CIP in Freeze Dryers: Principles, Systems, and Pharmaceutical Manufacturing Considerations

10/23/202615 min read

Why CIP Matters in Pharmaceutical Freeze Dryers
What Is Clean-in-Place (CIP)?
How CIP Systems Work in Freeze Dryers
Key Components of a Freeze Dryer CIP System
Critical Cleaning Parameters
CIP Design Challenges Specific to Freeze Dryers
CIP Cycle Development and Optimization
Cleaning Validation and Verification
Practical and Engineering Considerations
Technical Considerations
Frequently Asked Questions
Related Lyophilization Core Articles
Conclusion
References and Further Reading

1. Why CIP Matters in Pharmaceutical Freeze Dryers

A pharmaceutical freeze dryer may process products containing proteins, peptides, vaccines, small-molecule drugs, buffers, sugars, and other formulation components. During operation, residues can accumulate on product-contact surfaces, including chamber walls, shelves, drain lines, and other exposed components. These residues must be removed before the equipment is released for subsequent manufacturing operations.

The challenge is not simply to wash the chamber. A freeze dryer is a complex vacuum-rated system designed to operate across a wide temperature range, with internal geometries and equipment interfaces that can create difficult-to-clean locations. Shelves, support structures, drain connections, spray devices, and chamber penetrations can influence how cleaning fluid reaches surfaces and how effectively it drains afterward.

Clean-in-place (CIP) systems are designed to clean designated internal equipment surfaces without requiring routine dismantling of the equipment. In pharmaceutical freeze dryers, their effectiveness depends on the interaction between cleaning chemistry, temperature, fluid distribution, contact time, mechanical action, and equipment design.

A well-designed CIP system supports reproducible cleaning, reduces manual intervention, and helps maintain the hygienic condition of the equipment. However, installing automated spray devices does not, by itself, establish that a freeze dryer is clean. The cleaning process must be developed, qualified, and validated for the equipment configuration, product residues, and intended manufacturing use.

This article explains the engineering principles behind freeze dryer CIP systems, the factors that determine cleaning effectiveness, and the considerations involved in developing a reliable pharmaceutical cleaning process.

2. What Is Clean-in-Place (CIP)?

CIP is an automated or semi-automated cleaning approach in which cleaning solutions are circulated, sprayed, or otherwise delivered across designated equipment surfaces without routine disassembly.

In pharmaceutical freeze dryers, CIP primarily addresses the removal of product residues and other relevant contaminants from the internal surfaces identified in the cleaning strategy.

CIP must be distinguished from three related activities:

Cleaning: Removal of product residues, cleaning agents, and other contaminants from equipment surfaces.
Sterilization-in-place (SIP): Application of a validated sterilization process to achieve the required microbial state of the equipment.
Cleaning verification and validation: Evidence that the cleaning procedure consistently meets predefined acceptance criteria.

CIP does not automatically sterilize a freeze dryer. Likewise, a successful SIP cycle does not demonstrate that product residues have been adequately removed. Cleaning and sterilization address different objectives and must be controlled accordingly.

2.1. Why freeze dryers require a specialized CIP approach

A freeze dryer differs from many conventional process vessels because its internal shelves, chamber geometry, condenser arrangement, and vacuum system impose distinct cleaning and drainage requirements.

For example:

Shelves can obstruct spray trajectories and create shadowed areas.
Chamber corners and penetrations may receive less effective spray coverage.
Drainage limitations can allow cleaning solution to accumulate.
Gaskets, valves, and instrument connections may create difficult-to-clean interfaces.
The condenser and associated vapor pathways may require a separate cleaning strategy, depending on the equipment design and product-contact assessment.

The scope of CIP must therefore be defined against the actual equipment configuration. Not every internal component is necessarily included in the same cleaning circuit, and not every freeze dryer uses the same CIP architecture.

For a broader understanding of the equipment involved, see Pharmaceutical Freeze Dryer Components Explained.

3. How CIP Systems Work in Freeze Dryers

A typical CIP cycle delivers cleaning fluids through a defined sequence intended to remove residues, rinse away cleaning agents, and leave the equipment in a condition suitable for the next manufacturing step.

The exact sequence varies with the equipment, formulation, cleaning chemistry, and validated procedure. A representative cycle may include the following stages.

3.1. Pre-rinse

Water is introduced to wet accessible surfaces and remove loosely attached or water-soluble residues. The selected water quality, temperature, volume, and duration depend on the process and cleaning strategy.

3.2. Detergent wash

A compatible cleaning solution is applied at a controlled concentration, temperature, and contact time. Depending on the formulation, the chemistry may promote dissolution, emulsification, or detachment of residues.

3.3. Intermediate rinse

Water removes loosened residues and residual detergent. Rinsing must be sufficient to meet the established chemical and cleanliness criteria.

3.4. Final rinse

A final rinse using the specified water quality removes remaining cleaning agents and soluble contaminants. The endpoint should be based on predefined, justified criteria rather than time alone.

3.5. Drainage and post-cleaning checks

Cleaning fluids are drained through the intended pathways. Where required, drying, inspection, sampling, and documented equipment-release checks follow the validated procedure.

Some systems incorporate additional rinses, recirculation steps, air purging, or other controlled operations. These should be selected based on demonstrated process needs rather than included automatically in every cycle.

3.6. How the cleaning mechanism removes residues

CIP effectiveness depends on several interacting mechanisms:

Dissolution: Water or a suitable cleaning solution dissolves soluble residues.
Chemical action: Detergents or other compatible agents help loosen residues that are not readily removed by water alone.
Mechanical action: Spray impact, fluid movement, and surface wetting contribute to residue removal.
Thermal action: Appropriate temperature can improve solubility and cleaning kinetics, provided the residue, equipment, and cleaning chemistry remain compatible.
Rinsing: Flowing water transports detached material and residual cleaning agents away from the equipment.

These mechanisms are interdependent. Increasing detergent concentration, temperature, or cleaning duration cannot reliably compensate for a surface that receives insufficient fluid coverage. The cycle must provide both suitable cleaning conditions and access to the surfaces requiring cleaning.

4. Key Components of a Freeze Dryer CIP System

CIP performance depends on the complete fluid-delivery and control system, not just the spray devices installed inside the chamber. Each component influences cleaning coverage, solution delivery, repeatability, or the ability to demonstrate that the cleaning cycle operated as intended.

4.1. Spray devices and distribution manifolds

Spray balls, rotary spray devices, or other engineered distributors deliver cleaning fluid to designated surfaces. Their selection depends on chamber geometry, required coverage, operating conditions, and the cleaning mechanism established during qualification.

4.2. Cleaning solution supply and pumping system

Pumps, supply lines, and associated equipment provide the required flow and pressure. The design must account for hydraulic resistance, flow distribution, solution compatibility, and the operating limits of the freeze dryer.

4.3. Valves and cleaning circuits

Automated valves route cleaning fluids through the intended circuits. Correct valve sequencing is important because a blocked, incorrectly aligned, or inadequately supplied circuit can compromise cleaning even when the overall cycle appears normal.

4.4. Instrumentation and control system

Temperature, pressure, flow, conductivity, or other relevant measurements may be used to monitor the cleaning process. The parameters measured should correspond to the variables needed to control and demonstrate the effectiveness of the validated cycle.

4.5. Drainage and return system

Drain connections and return piping remove used cleaning fluid. Drainability is particularly important in freeze dryers because retained liquid can affect post-cleaning condition and create locations that are difficult to inspect or assess.

4.6. The role of the freeze dryer condenser

The condenser captures water vapor during primary drying and may contain ice or residues depending on the product, process, and equipment arrangement. Its cleaning requirements must be assessed separately from those of the product chamber.

Some freeze dryers use configurations in which condenser cleaning is incorporated into a dedicated cleaning sequence; others may have different arrangements or operational restrictions. The cleaning strategy must account for the condenser's geometry, drainability, material compatibility, and relationship to the chamber.

For a more detailed explanation of condenser operation, see Condensers in Pharmaceutical Freeze Dryers and Condenser Performance Optimization.

The vacuum system also requires consideration. Vacuum pumps and associated components should not be exposed to cleaning fluids unless the equipment has been specifically designed for that purpose. Valves, traps, and isolation arrangements must protect components outside the intended cleaning boundary.

Related reading: Vacuum Systems in Freeze Drying and Vacuum Leak Testing.

5. Critical Cleaning Parameters

Cleaning effectiveness depends on controlling several process variables together. A cycle that meets its programmed duration may still be ineffective if the detergent concentration is incorrect, the spray coverage is inadequate, or the cleaning fluid does not reach the required temperature.

The critical parameters should be identified through cleaning development and risk assessment.

5.1. Cleaning-agent concentration

Cleaning-agent concentration influences the chemical action and ability to remove targeted residues. Both insufficient and unnecessarily high concentrations can create problems. Concentration limits should be supported by cleaning studies, material compatibility, and the cleaning-agent manufacturer's recommendations.

5.2. Temperature

Temperature can affect residue solubility, cleaning kinetics, and detergent performance. However, higher temperatures are not always better. The selected conditions must remain compatible with the residue, cleaning chemistry, seals, gaskets, and equipment materials.

5.3. Contact time

Contact time determines how long the cleaning chemistry acts on contaminated surfaces. The required duration depends on residue characteristics, cleaning-agent performance, temperature, and the effectiveness of fluid delivery.

5.4. Flow rate and pressure

Flow rate and pressure influence fluid delivery and spray-device performance. Pressure measured at a supply line does not, by itself, demonstrate adequate spray coverage at every chamber surface. Hydraulic performance must be assessed within the actual cleaning configuration.

5.5. Surface coverage

All designated surfaces must receive effective cleaning exposure. Shelves, supports, chamber corners, and internal projections may obstruct spray trajectories or reduce wetting. Coverage studies should identify locations that may require design modifications or additional cleaning measures.

5.6. Water quality

Water quality affects rinse performance and the risk of introducing additional contaminants. The specified grade should be appropriate for the intended manufacturing application and established cleaning procedure.

5.7. Drainage

Drainability determines whether used cleaning solution and rinse water can be effectively removed. Poor drainage can leave liquid in low points, connections, or other locations, complicating post-cleaning checks and subsequent equipment use.

5.8. Cycle sequence

The sequence of washing, rinsing, drainage, and any required post-cleaning operations must be controlled. A deviation in valve sequencing or a missed rinse can affect the overall outcome even when individual process parameters appear acceptable.

5.9. Cleaning chemistry and product residues

The cleaning agent must be selected according to the nature of the residues expected from the products manufactured in the freeze dryer.

Potential residues include proteins, sugars, buffers, salts, and other formulation constituents. Their cleaning behavior depends on properties such as solubility, surface interaction, aggregation, and the conditions experienced during processing.

Water may be sufficient for some highly soluble residues. Other residues may require a compatible detergent or a more carefully designed sequence.

Cleaning-agent selection should consider its ability to remove the target residue, compatibility with stainless steel and other wetted materials, ease of removal during rinsing, potential detergent carryover, and suitability for the equipment's operating conditions.

For biologics, the cleaning strategy may need to address protein residues that can adsorb to surfaces or become more difficult to remove after drying. Protein removal should be demonstrated using an appropriate analytical method rather than assumed from visual appearance.

Related reading: Lyophilization of Monoclonal Antibodies, Protein Stability in Lyophilized Formulations, and GMP Considerations for Lyophilized Products.

6. CIP Design Challenges Specific to Freeze Dryers

6.1. Complex chamber geometry

Freeze dryer chambers contain shelves, support structures, penetrations, and other components that influence fluid distribution. The arrangement can make it difficult to deliver cleaning solution uniformly to all required surfaces.

The engineering response is to assess coverage across the chamber's full configuration, including locations that may be partially obstructed. If a design limitation cannot be resolved through the cleaning circuit, it may require equipment modification or a justified supplementary cleaning approach.

6.2. Drainability and retained liquid

Freeze dryers are designed primarily for freezing, vacuum operation, and drying rather than unrestricted liquid handling. Their internal surfaces and piping must therefore be evaluated for their ability to drain after CIP.

Poor drainability can leave liquid in low points, connections, or other locations. This may prolong drying, complicate inspection, and undermine confidence in the post-cleaning condition.

Drainability should be addressed during equipment design through appropriate slopes, drain placement, piping configuration, and verification under representative conditions.

6.3. Material and component compatibility

Cleaning agents, temperatures, and repeated exposure cycles can affect seals, elastomers, gaskets, instrument components, and surface finishes. The cleaning process must remain within the qualified operating limits of the equipment.

Compatibility assessments should consider both chemical exposure and the combined effect of temperature, concentration, and exposure duration.

6.4. Protecting vacuum and refrigeration systems

CIP introduces liquids into equipment designed to operate under vacuum and low-temperature conditions. The system must prevent unintended fluid entry into vacuum pumps, refrigeration components, or other equipment outside the cleaning boundary.

This requires suitable isolation, valve sequencing, drainage, and control interlocks. Equipment-specific design requirements should determine the permitted sequence for cleaning and subsequent return to service.

6.5. Cleaning between different products

A freeze dryer used for multiple products may require different cleaning conditions depending on the residue and the risk of carryover.

The cleaning strategy should identify the relevant product-contact surfaces, target residues, and worst-case cleaning challenges. Where products differ substantially in composition or cleaning behavior, a single cleaning procedure should not be assumed to be suitable for every product without supporting evidence.

Related reading: Root Cause Analysis of Lyophilization Failures provides a broader framework for investigating process and manufacturing problems.

7. CIP Cycle Development and Optimization

Developing a CIP cycle requires more than selecting a standard wash duration and detergent concentration. The procedure should be based on the equipment design, residue characteristics, intended manufacturing use, and evidence that the selected conditions achieve the required cleaning outcome.

7.1. Define the cleaning scope

Identify the equipment surfaces and circuits to be cleaned, including the chamber, shelves, drain paths, and any condenser surfaces included in the cleaning strategy.

7.2. Characterize the residues

Assess the residues expected from the manufacturing process, including their solubility, potential for surface attachment, and analytical detectability.

7.3. Establish the cleaning conditions

Select appropriate cleaning chemistry, concentration, temperature, contact time, flow conditions, rinse sequence, and drainage requirements.

7.4. Evaluate performance

Assess spray coverage, operating parameters, residue removal, rinse effectiveness, and the repeatability of the cycle under representative conditions.

7.5. Qualify and validate the procedure

Establish documented evidence that the equipment and cleaning procedure consistently meet predefined requirements. Maintain the validated state through change control and periodic review.

For the equipment qualification framework, see IQ/OQ/PQ Qualification.

7.6. Avoid optimizing only for cycle duration

Reducing cleaning time can improve equipment availability, but a shorter cycle is beneficial only if cleaning performance remains acceptable and reproducible.

Optimization should focus on the relationship between cleaning effectiveness and operating conditions. For example, a better spray arrangement may improve coverage more effectively than simply increasing the wash duration. Likewise, an appropriate detergent may remove a difficult residue more efficiently than an extended water rinse.

The selected cycle should provide a justified operating range for critical parameters and an appropriate response when those parameters fall outside established limits.

8. Cleaning Validation and Verification

A CIP system is only effective for pharmaceutical manufacturing when there is documented evidence that the cleaning process achieves its intended outcome. Cleaning validation establishes that the procedure is capable of consistently meeting predefined acceptance criteria, while routine verification provides evidence that cleaning has been performed acceptably for a particular cycle or defined situation.

8.1. Selecting appropriate sampling locations

Sampling locations should be selected through a documented assessment of cleaning risk. Priority should be given to surfaces that are difficult to clean, difficult to drain, or likely to retain residues.

Potential locations include chamber corners and internal penetrations, shelf surfaces and areas beneath or behind structural components, drain connections and low points, gaskets and seals, and condenser surfaces where included in the cleaning scope.

These are examples rather than a universal sampling list. The actual locations depend on the freeze dryer design, product-contact assessment, and cleaning validation strategy.

8.2. Analytical methods for cleaning assessment

Visual inspection detects visible residue, films, or deposits, but does not establish the absence of invisible contamination.

Total organic carbon (TOC) measures organic carbon and may be suitable for monitoring relevant organic residues when appropriately validated.

Product-specific assays detect or quantify a defined product residue using a suitable analytical method.

Protein-specific assays evaluate protein residues when the method is appropriate for the target material and required sensitivity.

Conductivity can help assess ionic residues or rinse endpoints, but is not a universal indicator of cleanliness.

Detergent-specific testing assesses cleaning-agent residues where required by the cleaning strategy.

Swab sampling can provide localized information about surface cleanliness, while rinse sampling can assess residues recovered from a defined cleaning circuit. Each approach has limitations: swab recovery depends on the surface and sampling technique, whereas rinse results can be influenced by dilution and the ability of the rinse fluid to recover residues from the relevant locations.

Acceptance criteria should be scientifically justified and established before validation. They should consider product carryover risk, relevant toxicological information, analytical capability, and applicable regulatory expectations. A single generic residue limit should not be applied indiscriminately to every product and equipment configuration.

8.3. Documenting a successful CIP cycle

A completed automated cycle is not necessarily a successfully cleaned system. Batch or equipment records should provide sufficient evidence that the approved cleaning procedure was executed within its defined parameters.

Depending on the system, records may include the cleaning recipe and equipment identification, cleaning-agent concentration and temperature, relevant flow, pressure, or conductivity measurements, wash and rinse durations, alarm conditions, deviations and corrective actions, drainage or post-cleaning checks, and required sampling results and equipment-release approval.

The precise requirements should be established within the site's quality system and applicable GMP framework.

Related reading: Process Validation, Risk Assessment in Freeze Drying, and Continued Process Verification (CPV).

9. Practical and Engineering Considerations

9.1. CIP and SIP must be designed as complementary processes

CIP removes residues; SIP establishes the required sterilization state. In sterile pharmaceutical manufacturing, both processes may be necessary, but their sequence and interfaces must be defined for the specific equipment.

For example, residual cleaning agents or retained water may affect subsequent operations. The cleaning process must therefore be compatible with the sterilization procedure and the requirements for returning the freeze dryer to manufacturing service.

The related article SIP in Freeze Dryers should address the separate principles of in-place sterilization, including temperature distribution, sterilization parameters, and validation.

9.2. CIP must not compromise vacuum performance

Freeze dryers depend on controlled chamber pressure during operation. Cleaning fluid entering an unintended vacuum pathway, or retained liquid remaining in a poorly drained location, can complicate the return to service.

Equipment design should establish the cleaning boundary, protect components that must remain isolated, and define the required checks before vacuum operation resumes. Any post-cleaning leak test or functional check should be determined by the equipment design and approved procedure rather than assumed to be necessary after every cycle.

9.3. Automation improves repeatability but does not guarantee cleanliness

Automated systems reduce dependence on manual execution and allow process parameters to be recorded consistently. However, an automated sequence can repeatedly deliver an ineffective cleaning process if its design or recipe is inadequate.

For this reason, qualification should establish that the system performs as intended, while cleaning validation should demonstrate that the procedure achieves the required cleaning outcome.

9.4. Cleaning time affects manufacturing availability

CIP can contribute significantly to equipment turnaround time, particularly when washing, rinsing, drainage, drying, and subsequent sterilization are all required.

Cycle optimization should consider the complete return-to-service sequence rather than wash duration alone. A reduction in detergent-wash time may provide little operational benefit if the final rinse or post-cleaning drying stage becomes the limiting step.

9.5. Change control protects the validated state

Changes to formulations, cleaning agents, spray devices, shelf configurations, piping, software recipes, or equipment components may affect cleaning performance.

The impact of each change should be assessed to determine whether additional testing, requalification, or revalidation is required. This is especially important when a change alters the surfaces exposed to the product or the conditions under which residues are removed.

Related reading: Technology Transfer, Regulatory Expectations, and Quality by Design (QbD).

10. Technical Considerations

10.1. Spray coverage versus demonstrated cleaning effectiveness

Spray coverage and cleaning effectiveness are related but distinct. A coverage study may demonstrate that fluid reaches a surface, but it does not necessarily establish that the fluid removes the relevant residue under the selected cleaning conditions.

A robust assessment combines engineering evidence of fluid distribution with cleaning-performance evidence. Where necessary, residue studies should challenge locations that are difficult to clean or represent credible worst-case conditions.

10.2. Cleaning dried residues

Residues may become more difficult to remove after drying or prolonged exposure to process conditions. This can be relevant to protein-containing formulations and other products that leave deposits on equipment surfaces.

Cleaning development should therefore consider the expected condition of residues at the point when cleaning begins. A procedure demonstrated against freshly deposited material may not be adequate if the manufacturing process allows residues to dry before cleaning.

10.3. The importance of worst-case selection

Worst-case product and equipment selection should be based on a documented scientific rationale. Relevant considerations may include residue solubility, cleanability, potency, toxicity, analytical detectability, surface accessibility, and the time between production and cleaning.

The product that is hardest to clean is not necessarily the product with the greatest toxicological risk. These factors should be evaluated separately and integrated into the overall cleaning validation strategy.

10.4. Equipment-specific operating limits

Cleaning conditions must remain compatible with the freeze dryer's pressure boundary, materials, instrumentation, and other equipment systems. Spray pressure, temperature, and fluid volumes should be established using the manufacturer's design limits and appropriate engineering qualification.

Generic CIP parameters should not be transferred directly between freeze dryers without assessing differences in chamber geometry, spray arrangements, piping, drainage, and intended use.

11. Frequently Asked Questions

11.1. What is CIP in a pharmaceutical freeze dryer?

CIP is a cleaning process that delivers cleaning fluids to designated internal equipment surfaces without routine dismantling. Its purpose is to remove product residues and other relevant contaminants using a defined, controlled, and validated procedure.

11.2. Is CIP mandatory for every pharmaceutical freeze dryer?

Not necessarily as a universal equipment-design requirement. The cleaning approach depends on the equipment, manufacturing process, product-contact surfaces, contamination risks, and applicable GMP requirements. Automated CIP may be appropriate for many systems, but the cleaning strategy must be justified for the specific application.

11.3. What is the difference between CIP and SIP?

CIP removes product residues, cleaning agents, and other contaminants. SIP sterilizes the designated equipment surfaces using a validated sterilization process. Cleaning does not automatically establish sterility, and sterilization does not demonstrate adequate residue removal.

11.4. How is CIP effectiveness demonstrated?

Effectiveness is demonstrated through an appropriate combination of equipment qualification, cleaning validation, analytical testing, inspection, and routine cycle monitoring. The evidence should show that the procedure consistently meets predefined acceptance criteria.

11.5. Can water alone be used for CIP?

Water may be sufficient for certain readily soluble residues, but it cannot be assumed to remove every formulation component effectively. The cleaning chemistry should be selected based on the residue characteristics and demonstrated cleaning performance.

11.6. Does a successful CIP cycle mean the freeze dryer is ready for production?

Not automatically. Equipment release may require review of cycle records, resolution of alarms or deviations, satisfactory verification results, drainage or drying checks, and subsequent sterilization where required. Release must follow the approved procedure.

13. Conclusion

CIP in pharmaceutical freeze dryers is an engineering and quality-control process that must reliably remove residues from designated equipment surfaces without compromising the equipment or subsequent manufacturing operations.

Its effectiveness depends on more than detergent concentration or wash duration. Spray coverage, cleaning chemistry, temperature, contact time, fluid distribution, drainage, material compatibility, and the characteristics of product residues must work together as part of a defined cleaning strategy.

For pharmaceutical manufacturers, the central objective is to establish a reproducible cleaning process supported by appropriate qualification, validation, analytical evidence, and documented equipment release. Automation can improve repeatability, but the cleaning procedure must still demonstrate that it achieves the required outcome.

A well-designed CIP system therefore contributes to contamination control, equipment reliability, manufacturing efficiency, and the consistent execution of pharmaceutical lyophilization processes.

14. References and Further Reading

14.1. Regulatory and technical resources

U.S. FDA — Guide to Inspections of Validation of Cleaning Processes
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/validation-cleaning-processes-793
European Medicines Agency — EudraLex, Volume 4: EU Guidelines for Good Manufacturing Practice
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en
ISPE — International Society for Pharmaceutical Engineering
https://ispe.org/

Educational Disclaimer

The information presented in this article is intended exclusively for educational and informational purposes as part of the Lyophilization Core scientific knowledge base. It is designed to support the understanding of pharmaceutical lyophilization science, engineering principles, formulation development, process development, and manufacturing concepts.

This content should not be interpreted as regulatory guidance, GMP instructions, manufacturing procedures, process validation protocols, engineering specifications, or professional consulting advice. The suitability of any lyophilization process, formulation, equipment, or operating condition must be evaluated based on product-specific scientific data, validated procedures, applicable regulatory requirements, and qualified scientific and engineering judgment.

Pharmaceutical development and commercial manufacturing should always be conducted in accordance with applicable Good Manufacturing Practices (GMP), relevant regulatory guidance, approved quality systems, and site-specific standard operating procedures.