 65
21. Application of Single-Use Systems in Pharmaceutical Manufacturing| PDA TR 66
22. Bioburden and Biofilm Management in Pharmaceutical Manufacturing Operations| PDA TR 69
23. Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing Facilities | PDA TR 70
24. Manufacture of Sterile Pharmaceutical Products Using Blow-Fill-Seal Technology| PDA TR 77
25. Data Integrity Management System for Pharmaceutical Laboratories| PDA TR 80
26. Contamination Control Strategy Development in Pharmaceutical Manufacturing| PDA TR 90

1. Validated Excel Sheet for Assay Calculation of Solid Dosage Form-By UV
2. Validated Excel Sheet for Injector Linearity for HPLC Calibration
3. Validated Excel Sheet for Assay Calculation-Solid Dosage Form-by HPLC/UV (Up to 3 Sample)
4. Validated Excel Sheet for Assay Calculation-Raw Material-by Titrimetry
5. Validated Excel Sheet for Assay Calculation of Raw Material by Titrimetry-Back Titration Method
6. Validated Excel Sheet for Dissolution Calculation for Tablet/Capsule by HPLC/UV
7. Validated Excel Sheet for Dissolution Calculation by HPLC/UV-Multipoint
8. Validated Excel Sheet for Calculation of Impurities (RS) by Area Normalisation Method
9. Validated Excel Sheet for Calculation of Related Substances-with standard-Tablet/Capsule
10. Validated Excel Sheet for Related Substances - Calculation against diluted sample
11. Validated Excel Sheet for % Dissolution calculation for Dissolution Tester by UV
12. Validated Excel Sheet for Assay Calculation - Liquid / Suspension Injection Dosage Form - by HPLC/UV
13. Validated Excel Sheet for Assay Calculation - Solid Dosage Form - by HPLC/UV
14. Validated Excel Sheet for Calculation Content Uniformity of Tablets/Capsule By HPLC and UV
15. Validated Excel Sheet for Calculation of Acceptance Value for Content Uniformity - L1 stage
16. Validated Excel Sheet for Calculation of Uniformity of dosage unit as % Content
17. Validated Excel Sheet for Calculation of Uniformity of Dosages by Weight Variation
18. Validated Excel Sheet for Linearity Calculation with Graph
19. Validated Excel Sheet for Tablets Physical Parameters Calculation
20. Validated Excel Sheet for Balance Calibration Repeatability Test
21. Validated Excel Sheet for Net Fill Content Weight for Capsules
22. Validated Excel Sheet for % RSD Calculation

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