Precision, uniformity and adherence to stringent regulations are the requirements of drug manufacturing. Drugs are produced using active pharmaceutical ingredients which will always control the effectiveness and safety of the drug for the consumer.
Pharma manufacturers ensure compliance to the GMP through in-process controls. These methods provide documentation throughout the production process and give confidence that the production is occurring within the defined operation ranges.
Regulatory agencies do require manufacturers to establish in-process controls, but compliant manufacturers as part of their overall drug product quality assurance system use detailed in-process controls in the manufacture of drug products.
This article explains the definition of in-process control, why in-process control is essential in manufacturing active pharmaceutical ingredients and what are the ways manufacturers can demonstrate that their production processes are compliant, effective and consistent through in-process control?
As per ICH Q7 (Good Manufacturing Practice (GMP) for APIs), "IPC's should be performed at appropriate stages during the manufacturing process in order to assure that the intermediate/API meets the specified acceptance criteria prior to final approval and shipment."
Essentially, IPCs are built into every stage of the manufacturing process from receipt of raw materials to crystallization and drying of the final product.
1. Monitor for consistency throughout the manufacturing process and detect deviations early.
2. Verify required parameters and specifications to ensure product quality.
3. Control the variability of raw materials, intermediates and environmental conditions.
4. Maintain uniformity between batches to produce consistent results.
5. Ensure compliance with FDA, EMA and WHO regulations for good manufacturing practices.
The ultimate purpose of IPC is to protect the product, process and patient.
Examples of IPC checks include:
- Visual appearance and labeling.
- Verification of identity using tests such as FTIR or NIR.
- Analysis of moisture content via Karl Fischer titration.
- Verification of pH and assay values.
Common control mechanisms for this stage include:
- Monitoring of temperature and Pressure on a continual basis.
- Adjusting pH in the end of the reaction.
- Verifying that the reaction has been completed by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
Samples collected from the Intermediate (Assay and Purity) will be used during the IPC process to verify that the reactions will occur as specified, thereby eliminating the possibility of under reactions or generation of unintended impurities.
Examples of the IPC checks done at this stage include:
- Checking clarity of filtration by visual inspection or turbidity.
- Checking the amount of solvent residue remaining in the filtrate.
- Measuring the pH of the wash solution to ensure the removal of all impurities.
Washing properly ensures that the purity of the manufactured product is protected from cross contamination created by residual solvent in the manufacturing process.
The IPCs critical to your API include:
- Temperature profile during cooling
- The level of supersaturation present
- The method and speed of seeding
- The particle size distribution (which can be either through laser diffraction or by microscopy)
- The amount of solvent relative to the amount of solid present
When crystallization is consistent, the product has typically created a consistent formation of API, with respect to material properties like bioavailability and dissolution rate.
The key IPC parameters for drying include:
- The control of inlet and outlet temperatures during the drying process
- The amount of time and the vacuum levels used during drying
- Loss on Drying (LOD) determined by using infrared balances or moisture analyzers
- Residual solvent determined using GC
The efficiency of the drying process is critical to the overall stability of the finished API.
Key IPC controls for milling are:
- The integrity of the sieve
- The analysis of the particle size distribution
- The uniformity testing of blends
- Errors in milling can create inconsistencies in flow, build-up of fines and also result in differing dissolution rates.
The checks for packaging include:
- Cleanliness/integrity of the container
- Accuracy of the label information (batch number, expiration date)
- Verification of weight and sealing.
1. HPLCs are employed for quantitative analysis, including monitoring ongoing reactions, with regard to both assay results and impurity profiles.
2. GCs enable the quantification of residual solvents at key stages (e.g. drying and purification).
3. TLCs provide in-process sampling points or checks on reaction progress, confirming whether the reaction is complete or has reached the correct endpoint.
4. UV/Visible Spectrophotometry determines the concentration of an intermediate.
5. Infrared (IR) or Near-Infrared (NIR) Spectroscopy can identify the chemical structure or purity of raw materials used to manufacture drug products.
6. Karl Fischer Titration quantifies moisture contained within materials being treated or stored at various stages such as drying, storing and preparing for production.
7. Laser Diffraction is used to determine the particle size distributions produced during the crystallization and milling stages.
These analytical methods provide real-time data directly to process operators that help them to modify their procedures at critical times and produce high-quality products consistently.
CPP Include the following:
- Reaction temperature and pH.
- Mixing speed and mixing time.
- Temperature gradient during crystallization.
- The temperature at which to dry and the pressure under which to dry.
- Starting material, crud purity and concentration.
IPC uses on-line monitoring and statistical process control (PCP) techniques to ensure that these parameters remain within their validated limits.
Some Considerations for Implementing PAT:
- Utilize NIR spectroscopy for detection of moisture content, composition and homogeneity.
- Use Raman spectroscopy for reaction monitoring as well as for identifying polymorphs.
- Implement automated feedback loops to allow for tight control of process parameters (temperature, pH & flow).
- Implement on-line analytical techniques such as HPLC or GC for impurity identification, characterization and quantification.
By merging PAT and IPC together manufacturers are taking the necessary steps towards the development of continuous manufacturing and Real Time Release Testing Methods (RTRT).
The following information must be included in the documentation:
- Sampling technique
- Testing method & acceptance criteria
- Result and analyst signature/date
- Plan of action on out of spec (OOS) or out of trend (OOT) results
Documenting information in compliance with the guidelines supports the integrity of the data (ALCOA+) and provides for traceability during GMP audits and regulatory inspections.
- Methods for sampling.
- Methods for operating and maintaining equipment.
- Methods for executing analytical methods and calibrating analytical equipment.
- Methods for managing deviations.
- Health & safety and practices associated with handling solvents and intermediates.
Ongoing training, review and validations help to assure the continued consistency of the operations while minimizing the potential for human error.
- Stop production immediately
- Notify QA and the head of production
- Investigate why the IPC results are not within specifications (i.e. instrument error, contamination of the sample or deviation of the process from what is expected).
- Take steps to correct the problem (CAPAs)
- After corrective actions have been taken re-sample and retest.
Quickly dealing with OOS results prevents defective APIs from going on to the next stage and eventually entering into commerce.
The following Guidelines are referenced below that support the need for Manufacturers to implement robust IPC Systems:
1. ICH Q7: Guidelines for Good Manufacturing Practices (GMP) for APIs
2. 21 CFR Part 211: Standards of Practice for Finished Pharmaceuticals (GMP).
3. WHO TRS 1019, Annex 2: GMP requirements specific to the manufacture of APIs.
Numerous warning letters issued by the FDA cite that manufacturers do not maintain adequate in process control systems and therefore make it a business financially critical factor for manufacturers to comply with applicable regulations.
In-process control (IPC) methods are core components of quality assurance in API manufacturing. They provide assurance that each manufacturing stage, from raw material verification through drying, packaging etc. is achieving a validated operational limit, resulting in an API that meets purity, potency and safety standards.
By combining analytical methods, PAT tools and quality documentation, manufacturers can monitor in real-time reduce deviations from norms and produce quality APIs with consistency.
IPC must create confidence in every single batch manufactured, in every individual measurement taken and in every process step completed.
Pharma manufacturers ensure compliance to the GMP through in-process controls. These methods provide documentation throughout the production process and give confidence that the production is occurring within the defined operation ranges.
This article explains the definition of in-process control, why in-process control is essential in manufacturing active pharmaceutical ingredients and what are the ways manufacturers can demonstrate that their production processes are compliant, effective and consistent through in-process control?
What are In-Process Controls (IPCs)?
In-process controls (IPCs), which are a type of test or verification procedure that is used to confirm that the manufacturing process remains within the predefined limits and to ensure that the product being manufactured meets the defined specifications prior to completion. These control methods also help to identify any potential deviations or errors in the manufacturing process early. This helps to minimize the chances of having to reprocess, reject or perform lengthy investigations about the product once it is complete.As per ICH Q7 (Good Manufacturing Practice (GMP) for APIs), "IPC's should be performed at appropriate stages during the manufacturing process in order to assure that the intermediate/API meets the specified acceptance criteria prior to final approval and shipment."
Essentially, IPCs are built into every stage of the manufacturing process from receipt of raw materials to crystallization and drying of the final product.
Objectives of In-Process Control in API Manufacturing
Process Control (IPC) for APIs have the following objectives.1. Monitor for consistency throughout the manufacturing process and detect deviations early.
2. Verify required parameters and specifications to ensure product quality.
3. Control the variability of raw materials, intermediates and environmental conditions.
4. Maintain uniformity between batches to produce consistent results.
5. Ensure compliance with FDA, EMA and WHO regulations for good manufacturing practices.
The ultimate purpose of IPC is to protect the product, process and patient.
Key Stages Requiring In-Process Control in API Manufacturing
There are multiple steps involved in the API production process, therefore, at each point in the manufacturing process, an in-process control (IPC) check should be performed for that particular step.A. Verification of Raw Materials
All raw materials (both active and inactive) will need to be verified prior to the start of manufacturing in terms of their identity, purity and quality.Examples of IPC checks include:
- Visual appearance and labeling.
- Verification of identity using tests such as FTIR or NIR.
- Analysis of moisture content via Karl Fischer titration.
- Verification of pH and assay values.
B. Monitoring the Reaction Phase
The reaction stage takes the starting materials and converts them to intermediate products or crude APIs. This is also the most critical stage for the in-process control system.Common control mechanisms for this stage include:
- Monitoring of temperature and Pressure on a continual basis.
- Adjusting pH in the end of the reaction.
- Verifying that the reaction has been completed by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
Samples collected from the Intermediate (Assay and Purity) will be used during the IPC process to verify that the reactions will occur as specified, thereby eliminating the possibility of under reactions or generation of unintended impurities.
C. Filtration and Washing
Filtration will remove the solid by-products or waste from the liquid products of the reactions. Washing removes impurities and unreacted materials.Examples of the IPC checks done at this stage include:
- Checking clarity of filtration by visual inspection or turbidity.
- Checking the amount of solvent residue remaining in the filtrate.
- Measuring the pH of the wash solution to ensure the removal of all impurities.
Washing properly ensures that the purity of the manufactured product is protected from cross contamination created by residual solvent in the manufacturing process.
D. Crystallization and Precipitation
This step determines physical properties of the active pharmaceutical ingredient (API) for particle size, crystal structure and polymorphic form.The IPCs critical to your API include:
- Temperature profile during cooling
- The level of supersaturation present
- The method and speed of seeding
- The particle size distribution (which can be either through laser diffraction or by microscopy)
- The amount of solvent relative to the amount of solid present
When crystallization is consistent, the product has typically created a consistent formation of API, with respect to material properties like bioavailability and dissolution rate.
E. Drying
Drying serves to remove residual moisture and solvents from the product. Residual water can cause the degradation, microbial growth or instability of a product.The key IPC parameters for drying include:
- The control of inlet and outlet temperatures during the drying process
- The amount of time and the vacuum levels used during drying
- Loss on Drying (LOD) determined by using infrared balances or moisture analyzers
- Residual solvent determined using GC
The efficiency of the drying process is critical to the overall stability of the finished API.
F. Milling and Sieving
The reduction in particle size improves consistency in the final product and improves the ability to formulate.Key IPC controls for milling are:
- The integrity of the sieve
- The analysis of the particle size distribution
- The uniformity testing of blends
- Errors in milling can create inconsistencies in flow, build-up of fines and also result in differing dissolution rates.
G. Packaging and Labeling
Through the use of in-process controls, you can verify the API has been packaged, labeled and stored correctly, right through to the final stages of the manufacturing process.The checks for packaging include:
- Cleanliness/integrity of the container
- Accuracy of the label information (batch number, expiration date)
- Verification of weight and sealing.
Common Analytical Techniques Used in In-Process Controls
Analytical methods for in-process testing are generally applicable at the various stages of API production. Some of the common analytical techniques and their associated uses are as follows:1. HPLCs are employed for quantitative analysis, including monitoring ongoing reactions, with regard to both assay results and impurity profiles.
2. GCs enable the quantification of residual solvents at key stages (e.g. drying and purification).
3. TLCs provide in-process sampling points or checks on reaction progress, confirming whether the reaction is complete or has reached the correct endpoint.
4. UV/Visible Spectrophotometry determines the concentration of an intermediate.
5. Infrared (IR) or Near-Infrared (NIR) Spectroscopy can identify the chemical structure or purity of raw materials used to manufacture drug products.
6. Karl Fischer Titration quantifies moisture contained within materials being treated or stored at various stages such as drying, storing and preparing for production.
7. Laser Diffraction is used to determine the particle size distributions produced during the crystallization and milling stages.
These analytical methods provide real-time data directly to process operators that help them to modify their procedures at critical times and produce high-quality products consistently.
Control of Critical Process Parameters (CPPs)
API production processes include critical process parameters with measurable characteristics that directly impact the critical quality attributes (CQAs) of an API.CPP Include the following:
- Reaction temperature and pH.
- Mixing speed and mixing time.
- Temperature gradient during crystallization.
- The temperature at which to dry and the pressure under which to dry.
- Starting material, crud purity and concentration.
IPC uses on-line monitoring and statistical process control (PCP) techniques to ensure that these parameters remain within their validated limits.
Role of Process Analytical Technology (PAT)
Process Analytical Technology (PAT) has become an integral part of many modern pharmaceutical facilities when implementing more robust controls of in-process operations. The incorporation of advanced instrumentation and technologies for on-line, real-time analysis of several critical product quality parameters (including moisture, composition and homogeneity) enhanced the ability for pharmaceutical companies to closely monitor these attributes while also ensuring that products are manufactured according to established specifications.Some Considerations for Implementing PAT:
- Utilize NIR spectroscopy for detection of moisture content, composition and homogeneity.
- Use Raman spectroscopy for reaction monitoring as well as for identifying polymorphs.
- Implement automated feedback loops to allow for tight control of process parameters (temperature, pH & flow).
- Implement on-line analytical techniques such as HPLC or GC for impurity identification, characterization and quantification.
By merging PAT and IPC together manufacturers are taking the necessary steps towards the development of continuous manufacturing and Real Time Release Testing Methods (RTRT).
Documentation and Traceability
All IPC activities must be recorded at the time of activity using "Good Documentation Practice" (GDP) guidelines.The following information must be included in the documentation:
- Sampling technique
- Testing method & acceptance criteria
- Result and analyst signature/date
- Plan of action on out of spec (OOS) or out of trend (OOT) results
Documenting information in compliance with the guidelines supports the integrity of the data (ALCOA+) and provides for traceability during GMP audits and regulatory inspections.
Importance of Training and Competency
All operators and analysts responsible for conducting in-process controls need to be trained on the following:- Methods for sampling.
- Methods for operating and maintaining equipment.
- Methods for executing analytical methods and calibrating analytical equipment.
- Methods for managing deviations.
- Health & safety and practices associated with handling solvents and intermediates.
Ongoing training, review and validations help to assure the continued consistency of the operations while minimizing the potential for human error.
Handling Out-of-Specification (OOS) Results
If the IPC results of a batch are not within the specifications set out by the appropriate regulatory agencies then:- Stop production immediately
- Notify QA and the head of production
- Investigate why the IPC results are not within specifications (i.e. instrument error, contamination of the sample or deviation of the process from what is expected).
- Take steps to correct the problem (CAPAs)
- After corrective actions have been taken re-sample and retest.
Quickly dealing with OOS results prevents defective APIs from going on to the next stage and eventually entering into commerce.
Regulatory Expectations for IPC in APIs
Regulatory Agencies such as the FDA, EMA and WHO require that pharmaceutical manufacturers implement a comprehensive system of process controls throughout the manufacturing of APIs as part of the overall Quality Assurance (QA) System.The following Guidelines are referenced below that support the need for Manufacturers to implement robust IPC Systems:
1. ICH Q7: Guidelines for Good Manufacturing Practices (GMP) for APIs
2. 21 CFR Part 211: Standards of Practice for Finished Pharmaceuticals (GMP).
3. WHO TRS 1019, Annex 2: GMP requirements specific to the manufacture of APIs.
Numerous warning letters issued by the FDA cite that manufacturers do not maintain adequate in process control systems and therefore make it a business financially critical factor for manufacturers to comply with applicable regulations.
In-process control (IPC) methods are core components of quality assurance in API manufacturing. They provide assurance that each manufacturing stage, from raw material verification through drying, packaging etc. is achieving a validated operational limit, resulting in an API that meets purity, potency and safety standards.
By combining analytical methods, PAT tools and quality documentation, manufacturers can monitor in real-time reduce deviations from norms and produce quality APIs with consistency.
IPC must create confidence in every single batch manufactured, in every individual measurement taken and in every process step completed.
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